WO2008040951A1 - Compounds - Google Patents

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Publication number
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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French (fr)
Inventor
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/en

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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

There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof. There is also provided a process for the manufacture of the compound of formula (I), and the use of the compound of formula (I) as a medicament and in the treatment of cancer.

Description

COMPOUNDS
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.
Many of the current treatment regimes for cell proliferation diseases such as cancer and psoriasis utilise compounds that inhibit DNA synthesis. Compounds that inhibit DNA synthesis may often prove to be toxic to many types of cells. However, the marked toxic effect on rapidly dividing cells such as tumour cells is often seen to offer a benefit in light of the general toxic nature of such compounds. Therefore, alternative antiproliferative agents that act by mechanisms other than the inhibition of DNA synthesis may offer the potential for selective targeting of the proliferating cells.
The Cyclin dependent kinase family (Cdks) 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).
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. The conclusion that Plkl elevation is a cause and not a consequence of oncogenesis resulted from a study demonstrating that over-expression or constitutive expression of PIk 1 induces malignant transformation of mammalian cells, causing tumour formation in nude mice (Smith et al 1997, Biochem. Biophys. Res. Commun 234:397-405)
Therapeutic potential for 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. These cells displayed abnormal distribution of chromatin and monoastral microtubules while normal fibroblast cells arrested transiently in G2 phase of cell cycle as single mononucleated cells (Lane & Nigg 1996 J.Cell Biol. 135:1701-1713). These results suggest that Plkl inhibition specifically targets cancer cells with checkpoint defects while cells with intact checkpoint pathways are less affected. Although the exact functions of the other family members remains largely unknown, silencing of Plk2 in the presence of taxol or nocodazole significantly increases apoptosis suggesting Plk2 may prevent mitotic catastrophe following spindle damage (Burns et al. 2003, MoI Cell Biol 23: 5556-5571). Likewise silencing of Plk4 in mammalian cells induces apoptosis (Li et al. 2005, Neoplasia 7: 312-323) and plk4 null mouse embryos arrest with an increase in mitotic and apoptotic cells (Hudson et al. 2001, Curr Biol 11 : 441-446).
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).
These findings suggest that pharmacological inhibitors of 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. In addition 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.
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):
Figure imgf000004_0001
(I) wherein
R . 11 represents represents hydrogen, -NH2, -OH, -CN, -C≡CH, -C(=O)NH2, C1-3alkyl, C-1-3 alky lamino, Ci-3alkylthio, d^alkyloxy, Ci-3alkylcarbonyl, -CHO, or -SO2Me; R2 represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group;
R3 represents hydrogen, an optionally substituted Ci-i2alkyl group, an optionally substituted C2-i2alkenyl group, an optionally substituted C2-i2alkynyl group, an optionally substituted C6-i4aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl 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 R2 and R3, together represent a saturated or unsaturated C1-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C^alkyloxy group, an optionally substituted
C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulfoxo group or an optionally substituted C1-6alkylsulfonyl group, or when p is 2 and when each R4 is adjacent, both R4 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;
Q is -Ln-R5 m, -C(=X)-Ln-R5 m -C(=X)-NRaRb, -(optionally substituted C1-3alkyl)g-NRa2Rb2, -S(O)2-NRa3Rb3, -NH-SO2-NRa4RM, -S(O)k-Ra5, -C(=X)-ORa6, -ORa7, -NH-C(=X)-Ra8, -NH-SO2-Ra9 or -(5- or 6-membered aromatic or heteroaromatic ring optionally comprising one or more heteroatoms selected from nitrogen, oxygen or sulphur)-Ln-R5 m; g is 0 or 1 ; k is 0, 1 or 2; Ra represents H or an optionally substituted C1-6alkyl group, and Rb represents H, an optionally substituted Ci-6alkyl group, -Ln-R5 m, or Ra and Rb 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; Ra2 represents H or an optionally substituted C^alkyl group, and Rb2 represents -Ln-R5 mj or Ra2 and Rb2 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;
Ra3 represents H or an optionally substituted C^alkyl group, and Rb3 represents
-Ln-R5 m, or Ra3 and Rb3 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;
Ra3 represents H or an optionally substituted C1-6alkyl group, and Rb3 represents
-Ln-R5 H1, or Ra3 and Rb3 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;
Ra5 represents -Ln-Rs m;
Ra6 represents ~Ln-R5 m;
Ra7 represents -Ln-R5 m;
Ra8 represents -Ln-R5 m; Ra9 represents -Ln-R3 m;
L represents a linker selected from optionally substituted C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C6-i4aryl, optionally substituted
-C2-4alkyl-C6-14aryl, optionally substituted
Figure imgf000006_0001
optionally substituted
C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among hydrogen, 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 and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group;
R8, R9 each independently represents hydrogen, an optionally substituted -C1-6alkyl, an optionally substituted -Ci.4alkyl-C3-10cycloalkyl, an optionally substituted
-C3-1ocycloalkyl, an optionally substituted -C6-i4aryl, an optionally substituted -Ci-4alkyl-C6-i4aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted -C1-4alkyloxycarbonyl, an optionally substituted -C6-i4arylcarbonyl, an optionally substituted -C1-4alkylcarbonyl, an optionally substituted -C6.i4arylmethyloxycarbonyl, an optionally substituted -C6.14arylsulfonyl, an optionally substituted
Figure imgf000007_0001
or an optionally substituted -C6-i4aryl-C1-4alkylsulfonyl; X is O5 S or H2; and
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.
According to a second aspect of the present invention there is provided a compound of formula (I):
Figure imgf000007_0002
(I) wherein
R1 represents represents hydrogen, -NH2, -OH, -CN, -C≡CH, -C(=O)NH2, C1-3alkyl, C-1-3alkylamino, C1-3 alky lthio, Cι-3alkyloxy, Ci-3alkylcarbonyl, -CHO, or -SO2Me; R2 represents hydrogen, an optionally substituted Ci-6alkyl group or an optionally substituted C3-6cycloalkyl group;
R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-i2alkenyl group, an optionally substituted C2-i2alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3-]2cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted Cγ.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 R2 and R3, together represent a saturated or unsaturated C^aUcyl bridge optionally comprising 1 heteroatom; R4 each independently represent -CN, hydroxy, -NR R7, halogen, an optionally substituted Ci.6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted Ci-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulfoxo group or an optionally substituted
C1-6alkylsulfonyl group; p is 0, 1 or 2;
Q is -C(=X)-NRaRb, -NR32R132, -S(O)2-NRa3Rb3, -NH-SO2-NRa4Rb4, -S(O)k-Ra5, -C(=X)-ORa6, -ORa7, -NH-C(=X)-Ra8, -NH-SO2-Ra9; k is 0, 1 or 2;
Ra represents H or an optionally substituted Ci-6alkyl group, and Rb represents H, an optionally substituted Ci_6alkyl group, -Ln-R5 m, or Ra and Rb 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, and Rb2 represents
-Ln-R5 m, or Ra2 and Rb2 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; Ra3 represents H or an optionally substituted C1-6alkyl group, and Rb3 represents -Ln-R5 m, or Ra3 and Rb3 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;
Ra3 represents H or an optionally substituted C^aUcyl group, and Rb3 represents -Ln-R5 In, or Ra3 and Rb3 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; Ra5 represents ~Ln-R5 m; Ra6 represents -Ln-R5 m;
R represents -Ln-R m; Ra8 represents -Ln-R5 m;
Ra9 represents -Ln-R5 m;
L represents a linker selected from optionally substituted C2-1oalkyl, optionally substituted C2.10alkenyl, optionally substituted C6.14aryl, optionally substituted
-C2-4alkyl-C6-i4aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-i2cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among 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 and -NR R ;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group;
R8, R9 each independently represents hydrogen, an optionally substituted -C1-6alkyl, an optionally substituted -C1-4alkyl-C3-iocycloalkyl, an optionally substituted
-C3-iocycloalkyl, an optionally substituted -Cό-waryl, an optionally substituted -C1-4alkyl-C6-i4aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted -Cualkyloxycarbonyl, an optionally substituted -Cό-πarylcarbonyl, an optionally substituted -Ci-4alkylcarbonyl, an optionally substituted -Cό-πarylmethyloxycarbonyl, an optionally substituted -Cδ-πarylsulfonyl, an optionally substituted -C1-4alkylsulfonyl or an optionally substituted
Figure imgf000010_0001
X is O, S or H2; and 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.
The term 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 Ct-πalkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl groups. Unless otherwise stated, the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl include all the possible isomeric forms.
For example, the term propyl includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec-butyl and tert-butyl, the term pentyl includes iso- pentyl, neopentyl, etc.
In the above mentioned alkyl groups, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, alkyl groups may be substituted by the following substituent groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted Ci.ioalkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; -COOH; optionally substituted -NHCi-3alkyl, for example NHMe, NHEt, NHiPr; optionally substituted -N(C1-3alkyl)2, for example NMe2, NEt2, NMeEt; -COO-C i-4alkyl, for example -COOMe or - COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond. All the hydrogen atoms of the alkyl group may optionally be replaced by substituent groups, for example a trifluoromethyl group is a methyl group wherein all the hydrogen atoms have been replaced with fluorine atoms.
The term alkyl bridge, unless otherwise stated, 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.
The term alkenyl groups (including those which are a part of other groups), unless otherwise stated, includes branched and unbranched alkylene groups with 2 to 10 carbon atoms comprising at least one carbon-carbon double bond. Examples of C2-10alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl groups. Unless otherwise stated, the abovementioned terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl also include all the possible isomeric forms. For example, the term 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.
In the above mentioned alkenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, alkenyl groups may be substituted by the following substituent groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C1-loalkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OCi^alkyl, for example OMe, OEt, -OCHF2, -OCF3; optionally substituted -NHC1-3alkyl, for example NHMe, NHEt, NHiPr; optionally substituted -N(C1-3alkyl)2, for example NMe2, NEt2, NMeEt; -COOH; -COO-C l-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond. AU the hydrogen atoms of the alkenyl group may optionally be replaced, for example a trifluoroethylene group is an ethylene group wherein all the hydrogen atoms have been replaced with fluorine atoms.
The term alkynyl groups (including those which are a part of other groups), unless otherwise stated, includes branched and unbranched alkynyl groups with 2 to 10 carbon atoms comprising at least one triple bond. Examples of C2-10alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl groups. Unless otherwise stated, the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl also include all the possible isomeric forms. For example, the term butynyl includes 1 -butynyl, 2-butynyl, 3 -butynyl and l-methyl-2-propynyl.
In the above mentioned alkynyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, alkynyl groups may be substituted by the following substituents groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted Ci_ioalkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OCi-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; optionally substituted -NHC1-3alkyl, for example NHMe, NHEt, NHiPr; optionally substituted -N(C1-3alkyl)2, for example NMe2, NEt2, NMeEt; -COOH; -COO-C I-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond. AU the hydrogen atoms of the alkynyl group may optionally be replaced.
The term 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. Examples of C6-14aryl groups include phenyl (C6), indenyl (Cg), naphthyl (Cio), fluorenyl (C13), anthracyl (Ci4), and phenanthryl (Ci4). In the above mentioned aryl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, aryl groups may be substituted by the following substituents groups: OH; NO2; CN; NH2; halogen, for example fluorine or chlorine; optionally substituted Ci-ioalkyl, for example methyl, ethyl, propyl or CF3; optionally substituted -OCi-3alkyl, for example -OMe, -OEt, OCHF2, or OCF3; optionally substituted -NHC1-3alkyl, for example NHMe, NHEt, NHiPr; optionally substituted -N(C1-3alkyl)2, for example NMe2, NEt2, NMeEt; -COOH, -COO-C1-4alkyl, for example -COOMe or -COOEt, or -CONH2.
The term 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. Examples of 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. Each of the aforementioned examples of heteroaryl rings may optionally also be anellated by a further ring, for example a benzene ring. Examples of 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. In the above mentioned heteroaryl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, heteroaryl groups may be substituted by the following substituents groups: F; Cl; Br; OH; OMe; Me; Et; CN; NH2; CONH2; optionally substituted phenyl; and optionally substituted heteroaryl, for example optionally substituted pyridyl.
The term cycloalkyl groups, unless otherwise stated, includes cycloalkyl groups comprising 1 ring with 3 to 12 carbon atoms. Examples of C3-i2cycoalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. In the abovementioned cycloalkyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, cycloalkyl groups may be substituted by the following substituents groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted Cj.ioalkyL for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe5 OEt, -OCHF2, -OCF3; optionally substituted -NHC1-3alkyl, for example NHMe, NHEt, NHiPr; optionally substituted - N(C1-3alkyl)2, for example NMe2, NEt2, NMeEt; -COOH; -COO-C 1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond. The term cycloalkenyl, unless otherwise stated, includes cycloalkenyl groups with 3 to
12 carbon atoms comprising one ring, said ring comprising at least one carbon-carbon double bond. Examples of C3.i2cycloakenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl groups. In the abovementioned cycloalkenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, cycloalkenyl groups may be substituted by the following substituent groups: =0; OH; NO2; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C^oalkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; optionally substituted -NHCι-3alkyl, for example NHMe, NHEt, NHiPr; optionally substituted - N(Ci-3alkyl)2, for example NMe2, NEt2, NMeEt; -COOH; -COO-C 1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond.
The terms heterocycloalkyl and heterocycloakenyl, unless otherwise described in the definitions, includes 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, and heterocycloakenyl denotes an unsaturated heterocycle. Examples of heterocycloalkyl or heterocycloakenyl groups include tetrahydrofuran, tetrahydrofuranone, gαmrøα-butyrolactone, alpha-pyran, gαmmα-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. In the abovementioned heterocycloalkyl or heterocycloakenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other substituent groups. For example, heterocycloalkyl or heterocycloakenyl groups may be substituted by the following substituents groups: =0; OH; CN; -NH2; halogen, for example fluorine or chlorine; optionally substituted C1-4alkyl, for example methyl, ethyl, propyl, trifluoromethyl; optionally substituted -OC1-3alkyl, for example OMe, OEt, -OCHF2, -OCF3; optionally substituted -NHC1-3alkyl, for example NHMe, NHEt, NHiPr; optionally substituted -N(C1-3alkyl)2, for example NMe2, NEt2, NMeEt; -COOH; -COO-C1-4alkyl, for example -COOMe or -COOEt; or -CONH2. "=0" denotes an oxygen atom linked via a double bond.
The term polycycloalkyl, unless otherwise stated, 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. The term 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. Examples of 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. The term 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.
The term 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.
The term 3- to 6-membered saturated or unsaturated ring optionally comprising 1 to 2 heteroatoms includes optionally substituted C3-6cylcoalkyl and optionally substituted C3.6cylcoalkenyl groups, and optionally substituted 3- to 6-membered heterocylcoalkyl and optionally substituted 3- to 6-membered heterocylcoalkenyl groups each with 1 or 2 heteroatoms.
The term 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 The term halogen includes fluorine, chlorine, bromine or iodine.
The terms 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. The terms alkylthio, alkylsulfoxo and alkylsulfono denotes an -S(O)xR group wherein x=0, 1 or 2 respectively and R is an alkyl group as hereinbefore described above.
The term -alkyl-aryl refers to an alkyl group with an aryl substituent. The term -alkyl-cycloalkyl refers to an alkyl group with a cycloalkyl substituent. The term -aryl-alkyl refers to an aryl group with an alkyl substituent. The terms alkoxycarbonyl (-(O=)OR), alkylcarbonyl (-COR) and arylcarbonyl (-COR) refer to a carbonyl group with an alkoxy, alkyl or aryl substituent.
When R3 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 R8. ' When R5 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 R8. When R5 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 .
All the groups mentioned in the definition of R1 to R9, Ra to Ra6, and Rb to Rb3 may optionally be branched and/or substituted.
According to a third aspect of the present invention there is provided a compound of formula (II):
Figure imgf000016_0001
(H) wherein
R2 represents hydrogen or an optionally substituted Ci-6alkyl group; R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-i2alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-i4aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3.]2cycloalkenyl group, an optionally substituted
C7-i2polycycloalkyl group, an optionally substituted C7-i2polycycloalkenyl 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
R2 and R3 together represent a saturated or unsaturated C3-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-salkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted Ci-6alkythio group, an optionally substituted Ci-όalkylsulfoxo group or an optionally substituted Ci-όalkylsulfonyl group, or when p is 2 and when each R is adjacent, both R4 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; L represents a linker selected from optionally substituted Cj.ioalkyl, optionally substituted C2.10alkenyl, optionally substituted C6.14aryl, optionally substituted
-C2-4alkyl~C6-14aryl, optionally substituted ~C6-i4aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl, and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among optionally substituted morpholinyl, granatanyl, oxogranatanyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR8R9; R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group; and R8, R9 each independently represents hydrogen, an optionally substituted C1-6alkyl, an optionally substituted -C1-4alkyl-C3-1ocycloalkyl, an optionally substituted -C3-10cycloalkyl, an optionally substituted -Cό-uaryl, an optionally substituted -Ci-4alkyl-C6-14aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted
-Ci-4alkyloxycarbonyl, an optionally substituted -C6-i4arylcarbonyl, an optionally substituted -C^alkylcarbonyl, an optionally substituted -Ce-uarylmethyloxycarbonyl, an optionally substituted -C6-14arylsulfonyl, an optionally substituted -Ci-4alkylsulfonyl and an optionally substituted C6-14aryl-C1-4alkylsulfonyl, or pharmacologically acceptable salts thereof.
According to a fourth aspect of the present invention there is provided a compound of formula (II):
Figure imgf000018_0001
(II) wherein
R2 represents hydrogen or an optionally substituted C1-6alkyl group; R3 represents hydrogen, an optionally substituted Q.^alkyl group, an optionally substituted C2-i2alkenyl group, an optionally substituted C2-j2alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3-i2cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted
C7-12polycycloalkyl group, an optionally substituted C7-i2polycycloalkenyl group, an optionally substituted C5-i2spirocycloalkyl 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
R2 and R3 together represent a saturated or unsaturated C3-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-salkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulfoxo group or an optionally substituted C 1-6alkylsulfony 1 group; p is 0, 1 or 2;
L represents a linker selected from optionally substituted C2-ioalkyl, optionally substituted C2-10alkenyl, optionally substituted C6.14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted
Figure imgf000019_0001
optionally substituted C3-i2cycloalkyl, and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2; R5 represents a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted Ci-4alkyl group; and R8, R9 each independently represents hydrogen, an optionally substituted Ci-6alkyl, an optionally substituted -Ci-4alkyl-C3-i0cycloalkyl, an optionally substituted -Q.iocycloalkyl, an optionally substituted -C6-i4aryl, an optionally substituted -Ci-4alkyl-C6-j4aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted
Figure imgf000020_0001
an optionally substituted -C6-14arylcarbonyl, an optionally substituted
Figure imgf000020_0002
an optionally substituted -Cό-πarylmethyloxycarbonyl, an optionally substituted -Cό-warylsulfonyl, an optionally substituted -C1-4alkylsulfonyl and an optionally substituted C6-14aryl-Ci-4alkylsulfonyl, or pharmacologically acceptable salts thereof.
According to a fifth aspect of the present invention there is provided a compound of formula (Ha):
Figure imgf000020_0003
(Ha) wherein
R2 represents hydrogen or an optionally substituted C1-6alkyl group; R3 represents hydrogen, an optionally substituted C].i2alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted Cβ-πaryl group, an optionally substituted C3.i2cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-i2polycycloalkyl 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
1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen or sulphur, or
R2 and R3 together represent a saturated or unsaturated C3.4alkyl bridge optionally comprising 1 heteroatom;
R4a, R4b and R4c each independently represent hydrogen, -CN, hydroxy, -NR6R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted
C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulfoxo group or an optionally substituted C1-6alkylsulfonyl group, or R4a and R4b together with the carbon atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 or more heteroatoms;
L represents a linker selected from optionally substituted C1-10alkyl, optionally substituted C2-ioalkenyl, optionally substituted C6-i4aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl, and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among optionally substituted morpholinyl, granatanyl, oxogranatanyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group; and R8, R9 each independently represents hydrogen, an optionally substituted C1-6alkyl, an optionally substituted -Cj-4alkyl-C3-jocycloalkyl, an optionally substituted
-C3-i0cycloalkyl, an optionally substituted -C6-14aryl, an optionally substituted -C1-4alkyl-C6-i4aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted
-C1-4alkyloxycarbonyl, an optionally substituted -C6-i4arylcarbonyl, an optionally substituted -C1-4alkylcarbonyl, an optionally substituted -C6-i4arylniethyloxycarbonyl, an optionally substituted -C6-14arylsulfonyl, an optionally substituted
Figure imgf000022_0001
and an optionally substituted C6-i4aryl-C1-4alkylsulfonyl, or pharmacologically acceptable salts thereof.
In one embodiment, for compounds of the first and second aspect of the present invention, 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.
In one embodiment, for compounds of the first and second aspect of the present invention, the group R1 represent hydrogen, -NH2, -OH, -CN, -C≡CH, -C(=O)NH2, C1-3alkyl, C-1-3alkylamino, C1-3alkylthio, C1-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me. In another embodiment, for compounds of the first and second aspect, the group R1 represents hydrogen or a methyl or ethyl group.
In another embodiment, for compounds of the first and second aspect, the group R1 represents a methyl group.
In one embodiment, for compounds of the first, second, third, fourth and fifth aspects, the group R2 represents hydrogen or a C1-6alkyl group optionally substituted by one or more substituents selected from Ci_3alkyloxy, Ci-3 alky lthio, C1-3alkyl-S(O)2, C1-3alkylamino and di- (C1-3alkyl)amino.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the group R2 represents hydrogen or a methyl or ethyl group. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the group R2 represents a methyl or ethyl group.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the group R2 represents an ethyl group.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R3 represents hydrogen; a Ci-i2alkyl, for example ethyl, propyl, butyl, pentyl or hexyl, optionally substituted by one or more substituents selected from Ci-3alkyloxy, Ci.3alky.thi0, C1-3alkyl-S(O)2, Ci.3alkylamino and di-(Ci.3alkyI)amino; a C2-12alkenyl, for example C5-7alkenyl, optionally substituted by one or more substituents selected from C^alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Cι-3alkylamino and di-(C1-3alkyl)amino; C2. 12alkynyl, for example C5-7alkynyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C^alkylthio, Ci-3alkyl-S(O)2, C^alkylamino and di-(Ci-3alkyl)amino; a C6.i4aryl, for example phenyl, optionally substituted by one or more substituents selected from C^alkyloxy, Ci.3alkylthio, Ci.3alkyl-S(O)2, C1-3 alky lamino and di-(Ci-3alkyl)amino; a C3-i2cycloalkyl, for example cyclopentyl or cyclohexyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, C1-3alkyl-S(O)2, C^alkylamino and di- (Ci-3alkyl)amino; a C3-[2cycloalkenyl, for example C5-7cycloalkenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-salkylamino and di-(Ci-3alkyl)amino; C7-12polycycloalkyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci.3alkylamino and di-(C1-3alkyl)amino; C7-12polycycloalkenyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-3 alky lamino and dKC^alkyFjamino; Cs-^spirocycloalkyl optionally substituted by one or more substituents selected from C1-3 alky loxy, C)-3alkylthio, Ci-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; 3-12 membered heterocycloalkyl which contains 1 to 2 heteroatoms selected from oxygen, nitrogen or sulfur, for example pyranyl or piperidinyl, pyrrolidinyl, pyrazinyl or morpholinyl, optionally substituted by one or more substituents selected from d^alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; and 3- to 12-membered heterocycloalkenyl which contains 1 to 2 heteroatoms selected from oxygen, nitrogen or sulfur, optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R3 represents isopropyl, isobutyl, isopentyl, cyclopentyl, phenyl or cyclohexyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R3 represents cyclopentyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R2 and R3 together represent a saturated or unsaturated C3-C4alkyl bridge optionally comprising 1 heteroatom selected from oxygen or nitrogen. In another embodiment, for compounds of the first, second, third and fourth aspects, R4 represents a group selected from among -CN; hydroxyl; -NR6R7; halogen, for example chlorine or fluorine; C1-6alkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from halogen, Ci-3alkyloxy, C^alkylthio, Ci_3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; C2-6alkenyl, for example ethenyl or propenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, Ci-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C2-6alkynyl, for example ethynyl, propynyl or butynyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio,
Figure imgf000024_0001
C1-3 alky lamino and di-(Ci.3alkyl)amino; C^alkyloxy, for example methoxy, ethoxy or propargyloxy, optionally substituted by one or more substituents selected from halogen, Ci-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C^alkylamino and di-(Ci-3alkyl)amino; C2-5alkenyloxy optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; C2-5alkynyloxy optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, Ci-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; C1-6alkylthio optionally substituted by one or more substituents selected from halogen C^alkyloxy, Ci-3alkylthio, C1-3alkyl-S(O)2, C1-3 alky lamino and di- (Ci.3alkyl)amino; C1-6alkylsulfoxo optionally substituted by one or more substituents selected from C1-3alkyloxy,
Figure imgf000024_0002
Ci-3alkyl-S(O)2, C1-3alkylamino and di-(C1_3alkyl)amino and C1-6alkylsulfonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C^alkylthio, Ci-3alkyl-S(O)2, Ci-3alkylamino and di-(Ci-3alkyl)amino.
In another embodiment, for compounds of the first, second, third and fourth aspects, R4 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,
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents a group selected from among -CN; hydroxyl; -NR6R7; halogen, for example chlorine or fluorine; C1-6alkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from
Figure imgf000024_0003
Ci-3alkyl- S(O)2, C]_3alkylamino and di-(C1-3alkyl)amino; C2-6alkenyl, for example ethenyl or propenyl, optionally substituted by one or more substituents selected from C^alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci.3alkylamino and di-(Ci-3alkyl)amino; C2-6alkynyl, for example ethynyl, propynyl or butynyl, optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, d^alkylamino and di-(Ci-3alkyl)amino; C1-5alkyloxy, for example methoxy, ethoxy or propargyloxy, optionally substituted by one or more substituents selected from C^alkyloxy, C1.3alkyltb.io, C1-3alkyl-S(O)2, Ci.3alkylamino and di-(Ci-3alkyl)amino; C2-5alkenyloxy optionally substituted by one or more substituents selected from d^alkyloxy, Ci-3alkylthio, Ci-3alkyl-S(O)25 C1-3alkylamino and di-(C1-3alkyl)amino; C2-5alkynyloxy optionally substituted by one or more substituents selected from
Figure imgf000025_0001
and di-(Ci-3alkyl)amino; C1-6alkylthio optionally substituted by one or more substituents selected from
Figure imgf000025_0002
Ci-3alkyl-S(O)2, Ci-3alkylamino and di-(Ci-3alkyl)amino; C1-6alkylsulfoxo optionally substituted by one or more substituents selected from C1-3alkyloxy,
Figure imgf000025_0003
and Ci-6alkylsulfonyl optionally substituted by one or more substituents selected from Ci-3alkyloxy,
Figure imgf000025_0004
and di-(C1-3alkyl)amino.
In another embodiment, for compounds of the first and second aspects, when p is I5 R4 represents methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 0.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents methoxy, methyl, ethoxy, ethyl, chlorine or fluorine.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents methoxy. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1 , R4 represents methyl.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents ethoxy.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents ethyl. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents propargyloxy.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents chlorine. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 1, R4 represents fluorine.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 2, each R may be the same or different and selected from methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine or fluorine. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 2 and when each R4 is adjacent, both R4 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. In a further embodiment, the heteroatoms are selected from oxygen, sulphur or nitrogen. In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 2 and when each R4 is adjacent, both R4 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.
In another embodiment, for compounds of the first, second, third and fourth aspects, when p is 2 and when each R4 is adjacent, both R4 together with the aromatic ring atoms to which they are attached form a OCH2O bridge, a OCH2CH2O bridge, a CH2CH2CH2 bridge, a CH-CH-CH=CH bridge, a CH=CHNH bridge, a CH=CMeNH bridge, a CH=CHNMe bridge, a CH=CHN(COMe) bridge, a CH=NNH bridge, a N=CH-S bridge, a N=C(Me)-S bridge, a N=NNH bridge, a C(=0)NHC(=0) bridge, a N=CH-CH=N bridge, or a CMe=CH-C(=O)-NH bridge.
In another embodiment, for compounds of the fifth aspect, R4a and R4b 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. In a further embodiment, the heteroatoms are selected from oxygen, sulphur or nitrogen. In another embodiment, for compounds of the fifth aspect, R4b and R4c are hydrogen and R4a represents hydrogen, methoxy, methyl, ethoxy, chlorine or fluorine. In another embodiment, for compounds of the fifth aspect, R4b and R4c are hydrogen and R4a represents methoxy, methyl, ethoxy, chlorine or fluorine.
In another embodiment, for compounds of the fifth aspect, R and R c are hydrogen and R4a represents methoxy. In another embodiment, for compounds of the fifth aspect, R4b and R4c are hydrogen and R4a represents methyl.
In another embodiment, for compounds of the fifth aspect, R4b and R4c are hydrogen and R4a represents ethoxy.
In another embodiment, for compounds of the fifth aspect, R4b and R4c are hydrogen and R4a represents chlorine.
In another embodiment, for compounds of the fifth aspect, R4 and R c are hydrogen and R4a represents fluorine.
In another embodiment, for compounds of the fifth aspect, R4b is hydrogen and R a and R4Q may be the same or different and selected from methoxy, chlorine or fluorine. In another embodiment, for compounds of the fifth aspect, R4b is hydrogen and R4a and R4c may be the same or different and selected from methoxy, methyl, ethoxy, chlorine or fluorine.
In another embodiment, for compounds of the fifth aspect, R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine. In another embodiment, for compounds of the fifth aspect, R4c is hydrogen and R4a and R4b together form a OCH2O bridge.
In another embodiment, for compounds of the first, third and fifth aspects, 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 C1-3alkyloxy, C1-3alkylthio, Ci-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C2-1oalkenyl, optionally substituted by one or more substituents selected from C^alkyloxy, Ci-3 alky lthio,
Ci-3alkyl-S(O)2, Ci_3alkylamino and di-(Ci.3alkyl)amino; C6-i4aryl, for example phenyl, optionally substituted by one or more substituents selected from
Figure imgf000027_0001
Ci-3alkyl-S(O)2, Cj-3alkylamino and di-(Ci-3alkyl)amino; -C2-4alkyl-C6-14aryl optionally substituted by one or more substituents selected from Cj-3alkyloxy,
Figure imgf000027_0002
Ci-3alkyl-
S(O)2, C1-3alkylamino and di-(C].3alkyl)amino; -C6-i4aryl-C]-4alkyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; C3-i2cycloalkyl, for example cyclohexyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, Ci-3alkyl- S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; and heteroaryl which contains 1 or 2 nitrogen atoms optionally substituted by one or more substituents selected from C1-3alkyloxy, C]_3alkylthio, Ci-3alkyl-S(O)2, Cwalkylamino and di-(C1.3alkyl)amino.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, L represents a linker selected from among C2_iOalkyl, for example ethyl, propyl, butyl or pentyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, Ci-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; C2-ioalkenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, Ci-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C6-i4aryl, for example phenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; -C2-4alkyl-C6-14aryl optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio,
Figure imgf000028_0001
S(O)2, Ci-3alkylamino and di-(C1.3alkyl)amino; -Co-naryl-Q^alkyl optionally substituted by one or more substituents selected from C^alkyloxy, Ci.3alkylthio, C1-3alkyl-S(O)2, C1-3 alky lamino and di-(C1-3alkyl)ammo; C3-12cycloalkyl, for example cyclohexyl, optionally substituted by one or more substituents selected from C[-3alkyloxy, C^alkylthio, Ci-3alkyl- S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; and heteroaryl which contains 1 or 2 nitrogen atoms optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci_3alkylthio, Ci-3alkyl-S(O)2, C1-3alkylamino and di-(Ci-3alkyl)amino.
In another embodiment, for compounds of the first, third and fifth aspects, when n is 1, L represents an optionally substituted C1-10alkyl or C3-12cycloalkyl linker. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, when n is 1, L represents an optionally substituted a C2-10alkyl linker.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, when n is 1, L represents -C(CHb)2-CH2-, -CH2-C(CH3)2-CH2- or a cyclohexyl linker. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, when n is 1, L represents -C(CH3)2-CH2- or -CH2-C(CH3)2-CH2-. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, when n is 1 , L represents a cyclohexyl linker.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, n is 0. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, m is 1.
In another embodiment, for compounds of the first and second aspect, R5 represents a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR8R9.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -NR8R9 and azacycloheptyl wherein each morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -NR8R9 and azacycloheptyl is optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 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 -NR8R9 and optionally substituted azacycloheptyl wherein each morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, -NR R and azacycloheptyl is optionally substituted by one or more groups as defined for R8. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents piperidinyl, morpholinyl, pyrrolidinyl, sulfoxomorpholinyl, piperazinyl, thiomorpholinyl or tropenyl each optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents hydrogen, -NR8R9 or a piperidinyl, morpholinyl, pyrrolidinyl, sulphoxomorpholiny, piperazinyl, thiomorpholinyl, tropenyl, granatanyl, oxogranatanyl or azacycloheptyl each optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents piperidinyl optionally substituted by one or more groups as defined for R8. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents piperidinyl which is bound to L by carbon and optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents piperidinyl which is bound to L by carbon and substituted on nitrogen by R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents pyrrolidinyl optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents pyrrolidinyl which is bound to L by carbon and optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents pyrrolidinyl which is bound to L by carbon and substituted on nitrogen by R8. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R represents granatanyl optionally substituted by one or more groups as defined for R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents granatanyl which is bound to L by carbon and optionally substituted by one or more groups as defined for R8. In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R5 represents granatanyl which is bound to L by carbon and substituted on nitrogen by R8.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups R6 and R7 may be identical or different and represent hydrogen or for example methyl or ethyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, the groups R8 and R9 may be identical or different and represent hydrogen; a C1- βalkyl, for example methyl, ethyl or propyl, optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, Ci-3alkyl-S(O)2, C1-3alkylamino and di- (C1-3alkyl)amino; -C1-4alkyl-C3-1ocycloalkyl, for example -CH2-cyclopropyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, Ci-3alkyl- S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C3-iocycloalkyl optionally substituted by one or more substituents selected from C^alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C6-i4aryl, for example phenyl, optionally substituted by one or more substituents selected from C1-3alkyloxy, d^alkylthio, C1-3alkyl-S(O)2,
Figure imgf000031_0001
for example benzyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl- S(O)2, C^alkylamino and di-(C1-3alkyl)amino; pyranyl optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C^alkylamino and di- (Ci-3alkyl)amino; pyridinyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyi)amino; pyrimidinyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino; pyranyl optionally substituted by one or more substituents selected from Q^alkyloxy, C1-3alkylthio, C^alkyl- S(O)2, C1-3alkylamino and di-(Ci-3alkyl)amino; C1-4alkyloxycarbonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, Ci-3alkylthio, C1-3aIkyl-S(O)2, d-salkylamino and di-(Ci-3alkyl)amino; Ce-uarylcarbonyl optionally substituted by one or more substituents selected from Ci-3alkyloxy, C1-3alkylthio, Ci-3alkyl-S(O)2, C1-3alkylamino and di-(C1-3alkyl)amino; C1-4alkylcarbonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci-3 alky lamino and di-(Ci-3alkyl)amino; C6-I4 arylmethyloxycarbonyl optionally substituted by one or more substituents selected from C^alkyloxy, Ci-3alkylthio, C1-3alkyl-S(O)2, d-salkylamino and di^C^alky^amino; C6-14arylsulfonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, C1-3alkyl-S(O)2, Ci.3alkylamino and di-(C1-3alkyl)amino; C1-4alkylsulfonyl optionally substituted by one or more substituents selected from C1-3alkyloxy, C1-3alkylthio, Ci-3alkyl-S(O)2, Ci-3alkylamino and di-(C1-3alkyl)amino and C6-l4aryl-C1-4alkylsulfonyl optionally substituted by one or more substituents selected from
Figure imgf000032_0001
and di-(C 1-3 alkyl)amino . In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R represents methyl, ethyl or propyl.
In another embodiment, for compounds of the first, second, third, fourth and fifth aspects, R9 represents methyl, ethyl or propyl.
In another embodiment, for the compound of formula (I), Q represents -C(=X)-NRaRb and X is O or H2.
In another embodiment, for the compound of formula (I), Q is selected from hydrogen, -OMe, -OEt, -OPr, -OiPr, -OCF3, -OCHF2, _-OPh, -OCH2Ph, -CH2Ph, -SMe, -SCF3, -SCHF2, -SO2Me, -SO2NH2, -SO2NMe2, -SO2NEt2, -NMe2, -C(O)NH2, C(=0)NHMe, -C(=O)NHPh, -C(=O)NHCH2CH2NMe2, -C(=O)NHCH2CMe2CH2NMe2, -CC=O)NHCH2CH2CH2NMe2, -C(=O)NHCH2CH2(piperidin-4-yl), -C(=0)NH-(piperidin-4-yl), -C(O)NH-(I- methylpiperidin-4-yl), -C(O)NH-(I -methylpyrrolidin-3-yl), -C(=O)NH-(granatanyl) -C(O)NH-(I -ethylpiperidin-4-yl), -C(=O)NH-CH2(cyclopropyl), -C(=O)NH-(cyclohexyl)- NMe2, -NHC(=O)CH3, -NHC(=O)Ph, -N(CH3)C(O)CH3, -NHSO2Me, -SO2CH2CH2OH, -SO2(piperidin-l -yl), -SO2(pyrrolidin- 1 -yl), -SO2NH(3 ,4-dimethylisoxazol-5-yl), -SO2(indazol-50yl), -C(0)-(morpholinyl), -C(O)-(ρiperidin-4-yl), -CH2(pyridin-l-yl), morpholinyl, piperidinyl, thiomorpholinyl-S,S-dioxide, 1,2,4-triazol-l-yl, 2-methylpyrimidin- 4-yl, oxazol-5-yl, oxazol-2-yl, pyroll-1-yl, pyrazol-1-yl and l-methyl-l,3,4-triazol-2-yl. In another embodiment, for the compound of formula (I), (II) or (Ha), n is 1 and L is an optionally substituted C1-10alkyl or C3-12cycloalkyl linker. In another embodiment, for the compound of formula (I), (II) or (Ha), n is 1 and L is an optionally substituted C2-10alkyl linker. In another embodiment, for the compound of formula (I), (II) or (Ha), n is 0 and m is 1.
In a further embodiment of the invention there is provided a subset of the compounds of formula (II) wherein R2 to R4, R6 and R7 are as hereinbefore defined; and L represents a linker selected from among optionally substituted C1-10alkyl, optionally substituted C2-ioalkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-i4aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 1; m denotes 1 or 2; R5 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, optionally substituted diketomethylpiperazinyl, optionally substituted sulfoxomorpholinyl, optionally substituted sulfonylmorpholinyl, optionally substituted thiomorpholinyl, -NR R and optionally substituted azacycloheptyl; R8, R9 independently represent hydrogen, C1-6alkyl, -C1-4alkyl-C3-1ocycloalkyl, C3-10cycloalkyl, C6-14aryl, -C1-4alkyl-C6-14aryl, pyranyl, pyridinyl, pyrimidinyl, C^alkyloxycarbonyl, C6-14arylcarbonyl, C^alkylcarbonyl,
Co-narylmethyloxycarbonyl, Cό-warylsulfonyl,
Figure imgf000033_0001
and
C6-14aryl-C1-4alkylsulfonyl, or pharmacologically acceptable salts thereof.
In a further embodiment of the invention there is provided a subset of the compounds of formula (II) wherein R2 to R4, R and R7 are as hereinbefore defined; and L represents a linker selected from among optionally substituted C2-10alkyl, optionally substituted C2-1oalkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-i4aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 1; m denotes 1 or 2; R5 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, optionally substituted diketomethylpiperazinyl, optionally substituted sulfoxomorpholinyl, optionally substituted sulfonylmorpholinyl, optionally substituted thiomorpholinyl, -NR8R9 and optionally substituted azacycloheptyl; R , R independently represent hydrogen, C1-6alkyl, -CMalkyl-C^ocycloalkyl, C3-i0cycloalkyl, C6-14aryl, -C1_4alkyl-C6-i4aryl, pyranyl, pyridinyl, pyrimidinyl, Ci-4alkyloxycarbonyl, C6-i4arylcarbonyl, Cualkylcarbonyl,
C^πarylmethyloxycarbonyl, C6-i4arylsulfonyl, Ci-4alkylsulfonyl and
C6-14aryl-C1-4alkylsulfonyl, or pharmacologically acceptable salts thereof.
In a still further embodiment of the invention there is provided another subset of the compounds of formula (II) wherein R2 to R4, R6 and R7 are as hereinbefore defined; L represents a linker selected from optionally substituted d-ioalkyl, optionally substituted C2-]0alkenyl, optionally substituted C6-i4aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1 ; m denotes 1 or 2; R5 denotes a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl and azacycloheptyl each optionally substituted by one or more groups as defined for R8; and R8, R9 independently represent hydrogen, C1-6alkyl, -C1-4alkyl-C3-1ocycloalkyl, C3-iocycloalkyl, C6-14aryl, -C1-4alkyl-C6-14aryl, pyranyl, pyridinyl, pyrimidinyl, C1-4alkyloxycarbonyl, C6-14arylcarbonyl, C^alkylcarbonyl, Ce-warylmethyloxycarbonyl, Cβ-warylsulfonyl, C1-4alkylsulfonyl and
Figure imgf000034_0001
or pharmacologically acceptable salts thereof.
In a still further embodiment of the invention there is provided another subset of the compounds of formula (II) wherein R2 to R4, R6 and R7 are as hereinbefore defined; L represents a linker selected from optionally substituted C2,10alkyl, optionally substituted C2-]0alkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-i4aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-i2cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1 ; m denotes 1 or 2; R5 denotes a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl and azacycloheptyl each optionally substituted by one or more groups as defined for R8; and R8, R9 independently represent hydrogen, Ci-6alkyl, -CMalkyl-Q.iocycloalkyl, C3.iocycloalkyl, C6-i4aryl, -Ci-4alkyl-C6-i4aryl, pyranyl, pyridinyl, pyrimidinyl, Ci-4alkyloxycarbonyl, C6-14arylcarbonyl, C^alkylcarbonyl, C^Harylmethyloxycarbonyl, C6-14arylsulfonyl, Ci-4alkylsulfonyl and C6-14aryl-Cj.4alkylsulfonyl, or pharmacologically acceptable salts thereof. In a still further embodiment of the invention there is provided another subset of the compounds of formula (II) wherein R2 to R4, R6 and R7 are as hereinbefore defined; L represents a linker selected from optionally substituted Cnoalkyl, optionally substituted C2-ioalkenyl, optionally substituted C6-i4aryl, optionally substituted -C2-4alkyl-C6-i4aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen ring atoms; n denotes 0 or 1 ; m denotes 1 or 2; R5 denotes a group which is bound to L via a carbon atom, selected from among piperidinyl, piperazinyl, pyrrolidinyl, piperazinylcarbonyl, tropenyl, morpholinyl, granatanyl, oxogranatanyl and azacycloheptyl each optionally substituted by one or more groups as defined for R8; and R8, R9 independently represent hydrogen, Ci-6alkyl,
Figure imgf000035_0001
pyranyl, pyridinyl, pyrimidinyl,
Figure imgf000035_0002
Co-^arylmethyloxycarbonyl, C6-14arylsulfonyl, C1-4alkylsulfonyl and
C6-14aryl-C1-4alkylsulfonyl, or pharmacologically acceptable salts thereof. In an additional embodiment of the invention there is provided an additional subset of the compounds of formula (II) wherein L, m, n and R3 to R9 are as hereinbefore defined; and R2 represents hydrogen, Me, Et or Pr, or optionally the pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of the compounds of formula (II) wherein L, m, n and R3 to R9 are as hereinbefore defined; and R2 represents Et , or optionally the pharmacologically acceptable salts thereof.
In a further additional embodiment of the invention there is provided an additional subset of the compounds of formula (II) wherein R2, m, n and R5 to R8 are as hereinbefore defined; and R3 represents an optionally substituted d-ioalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl or optionally substituted C6-i4aryl group or R2 and R3 together represent a saturated or unsaturated C3-4alkyl bridge optionally comprising 1 or 2 heteroatoms; R4 represents hydrogen, OMe, OH, Me, Et, Pr, OEt, NHMe, NH2, F, Cl, Br, O-propargyl, O-butynyl, CN, SMe, NMe2, CONH2, ethynyl, propynyl, butynyl and allyl; and L denotes a linker selected from among optionally substituted phenyl, phenylmethyl, cyclohexyl and branched C1-6alkyl, or pharmacologically acceptable salts thereof. In a further additional embodiment of the invention there is provided an additional subset of the compounds of formula (II) wherein R2 represents hydrogen or a methyl or ethyl group; R3 represents isopropyl, isobutyl, isopentyl, cyclopentyl, phenyl or cyclohexyl; p is 1 or 2; R4 represents methoxy, methyl, ethoxy, ethyl, propargyloxy, fluorine or chlorine; m is 0; n is 1; R5 denotes a group selected from piperidinyl, morpholinyl, pyrrolidinyl, sulfoxomorpholinyl, piperazinyl, thiomorpholinyl or tropenyl each optionally substituted by one or more groups as defined for R8; and R8 is methyl, ethyl or propyl, or pharmacologically acceptable salts thereof.
In a further additional embodiment of the invention there is provided an additional subset of the compounds of formula (II) wherein R2 represents a methyl or ethyl group; R3 represents a cyclopentyl; p is 0, 1 or 2; each R4 represents methoxy, methyl, ethoxy, ethyl, propargyloxy, fluorine or chlorine, or two adjacent R4 are linked to form an OCH2O bridge; m is 0; n is 1; R5 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 R8; and R8 is methyl, ethyl or propyl, or pharmacologically acceptable salts thereof.
In a further additional embodiment of the invention there is provided an additional subset of the compounds of formula (II) wherein R2 represents an ethyl group; R3 represents a cyclopentyl; p is 0, 1 or 2; each R4 represents methoxy, methyl, fluorine or chlorine, or two adjacent R4 are linked to form an OCH2O bridge; m is 0 or 1; L represents a linker selected from optionally substituted Cj.ioalkyl or optionally substituted C3-12cycloalkyl; n is 1; R5 denotes a group selected from NR8R9, piperidinyl, granatanyl and pyrrolidinyl each optionally substituted by one or more groups as defined for R8; and R8 and R9 are each independently methyl, ethyl or propyl, or pharmacologically acceptable salts thereof. In a further additional embodiment of the invention there is provided an additional subset of the compounds of formula (II) wherein R2 represents an ethyl group; R3 represents a cyclopentyl; p is 0, 1 or 2; each R4 represents methoxy, methyl, fluorine or chlorine, or two adjacent R4 are linked to form an OCH2O bridge; m is 0 or 1; L is cyclohexyl; n is 1; R5 denotes a group selected from NR8R9, piperidinyl, granatanyl and pyrrolidinyl each optionally substituted by one or more groups as defined for R8; and R8 and R9 are each independently methyl, ethyl or propyl, or pharmacologically acceptable salts thereof. In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R2 represents a Ci_3alkyl group; R3 represents an optionally substituted C1-10alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; L represents a linker selected from optionally substituted Ci_ioalkyl or optionally substituted C3_i2cycloalkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and piperidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; and wherein when both R and R4° are hydrogen, R4a represents hydrogen, methoxy, methyl, ethoxy, chlorine or fluorine; and when only one of R4b or R4c is hydrogen, then when R4b is hydrogen, R4a and R4c may be the same or different and are selected from methoxy, methyl, ethoxy, chlorine or fluorine, and when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R2 represents a C1-BaIlCyI group; R3 represents an optionally substituted CMoalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; L represents a linker selected from optionally substituted C1-10alkyl or optionally substituted C3-i2cycloalkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NRSR9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; and wherein when both R4b and R4c are hydrogen, R4a represents hydrogen, methoxy, methyl, ethoxy, chlorine or fluorine; and when only one of R4b or R4c is hydrogen, then when R4b is hydrogen, R4a and R4c may be the same or different and are selected from methoxy, methyl, ethoxy, chlorine or fluorine, and when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof. In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R2 is C1-3alkyl group; R3 represents an optionally substituted Q.ioalkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-6heterocycloalkyl; L represents a linker selected from optionally substituted Cj.joalkyl or optionally substituted C3-i2cycloalkyl; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R and granatanyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent C1-6alkyl; and wherein when both R4b and R4c are hydrogen, R4a represents methoxy, methyl, ethoxy, chlorine or fluorine; and when only one of R4b or R4c is hydrogen, then when R4b is hydrogen, R4a and R4c may be the same or different and are selected from methoxy, methyl, ethoxy, chlorine or fluorine, and when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R represents an ethyl group; R represents a cyclopentyl; L represents a cyclohexyl linker; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR R and piperidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent methyl or ethyl groups; and wherein when both R4b and R4c are hydrogen, R4a represents hydrogen, methoxy, chlorine or fluorine; and when only one of R4b or R4e is hydrogen, then when R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine, or when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof. In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R2 represents an ethyl group; R3 represents a cyclopentyl; L represents a cyclohexyl linker; n denotes 0 or 1 ; m denotes 1 or 2; R5 denotes a group selected from among -NR R9 and pyrrolidinyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent methyl or ethyl groups; and wherein when both R4b and R4c are hydrogen, R4a represents hydrogen, methoxy, chlorine or fluorine; and when only one of R4b or R4c is hydrogen, then when R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine, or when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R2 represents an ethyl group; R3 represents a cyclopentyl; L represents a cyclohexyl linker; n denotes 0 or 1; m denotes 1 or 2; R5 denotes a group selected from among -NR8R9 and granatanyl each optionally substituted by one or more groups as defined for R8; R8, R9 each independently represent methyl or ethyl groups; and wherein when both R4b and R4c are hydrogen, R4a represents hydrogen, methoxy, chlorine or fluorine; and when only one of R4b or R4° is hydrogen, then when R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine, or when R4° is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R2 represents an ethyl group; R3 represents a cyclopentyl; n denotes 0; m denotes 1 or 2; R5 denotes a piperidinyl optionally substituted by one or more groups as defined for R8; R8 represent a methyl or ethyl group; and wherein when both R4b and R4c are hydrogen, R4a represents hydrogen, methoxy, chlorine or fluorine; and when only one of R4b or R4c is hydrogen, then when R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine, or when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof. In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R represents an ethyl group; R represents a cyclopentyl; n denotes 0; m denotes 1 or 2; R5 denotes a pyrrolidinyl optionally substituted by one or more groups as defined for R ; R represent a methyl or ethyl group; and wherein when both R4b and R4c are hydrogen, R4a represents hydrogen, methoxy, chlorine or fluorine; and when only one of R4b or R4c is hydrogen, then when R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine, or when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
In an additional embodiment of the invention there is provided an additional subset of compounds of formula (Ha) wherein R2 represents an ethyl group; R3 represents a cyclopentyl; n denotes 0; m denotes 1 or 2; R5 denotes a granatanyl optionally substituted by one or more groups as defined for R ; R represents a methyl or ethyl group; and wherein when both R4b and R4c are hydrogen, R4a represents hydrogen, methoxy, chlorine or fluorine; and when only one of R4b or R4c is hydrogen, then when R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine, or when R4c is hydrogen, R4a and R4b together form a OCH2O bridge, or pharmacologically acceptable salts thereof.
In a further aspect of the invention, a particular compound of the invention is the compound of Examples 1 or the pharmacologically acceptable salts thereof.
In a further aspect of the invention, particular compounds of the invention are compounds selected from any of the Examples or the pharmacologically acceptable salts thereof. In a further aspect of the invention, particular compounds of the invention are compounds selected from any of Examples 1, 136, 179, 180, 181, 182, 183, 184, 185, 186,
187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205,
206, 207, 208, 209, 210, 211, 212, 213 and 214, or the pharmacologically acceptable salts thereof.
In a further aspect of the invention, 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.
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.
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
Figure imgf000041_0001
(H) wherein R2-R5, m, n, p and L are as hereinbefore defined, comprising reacting a compound of general formula (III),
Figure imgf000041_0002
(HI) wherein R2 and R3 are as hereinbefore defined and A is a leaving group, with an optionally substituted compound of general formula (IV):
Figure imgf000041_0003
wherein R4 is as hereinbefore defined; and R10 denotes OH, NH-Lm-R5 n, OMe, OEt, and, when R10 denotes OH, OMe or OEt, optionally after previous hydrolysis of the ester group -COR10, reacting with an amine of general formula (VI):
Figure imgf000042_0001
(VI) wherein R5, L and m are as hereinbefore defined to give a compound of formula (II). In one embodiment R10 is a substituent selected from among OH, NH-LR5, -O-methyl and -O-ethyl.
The term leaving group includes leaving groups such as for example -O-methyl, -SCN, fluoride, chloride, bromide, iodide, methanesulfonyl, trifluoromethanesulfonyl or jø-toluenesulfonyl. In one embodiment the leaving group A is chloride. The 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),
Figure imgf000042_0002
(II) wherein R2-R5, m, n, p and L are as hereinbefore defined, comprising reacting a compound of general formula (V),
Figure imgf000043_0001
(V) wherein R2 and R3 are as hereinbefore defined, with an optionally substituted compound of general formula (VII):
Figure imgf000043_0002
(VII) wherein R4 is as hereinbefore defined and Z is a leaving group; and R10 denotes OH, NH-Lra-R5 n, OMe, OEt, and, when R10 denotes OH, OMe or OEt, optionally after previous hydrolysis of the ester group -COR10, reacting with an amine of general formula (VI):
NH2 -Lm-R5 n
(VI) wherein R5, L and m are as hereinbefore defined to give a compound of formula (II).
In one embodiment R10 is a substituent selected from among OH, NH-LR5, -O-methyl and -O-ethyl.
The term leaving group includes leaving groups such as for example -O-methyl, -SCN, fluoride, chloride, bromide, iodide, methanesulfonyl, trifluoromethanesulfonyl or j9-toluenesulfonyl. In one embodiment the leaving group A is chloride.
Compounds of formula (I) may be made by analogous processes to those used in the preparation of compounds of formula (II), for example a compound of formula (I) may be prepared by reacting a compound of general formula (III),
Figure imgf000044_0001
(III) wherein R2 and R3 are as hereinbefore defined and A is a leaving group, with an optionally substituted compound of general formula (IVa):
Figure imgf000044_0002
(IVa) wherein Ar, Q, p and R4 are as hereinbefore defined.
Methods for the preparation of compounds of Formula (IV), are described in WO04/076454, WO03/020722 and WO06018220 and are incorporated herein by reference. Compounds of Formula (V) may be obtained by reaction of a compound of formula
(III) with ammonia or an ammonia equivalent.
Compounds of Formula (III) may be obtained by reaction of a compound of formula (VIII)
Figure imgf000044_0003
(VIII) wherein R2, R3 and A are as hereinbefore defined, with a methylating reagent.
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. Compounds of Formula (VIII) may be obtained by the reduction and cyclisation of a compound of formula (IX)
Figure imgf000045_0001
(IX) wherein R° is a C1-2 alkyl group; and
R2 to R4, 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;
Alternatively, compounds of Formula (VIII) may be obtained by the cyclisation of a compound of formula (X)
Figure imgf000045_0002
(X)
wherein R0 is a C1-2 alkyl group; and
R2 to R4, and A are as hereinbefore defined.
Compounds of Formula (IX) may be obtained by the reaction of a compound of formula (XI)
Figure imgf000045_0003
(XI) wherein A is as hereinbefore defined, with a compound of formula (XII)
Figure imgf000046_0001
(XII) wherein R°, R2 and R3 are as hereinbefore defined, Compounds of formula (XII) may be obtained by any method suitable for the preparation of tri-substituted hydrazines. For example, compounds where R2 is an optionally substituted C2-6alkyl and R3 represents an optionally substituted C2-12alkyl group, or an optionally substituted C3-12cycloalkyl group may be obtained by analogous means to the following method for the preparation of a compound of formula (XII) where R2 ethyl and R3 is cyclopentyl:-
Figure imgf000046_0002
Coupling and reduction
Figure imgf000046_0003
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I), (II) or (Ha) may involve, at various stages, the addition and removal of one or more protecting groups.
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.
In one embodiment of the invention, 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.
These findings suggest that pharmacological inhibitors of PIk should be of therapeutic value for treatment of proliferative disease including solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In addition 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. Such 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:
(1) carcinoma, including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, thyroid and skin;
(2) hematopoietic tumours of lymphoid lineage, including acute lymphocytic leukaemia, B cell lymphoma and Burketts lymphoma;
(3) hematopoietic tumours of myeloid lineage, including acute and chronic myelogenous leukaemias and promyelocytic leukaemia;
(4) tumours of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and (5) other tumours, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
In one embodiment, the compounds of formula (I) and (II) are useful in the treatment of tumours of the lung, breast and prostate.
Thus, 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.
In a further aspect, the present invention provides the use of a compound of formula
(I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, 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.
5 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.
The compounds of formula (I) and (II), and pharmaceutically acceptable salts and
10 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. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99%w (per cent by weight), more preferably from 0.05 to
15 80%w, still more preferably from 0.10 to 70%w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides 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
20 carrier.
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.
25 The pharmaceutical 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
30 by rectal administration in the form of suppositories; or transdermally. The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, 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.
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.
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 monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p- hydroxybenzoate, anti oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. 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.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. 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, 30μ 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.
For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansen; Chairman of Editorial Board), Pergamon Press 1990.
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.
In general, 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. Thus, for example, for intravenous administration, a dose in the range, for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used. Also, for example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient.
For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The anti cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :-
(i) other 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, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) 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-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2- chloro-6-niethylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazm-l-yl]-2-methylpyrimidin-4- ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658- 6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [Herceptin™], 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. 54, pp 11-29); such 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-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZDl 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; (v) antiangio genie agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4- (4-bromo-2-fluoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy- 7-(3-pyrrolidin-l-ylρropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin);
(vi) 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;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) 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;
(ix) 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.
Examples
The invention will now be further described with reference to the following illustrative examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mniHg) with a bath temperature of up to 6O0C; (iii) chromatography means flash chromatography on silica gel; (iv) SCX-2 cartridges are Ion Exchange SPE columns where the stationary phase is polymeric propylsulfonic acid. These are used to isolate amines.
(v) in general, the course of reactions was followed by TLC or LCMS and reaction times are given for illustration only; (vi) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data;
(vii) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (viii) when given, 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 CDCl3, DMSOd6 or DMSO-dό + d4-AcOH unless otherwise indicated;
(ix) chemical symbols have their usual meanings; SI units and symbols are used; (x) solvent ratios are given in volume: volume (v/v) terms; and
(xi) Mass spectra (MS) data was generated on an LCMS system where the 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 wateπacetonitrile (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 spectrometer scanning over an appropriate mass range. Chromatograms for Electrospray (ESI) positive and negative Base Peak Intensity, and UV Total Absorption Chromatogram from 220-3 OOnm, are generated and values for m/z are given; generally, only ions which indicate the parent mass are reported and unless otherwise stated the value quoted is the (M+H)+ for positive ion mode and (M-H)- for negative ion mode; (xii) the following abbreviations have been used:
AcOH acetic acid d4-Ac0H tetradeuteroacetic acid
CDCl3 deuterochloroform
DCM dichloromethane
DIPEA iVJV-diisopropylethylamine
DMA AζiV-dimethylacetamide
DMF JV,iV-dimethylformamide
DMSO dimethylsulfoxide
DMSO-d6 hexadeuterodimethylsulfoxide
EtI ethyl iodide
EtOH ethanol
EtOAc ethyl acetate
HATU 6>-(7-azabenzotriazole- 1 -yϊ)-N,N,N'N'- tetr amethy luronium hexafluoropho sphate
HPLC high performance liquid chromatography
MeCN acetonitrile
MeOH methanol
MeI methyl iodide
MS mass spectroscopy m/z mass to charge ratio
NMR nuclear magnetic resonance
SCX-2 ion exchange SPE column (polymeric propylsulfonic acid stationery phase)
THF tetrahydrofuran
NH3 or NH3 ammonia
SCX-3 ion exchange column (polymeric propylsulfonic acid stationary phase) Example 1;
4- \ ( 5-Cy clopentyl-4-ethyI-2-methyl-3-oxo-2,4.,5,7,9-pentazabicvclo F4.4.01 deca-7,9,11 - trien-8-vI)amino]-3-methoxy-AL(l-methyl-4-piperidyl)benzainide
Figure imgf000058_0001
8-Chloro-5-cyclopentyl-4-ethyl-2-methyl-2,4,5,7,9-pentazabicyclo[4.4.0]deca-7,9,l l-trien-3- one (Intennediate 1; 57 mg, 0.19 mmol), 4-amino-3-methoxy-iV-(l-rnethyl-4- piperidyl)benzamide (WO06018220; 51 mg, 0.19 mmol) and j^-toluene sulfonic acid (91 mg, 0.48 mmol) were dissolved in (i?/«S)-4-methyl-2-pentanol (5 mL) and refluxed under nitrogen for 24 hours. The reaction mixture was cooled and passed through an SCX-2 column washed with MeOH (50 mL). The crude product was washed off with the SCX-2 column with NH3 (7N in MeOH, 50 mL) and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, eluent gradient 0-10% NH3 (7N in MeOH) in DCM) provided the title compound (23.4 mg, 23%) as a solid.
1H NMR (400 MHz, CDCl3) δH 1.10 (t, 3H), 1.50 - 1.91 (m, 8H), 2.06 (m, 3H), 2.24 (t, 3H), 2.35 (s, 3H), 2.89 (d, 2H), 3.22 (s, 3H), 3.60 (q, 2H), 3.97 (s, 3H), 4.05 (m, IH), 5.98 (d, IH), 7.28 (d, IH), 7.44 (d, IH), 7.80 (s, IH), 7.80 (s, IH), 8.55 (d, IH); MS m/z 523.45 [M+H]+. PLKl Enzyme IC50 = 0.066μM.
Examples 2 - 178
Using an analogous procedure to that described in Example 1, 4-chloro-7-cyclopentyl-8- ethyl-10-methyl-3,5,7,8,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-9-one (Intermediate 1) was reacted with an appropriately substituted, commercially available, aniline intermediate to give the compounds described below. Example 2;
3-[(3-chIoro-2-methoxy-phenyl)amino]-10-cycIopentyl-9-ethyI-7-methyI-2,4,7,9»10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000059_0001
MS m/z 417 [M+H]+, Retention Time = 2.14 minutes PLKl Enzyme IC50 = 7.402 uM
Example 3;
1O-cyclopentyl-9-ethyl-7-methyl--3-[(4-thiadiazol-4-yl)phenyl]amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000059_0002
MS τaJz 437 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 0.1051 uM
Example 4:
10-cyclopentyl-9-ethyl-7-raethyl-3-[[4-(l-piperidylsulfonyl)pheny]]amino)-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000059_0003
MS m/z 500 [M+H]+, Retention Time = 1.95 minutes PLKl Enzyme IC50 = 15.23 uM Example 5;
N-[3-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.01]deca-1,3,5- trien-3-yl)amino]phenyl]acetamide
Figure imgf000060_0001
MS m/z 410 [M+H]+, Retention Time = 1.7 minutes PLKl En2yme IC50 = 0.2985 uM
Example 6:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-methylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000060_0002
MS m/z 367 [M+H]+, Retention Time = 2 minutes PLKl Enzyme IC50 = 2.782 uM
Example 7;
10-cyclopentyl-3-[(3,5-dimethiylphenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000060_0003
MS m/z 381 [M+H]+, Retention Time = 2.09 minutes PLKl Enzyme IC50 = 15.69 uM Example 8:
3-[(10-cycIopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yl)amino]-4-methoxy-N-phenyl-benzamide
Figure imgf000061_0001
MS m/z 502 [M+H]+, Retention Time = 1.95 minutes PLKl Enzyme IC50 - 3.637 uM
Example 9:
3-(benzo[l,3]dioxol-5-ylamino)-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000061_0002
MS m/z 397 [M+H]+, Retention Time = 1.89 minutes PLKl Enzyme IC50 = 1.128 uM
Example 10: 3-[(2-chloro-3-fluoro-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000061_0003
MS m/z 405 [M+H]+, Retention Time = 2.12 minutes PLKl Enzyme IC50 = 3.748 uM Example 11:
10-cycIopentyl-3-[[4-(difluoromethoxy)phenyI]amino]-9-ethyl-7-methyI-2,4,7,9,10- 5 pentazabicy clo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000062_0001
MS m/z 419 [M+H]+, Retention Time = 1.94 minutes PLKl Enzyme IC50 = 100 uM
Example 12:
15 10-cyclopentyl-9-ethyl-3-[(3-fluoro-4-methoxy-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000062_0002
MS m/z 401 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 0.6633 uM
25 Example 13:
10-cyclopentyl-9-ethyl-7-methyl-3-[[4-(trifluoromethoxy)phenyI]amino]-2,4,7,9,10- pentazabicycIo[4.4.0]deca-l,3»5-trien-8-one
Figure imgf000062_0003
MS m/z 437 [M+H]+, Retention Time - 2.11 minutes PLKl Enzyme IC50 = 0.1 uM
35 Example 14;
10-cyclopentyl-3-[(3-ethoxyphenyl)amino]-9-ethyI-7-methyI-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000063_0001
MS m/z 397 [M+H]+, Retention Time = 2 minutes PLKl Enzyme IC50 = 3.984 uM
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
Figure imgf000063_0002
MS m/z 381 [M+H]+, Retention Time = 2.07 minutes PLKl Enzyme IC50 = 2.827 uM
Example 16:
10-cyclopentyl-9-ethyl-3-[[3-methoxy-5-(trifluoromethyl)phenyl]amino]-7-methyl- 2,4,7,9,10-pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000063_0003
MS m/z 451 [M+H]+, Retention Time = 2.13 minutes PLKl Enzyme IC50 = 100 uM Example 17:
10-cycIopentyI-9-ethyl-3-[[2-methoxy-5-(trifluoromethyl)phenyI]amino]-7-methyI- 2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8~one
Figure imgf000064_0001
MS nVz 451 [M+H]+, Retention Time = 2.16 minutes PLKl Enzyme IC50 = 100 uM
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
Figure imgf000064_0002
MS m/z 405 [M+H]+, Retention Time = 2.17 minutes PLKl Enzyme IC50 = 6.554 uM
Example 19:
10-cyclopentyl-9-ethyl-7-methyl-3-[[3-(2-methyl-l,3-thiazol-4-yl)phenyl]amino]- 2,4,7,9,10-pentazabicycIo[4.4.0]deca-l,3>5-trien-8-one
Figure imgf000064_0003
MS m/z 450 [M+H]+, Retention Time = 2 minutes PLKl Enzyme IC50 = 3.46 uM Example 20:
10-cyclopentyI-9-ethyI-7-methyI-3-[(3-pyrrolidin-1-yIsulfonyIphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000065_0001
MS m/z 486 [M+H]+, Retention Time = 1.85 minutes PLKl Enzyme IC50 = 2.269 uM
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
Figure imgf000065_0002
MS m/z 421 [M+HJ+, Retention Time = 2.08 minutes PLKl Enzyme IC50 = 7.035 uM
Example 22:
3-[(4-bromophenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10-pentazabicyclo [4.4.0] deca-1,3,5-trien-8-one
Figure imgf000065_0003
MS m/z 431 [M+H]+, Retention Time = 2.1 minutes PLKl Enzyme IC50 = 5.383 uM Example 23:
10-cycIopentyl-9-ethyI-7-methyI-3-[[4-(trifluoromethyIsuIfanyl)phenyI]amino]- 5 2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000066_0001
MS m/z 453 [M+H]+, Retention Time = 2.22 minutes PLKl Enzyme IC50 = 15.73 uM
Example 24:
15 10-cyclopentyl-9-ethyl-7-methyl-3-[[4-(morpholine-4-carbonyl)phenyl]amino]-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien~8-one
Figure imgf000066_0002
MS m/z 466 (MfH]+, Retention Time = 1.69 minutes PLKl Enzyme IC50 = 1.269 uM
25 Example 25:
10-cyclopentyl-9-ethyl-7-methyl-3-[(2-methylbenzothiazol-6-yl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000066_0003
MS m/z 424 [M+H]+, Retention Time = 1.93 minutes PLKl Enzyme IC50 = 0.9641 uM
35 Example 26:
3-(lH-benzotriazoI-5-ylamino)-10-cyclopentyI-9-ethyl-7-methyI-2,4,7,9,10- 5 pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000067_0001
MS m/z 394 [M+H]+, Retention Time = 1.69 minutes PLKl Enzyme IC50 = 0.2591 uM
Example 27:
15 10-cyclopentyl-3-[[4-(difluoromethylsulfanyl)phenyl]amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicycIo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000067_0002
MS m/z 435 [M+H]+, Retention Time = 2.06 minutes PLKl Enzyme IC50 = 98.27 uM
25 Example 28:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-phenoxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
so 9 9
XCf
MS m/z 445 [M+H]+, Retention Time = 2.16 minutes PLKl Enzyme IC50 = 100 uM
35 Example 29:
10-cyclopentyl-9-ethyI-7-methyI-3-[[3-(l-piperidylsuIfonyI)phenyI]amino]-2,4,7,9,10- 5 pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000068_0001
MS m/z 500 [M+H]+, Retention Time = 1.94 minutes PLKl Enzyme IC50 = 12.84 uM
Example 30:
15 10-cyclopentyl-9-ethyl-7-methyl-3-[[4-(pyrrolidine-l-carbonyl)phenyl] amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000068_0002
MS m/z 450 [M+H]+, Retention Time = 1.81 minutes PLKl Enzyme IC50 = 2.248 uM
25 Example 31:
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]-N-(2-hydroxyethyl)benzenesulfonamide
Figure imgf000068_0003
MS m/z 476 [M+H]+, Retention Time = 1.62 minutes PLKl Enzyme IC50 - 9.109 uM
35 Example 32:
10-cyclopentyI-9-ethyl-7-methyI-3-[[2-(trifluoromethyI)-lH-benzoimidazoI-5-yI]amino]- 2,4,7,9,10-pentazabicy clo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000069_0001
MS m/z 461 [M+H]+, Retention Time = 1.86 minutes PLKl Enzyme IC50 = 0.5512 uM
Example 33: 3-[(2-chloro-6-methyl-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-oπe
Figure imgf000069_0002
MS m/z 401 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 6.073 uM
Example 34:
10-cyclopentyI-3-[(4-dimethylaminophenyl)amino]-9-ethyl-7-methyl-2,4, 7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000069_0003
MS m/z 396 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 2.979 uM Example 35;
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]-4-methyI-benzamide
Figure imgf000070_0001
MS m/z 410 [M+H]+, Retention Time = 1.62 minutes PLKl Enzyme IC50 = 0.6808 uM
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
Figure imgf000070_0002
MS m/z 424 [M+H]+, Retention Time = 1.64 minutes PLKl Enzyme IC50 = 0.4509 uM
Example 37:
10-cyclopentyl-9-ethyl-7-methyl-3-[(2-methylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3j5-trien-8-one
Figure imgf000070_0003
MS m/z 367 [M+H]+, Retention Time = 1.94 minutes PLKl Enzyme IC50 = 7.885 uM Example 38:
10-cyclopentyl-3-[(2,5-dimethyIphenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000071_0001
MS m/z 381 [MH-H]+, Retention Time = 2.02 minutes PLKl Enzyme IC50 = 4.012 uM
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
Figure imgf000071_0002
MS m/z 516 [M+HJ+, Retention Time = 1.92 minutes PLKl Enzyme IC50 = 2.235 uM
Example 40:
3-[(4-chloro-2-methyl-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,S-trien-8-one
Figure imgf000071_0003
MS m/z 401 [M+H]+, Retention Time = 2.06 minutes PLKl Enzyme IC50 = 4.209 uM Example 41:
10-cyclopentyl-3-[(2,6-difluorophenyl)amino]-9-ethyI-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000072_0001
MS m/z 389 [M+H]+, Retention Time = 1.79 minutes PLKl Enzyme IC50 = 2.853 uM
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
Figure imgf000072_0002
MS m/z 401 [M+H]+, Retention Time = 2.04 minutes PLKl Enzyme IC50 = 3.824 uM
Example 43:
3-[(3-chloro-4-morpholin-4-yl-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl- 2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000072_0003
MS m/z 472 [M+H]+, Retention Time = 2.01 minutes PLKl Enzyme IC50 = 2.252 uM Example 44:
10-cycIopentyl-9-ethyl-7-methyl-3-[[2-(trifluoromethoxy)phenyl]amino]-2,4,7,9,10- 5 pentazabicyclo[4.4.0]deca-l,355-trien-8-one
Figure imgf000073_0001
MS m/z 437 [M+H]+, Retention Time = 2.09 minutes PLKl Enzyme IC50 = 6.166 uM
Example 45:
15 10-cyclopentyl-9-ethyl-7-methyl-3-(naphthalen-l-ylamino)-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000073_0002
MS m/z 403 [M+H]+, Retention Time = 2 minutes PLKl Enzyme IC50 = 2.27 uM
25 Example 46:
10-cyclopentyl-9-ethyl-7-methyl-3-[(2-morpholin-4-ylphenyl)amino]-2,4,7,9,10- pentazabicycIo[4.4.0]deca-l,3?5-trien-8-one
Figure imgf000073_0003
MS m/z 438 [M+H]+, Retention Time = 2.05 minutes PLKl Enzyme IC50 = 92.99 uM
35 Example 47:
3-[(5-chloro-2-methyl-phenyl)amino]-10-cyclopentyl-9-ethyI-7-methyI-2,4,7,9,10- 5 pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000074_0001
MS m/z 401 [M+H]+, Retention Time = 2.1 minutes PLKl Enzyme IC50 = 5.589 uM
Example 48:
15 10-cyclopentyl-3-(2,5-dioxabicyclo[4.4.0]deca-7,9,ll-trien-9-ylamino)-9-ethyl-7-methyl- 2,4,7,9,10-pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000074_0002
MS m/z 411 [M+HJ+, Retention Time = 1.86 minutes PLKl Enzyme IC50 = 2.217 uM
25 Example 49:
3-[(l-acetyl-2,3-dihydroindol-6-yl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicy clo [4.4.0] deca-1 ,3 ,5-trien-8-one
Figure imgf000074_0003
MS m/z 436 [M+H]+, Retention Time = 1.81 minutes PLKl Enzyme IC50 = 5.102 uM
35 Example 50:
10-cyclopentyl-9-ethyl-3-[(2-fluoro-5-methyIsuϊfonyI-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000075_0001
MS m/z 449 [M+H]+, Retention Time = 1.71 minutes PLKl Enzyme IC50 = 4.265 uM
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
Figure imgf000075_0002
MS m/z 396 [M+H]+, Retention Time = 1.62 minutes PLKl Enzyme IC50 = 0.953 uM
Example 52:
10-cyclopentyl-9-ethyl-3-[[2-(2-hydroxyethyl)phenyl]amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3>5-trien-8-one
Figure imgf000075_0003
MS m/z 397 [M+H]+, Retention Time = 1.79 minutes PLKl Enzyme IC50 = 6.07 uM Example 53:
10-cyclopentyl-9-ethyl-7-methyl-3-[(3-morphoIin-4-ylphenyl)amino]-2,4,7,9,10- 5 pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000076_0001
MS m/z 438 [M+H]+, Retention Time = 1.88 minutes PLKl Enzyme IC50 = 1.601 uM
Example 54:
15 10-cyclopentyl-9-ethyl-3-[(3-fluoro-2-methyl-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicy clo [4.4.0] deca-1 ,355-trien-8-one
Figure imgf000076_0002
MS m/z 385 [M+H]+, Retention Time = 1.96 minutes PLKl Enzyme IC50 = 4.639 uM
25 Example 55:
4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-y l)amino] benzamide
Figure imgf000076_0003
MS m/z 396 [M+H]+, Retention Time = 1.6 minutes PLKl Enzyme IC50 = 0.06687 uM
35 Example 56:
3-(benzothiazol-6-ylamino)-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000077_0001
MS m/z 410 [M+H]+, Retention Time = 1.84 minutes PLKl Enzyme IC50 = 1.188 uM
Example 57:
N-[4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicycIo[4.4.0]deca-l,3,5- trien-3-yl)amino]phenyl]-N-methyl-acetamide
Figure imgf000077_0002
MS m/z 424 [M+H]+, Retention Time = 1.75 minutes PLKl Enzyme IC50 = 4.522 uM
Example 58:
10-cyclopentyl-9-ethyl-7-methyl-3-[[3-(4-methyl-l,2,4-triazol-3-yl)phenyl]amino]- 2,4,7,9,10-pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000077_0003
MS m/z 434 [M+H]+, Retention Time = 1.62 minutes PLKl Enzyme IC50 = 1.808 uM
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
Figure imgf000078_0001
MS m/z 420 [M+H]+, Retention Time = 1.88 minutes PLKl Enzyme IC50 = 0.2415 uM
Example 60:
10-cyclopentyl-9-ethyl-3-[(4-fluoro-3-methyl-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000078_0002
MS m/z 385 [M+H]+, Retention Time = 2.03 minutes PLKl Enzyme IC50 = 4.197 uM
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
Figure imgf000078_0003
MS m/z 419 [M+H]+, Retention Time = 1.87 minutes PLKl Enzyme IC50 = 0.3334 uM
Example 62;
10-cycIopentyl-3-[(2,4-dimethoxyphenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000079_0001
MS m/z 413 [M+H]+, Retention Time = 1.96 minutes PLKl Enzyme IC50 = 0.9313 uM
Example 63:
3-[(5-chloro-2-methoxy-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicycIo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000079_0002
MS m/z 417 [M+H]+, Retention Time = 2.18 minutes PLKl Enzyme IC50 = 5.15 uM
Example 64:
3-[(4-chloro-2,5-dimethoxy-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000079_0003
MS m/z 447 [M+H]+, Retention Time = 2.14 minutes PLKl Enzyme IC50 = 19.89 uM 5
Example 65:
2-[4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,355- trien-3-yl)amino] phenyl] acetonitrile
Figure imgf000080_0001
15 MS m/z 392 [M+H]+, Retention Time = 1.76 minutes PLKl Enzyme IC50 = 1.028 uM
Example 66:
3-[(3-chloro-4-methoxy-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- 20 pentazabicyclo[4.4.0]deca-l,3?5-trien-8-one
Figure imgf000080_0002
MS m/z 417 [M+H]+, Retention Time = 1.97 minutes PLKl Enzyme IC50 = 34.36 uM
Example 67:
30 10-cyclopentyl-9-ethyl-3-[(2-methoxy-5-methyl-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3?5-trien-8-one
Figure imgf000080_0003
MS m/z 397 [M+H]+, Retention Time = 2.12 minutes PLKl Enzyme IC50 = 4.859 uM
Example 68:
3-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yI)amino]-N,N-diethyl-4-methoxy-benzenesuIfonamide
Figure imgf000081_0001
MS m/z 518 [M+H]+, Retention Time = 1.94 minutes PLKl Enzyme IC50 = 18.7 uM
Example 69:
3-[(5-chloro-2,4-dimethoxy-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.01deca-l,3?5-trien-8-one
Figure imgf000081_0002
MS m/z 447 [M+H]+, Retention Time = 2.05 minutes PLKl Enzyme IC50 = 2.914 uM
Example 70:
10-cyclopentyl-9-ethyI-3-[(3-methoxyphenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000081_0003
MS m/z 383 [M+H]+, Retention Time = 1.92 minutes PLKl Enzyme IC50 = 2.206 uM
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
Figure imgf000082_0001
MS m/z 429 [M+H]+, Retention Time = 2.19 minutes PLKl Enzyme IC50 = 42.19 uM
Example 72:
3-[(3-chloro-4-fluoro-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3>5-trien-8-one
Figure imgf000082_0002
MS m/z 405 [M+H]+, Retention Time = 2.09 minutes PLKl Enzyme IC50 = 4.701 uM
Example 73:
3-[(4-chloro-3-methoxy-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000082_0003
MS m/z 417 [M+H]+, Retention Time = 2.03 minutes PLKl Enzyme IC50 = 7.241 uM
Example 74:
3-[(4-benzoylphenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000083_0001
MS m/z 457 [M+HJ+, Retention Time = 2.05 minutes PLKl Enzyme IC50 = 6.199 uM
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
Figure imgf000083_0002
MS m/z 367 [M+H]+, Retention Time = 2.01 minutes PLKl Enzyme IC50 = 3.504 uM
Example 76:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-phenylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000083_0003
MS m/z 429 [M+H]+, Retention Time = 2.2 minutes PLKl Enzyme IC50 = 3.334 uM Example 77;
10-cyclopentyl-9-ethyl-3-[(4-methoxynaphthalen-2-yl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000084_0001
MS m/z 433 [M+H]+, Retention Time = 2.16 minutes PLKl Enzyme IC50 = 3.67 uM
Example 78:
10-cyclopentyl-3-[(3,5-dimethoxyphenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000084_0002
MS m/z 413 [M+H]+, Retention Time = 1.93 minutes PLKl Enzyme IC50 = 0.1666 uM
Example 79:
10-cyclopentyl-9-ethyI-7-methyl-3-[(3-propan-2-yloxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000084_0003
MS m/z 411 [M+H]+, Retention Time = 2.04 minutes PLKl Enzyme IC50 = 3.84 uM Example 80:
3-[(3-benzylphenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000085_0001
MS m/z 443 [M+H]+, Retention Time = 2.21 minutes PLKl Enzyme IC50 = 4.179 uM
Example 81:
4-[(10-cyclopentyl-9-ethyl-7-methyI-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yl)amino]benzonitrile
Figure imgf000085_0002
MS m/z 378 [M+H]+, Retention Time = 1.87 minutes PLKl Enzyme IC50 = 17.06 uM
Example 82:
10-cyclopentyl-9-ethyl-3-[(2-methoxyphenyI)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Q
MS m/z 383 [M+H]+, Retention Time = 2.03 minutes PLKl Enzyme IC50 = 1.317 uM Example 83:
3-anilino-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-8-one
Figure imgf000086_0001
MS m/z 353 [M+H]+, Retention Time = 1.92 minutes PLKl Enzyme IC50 = 1.393 uM
Example 84:
10-cyclopentyl-9-ethyl-3-[(3-ethynylphenyl)amino]-7-methy]-2,4,7,9,10- pentazabicy clo [4.4.0]deca- 1 ,3 ,5-trien-8-one
Figure imgf000086_0002
MS m/z 377 [M+H]+, Retention Time = 1.96 minutes PLKl Enzyme IC50 = 90.97 uM
Example 85:
10-cyclopentyl-9-ethyIO-[(3-fluorophenyl)amino]-7--methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3j5-trien-8-one
Q
MS m/z 371 [M+H]+, Retention Time = 1.98 minutes PLKl Enzyme IC50 - 2.275 uM Example 86:
10-cyclopentyl-9-ethyl-7-methyl-3-[(3-propan-2-ylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000087_0001
MS m/z 395 [M+H]+, Retention Time = 2.15 minutes PLKl Enzyme IC50 = 4.983 uM
Example 87:
3-(benzothiazol-5-ylamino)-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000087_0002
MS m/z 410 [M+H]+, Retention Time = 1.85 minutes PLKl Enzyme IC50 = 0.5114 uM
Example 88:
10-cyclopentyl-3-[(2,4-difluorophenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000087_0003
MS m/z 389 [M+H]+, Retention Time = 1.95 minutes PLKl Enzyme IC50 = 1.851 uM Example 89:
10-cyclopentyl-3-(2,3-dihydro-1H-inden-5-ylamino)-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000088_0001
MS m/z 393 [M+H]+, Retention Time = 2.12 minutes PLKl Enzyme IC50 = 1.646 uM
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
Figure imgf000088_0002
MS m/z 392 [M+H]+, Retention Time = 1.95 minutes PLKl Enzyme IC50 = 3.146 uM
Example 91:
10-cycIopentyl-9-ethyl-7-methyl-3-[(3-pyrrol-1-ylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000088_0003
MS m/z 418 [M+H]+, Retention Time = 2.09 minutes PLKl Enzyme IC50 = 11.68 uM Example 92:
3-[(3-bromophenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicycIo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000089_0001
MS m/z 431 [M+H]+, Retention Time = 2.1 minutes PLKl Enzyme IC50 = 5.59 uM
Example 93:
10-cyclopentyl-9-ethyl-3-[(3-fluoro-4-methyI-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1 ,3,5-trien-8-one
Figure imgf000089_0002
MS m/z 385 [M+H]+, Retention Time = 2.06 minutes PLKl Enzyme IC50 = 6.317 uM
Example 94:
3-[(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]benzonitrile
Figure imgf000089_0003
MS m/z 378 [M+H]+, Retention Time = 1.88 minutes PLKl Enzyme IC50 = 7.959 uM Example 95:
3- [(3-benzoylphenyl)amino]-10-cycIopentyl-9-ethyl-7-methy 1-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3,5-trien-8-one
Figure imgf000090_0001
MS m/z 457 [M+H]+, Retention Time = 2.03 minutes PLKl Enzyme IC50 = 2.143 uM
Example 96:
10-cyclopentyl-9-ethyl-3-[[4-(2-hydroxyethyl)phenyl]amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3>5-trien-8-one
Figure imgf000090_0002
MS m/z 397 [M+H]+, Retention Time = 1.74 minutes PLKl Enzyme IC50 = 0.6087 uM
Example 97:
3-[(4-chloro-2-fluoro-phenyI)amino]-10-cyclopentyl-9-ethyI-7-methyI-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000090_0003
MS m/z 405 [M+H]+, Retention Time = 2.11 minutes PLKl Enzyme IC50 = 1.785 uM Example 98:
10-cyclopentyl-3-[(3,4-difluorophenyl) amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000091_0001
MS m/z 389 [M+H]+, Retention Time = 2.01 minutes PLKl Enzyme IC50 = 4.786 uM
Example 99:
10-cyclopentyl-9-ethyl-3-[[3-(hydroxymethyl)phenyl]amino]-7-methyl-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3 ,5-trien-8-one
Figure imgf000091_0002
MS m/z 383 [M+H]+, Retention Time = 1.72 minutes PLKl Enzyme IC50 = 0.192 uM
Example 100:
10-cyclopentyl-9-ethyl-7-methyl-3-[(3-phenylmethoxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1 ,3,5- trien-8-one
Figure imgf000091_0003
MS m/z 459 [M+H]+, Retention Time = 2.17 minutes PLKl Enzyme IC50 = 4.571 uM Example 101:
3-[(3-chloro-2-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
Figure imgf000092_0001
MS m/z 405 [M+H]+, Retention Time = 2.07 minutes PLKl Enzyme IC50 = 2.36 uM
Example 102:
10-cyclopentyl-9-ethyl-3-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-7-methyl- 2,4,7 ,9,10-pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000092_0002
MS m/z 439 [M+H]+, Retention Time = 2.09 minutes PLKl Enzyme IC50 = 26.35 uM
Example 103:
10-cyclopentyI-9-ethyl-7-methyl-3-[(4-pyrroI-l-ylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000092_0003
MS m/z 418 [M+H]+, Retention Time = 2.06 minutes PLKl Enzyme IC50 = 3.504 uM Example 104:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-methylsulfanylphenyl)amino]-2,4,7,9,10- pentazabicycIo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000093_0001
MS m/z 399 [M+H]+, Retention Time = 2.02 minutes PLKl Enzyme IC50 = 0.04825 uM
Example 105:
10-cyclopentyl-9-ethyl-3-[(4-fluoro-2-methyI-phenyI)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1-3,5-trien-8-one
Figure imgf000093_0002
MS m/z 385 [M+H]+9 Retention Time = 1.92 minutes PLKl Enzyme IC50 = 6.757 uM
Example 106:
10-cyciopentyl-9-ethyl-7-methyl-3-[[4-(pyridin-4-yImethyI)phe nyI]amino]-2,4,7,9,10- pentazabicyclo[4.4.0Jdeca-1,3,5-trien-8-one
Figure imgf000093_0003
MS m/z 444 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 4.131 uM Example 107:
3-[(2-chloro-5-fluoro-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9!,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000094_0001
MS m/z 405 [M+H]+, Retention Time = 2.19 minutes PLKl Enzyme IC50 = 100 uM
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
Figure imgf000094_0002
MS m/z 443 [M+H]+, Retention Time = 2.22 minutes PLKl Enzyme IC50 = 8.376 uM
Example 109:
10-cyclopentyl-3-[(2,6-dimethoxyphenyl)amino]-9-ethyI-7-methyI-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000094_0003
MS m/z 413 [M+H]+, Retention Time = 1.74 minutes PLKl Enzyme IC50 = 1.773 uM Example 110:
10-cyclopentyl-9-ethyl-7-methyl-3-[(3-methylsulfonyIphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000095_0001
MS m/z 431 [M+H]+, Retention Time = 1.68 minutes PLKl Enzyme IC50 = 1.587 uM
Example 111:
N-[3-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-y l)amino] phenyl] benzamide
Figure imgf000095_0002
MS m/z 472 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 4.253 uM
Example 112:
10-cyclopentyl-9-ethyl-7-methyl-3-[[3-(l,3-oxazol-5-yl)phenyl]amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3j5-trien-8-one
Figure imgf000095_0003
MS m/z 420 [M+H]+, Retention Time = 1.88 minutes PLKl Enzyme IC50 = 3.942 uM Example 113:
N-[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-phenyI]methanesulfonamide
Figure imgf000096_0001
MS m/z 460 [M+H]+, Retention Time = 1.71 minutes PLKl Enzyme IC50 = 0.5323 uM
Example 114;
10-cyclopentyl-9- ethyl-3-[(3-ethylphenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1 ,3,5-trien-8-one
Figure imgf000096_0002
MS m/z 381 [M+H]+, Retention Time = 2.08 minutes PLKl Enzyme IC50 = 1.536 uM
Example 115:
3-[(10-cycIopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-1,3,5- trien-3-yl)amino] -N-methyl-benzamide
Figure imgf000096_0003
MS m/z 410 [M+H]+, Retention Time = 1.67 minutes PLKl Enzyme IC50 = 0.5702 uM Example 116:
10-cyclopentyl-9-ethyl-3-[(3-methoxy-4-methyl-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000097_0001
MS m/z 397 [M+H]+, Retention Time = 2.04 minutes PLKl Enzyme IC50 = 2.327 uM
Example 117:
10-cyclopentyl-9-ethyl-3-[[4-methoxy-3-(trifluoromethyl)phenyl]amino]-7-methyl- 2,4,7 ,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000097_0002
MS m/z 451 [M+H]+, Retention Time = 2 minutes PLKl Enzyme IC50 = 3.926 uM
Example 118:
3-[(4-chloro-3-methyl-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclol4.4.0]deca-l,3?5-trien-8-one
Figure imgf000097_0003
MS m/z 401 [M+H]+, Retention Time = 2.16 minutes PLKl Enzyme IC50 = 9.962 uM Example 119:
10-cyclopentyl-9-ethyl-7-methyI-3-[[3-(trifluoromethyIsulfanyl)phenyl]amino]-
2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,355-trien-8-one
Figure imgf000098_0001
MS m/z 453 [M+H]+, Retention Time = 2.18 minutes PLKl Enzyme IC50 = 5.456 uM
Example 120:
3-[(4-chloro-3-fluoro-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyI-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000098_0002
MS m/z 405 [M+H]+, Retention Time = 2.12 minutes PLKl Enzyme IC50 = 2.708 uM
Example 121:
4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicycIo[4.4.0]deca-l,3,5- trien-3-yl)amino]-N,N-dimethyl-benzenesulfonamide
Figure imgf000098_0003
MS m/z 460 [M+H]+, Retention Time = 1.78 minutes PLKl Enzyme IC50 = 100 uM Example 122;
10-cyclopentyl-9-ethyl-3-[[2-fluoro-3-<trifluoromethyl)phenyI]amino]-7-methyI- 2,4,7,9,10-pentazabicyclo[4.4.01deca-1,3,5-trien-8-one
Figure imgf000099_0001
MS m/z 439 [M+H]+, Retention Time = 2.08 minutes PLKl Enzyme IC50 = 4.769 uM
Example 123:
10-cyclopentyl-9-ethyl-3-[(2-fluorophenyI)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000099_0002
MS m/z 371 [M+H]+, Retention Time = 1.96 minutes PLKl Enzyme IC50 = 0.1469 uM
Example 124:
1O-cyclopenty-9-ethyl-7-methyl-3- [(3-tert-butylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000099_0003
MS m/z 409 [M+H]+, Retention Time = 2.22 minutes PLKl Enzyme IC50 = 5.49 uM Example 125:
10-cyclopentyl-9-ethyl-3-[[2-fluoro-4-(trifluoromethyl)phenyl]amino]-7-methyl-
2,4,7,9,10-pentazabicyclo[4.4.0]deca~l,3,5-trien-8-one
Figure imgf000100_0001
MS m/z 439 [M+H]+, Retention Time = 2.17 minutes PLKl Enzyme IC50 = 3.244 uM
Example 126:
10-cyclopentyl-9-ethyl-7-methyl-3-[[3-(2-methylpyrimidin-4-yl)phenyl]amino]- 2,4,7 ,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000100_0002
MS m/z 445 [M+H]+, Retention Time = 1.92 minutes PLKl Enzyme IC50 = 3.511 uM
Example 127:
10-cyclopentyl-9-ethyl-3-[(2-fluoro-4-methyl-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000100_0003
MS m/z 385 [M+H]+, Retention Time = 2.03 minutes PLKl Enzyme IC50 = 1.061 uM Example 128;
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]benzenesulfonamide
Figure imgf000101_0001
MS ro/z 432 [M+H]+, Retention Time = 1.59 minutes PLKl Enzyme IC50 = 0.4345 uM
Example 129;
10-cyclopentyl-3-[[4-(l,l-dioxo-l,4-thiazinan-4-yl)phenyl]amino]-9-ethyI-7-methyl-
2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000101_0002
MS m/z 486 [M+H]+, Retention Time = 1.67 minutes PLKl Enzyme IC50 = 0.9763 uM
Example 130;
10-cyclopentyl-9-ethyl-3-(lH-indazol-6-ylamino)-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3?5-trien-8-one
Figure imgf000101_0003
MS m/z 393 [M+H]+, Retention Time = 1.76 minutes PLKl Enzyme IC50 = 3.343 uM Example 131:
10-cyclopentyl-9-ethyl-7-methyl-3-(naphthalen-2-ylamino)-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3?5-trien-8-one
Figure imgf000102_0001
MS m/z 403 [M+H]+, Retention Time = 2.1 minutes PLKl Enzyme IC50 = 42.74 uM
Example 132:
4-[(10-cycIopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yl)amino]benzenesulfonamide
Figure imgf000102_0002
MS m/z 432 [M+H]+, Retention Time = 1.57 minutes PLKl Enzyme IC50 = 0.365 uM
Example 133:
10-cyelopentyl-9-ethyl-7-methyl-3-[(2-methyl-lH-indol-5-yl)amino]-2,4,7,9,10- pentazabicyclo [4.4.0] deca-1 ,3?5-trien-8-one
Figure imgf000102_0003
MS m/z 406 [M+H]+, Retention Time = 1.84 minutes PLKl Enzyme IC50 = 0.9994 uM Example 134:
10-cyclopentyl-9-ethyl-7-methyl-3-[[3-(trifluoromethoxy)phenyl]amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000103_0001
MS m/z 437 [M+H]+, Retention Time = 2.09 minutes PLKl Enzyme IC50 = 6.886 uM
Example 135:
10-cyclopentyl-9-ethyl-3-[[2-fluoro-5-(trifluoromethyl)phenyl]amino]-7-methyl-
2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000103_0002
MS m/z 439 [M+H]+, Retention Time = 2.12 minutes PLKl Enzyme IC50 = 6.936 uM
Example 136:
4-[(10-cydopentyl-9-ethyl-7-methyI-8-oxo-2,4,7,9,10-pentazabicycIo[4.4.0]deca-l,3,5- trien-3-yl)amino] -N-(2-diethylaminoethyI)benzamide
Figure imgf000103_0003
MS m/z 495 [M+H]+, Retention Time = 1.56 minutes PLKl Enzyme IC50 = 0.1298 uM Example 137:
3-[(3--chlorophenyl)amino]-10-cyclopent1yl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000104_0001
MS m/z 387 [M+H]+, Retention Time = 2.07 minutes PLKl Enzyme IC50 = 1.577 uM
Example 138:
10-cyclopentyl-9-ethyI-3-[[3-fluoro-4-(trifluoromethyl)phenyl]amino]-7-methyI-
2,4,7,9,10-pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000104_0002
MS m/z 439 [M+H]+, Retention Time = 2.14 minutes PLKl Enzyme IC50 = 100 uM
Example 139:
10-cyclopentyl-9-ethyl-7-methyl-3-[(3-methylsuIfanylphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000104_0003
MS m/z 399 [M+H]+, Retention Time = 2.03 minutes PLKl Enzyme IC50 - 3.243 uM Example 140:
10-cyclopentyl-3-[(2,5-dimethoxyphenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000105_0001
MS m/z 413 [M+H]+, Retention Time = 2.03 minutes PLKl Enzyme IC50 = 1.543 uM
Example 141:
10-cyclopentyl-9-ethyl-7-methyl-3-[(3-phenoxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000105_0002
MS m/z 445 [M+H]+, Retention Time = 2.17 minutes PLKl Enzyme IC50 = 3.941 uM
Example 142:
10-cyclopentyl-9-ethyl-3-(1H-indazol-5-ylamino)-7-methyI-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000105_0003
MS m/z 393 [M+H]+, Retention Time = 1.69 minutes PLKl Enzyme IC50 = 0.1177 uM Example 143:
10-cyclopentyl-9-ethyl-7-methyl-3-[(1-methylindol-5-yl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trie n-8-one
Figure imgf000106_0001
MS m/z 406 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 0.832 uM
Example 144:
3-[(1-acetyl-2,3-dihydroindol-7-yl)amino]-10-cyclopeiityl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-o ne
Figure imgf000106_0002
MS m/z 436 [M+H]+, Retention Time = 1.85 minutes PLKl Enzyme IC50 = 47.61 uM
Example 145:
4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pen<azabicyclo[4.4.01deca-1,3,5- trien-3-yl)amino]-N-phenyl-benzamide
Figure imgf000106_0003
MS m/z 472 [M+H]+, Retention Time = 1.93 minutes PLKl Enzyme IC50 = 3.92 uM Example 146:
10-cyclopentyl-3-[(2,6-dimethylphenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000107_0001
MS m/z 381 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 19.98 uM
Example 147:
10-cyclopentyl-9-ethyl-7-methyl-3-(quinoxalin-6-ylamino)-2,4,7,9,10- pentazabicy clo [4.4.0] deca-1 ,3 ,5-trien-8-one
Figure imgf000107_0002
MS m/z 405 [M+H]+, Retention Time = 1.81 minutes PLKl Enzyme IC50 = 1.568 uM
Example 148:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-propan-2-yloxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3j5-trien-8-one
Figure imgf000107_0003
MS m/z 411 [M+H]+, Retention Time = 2 minutes PLKl Enzyme IC50 = 18.14 uM Example 149:
N-[4-chloro-3-[(10-cyclopentyl-9-ehtyl-7-methyl-8-oxo-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-3-yl)amino]phenyI]acetamide
Figure imgf000108_0001
MS m/z 444 [M+H]+, Retention Time = 1.88 minutes PLKl Enzyme IC50 = 0.7451 uM
Example 150:
4-[(10-cycIopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-1,3,5- trien-3-yl)amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide
Figure imgf000108_0002
MS m/z 527 [M+H]+, Retention Time = 1.61 minutes PLKl Enzyme IC50 = 0.5797 uM
Example 151:
10-cyclopentyl-3-[(2,5-difluorophenyl)amino]-9-ethyI-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000108_0003
MS m/z 389 [M+H]+, Retention Time = 2.04 minutes PLKl Enzyme IC50 = 11.2 uM Example 152:
10-cyclopentyl-9-ethyl-7-methyl-3-[[4-(l,2,4-triazol-l-yl)phenyl]amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3j5-trien-8-one
Figure imgf000109_0001
MS m/z 420 [M+H]+, Retention Time = 1.77 minutes PLKl Enzyme IC50 = 2.914 uM
Example 153:
10-cyclopentyl-9-ethyl-7-methyl-3-[[4-(l-piperidyl)phenyl]amino]-2,4,7,9,10- pentazabicy clo [4.4.0] deca-1 ,3,5-trien-8-one
0 9 9 cor MS m/z 436 [M+H]+, Retention Time = 2.06 minutes PLKl Enzyme IC50 = 4.052 uM
Example 154:
3-[(2-chloro-4-fluoro-phenyl)amino]-10-cyclopentyl-9-ethyI-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000109_0002
MS m/z 405 [M+H]+, Retention Time = 2.07 minutes PLKl Enzyme IC50 = 0.9825 uM Example 155:
3-[(2-chloro-5-methoxy-phenyl)amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000110_0001
MS m/z 417 [M+H]+, Retention Time = 2.14 minutes PLKl Enzyme IC50 = 2.418 uM
Example 156:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-propoxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3?5-trien-8-one
Figure imgf000110_0002
MS m/z 411 [M+H]+, Retention Time = 2.06 minutes PLKl Enzyme IC50 = 100 uM
Example 157:
4-[(10-cyclopentyl-9-ethyl-7-methyI-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yl)amino]-N-(lH-indazol-6-yl)benzenesulfonamide
Figure imgf000110_0003
MS m/z 548 [M+H]+, Retention Time = 1.73 minutes PLKl Enzyme IC50 = 6.344 uM Example 158:
3-[[4-(4-benzylpiperazin-l-yl)phenyl]amino]-10-cyclopentyl-9-ethyl-7-methyl-2,4,7,9,10- pentazabicycIo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000111_0001
MS m/z 527 [M+H]+, Retention Time = 2.1 minutes PLKl Enzyme IC50 = 2.557 uM
Example 159:
10-cyclopentyl-9-ethyl-3-[[3-fluoro-5-(trifluoromethyI)phenyl]amino]-7-methyl-
2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000111_0002
MS m/z 439 [M+H]+, Retention Time = 2.2 minutes PLKl Enzyme IC50 = 100 uM
Example 160:
10-cyclopentyl-9-ethyl-7-methyl-3-[(3,4,5-trimethoxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000111_0003
MS m/z 443 [M+H]+, Retention Time = 1.82 minutes PLKl Enzyme IC50 = 0.801 uM Example 161:
10-cyclopentyl-9-ethyl-3-(lH-indol-5-ylamino)-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000112_0001
MS m/z 392 [M+H]+, Retention Time = 1.77 minutes PLKl Enzyme IC50 = 0.5279 uM
Example 162:
10-cyclopentyl-3-[(3,5-dichlorophenyl)amino]-9-ethyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3?5-trien-8-one
Figure imgf000112_0002
MS m/z 421 [M+H]+, Retention Time = 2.3 minutes PLKl Enzyme IC50 = 58.46 uM
Example 163:
10-cyclopentyl-9-ethyl-7-methyl-3-[[4-(piperidine-l-carbonyl)phenyI]amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000112_0003
MS m/z 464 [M+H]+, Retention Time = 1.89 minutes PLKl Enzyme IC50 = 1.499 uM Example 164:
10-cyclopentyl-9-ethyl-3-[[3-(2-hydroxyethylsulfonyl)phenyI]amino]-7-methyl-2,4,7,9!110- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000113_0001
MS m/z 461 [M+H]+, Retention Time = 1.61 minutes PLKl Enzyme IC50 = 1.872 uM
Example 165:
4-[(10-cyclopentyl-9-ethyI-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-l,3,5- trien-3-yl)amino]-3-methyl-benzonitrile
Figure imgf000113_0002
MS m/z 392 [M+H]+, Retention Time = 1.9 minutes PLKl Enzyme IC50 = 3.909 uM
Example 166:
10-cyclopentyl-9-ethyl-7-methyI-3-[(6-morphoϊin-4-yIpyridin-3-yl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000113_0003
MS m/z 439 [M+H]+, Retention Time = 1.76 minutes PLKl Enzyme IC50 = 0.3261 uM Example 167:
10-cyclopentyl-9-ethyl-7-methyl-3-[(2-methylbenzothiazol-5-yl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000114_0001
MS m/z 424 [M+H]+, Retention Time = 1.94 minutes PLKl Enzyme IC50 = 3.872 uM
Example 168:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-morpholin-4-ylphenyI)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000114_0002
MS m/z 438 [M+H]+, Retention Time = 1.82 minutes PLKl Enzyme IC50 = 0.7667 uM
Example 169:
10-cyclopentyl-3-[(3,4-dimethoxyphenyl)amino]-9-ehtyl-7-methyl-2,4,7,9,10- pentazabicyclo[4.4.0]deca-1,3,5-trien-8-one
Figure imgf000114_0003
MS m/z 413 [M+H]+, Retention Time = 1.79 minutes PLKl Enzyme IC50 = 0.7036 uM Example 170:
10-cyclopentyl-9-ethyl-3-[(4-fluoro-3-methoxy-phenyl)amino]-7-methyl-2,4,7,9,10- pentazabicycIo[4.4.0]deca-l,3,5-trien-8-one
Figure imgf000115_0001
MS m/z 401 [M+H]+, Retention Time = 1.92 minutes PLKl Enzyme IC50 = 3.27 uM
Example 171:
10-cyclopentyI-9-ethy]-7-methyl-3-[(4-methyl-2-oxo-lH-quinoIin-7-yl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-2,4,ll-trien-8-one
Figure imgf000115_0002
MS m/z 434 [M+H]+, Retention Time = 1.84 minutes PLKl Enzyme IC50 = 0.7275 uM
Example 172:
10-cyclopentyl-9-ethyl-7-methyl-3-[(4-phenyImethoxyphenyl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0] deca-2,4,1 l-trien-8-one
Figure imgf000115_0003
MS m/z 459 [M+H]+, Retention Time = 2.11 minutes PLKl Enzyme IC50 = 2.773 uM Example 173:
5-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca-2,4,ll- trien-3-yl)ammo]isoindole-l,3-dione
Figure imgf000116_0001
MS m/z 422 [M+H]+, Retention Time = 1.79 minutes PLKl Enzyme IC50 = 3.438 uM
Example 174; 10-cyclopentyl-9-ethyl-3-[[3-(hydroxymethyl)-2-methyl-phenyl]amino]-7-methyl-
2A7,9,10-pentazabicyclo[4.4.0]deca-2,4,ll-trien-8-one
Figure imgf000116_0002
MS m/z 397 [M+H]+, Retention Time = 1.68 minutes PLKl Enzyme IC50 = 1.199 uM
Example 175:
10-cyclopentyl-9-ethyI-3-[(2-hydroxyphenyl)amino]-7-methyI-2,4,7,9,10- pentazabicyclo[4.4.0]deca-2,4,ll-trien-8-one
Figure imgf000116_0003
MS m/z 369 [M+H]+, Retention Time = 1.85 minutes PLKl Enzyme IC50 = 1.14 uM Example 176:
10-cyclopentyl-9-ethyl-3-[[5-(hydroxymethyl)-2-methyl-phenyl]amino]-7-methyl-
2,4,7,9,10-pentazabicyclo[4.4.0]deca-2,4,11-trien-8-one
Figure imgf000117_0001
MS m/z 397 [M+H]+, Retention Time = 1.72 minutes PLKl Enzyme IC50 = 2.144 uM
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
Figure imgf000117_0002
MS m/z 393 [M+H]+, Retention Time = 1.82 minutes PLKl Enzyme IC50 = 11.13 uM
Example 178:
10-cyclopentyl-9-ethyl-7-methyl-3-[(5-tert-butyl-1,2-oxazoI-3-yl)amino]-2,4,7,9,10- pentazabicyclo[4.4.0]deca-2,4,11-trien-8-one
Figure imgf000117_0003
MS m/z 400 [M+H]+, Retention Time = 1.96 minutes PLKl Enzyme IC50 = 37.33 uM Example 179:
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-7,9,ll- trien-8-yl)amino]-3-methoxy-N-[(lS,5R)-9-methyI-9-azabicycIo[3.3.1]non-7- yl]benzamide
Figure imgf000118_0001
10 7-chloro-l-cyclopentyl-2-ethyl-4-methyl-l,2-dihydropyrimido[5,4-e][l,2,4]triazin-3(4H)-one (Intermediate 1; 52 mg, 0.18 mmol) and 4-ammo-3-methoxy-N-((lR,3r,5S)-9-methyl-9- azabicyclo[3.3.1]nonan-3-yl)benzamide (Intermediate 8; 54 mg, 0.18 mmol) were suspended in 4-methyl~2-pentanol (2 ml). p-Toluenesulfbnic acid monohydrate (67 mg, 0.35 mmol) was then added and reaction mixture sealed into a microwave tube. The reaction was heated to
15 160 °C for a total of 150 minutes in the microwave reactor and cooled to ambient temperature.
The 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
20 using 2M NH3/MeOH. Ammonical eluant was evaporated to dryness to afford the crude product, which was purified by flash silica chromatography, elution gradient 0 to 10% 2M ammonia/MeOH in DCM. Product containing fractions were evaporated to dryness to afford a colourless gum, which after trituration with diethyl ether/isohexane and drying, under vacuum at 500C, for 4 hours, afforded the title compound as a white solid (27.0 mg, 27%). 25 1H NMR (400.132 MHz, DMSO) δ 0.83 - 0.94 (5H, m), 1.34 - 1.50 (5H, m), 1.53 - 1.88 (8H, m), 1.94 - 2.02 (IH, m), 2.09 - 2.17 (2H, m), 2.35 (3H, s), 2.88 - 2.96 (2H, m), 3.07 (3H, s),
3.41 (2H, q), 3.88 (3H, s), 3.97 (IH, quintet), 4.21 - 4.32 (IH, m), 7.42 - 7.46 (2H, m), 7.83 -
7.86 (2H, m), 7.96 (IH, s), 8.26 (IH, d); MS m/z 563 [M+H]+.
PLKl Enzyme IC50 = 0.053 uM 30 Example 180: 4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000119_0001
4-chloro-7-cyclopentyl-8-ethyl-10-methyl-3,597,8,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-9- one (Intermediate 1 ; 50 mg, 0.17 mmol) and 4-amino-2-fluoro-5-methoxy-N-( 1 -methyl-4- piperidyl)benzamide (Intermediate 9; 48 mg, 0.17 mmol) were taken up in 4-methyl-2- pentanol (2 ml) and p-toluenesulfonic acid monohydrate (65 mg, 0.34 mmol) was added. The reaction was mixture heated to HO0C for 24 hours. The mixture was cooled, diluted with methanol (5 ml) and water (2 mL), and solution poured onto an SCX-3 (2 g) cartridge. Cartridge was washed through with methanol (~30 ml) before eluting crude products with a 2M solution of ammonia in methanol (~20 ml). Evaporation to dryness afforded the crude product, which was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% aq. ammonia solution) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the title compound (40 mg, 44%)
1HNMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.47 - 1.89 (12H, m), 1.93 - 2.01 (2H, m), 2.16 (3H, s), 2.70 - 2.76 (2H, m), 3.15 (3H, s), 3.49 (2H, q), 3.67 - 3.77 (IH, m), 3.91 (3H, s), 4.06 (IH, quintet), 7.19 (IH, d), 7.79 - 7.82 (IH5 m), 8.01 (IH, s), 8÷06 (IH, s), 8.28 (IH, d); MS m/z 541 [M+H]+.
PLKl Enzyme IC50 = 0.04 uM Examples 181 - 201
Using an analogous procedure to that described in Example 180, 4-chloro-7-cyclopentyl-8- ethyl-10-methyl-3,5,7,8,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-9-one (Intermediate l) was reacted with an appropriately substituted aniline intermediate as indicated to give the compounds described below.
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
Figure imgf000120_0001
Aniline intermediate 12 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.46 - 1.86 (12H, m), 1.91 - 1.99 (2H, m), 2.17 (3H, s), 2.74 - 2.80 (2H, m), 3.15 (3H, s), 3.49 (2H, q), 3.67 - 3.77 (IH, m), 4.02 (IH, quintet), 7.77 (4H, s), 7.96 (IH, d), 8.04 (IH, s), 9.68 (IH, s); MS m/z 493 [M+H]+. PLKl Enzyme IC50 = 0.007 uM
Example 182:
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-3-fluoro-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000120_0002
Aniline intermediate 13 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.98 (3H, t), 1.45 - 1.84 (12H, m), 1.91 - 1.97 (2H, m),
2.17 (3H, s), 2.74 - 2.80 (2H, m), 3.13 (3H, s), 3.47 (2H, q), 3.67 - 3.77 (IH, m), 4.00 (IH, quintet), 7.66 - 7.71 (2H, m), 7.99 (IH, s), 8.06 (IH, t), 8.14 (IH, d), 9.01 (IH, s); MS m/z
511 [MfH]+.
PLKl Enzyme IC50 = 0.109 uM
Example 183:
7-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(l-methyI-4-piperidyl)benzo[l,3]dioxole-4-carboxamide
Figure imgf000121_0001
Aniline intermediate 14 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.97 (3H, t), 1.45 - 1.84 (12H, m), 1.99 - 2.04 (2H, m), 2.17 (3H, s), 2.65 - 2.72 (2H, m), 3.12 (3H, s), 3.46 (2H, q), 3.71 - 3.79 (IH, m), 3.99 (IH, quintet), 6.12 (2H5 s), 7.22 (IH, d), 7.29 - 7.37 (2H, m), 7.95 (IH, s), 8.89 (IH, s); MS m/z 537 [M+H]+. PLKl Enzyme IC50 = 0.125 uM
Example 184:
4-[(5-cycIopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicycIo[4.4.0]deca-6,8,10- trien-8-yl)amino]-3-methyl-N-(l-methyl-4-piperidyI)benzamide
Figure imgf000121_0002
Aniline intermediate 16 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.45 - 1.81 (12H, m), 1.91 - 1.99 (2H, m), 2.18 (3H, s), 2.30 (3H, s), 2.75 - 2.81 (2H, m), 3.14 (3H, s), 3.47 (2H, q), 3.69 - 3.78 (IH, m), 3.98 (IH, quintet), 7.63 - 7.71 (2H, m), 7.77 (IH, d), 7.96 (IH, s), 8.03 (IH, d), 8.53 (IH, s); MS m/z 507 [M+H]+. PLKl Enzyme IC50 = 0.225 uM Example 185:
4-[(5-cyclopentyl-4-ethyl-2-methyI-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-3-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide
Figure imgf000122_0001
Aniline intermediate 18 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.47 - 1.86 (12H, m), 2.47 - 2.51 (4H, m), 2.58 (2H5 1), 3.14 (3H, s), 3.38 (2H, q), 3.48 (2H5 q), 3.93 (3H, s), 4.04 (IH, quintet), 7.47 - 7.51 (2H, m), 7.92 (IH5 s), 8.02 (IH, s), 8.29 (IH5 1), 8.32 - 8.35 (IH5 m); MS m/z 523 [M+H]+.
PLKl Enzyme IC50 = 0.109 uM
Example 186:
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yI)amino]-N-(2-dimethylaminoethyl)-3-methoxy-benzamide
Figure imgf000122_0002
Aniline intermediate 20 used in synthesis
IH NMR (400.132 MHz5 DMSO) δ 0.99 (3H5 1), 1.46 - 1.87 (8H5 m), 2.19 (6H5 s), 2.40 (2H5 t), 3.14 (3H5 s), 3.36 (2H5 q), 3.48 (2H5 q), 3.94 (3H5 s), 4.04 (IH5 quintet), 7.47 - 7.51 (2H5 m), 7.92 (IH, s), 8.02 (IH5 s), 8.24 (IH, t), 8.31 - 8.35 (IH, m); MS m/z 497 [M+H]+. PLKl Enzyme IC50 = 0.307 uM Example 187:
4-[(5-cycIopentyl-4-ethyl-2-methyI-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide
Figure imgf000123_0001
Aniline intermediate 22 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.89 (6H, s), 0.99 (3H, t), 1.46 - 1.87 (8H, m), 2.19 (2H, s), 2.28 (6H, s), 3.14 (3H, s), 3.20 (2H, d), 3.48 (2H, q), 3.94 (3H, s), 4.04 (IH, quintet), 7.44 - 7.48 (2H, m), 7.93 (IH, s), 8.01 (IH, s), 8.31 - 8.39 (2H, m); MS m/z 539 [M+H]+. PLKl Enzyme IC50 = 0.416 uM
Example 188: 4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(3-dimethylaminopropyl)-3-methoxy-benzamide
Figure imgf000123_0002
Aniline intermediate 24 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.47 - 1.87 (1OH, m), 2.19 (6H, s), 2.33 (2H, t), 3.14 (3H5 s), 3.28 (2H, m), 3.48 (2H, q), 3.94 (3H, s), 4.04 (IH5 quintet), 7.46 - 7.50 (2H, m), 7.92 (IH5 s), 8.02 (IH, s), 8.32 - 8.35 (IH5 m), 8.37 (IH5 1); MS m/z 511 [M+H]+. PLKl Enzyme IC50 = 0.129 uM
Example 189:
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicycIo[4.4.0]deca-6,8,10- trien-8-yl)amino]-2-fluoro-5-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
Figure imgf000124_0001
Aniline intermediate 26 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.48 - 1.56 (2H, m), 1.62 - 1.90 (7H, m), 2.13 - 2.21 (IH, m), 2.26 (3H, s), 2.33 - 2.44 (2H, m), 2.57 - 2.63 (IH, m), 2.66 - 2.70 (IH, m), 3.15 (3H, s), 3.49 (2H, q), 3.91 (3H, s), 4.06 (IH, quintet), 4.34 - 4.42 (IH, m), 7.21 (IH, d), 7.96 - 8.03 (2H, m), 8.06 (IH, s), 8.28 (IH, d); MS m/z 527 [M+H]+. PLKl Enzyme IC50 = 0.279 uM
Example 190:
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8?10" trien-8-yl)amino]-N-(l-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide
Figure imgf000124_0002
Aniline intermediate 29 used in synthesis
IHNMR (400.132 MHz, DMSO) δ 0.97 - 1.02 (6H5 m), 1.47 - 1.88 (12H, m), 1.92 - 2.01 (2H, m), 2.32 (2H, q), 2.79 - 2.85 (2H, m), 3.15 (3H, s), 3.49 (2H, q), 3.69 - 3.79 (IH5 m), 3.91 (3H5 s), 4.06 (IH5 quintet), 7.20 (IH5 d)5 7.80 (IH, dd), 8.01 (IH5 s), 8.06 (IH5 s), 8.28 (IH, d); MS m/z 555 [M+H]+. PLKl Enzyme IC50 = 0.288 uM
Example 191;
4-[(5-cyclopentyl-4-ethyl-2-methyI-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-2-fluoro-5-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide
Figure imgf000124_0003
Aniline intermediate 30 used in synthesis IH NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.47 - 1.56 (2H, m), 1.62 - 1.85 (1OH, m), 2.49 (4H, m), 2.58 (2H, t), 3.15 (3H, s), 3.39 (2H, q), 3.49 (2H, q), 3.92 (3H5 s), 4.06 (IH, quintet), 7.29 (IH, d), 7.89 (IH, q), 8.03 (IH5 s), 8.05 (IH, s), 8.30 (IH, d); MS m/z 541 [M+H]+.
PLKl Enzyme IC50 = 0.156 uM
Example 192;
4-[(5-cyclopentyl-4-ethyI-2-methyI-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-3-methoxy-N-(4-piperidyl)benzamide
Figure imgf000125_0001
Aniline intermediate 31 used in synthesis IH NMR (400.132 MHz, DMSO) δ 0.99 (3H5 1), 1.38 - 1.87 (13H5 m), 2.52 - 2.59 (2H, m),
2.96 - 3.03 (2H, m), 3.14 (3H, s), 3.48 (2H, q), 3.80 - 3.89 (IH, m), 3.94 (3H5 s), 4.04 (IH5 quintet), 7.49 - 7.52 (2H, m), 7.92 (IH, s), 8.02 (IH, s), 8.07 (IH5 d), 8.31 - 8.35 (IH, m); MS m/z 509 [M+H]+.
PLKl Enzyme IC50 = 0.111 uM
Example 193;
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-3-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide
Figure imgf000125_0002
Aniline intermediate 32 used in synthesis IH NMR (400.132 MHz, DMSO) δ 0.90 - 0.95 (2H, m), 0.98 (3H, t), 1.40 - 1.84 (1 IH, m), 1.86 - 1.95 (2H, m), 1.99 - 2.08 (IH, m), 2.15 - 2.22 (2H, m), 2.41 (3H, s), 2.95 - 3.00 (2H, m), 3.14 (3H, s), 3.47 (2H, q), 4.00 (IH, quintet), 4.25 - 4.37 (IH, m), 7.66 - 7.72 (2H, m), 7.99 - 8.08 (3H, m), 9.01 (IH, s); MS m/z 551 [M+H]+. PLKl Enzyme IC50 = 0.212 uM
Example 194:
4-[(5-cyclopentyl-4-ethyI-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(cycIopropylmethyl)-3-methoxy-benzamide
Figure imgf000126_0001
Aniline intermediate 33 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.24 - 0.28 (2H, m), 0.44 - 0.48 (2H, m), 1.01 (3H, t), 1.02 - 1.10 (IH, m), 1.48 - 1.89 (8H, m), 3.15 - 3.20(5H, m), 3.50 (2H, q), 3.96 (3H, s), 4.06 (IH, quintet), 7.52 - 7.54 (2H, m), 7.94 (IH, s), 8.04 (IH, s), 8.34 - 8.37 (IH, m), 8.42 (IH, t); MS m/z 480 [M+H]+. PLKl Enzyme IC50 = 0.366 uM
Example 195:
2-chloro-4- [(5-cyclopentyl-4-ethyl-2-methyI-3-oxo-2,4,5,7,9-pentazabicyclo [4.4.0] deca-
6,8,10-trien-8-yl)amino]-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000126_0002
Aniline intermediate 34 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.46 - 1.88 (12H, m), 1.93 - 2.00 (2H, m), 2.16 (3H, s), 2.70 - 2.77 (2H, m), 3.14 (3H, s), 3.48 (2H, q), 3.63 - 3.73 (IH, m), 3.91 (3H, s), 4.05 (IH5 quintet), 7.03 (IH, s), 7.94 (IH, s), 8.04 (IH5 s), 8.16 (IH, d), 8.41 (IH, s); MS m/z
557 [M+H]+.
PLKl Enzyme IC50 = 1.006 uM
Example 196:
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-2-fluoro-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000127_0001
Aniline intermediate 35 used in synthesis
IH NMR (400.132 MHz5 DMSO) δ 0.99 (3H5 1), 1.46 - 1.86 (12H5 m), 1.92 - 2.00 (2H, m), 2.16 (3H5 s), 2.68 - 2.75 (2H5 m), 3.15 (3H, s), 3.49 (2H5 q), 3.65 - 3.75 (IH5 m)5 4.03 (IH5 quintet), 7.43 (IH, dd), 7.53 (IH5 1), 7.77 (IH5 dd)5 7.83 (IH5 dd), 8.06 (IH, s), 9.89 (IH, s); MS m/z 511 [M+H]+. PLKl Enzyme IC50 = 0.239 uM
Example 197:
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(l-ethyl-4-piperidyl)-3-methoxy-benzamide
Figure imgf000127_0002
Aniline intermediate 37 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.97 - 1.02 (6H5 m), 1.48 - 1.87 (12H, m)5 1.90 - 1.97 (2H5 m)5 2.33 (2H, q), 2.86 - 2.91 (2H, m), 3.14 (3H5 s), 3.48 (2H, q), 3.71 - 3.80 (IH, m), 3.94 (3H5 s), 4.04 (IH5 quintet), 7.48 - 7.52 (2H, m), 7.92 (IH5 s), 8.02 (IH, s), 8.06 (IH5 d), 8.32 - 8.35 (IH, m); MS m/z 537 [M+H]+. PLKl Enzyme IC50 = 0.103 uM Example 198:
7-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)aminol-N-[(lS,5R)-9-methyl-9-azabicycIo[3.3.1]non-7-yI]benzo[l,3]dioxole-4- carboxamide
Figure imgf000128_0001
Aniline intermediate 39 used in synthesis
MS m/z 577 [M+H]+. Retention Time = 2.52 minutes PLKl Enzyme IC50 = 0.309 uM
Example 199: 4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicycIo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(l-ethyl-4-piperidyl)-2,5-difluoro-benzamide
Figure imgf000128_0002
Aniline intermediate 44 used in synthesis
IH NMR (400.132 MHz, DMSO) δ 0.97 - 1.01 (6H, m), 1.46 - 1.86 (12H, m), 1.91 - 2.00 (2H, m), 2.32 (2H, q), 2.79 - 2.86 (2H, m), 3.14 (3H, s), 3.49 (2H, q), 3.67 - 3.77 (IH, m), 4.03 (IH, quintet), 7.41 (IH, dd), 7.96 - 7.98 (IH, m), 8.04 (IH5 s), 8.12 (IH, dd), 9.22 (IH, s); MS m/z 543 [M+H]+. PLKl Enzyme IC50 = 0.082 uM
Example 200: 4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(4-dimethylaminocyclohexyl)-2-fluoro-5-methoxy-benzamide
Figure imgf000129_0001
Aniline intermediate 45 used in synthesis
IH NMR (400.132 MHz5 DMSO) δ 0.99 (3H, t), 1.48 - 1.90 (16H, m), 2.38 - 2.50 (7H, m), 3.15 (3H, s), 3.49 (2H, q), 3.92 (3H, s), 3.97 - 4.10 (2H, m), 7.19 (IH, d), 7.77 - 7.82 (IH, m), 8.03 (IH3 s), 8.05 (IH, s), 8.29 (IH, d); MS m/z 569 [M+H]+. PLKl Enzyme IC50 = 0.282 uM
Example 201;
4-[(5-cyclopentyl-4-ethyl-2-methyl-3-oxo-2,4,5,7,9-pentazabicyclo[4.4.0]deca-6,8,10- trien-8-yl)amino]-N-(4-dimethyIaminocyclohexyl)-2-fluoro-5-methoxy-benzamide
Figure imgf000129_0002
Aniline intermediate 46 used in synthesis IH NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.30 - 1.43 (4H, m), 1.48 - 1.56 (2H5 m),
1.61 - 1.98 (1OH, m), 2.32 - 2.41 (7H, m), 3.15 (3H, s), 3.49 (2H, q), 3.69 - 3.75 (IH, m), 3.91
(3H, s), 4.06 (IH, quintet), 7.19 (IH, d), 7.79 (IH5 dd), 8.02 (IH5 s), 8.06 (IH, s), 8.28 (IH, d); MS m/z 569 [M+H]+.
PLKl Enzyme IC50 = 0.045 uM
Example 202:
3-chloro-4-[(7-cyclopentyI-8-ethyI-10-methyl-9-oxo-3,5,7,8,10-pentazabicycIo[4.4.0]deca- l,3>5-trien-4-yl)amino]-N-(l-methyI-4-piperidyl)benzamide
Figure imgf000129_0003
4-chloro-7-cyclopentyl-8-ethyl- 10-methyl-3 ,5,7,8,10-pentazabicyclo[4.4.0]deca- 1 ,3 ,5-trien-9- one (Intermediate 1; 50 mg, 0.17 mmol) and 4-amino-3-chloro-N-(l-methyl-4- piperidyl)benzamide (Intermediate 41, 51 mg, 0.19 mmol) were taken up in 1,4 dioxane (3 ml) and caesium carbonate (122 mg, 0.37 mmol) was added. Reaction mixture was sparged with nitrogen for 15 minutes prior to addition of tris-dibenzylideneacetonedipalladium (II) (10 mg, 0.01 mmol), followed by 9,9-Dimethyl-4,5-Bis(Diphenylphosphino)Xanthene (10 mg, 0.017 mmol). The reaction mixture was heated to 1050C overnight. After being allowed to cool the reaction mixture was diluted to ~20 ml with DCM and filtered. Filtrate was poured directly onto an SCX-3 (2 g) cartridge. Cartridge was washed through with methanol (~50 ml), then the crude products eluted with a 2M solution of ammonia in methanol (~30 ml). Evaporation of ammoniacal fraction afforded the crude product which was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% aq. ammonia solution) and acetonitrile as eluants. . Fractions containing the desired compound were evaporated to dryness this afforded a gum. A few drops of diethyl ether were added and mixture sonicated for 5 minutes. The diethyl ether was then allowed to evaporate and the residue dried, under vacuum, at 6O0C, for 3 hours to afford the title compound (32 mg, 36%) as an off white foam. 1H NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.45 - 1.85 (12H, m), 1.91 - 1.99 (2H, m), 2.17 (3H5 s), 2.74 - 2.81 (2H, m), 3.14 (3H, s), 3.47 (2H, q), 3.67 - 3.77 (IH, m), 4.02 (IH, quintet), 7.80 - 7.82 (IH, m), 7.98 (IH, d), 8.00 (IH5 s), 8.16 (IH, d), 8.21 (IH, d), 8.43 (IH, s);
MS m/z 527 [M+H]+. PLKl Enzyme IC50 = 0.207 uM
Examples 202 - 214
Using an analogous procedure to that described in Example 201, 4-chloro-7-cyclopentyl-8- ethyl-10-methyl-3,5,7,8,10-pentazabicyclo[4.4.0]deca-l,3,5-trien-9-one (Intermediate 1) was reacted with an appropriately substituted aniline intermediate as indicated to give the compounds described below. Example 203:
3-chloro-4-[(10-cyclopentyI-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca- l,3,5-trien-3-yl)amino]-N-(2,2-dimethyI-3-pyrroHdin-l-yl-propyl)benzamide
Figure imgf000131_0001
Aniline intermediate 47 used in synthesis
1U NMR (400.132 MHz, DMSO) δ 0.91 (6H5 s), 0.98 (3H, t), 1.46 - 1.85 (12H, m), 2.43 (2H, s), 2.57 - 2.65 (4H, m), 3.14 (3H, s), 3.21 (2H5 d), 3.47 (2H, q), 4.02 (IH, quintet), 7.75 (IH5 dd), 7.87 (IH5 d), 7.99 (IH, s), 8.16 (IH, d), 8.46 (IH5 s), 8.72 (IH, t); MS m/z 569 [M+H]+. PLKl Enzyme IC50 = 6.502 uM
Example 204:
5-chloro-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-fluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
Figure imgf000131_0002
Aniline intermediate 48 used in synthesis
1H NMR (400.132 MHz5 DMSO) δ 0.99 (3H, t), 1.46 - 1.55 (2H, m), 1.61 - 1.87 (7H, m), 2.12 - 2.21 (IH, m), 2.25 (3H, s), 2.35 - 2.42 (2H, m), 2.56 - 2.61 (IH5 m), 2.67 - 2.71 (IH5 m), 3.15 (3H5 s), 3.49 (2H, q), 4.05 (IH5 quintet), 4.30 - 4.39 (IH, m), 7.68 (IH5 d), 8.05 (IH, s), 8.19 (IH5 d), 8.26 - 8.28 (IH5 m), 8.43 (IH, s); MS m/z 531 [M+H]+. PLKl Enzyme IC50 = 0.213 uM Example 205:
5-chloro-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]-N-(l-ethyl-4-piperidyI)-2-fluoro-benzamide
Figure imgf000132_0001
Aniline intermediate 52 used in synthesis 1H NMR (400.132 MHz5 DMSO) δ 0.90 - 0.95 (6H, m), 1.38 - 1.80 (12H, m), 1.85 - 1.93 (2H, m), 2.25 (2H, q), 2.73 - 2.79 (2H, m), 3.08 (3H, s), 3.42 (2H, q), 3.59 - 3.69 (IH, m), 3.98
(IH, quintet), 7.59 (IH, d), 7.97 (IH, s), 7.98 - 8.03 (IH, m), 8.10 - 8.16 (IH, m), 8.36 (IH, s); MS m/z 559 [M+H]+.
PLKl Enzyme IC50 = 0.337 uM
Example 206;
5-chloro-4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicyclo[4.4.0]deca- l,355-trien-3-yl)amino]-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide
Figure imgf000132_0002
Aniline intermediate 53 used in synthesis 1H NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.23 - 1.33 (2H, m), 1.46 - 1.56 (4H, m),
1.61 - 1.93 (1OH, m), 2.03 - 2.19 (7H, m), 3.15 (3H, s), 3.49 (2H, q), 3.61 - 3.95 (IH, m), 4.05
(IH, quintet), 7.64 - 7.66 (IH, m), 7.99 - 8.06 (2H, m), 8.16 - 8.22 (IH, m), 8.42 - 8.43 (IH, m); MS m/z 573 [M+H]+.
PLKl Enzyme IC50 = 0.529 uM
Example 207:
5-chloro-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-fluoro-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000133_0001
Aniline inteπnediate 54 used in synthesis
1R NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.47 - 1.87 (12H, m), 1.92 - 2.00 (2H, m), 2.16 (3H, s), 2.70 - 2.75 (2H, m), 3.15 (3H5 s), 3.49 (2H, q), 3.64 - 3.74 (IH, m), 4.05 (IH, quintet), 7.66 (IH, d), 8.04 - 8.09 (2H, m), 8.19 (IH, d), 8.43 (IH, s); MS m/z 545 [M+H]+. PLKl Enzyme IC50 = 0.551 uM
Example 208:
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]-2,5-difluoro-N-[[l-(pyrroIidin-l- ylmethyl)cyclopropyl]methyl]benzamide
Figure imgf000133_0002
Aniline intermediate 55 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.32 - 0.35 (2H, m), 0.49 - 0.51 (2H, m), 0.99 (3H, t), 1.47 - 1.87 (12H, m), 2.43 (2H, s), 2.45 - 2.53 (4H, m)[Obscured by DMSO signal], 3.15 (3H, s), 3.29 - 3.37 (2H, m)[ob$cιιred by water signal], 3.49 (2H, q), 4.04 (IH, quintet), 7.52 (IH, dd), 8.05 (IH, s), 8.19 (IH, dd), 8.49 (IH, q), 9.28 (IH, s); MS m/z 569 [M+H]+. PLKl Enzyme IC50 = 22.54 uM
Example 209: 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]-2,5-difluoro-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
Figure imgf000133_0003
Aniline intermediate 58 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.48 - 1.55 (2H, m), 1.61 - 1.86 (7H5 m), 2.12 - 2.20 (IH, m), 2.25 (3H, s), 2.33 - 2.42 (2H, m), 2.56 - 2.61 (IH, m), 2.67 - 2.71 (IH, m), 3.15 (3H, s), 3.49 (2H, q), 4.03 (IH, quintet), 4.31 - 4.39 (IH, m), 7.43 (IH, dd), 8.05 (IH, s), 8.10 - 8.17 (2H, m), 9.22 (IH, s); MS m/z 515 [M+H]+. PLKl Enzyme IC50 = 0.005 uM
Example 210:
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]-2,5-difluoro-N-(2-pyrrolidin-l-ylethyl)benzamide
Figure imgf000134_0001
Aniline intermediate 59 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.99 (3H, t), 1.46 - 1.55 (2H, m), 1.61 - 1.86 (1OH, m), 2.47 - 2.53 (4H, m) [Obscured by DMSO signal] , 2.57 (2H, t), 3.15 (3H, s), 3.37 (2H, q), 3.49 (2H, q), 4.04 (IH, quintet), 7.48 (IH, dd), 8.02 (IH, q), 8.04 (IH, s), 8.15 (IH, dd), 9.26 (IH, s); MS m/z 529 [M+H]+. PLKl Enzyme IC50 = 0.055 uM
Example 211:
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]-2,5-difluoro-N-(9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide
Figure imgf000134_0002
Aniline intermediate 60 used in synthesis 1H NMR (400.132 MHz, DMSO) δ 0.88 - 0.94 (2H, m), 0.99 (3H, t), 1.36 - 2.04 (14H, m), 2.17 - 2.25 (2H5 m), 2.40 (3H, s), 2.94 - 3.00 (2H, m), 3.15 (3H, s), 3.46 - 3.51 (2H, m), 4.03 (IH, quintet), 4.21 - 4.32 (IH, m), 7.43 (IH, dd), 7.83 (IH, dd), 8.05 (IH, s), 8.13 (IH, dd), 9.21 (IH, s); MS m/z 569 [M+H]+. PLKl Enzyme IC50 = 1.152 uM
Example 212:
3-chloro-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]-N-(l-ethyl-4-piperidyI)benzamide
Figure imgf000135_0001
Aniline intermediate 61 used in synthesis
1H NMR (400.132 MHz, DMSO) δ 0.97 - 1.02 (6H, m), 1.47 - 1.85 (12H, m), 1.90 - 1.97 (2H, m), 2.32 (2H, q), 2.85 - 2.90 (2H, m), 3.14 (3H, s), 3.47 (2H, q), 3.69 - 3.78 (IH, m), 4.02 (IH, quintet), 7.81 (IH, dd), 7.97 (IH, d), 8.00 (IH, s), 8.17 (IH, d), 8.21 (IH, d), 8.43 (IH, s); MS m/z 541 [M+H]+. PLKl Enzyme IC50 = 0.022 uM
Example 213:
3-chIoro-4-[(10-cyclopentyl-9-ethyl-7-methyl-8-oxo-2,4,7,9,10-pentazabicycIo[4.4.0]deca- l,3,5-trien-3-yl)amino]-N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide
Figure imgf000135_0002
Aniline intermediate 64 used in synthesis 1H NMR (400.132 MHz, DMSO) δ 0.88 (6H, s), 0.99 (3H, t), 1.45 - 1.84 (8H5 m), 2.17 (2H5 s), 2.27 (6H, s), 3.14 (3H, s), 3.19 (2H, d), 3.47 (2H, q), 4.02 (IH, quintet), 7.77 (IH, dd), 7.93 (IH, d), 7.99 (IH, s), 8.15 (IH, d), 8.41 - 8.47 (2H, m); MS nVz 543 [M+Hf. PLKl Enzyme IC50 = 4.977 uM
Example 214:
3-chloro-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]-N-(2-pyrrolidin-l-yIethyl)benzamide
Figure imgf000136_0001
Aniline intermediate 66 used in synthesis 1H NMR (400.132 MHz, CDC13) δ 1.11 (3H, t), 1.51 - 1.92 (12H, m), 2.54 - 2.60 (4H, m), 2.71 (2H5 1), 3.22 (3H, s), 3.55 (2H5 q), 3.61 (2H5 q), 4.07 (IH5 quintet), 6.74 - 6.78 (IH, m), 7.62 (IH5 s)5 7.68 (IH5 dd), 7.79 (IH, s), 7.87 (IH5 d), 8.67 (IH5 d); MS m/z 527 [M+H]+.
Intermediate 1; 8-Chloro-5-cvcIopentyl-4-ethvI-2-methyI-2,4,5J,9-pentazabicvcIof4.4.01deca-7,9.11- trien-3-one
Figure imgf000136_0002
To a solution of 8-chloro-5-cyclopentyl-4-ethyl-2,4,5,759-pentazabicyclo[4.4.0]deca-7,9,l l- trien-3-one (Intermediate 2; 93 mg5 0.33 mmol) in DMA (10 mL) was added MeI (23 μL, 0.36 mmol). The reaction mixture was cooled to 0 0C5 then NaH (15 mg, 60% dispersion in mineral oil, 0.35 mmol) was added. Stirring was continued at O0C for 30 minutes then ambient temperature for 1 hour. Ice/water was added and the solution was diluted with EtOAc (10 mL) and washed with brine (10 mL). The separated organics were dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (58 mg, 59%) as an oil.
1H NMR (400 MHz, CDCl3) δH 1.10 (t, 3H), 1.52 - 1.94 (m, 8H), 3.20 (s, 3H), 3.60 (q, 2H), 4.14 (m, IH), 7.73 (s, IH); MS m/z 296.15 [M+HJ+.
Intermediate 2: 8-Chloro-5-cvcIopentyl-4-ethyI-2,4,5,7,9-pentazabicycIoF4.4.01deca-7,9,ll-trien-3-one
Figure imgf000137_0001
A solution of ethyl #-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-Λr-ethyl- carbamate (Intermediate 3; 50 mg, 0.14 mmol) in AcOH (5 mL) was heated to 700C, then Fe
(50 mg, powdered) was added. Stirring was continued at 700C for 1 hour, then at 100°C for a further 2 hours. The reaction mixture was filtered hot through celite, the celite washed with
AcOH (30 mL) and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, eluent gradient 0-100% EtOAc in hexane) afforded the title compound (19.6 mg, 50%) as a solid.
1H NMR (400 MHz, CDCl3) δH 1.16 (t, 3H), 1.69 - 1.96 (m, 8H), 3.62 (q, 2H), 4.09 (m, IH), 7.76 (s, IH), 7.84 (s, IH); MS m/z 282.08 [M+H]+.
Intermediate 3: Ethyl iV-f(2-chloro-5-nitro-pyrimidin-4-yIVcycIopentyl-amino1-iV-ethyl-carbamate
Figure imgf000137_0002
To a solution of ethyl A/-(cyclopentylamino)-iV-ethyl-carbamate (Intermediate 4; 260 mg, 1.52 mmol) in acetone (15 mL) was added K2CO3 (215 mg, 1.55 mmol) followed and 2,4- dichloro-5-nitropyrimidine (324 mg, 1.67 mmol). The reaction mixture was then stirred at room temperature for 18 hours, then concentrated under reduced pressure. The crude material was dissolved in EtOAc (20 mL), washed with H2O (15 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated under redsuced pressure. Purification by flash column chromatography (SiO2, eluent: 10% EtOAc in hexane) provided the title compound (104.2 mg, 29%) as an oil.
1H NMR (400 MHz, DMSO-d6) δH 1.09 (t, 3H), 1.21 (t, 3H), 1.50 - 1.61 (m, 2H), 1.78 - 1.95 (m, 4H), 1.96 - 2.10 (m, 2H), 3.37 (q, 2H), 4.14 (q, 2H), 4.27 (quintet, IH), 8.78 (s, IH); MS m/z 358.60 [M+H]+.
Intermediate 4:
Ethyl JV-fcyclopentylamiiioViV-ethyl-carbamate
Figure imgf000138_0001
Cyclopentanone (1.26 mL, 14.20 mmol) was added to a stirred solution of ethyl N-amino-N- ethyl-carbamate hydrochloride (Intermediate 5; 2.40 g, 14.20 mmol) in /-PrOH (30 mL) and the mixture refluxed for 1 hour. The solution was cooled to room temperature, and then to O0C before adding NaCNBH3 (1.17 g, 18.46 mmol). AcOH was added dropwise until pH 4 obtained and then the solution stirred for a further 3 hours, maintaining pH 4 via AcOH additions. The volatiles were then removed under reduced pressure. The crude material was dissolved in EtOAc (30 mL), washed with H2O (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting solid was dissolved in MeOH (20 mL) and loaded onto an SCX-2 column and th column washed with MeOH (50 mL). The product was eluted from the column with NH3 (50 mL, 7N in MeOH) and the volatiles removed under reduced pressure to afford the title compound (760 mg, 27%) as an oil. 1H NMR (400 MHz, DMSO-d6) δH 1.04 (t, 3H), 1.20 (t, 3H), 1.35 - 1.71 (m, 8H), 3.32 (q, 2H), 3.46 - 3.53 (m, IH), 4.06 (q, 2H). Intermediate 5:
Ethyl iV-amino-iV-ethyl-carbamate hydrochloride
Figure imgf000139_0001
A solution of ethyl N-ethyl-N-[(2-niethylpropan-2-yl)oxycarbonylaniino]carbamate (63) (Intermediate 6; 4.21 g, 18.12 mmol) in HCl (217 mL, 4M in dioxane) was stirred at ambient temperature for 16 hours. The volatiles were removed under reduced pressure and the resultant slurry co-evaporated with CHCl3 (2 x 10 mL) and Et2O (2 x 10 mL). The material was dried under high vacuum for 16 h to afford the title compound (1.96 g, 82%) as a solid.
1H NMR (400 MHz, DMSO-d6) δH 1.15 (t, 3H), 1.25 (t, 3H), 3.60 (q, 2H), 4.19 (q, 2H).
Intermediate 6:
Ethyl iV-ethyl-iV-f(2-methylpropan-2-yl)oxycarbonylamino1carbamate
O førr-Butyl JV-ethylaminocarbamate (Intermediate 7; 2.01 g, 12.55 mmol) and Et3N (1.77 mL, 12.67 mmol) were dissolved in dry EtOH (25 mL) and cooled to O0C. Ethyl chloroformate
(1.22 mL, 12.67 mmol) was added dropwise and the reaction mixture stirred at O0C for 2 hours. The volatiles were removed under reduced pressure and the resulting crude material was dissolved in EtOAc (30 mL). The solution was washed with citric acid (IN aqueous, 25 mL), Na2CO3 (0.02M aqueous, 25 mL), H2O (20 mL), dried (MgSO4) and concentrated under reduced pressure to afford the title compound (2.56 g, 89%) as an oil.
1H NMR (400 MHz, DMSO) δH 1.03 (t, 3H), 1.19 (bt, 3H), 1.42 (s, 9H), 3.37 (bs, 2H), 4.04 (q, 2H), 9.09 (s, IH). Intermediate 7: tert-Butyl iV-ethvIaminocarbamate
Figure imgf000140_0001
To a solution of fe7-t-butyl JV-aminocarbamate (25) (2.99 g, 2.60 mmol) in THF (42 mL) was added freshly distilled acetaldehyde (4.18 mL, 74.70 mmol). The reaction mixture was stirred at room temperature for 24 hours. The volatiles were removed under reduced pressure to provide crude tert-bntyl iV-(ethylideneamino)carbamate as an oil (2.86 g, 80%). To a solution of the tert-buty\ iV-(ethylideneamino)carbamate (2.86 g, 18.10 mmol) in PhMe (80 mL) at - 780C was added DIBAL-H (39.8 mL, 1.5 M in PhMe). The reaction mixture was stirred at O0C for 1 hour, then room temperature for 1 hour. A potassium sodium tartrate solution (20%, 40 mL) was added and the reaction stirred at room temperature for 72 h before. The organic phase was washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound (2.16 g, 74%) as a colourless oil.
1H NMR (400 MHz, DMSO) δH 0.94 (t, 3H), 1.40 (s, 9H), 2.69 (q, 2H), 5.14 (s, IH), 8.14 (s, IH).
Intermediate 8: 4-amino-3-methoxy-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yI]benzamide
Figure imgf000140_0002
A mixture of 4-Amino-3-Methoxybenzoic Acid (Aldrich; 5.015 g, 30 mmol) and Endo-9- methyl-9-azabicyclo[3,3,l]nonane-3-one (Chempacific; 5.095 g, 33 mol) were dissolved in DMF (150 mL), and to the solution was added DIPEA (10.4 mL, 60 mmol). The reaction was cooled on an ice-bath, and to the reaction was added, portionwise, HATU (12.55 g, 33 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed by evaporation, and the residue was partitioned between Ethyl Acetate (200 mL), and saturated aqueous sodium carbonate solution (3 x 50 mL)., washed with brine (3 x 50 mL), dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation to give the crude product as an an oil (14g), which was purified on SCX-2 columns (4 x 50 g), developing and eluting with : 1) water; 2) MeOH ; and 3) 3.5M NH3- MeOH. The solvent was removed by evaporation to give the product as a semi-solid, which 5 was triturated with diethylether and filtered to yield the title compound as a tan coloured solid (4.84 g, 53%).
1HNMR (400.1MHz ; DMSO-d6) δ 0.88-0.96 (IH, d), 1.38-1.50 (3H, m), 1.86-1.96 (2H, m), 2.00-2.10 (IH, m), 2.10-2.20 (2H, m), 2.42 (3H, s), 2.92-3.00 (2H, d), 3.82 (3H, s), 4.22-4.38 (IH, m), 5.17 (2H, s), 6.58-6.62 (IH, d), 7.28 (IH, s), 7.30 (IH, s), 7.60-7.64 (IH, d). MS m/z 10 292 [M+H]+.
Intermediate 9: 4-amino-2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000141_0001
15
2-fluoro-5-methoxy-lSf-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 28; 1.3 g, 4.2 mmol) 10% Palladium on Carbon (100 mg) and Methanol (50 mL) were combined and stirred at 250C under Hydrogen at 1 bar pressure for 18 hours.
The reaction mixture was filtered through a plug of celite, washing with ethanol and 20 concentrated under reduced pressure to give the title compound (1.16 g, 100%.) as a yellow solid.
1H NMR (399.902 MHz, DMSO-D6) δ 1.54 (qd, 2H), 1.72 - 1.80 (m, 2H), 1.97 (td, 2H), 2.16
(s, 3H), 2.70 (br d, 2H), 3.67 - 3.74 (m, IH), 3.78 (s, 3H), 5.55 (s, 2H), 6.39 (d, IH), 7.05 (d,
IH), 7.34 (t, IH); MS m/z 282.27 [M+H]+. 25 Intermediate 10: 2-fluoro-5-methoxy-N-(l-methyl-4-piperidyl)-4-nitro-benzamide
Figure imgf000142_0001
To a stirred solution of 2-fluoiO-5-methoxy-4-nitro-benzoic acid (Intermediate 11; 861 mg, 4.00 mmol) in DMA (20 mL) was added 4-amino-l-methylpiperidine (Fluorochem; 503 mg, 4.40 mmol) followed by DIPEA (1.4 mL, 8.00 mmol) and HATU (1.68 g, 4.40 mmol) and the resulting yellow solution stirred at room temperature for 1 hr.. The solvent was removed under reduced pressure and the residue taken up in methanol (approx 10 mL) and loaded onto a 20 g SCX-2 cartridge washing with methanol (50 mL) and eluting with 7 N methanolic ammonia (50 mL) to give a yellow solid, 1.47 g. This was purified by flash silica chromatography (0-5% ammonia in methanol /.DCM) to give the desired product as a pale yellow solid (1.25g, 4.00 mmol, 100%.)
1H NMR (399.902 MHz, DMSO-D6) δ 1.54 (qd, 2H), 1.77 - 1.85 (m, 2H), 1.98 (td, 2H), 2.17 (s, 3H), 2.74 (br d, 2H), 3.72 (m, IH), 3.96 (s, 3H), 7.43 (d, IH), 7.98 (d, IH), 8.46 (d, IH); ); MS m/z 161.90 [M+H]+.
Intermediate 11: 2-fluoro-5-niethoxy-4-nitro~benzoic acid
Figure imgf000142_0002
2,5-Difluoro-4-nitrobenzoic acid (Fluorochem; 100 mg, 0.43 mmol) and caesium carbonate
(708 mg, 2.17 mmol) were taken up in dry DMF (2 mL) and dry methanol (120 uL, 2.88 mmol) was added and the reaction stirred at room temperature for 2 hrs. The reaction mixture was diluted with Ethyl Acetate (50 mL) and water (50 mL) and acidified to pHl with 2N HCl solution. The organics were removed and the aqueous further extracted with Ethyl Acetate (2 x 50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to give the title compound as a yellow solid (91 mg, 0.42 mmol, 98%). 1HNMR (399.902 MHz, CDC13) δ 4.00 (s, 3H), 7.63 (d, IH), 7.70 (d, IH), 10.78 (br s, IH); MS m/z 215.27 [M+H]+.
Intermediate 12: 4-Amino-JV-(l-methyl-4-piperidyl)benzamide
Figure imgf000143_0001
p-Aminobenzoic acid (137 mg, 1 mmol), 4-amino-iV-methylpiperidine (114 mg, 1 mmol) and DIPEA (522 uL, 3 mmol) were dissolved in DMA (5 mL). HATU (570 mg, 1.5 mmol) in DMA (5 mL) was added and the reaction stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and NaHCO3 (50 mL, sat. aq.) was added. The resulting precipitate was removed by filtration and the aqueous phase neutralised with HCL (2N). The reaction mixture was then loaded onto an SCX-2 cartridge washing with copious quantities of water. The crude product was the eluted from the SCX-2 cartridge with NH3 (60 mL, 7M in MeOH). Purification by column chromatography (SiO2, eluent: 10% NH3 [7M in MeOH] in DCM) afforded the title compound (167 mg, 72%) as a solid. 1H NMR (400 MHz, DMSO-d6) δH 1.50 - 1.60 (2H, m), 1.69 - 1.73 (IH, m), 1.72 (IH, t), 1.89 - 1.96 (2H, m), 2.16 (3H, s), 2.75 (2H, d), 3.65 - 3.71 (IH, m), 5.52 - 5.54 (IH, m), 6.52 - 6.55 (2H, m), 7.56 - 7.59 (2H, m), 7.69 (IH, d); MS m/z 234 [M+H]+.
Intermediate 13: 4-amino-3-fluoro-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000144_0001
4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-l-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0 - 10% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 5Og SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%) 1H NMR (399.902 MHz, CDC13) δ 1.55 (m, 2H), 2.03 (m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 2.81 (m, 2H), 3.95 (m, IH), 4.01 (s, 2H), 5.77 (d, IH), 6.75 (m, IH), 7.34 (m, IH), 7.45 (m, IH); MS m/z 252 [M+H]+.
Intermediate 14: 7-amino-N-(l-methyl-4-piperidyl)benzo[l,3]dioxole-4-carboxamide
Figure imgf000144_0002
N-(l-røethyl-4-piperidyl)-7-nitro-benzo[l,3]dioxole-4-carboxamide (Intermediate 15; 290 mg, 0.94 mmol) was suspended in methanol (50 mL) and the system purged with nitrogen. 10% Pd/C (30 mg) was added and the mixture stirred under a hydrogen atmosphere for 2 hours. The catalyst was filtered off and the filtrate evaporated to give the title compound as a white solid (249mg, 96%). 1H NMR (399.9 MHz, DMSO-dό) δ 1.43 - 1.53 (2H, m), 1.78 - 1.82 (2H, m), 1.98 - 2.05 (2H, m), 2.12 (3H, s), 2.67 (2H, d), 3.69 - 3.73 (IH, m), 5.48 (2H, d), 6.06 (2H, s), 6.32 (IH, d), 6.95 (IH, d), 7.11 (IH, d); MS m/z 278 [M+H]+.
Intermediate 15: N-(l-methyl-4-piperidyl)-7-nitro-benzo[l,3]dioxole-4-carboxamide
Figure imgf000145_0001
4-Amino-l-methylpiperidine (Fluorochem; 325 mg, 2.84 mmol), HATU (1.09 g, 2.84 mmol) and 7-nitrobenzo[l,3]dioxole-4-carboxylic acid (WO 2003082827; 400 mg, 1.89m mol) were stirred in DMF (5 mL) and diisopropylethylamine (0.99 ml, 5.68 mmol) added. The mixture was stirred for 2 hours at room temperature. The reaction mixture was loaded on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the solid suspended in methanol and filtered off to yield the title compound as a yellow solid (295mg, 51%). 1H NMR (399.9 MHz, DMSOd6) δ 1.50 - 1.60 (2H, m), 1.78 - 1.82 (2H, m), 1.96 - 2.03 (2H, m), 2.17 (3H, s), 2.72 (2H, d), 3.72 - 3.76 (IH5 m), 6.42 (2H, s), 7.28 (IH, d), 7.62 (IH, d), 7.94 (IH, d); MS m/z 308 [M+H]+.
Intermediate 16: 4-ammo-3-methyl-N-(l-methyl-4- piperidyI)benzamide
Figure imgf000145_0002
3-methyl-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 17: 3.34 g) 10% Palladium on Carbon (350 mg) and Methanol (50 mL) were combined and stirred at 250C under Hydrogen at 5 bar pressure for 16 hours..
The catalyst was filtered off and washed with EtOH. The filtrate was evaporated to yield a cream solid., which was triturated with DCM filtered and dried under vacuum to give the title compound as a white solid (1.2 g)
H NMR (400.132 MHz, DMSO-D6) δl.75 (m, 2H), 1.96 (m, 2H), 2.08 (s, 3H)9 2.74 (s, 3H), 3.04 (m, 2H), 3.38 (m, 2H), 3.96 (m, IH), 5.36 (s, 2H), 6.58 (d, IH), 7.47 (m, 2H), 7.86 (d, IH), 9.13 (s, IH); MS m/z 248 [M+H]+.
The following intermediate was prepared in a manner analogous to Intermediate 62 utilising 3-Methyl-4-nitrobenzoic acid, available form Aldrich, as the starting Nitro acid.
Intermediate 17:
3-methyl-N-(l-methyl-4-piperidyI)-4-nitro-benzamide
Figure imgf000146_0001
3-Methyl-4-nitrobenzoic acid, (Aldrich; 2.93 g, 16.21 mmol), 4-Amino-l-methylpiperidine (Fluorochem; 2.03 g, 17.83 mmol), HATU (6.77 g, 17.83 mmol), DIPEA (8.5 mL, 48.63 mmol) and DMF (3 0 mL) were combined and stirred at ambient temperature for 18 hrs.
Solvents evaporated and partitioned between DCM (200 ml) and water (100 ml). The aqueous phase was re-extracted with DCM (100 ml). The combined organic phases were dried
(MgSO4) and evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM then 5% 2M ammonia in
MeOH / DCM. Fractions containing product were combined and evaporated to give the title compound as a white solid (4.4 g, 98%) H NMR (400.132 MHz, DMSO-D6) δl.71 (m, 2H), 1.92 (m, 2H), 3.16 (m, 2H), 3.91 (m, IH), 7.86 (m, IH), 7.92 (s, IH), 8.06 (d, IH), 8.56 (d, IH); MS m/z 278 [M+H]+.
Intermediate 18; 4-amino-3-methoxy-N-(2-pyrrolidin- 1 -ylethyl)benzamide
Figure imgf000147_0001
A solution of 3-methoxy-4-nitro-N-(2-pyrrolidin-l-ylethyl)benzamide (Intermediate 19, 2 g, 0.81 mmol) in methanol (40 mL) was hydrogenated using 10% Pd/C catalyst. Catalyst was filtered off and solvent evaporated to yield the title compound (1.8 g, 100%) 1H NMR (399.9 MHz, DMSO-d6) δl.68 (4H, t), 2.49 (4H, s), 2.55 (2H, t), 3.36 (2H, d), 3.81 (3 H, s), 5.20 (2H, s), 6.59 - 6.62 (IH, m), 7.26 - 7.29 (IH, m), 7.31 (IH, s), 8.00 (IH, s); MS m/z 280 [M+H]+.
Intermediate 19: 3-methoxy-4-nitro-N-(2-pyrrolidin-l-ylethyl)benzamide
Figure imgf000147_0002
3-methoxy-4-nitrobenzoic acid (Aldrich, 9 g, 45.65mmol) was suspended in toluene (90 mL) and thionyl chloride (9.99 mL, 136.95 mmol) added. The mixture was heated at reflux for an hour and then concentrated to give 3-methoxy-4-nitro-benzoyl chloride as a brown solid in quantitative yield.
3-methoxy-4-nitro-benzoyl chloride (2 g, 9.28 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (1.94 mL, 11.13 mmol) added. The mixture was cooled in an ice/water bath and 2-pyrrolidin-l-ylethanamine (Aldrich, 1.06 g, 9.28 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was washed with brine, 2N NaOH, dried over MgSO4 and concentrated to give the title compound as a brown solid (2.3 g 85%). 1H NMR (399.9 MHz, DMSO-d6) δl.67 - 1.72 (4H, m), 2.47 - 2.54 (4H, m), 2.60 (2H, t), 3.39 - 3.44 (2H, m), 3.99 (3H, s), 7.54 - 7.56 (IH, m), 7.72 (IH, d), 7.96 (IH, d), 8.71 (IH, t); MS m/z 294 [M+H]+.
Intermediate 20; 4-amino-N-(2-dimethylaminoethyl)-3-methoxy-benzamide
Figure imgf000148_0001
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 18, on a 2 g scale utilising N-(2-dimethylaminoethyl)-3-methoxy- 4-nitro-benzamide (Intermediate 21).
1K NMR (399.9 MHz, DMSO-d6) 6 2.19 (6H, s), 2.38 (2H, t), 3.38 (2H, m), 3.81 (3H, s), 5.20 (2H, s), 6.61 (IH, d), 7.25 - 7.28 (IH, m), 7.30 (IH, s), 7.96 (IH, t); MS m/z 238 [MfH]+.
Intermediate 21:
Figure imgf000148_0002
The title compound was prepared by an analogous method to the preparation of Intermediate 19, on a 9.28 mmol scale utilising N,N-dimethylethane-l,2-diamine (Aldrich; 818 mg, 9.28 mmol), as a brown solid (2.5 g, 100%)
1HNMR (399.9 MHz, DMSO-d6) δ 2.24 (6H, s), 2.47 - 2.49 (2H, m), 3.37 - 3.41 (2H, m), 4.00 (3H, s), 7.55 - 7.57 (IH, m), 7.74 (IH, d), 7.96 (IH, d), 8.73 (IH, t); MS m/z 268 [M+H]+. Intermediate 22: 4-amino~N-(3-dimethylamino-2,2-dimethyl-propyl)~3-methoxy-benzamide
Figure imgf000149_0001
A suspension of N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-4-nitro-benzamide (Intermediate 23; 5.7 g, 18.40 mmol), 5% Pd on charcoal (569 mg) in EtOH (300 niL) was stirred at 40 0C under a hydrogen atmosphere for 16 h. The reaction mixture was then filtered through celite, washed with copious MeOH and the volatiles removed under reduced pressure to afford the title compound (5.36 g, Quant.) as a foam.
IH NMR (400 MHz, DMSO-d6): dH 0.88 (m, 6H), 2.18 (s, 2H), 2.28 (s, 6H), 3.18 (m, 2H), 3.82 (s, 3H), 5.21 (m, 2H), 6.63 (d, IH), 7.25 m, 2H), 8.11 (m, IH); MS m/z 280 [M+H]+.
Intermediate 23:
N-(3-Dimethylamino-2,2-dimethyl-propyl)-3-methoxy-4-nitro-benzamide
Figure imgf000149_0002
To a suspension of 4-nitro-3-methoxybenzoic acid (Aldrich; 5.0 g, 25.3 mmol), N,N-2- tetramethyl-l,3-propanediamine (Aldrich; 4.64 mL, 27.83 mmol) and DIPEA (8.8 mL, 50.60 mmol) in anhydrous DMA (100 mL) under nitrogen at ambient temperature was added HATU (10.6 g, 27.83 mmol) and the resulting reaction mixture was stirred at 50 0C for 3 h and ambient temperature for a further 12 h. Evaporation removed any volatiles and the residue was dissolved in DCM (100 mL) and washed with NaHCO3 (100 mL), brine (100 mL), dried (MgSO4) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 2-10% MeOH in DCM) afforded the title compound (5.7 g, 73%) as a solid. 1H NMR (400 MHz5 DMSO-d6): δH 1.06 (s, 6H), 2.42 (s, 2H), 2.82 (s, 6H), 3.30 (s, 2H), 3.98 (s, 3H), 7.57 (dd, IH), 7.71 (s, IH), 8.93 (d, IH); MS m/z 310 [M+H]+.
Intermediate 24: 4-amino-N-(3-dimethylammopropyl)-3-methoxy-benzamide
Figure imgf000150_0001
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 18, on a 2 g scale utilising N-(2-dimethylaminoethyl)-3-methoxy- 4-nitro-benzamide (Intermediate 25). IH NMR (399.9 MHz, DMSO-d6) dl.60 - 1.67 (2H, m), 2.14 (6H5 s), 2.25 (2H, t), 3.21 - 3.26 (2H, m), 3.81 (3H, s), 5.19 (2H, s), 6.61 (IH, d), 7.25 - 7.30 (2H, m), 8.09 (IH, t); MS m/z 252 [MH-H]+.
Intermediate 25: N-(3-dimethylaminopropyl)-3-methoxy-4-nitro-benzamide
Figure imgf000150_0002
The title compound was prepared by an analogous method to the preparation of Intermediate 19, on a 9.28 mmol scale utilising N,N-dimethylpropane- 1,3 -diamine (Aldrich; 948 mg, 9.28 mmol), as a brown solid (2.33 g, 90%)
1H NMR (399.9 MHz, DMSOd6) δl.65 - 1.72 (2H, m), 2.16 (6H, s), 2.29 (2H, t), 3.34 (2H, m), 4.00 (3H, s), 7.53 - 7.56 (IH, m), 7.72 (IH, d), 7.96 (IH, d), 8.77 (IH, t); MS m/z 282 [MH-H]+. Intermediate 26: 4-amino-2-fluoro-5-methoxy-N-[(3R)-l-methylpyrrolidin-3-yl]benzamide
Figure imgf000151_0001
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 27; 500 mg, 2.70 mmol), HATU (1.55 g, 4.05 mmol) and (3R)-l-methylpyrrolidin-3-amine dihydrochloride (Intermediate 51;
631 mg, 3.31 mmol) were stirred in DMF (7.5 mL) and diisopropylethylamine (2.36 ml, 13.50 mmol) added. The reaction mixture was stirred for 2 hours and then absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol.
Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a viscous brown oil. (662 mg, 92%).
1H NMR (399.9 MHz, DMSO-d6) δl.62 - 1.70 (IH, m), 2.11 - 2.20 (IH, m), 2.25 (3H, s),
2.32 - 2.46 (2H, m), 2.54 - 2.67 (2H, m), 3.78 (3H, s), 4.34 - 4.39 (IH, m), 5.57 (2H, s), 6.39
(IH, d), 7.07 (IH, d), 7.51 (IH, t); MS m/z 268 [M+H]+.
Intermediate 27:
4-amino-2-fluoro-5-methoxy-benzoic acid
Figure imgf000151_0002
2-fluoro-5-methoxy-4-nitrobenzoic acid (Intermediate 28; 7.76g, 36.1mmol) was stirred and dissolved in ethanol (200 mL) over 5% Pd/C (770mg) and hydrogenated at ambient temperature for 4 hours. During this time product precipitated in the reaction. DMF (20 mL) was added to give a solution. The catalyst was filtered off and washed with EtOH and the solvent evaporated. The residue was triturated with diethyl ether to yield the title compound as a dark brown solid (3.06 g, 46%) 1H NMR (400.132 MHz, DMSO-d6) δ 3.78 (s, 3H), 5.84 (bs, 2H), 6.37 (d, IH), 7.14 (d, IH), 12.25 (bs, IH). Intermediate 28; 2-fluoro-5-methoxy-4-nitro-benzoic acid
Figure imgf000152_0001
2,5-Difluoro-4-nitrobenzoic acid (Fluorochem; 100 nig, 0.43 mmol) and caesium carbonate (708 mg, 2.17 mmol) were taken up in dry DMF (2 niL) and dry methanol (120 uL, 2.88 mmol) was added and the reaction stirred at room temperature for 2 hrs. The reaction mixture was diluted with Ethyl Acetate (50 mL) and water (50 mL) and acidified to pHl with 2N HCl solution. The organics were removed and the aqueous further extracted with Ethyl Acetate (2 x 50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to give the title compound as a yellow solid (91 mg, 0.42 mmol, 98%).
1H NMR (399.902 MHz, CDC13) δ 4.00 (s, 3H), 7.63 (d, IH), 7.70 (d, IH), 10.78 (br s, IH); MS m/z 215.27 [M+H]+.
Intermediate 29: 4-amino-N-(l~ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide
Figure imgf000152_0002
4-amino-2-fluoro-5-methoxy-benzoic acid (Intermediate 27; 1.0 g, 5.43 mmol), HATU (2.27 g, 5.97 mmol) and DIPEA (2.8 mL, 16.29 mmol) were stirred together in DMF (10 mL) for 30mins. 4-amino-l-ethylpiperidine (Fluorochem; 0.77 g, 5.97 mmol) in DMF (1 mL) was added and the brown solution stirred at ambient temperature for 4 hours. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 column (20 g) pre- wet with MeOH. The column was washed with MeOH (2 colmun volumes) and the product eluted with 2M NH3/MeOH. Product containing fractions were evaporated and the resultant material purified by column chromatography on a silica column eluting with 0-10% 2M NH3/MeOH/DCM. Product containing fractions were evaporated to yield the title compound as a gum (1.21 g, 76%).
1H NMR (400.132 MHz, DMSO-d6) δ 0.99 (t, 3H), 1.52 (m, 2H), 1.78 (m, 2H), 1.97 (m, 2H), 2.31 (q, 2H), 2.80 (m, 2H), 3.72 (m, IH), 3.77 (s, 3H), 5.54 (bs, 2H), 6.39 (d, IH), 7.05 (d, IH), 7.33 (m, IH); MS m/z 296 [M+H]+.
Intermediate 30: 4-amino-2-fluoro-5-methoxy-N-(2-pyrrolidin-l-ylethyl)benzamide
Figure imgf000153_0001
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 27; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 mL, 12.21 mmol) were stirred together in DMF (10 rnL) for 25mins. N-(2-aminoethyl)pyrrolidine (Aldrich; 0.51 g, 4.48 mmol) in DMF (2 mL) was added and the solution stirred at ambient temp for 2 hours. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 Column (20 g), pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated to a brown gum, which was purified on a silica column eluting with 0-10% 2M NHs/MeOH/DCM. Product containing fractions were combined and evaporated to yield the title compound as a pale brown solid (948 mg, 83%)
1H NMR (400.132 MHz, DMSO-d6) δ 1.69 (m, 4H), 2.48 (m, 4H), 2.56 (t, 2H), 3.36 (m, 4H), 3.77 (s, 3H), 5.59 (s, 2H), 6.40 (d, IH), 7.13 (d, IH), 7.51 (m, IH); MS m/z 282 [M+H]+.
Intermediate 31: tert-butyl 4-[(4-amino-3-methoxy-benzoyl)amino]piperidine-l-carboxylate
Figure imgf000154_0001
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 2.4 g, 14.36 mmol) in DMF (100 niL) was added 4-amino-l-bocpiperidine (Aldrich; 3.15 g, 15.72 mmol) and DIPEA (7.5 mL, 43.06 mmol). The resultant solution was carefully treated portionwise (2-3 portions) with HATU (6.88 g, 18.09 mmol) and the resultant mixture was stirred, under nitrogen, at ambient temperature overnight.
The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic phase was separated and washed with water (150 mL) and brine (150 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on a silica cartridge eluting with a rising gradient of 0-10% Methanol in DCM. Product containing fractions were combined and evaporated to yield the title compound as a peach coloured foam (2.88 g, 57%) 1H NMR (400.132 MHz, DMSO) δ 1.35 - 1.47 (HH, m), 1.72 - 1.80 (2H, m), 2.76 - 2.90 (2H, m), 3.81 (3H, s), 3.91 - 4.00 (3H, m), 5.20 (2H, s), 6.61 (IH, d), 7.28 - 7.30 (2H, m), 7.80 (IH, d); MS m/z 348 [M-H]+.
Intermediate 32: 4-amino-3-fluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yI]benzamide
Figure imgf000154_0002
4-amino-3-fluorobenzoic acid (Fluorochem; 5.0 g, 32.2 mmol), HATU (13.5 g, 35.4 mmol) and DIPEA (18.5 mL, 106 mmol) were stirred together in anhydrous DMA (100 mL) for 25 minutes. Endo-9-methyl-9-azabicyclo[3,3,l]nonane-3-one (Chempacific; 5.5 g, 35.4 mmol) was added and the solution stirred at ambient temperature overnight. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 column (50g x 4) pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and the product eluted with 2MNH3/MeOH (2 column volumes). The ammoniacal solution was evaporated and the resultant material purified on a silica column eluted with 0- 10% 2NH3/MeOH/DCM. Product containing fractions were evaporated to yield the title compound as a white solid after trituration with ethyl acetate (5.7 g, 61%) 1H NMR (400.132 MHz, DMSO-d6) δ 0.91 (m, 2H)5 1.42 (m, 3H), 1.90 (m, 4H), 2.03 (m, IH), 2.14 (m, 3H), 2.40 (s, 3H), 2.96 (m, 2H), 4.27 (m, IH), 5.60 (bs, 2H), 6.74 (m, IH), 7.46 (m, IH), 7.53 (m, IH), 7.70 (d, IH); MS m/z 292 [M+H]+.
Intermediate 33: 4-amino-N-(eyclopropylmethyl)-3-methoxy-benzamide
Figure imgf000155_0001
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 1.1 g, 6.58 mmol) in DMF (25 mL) was added cyclopropylmethylamine (Aldrich; 504 mg, 7.07 mmol). And DIPEA (3.4 mL, 19.52 mmol) . HATU (3.18 g, 8.36 mmol) was added to the resultant solution giving a mild exotherm. .The resultant mixture was stirred, under nitrogen, at ambient temperature over the weekend.
The solvent was removed in vacuo and the resultant residue partitioned between DCM (100 mL) and a saturated aqueous solution of sodium hydrogen carbonate (100 mL). The organic phase was separated, washed with brine, dried over magnesium sulphate and evaporated to give a dark amber oil which was purified by flash column chromatography on silica (12O g cartridge), eluting with 50-100% ethyl acetate in isohexane. Product containing fractions were combined and evaporated to afford a the title compound as a viscous amber gum (665 mg, 46%) 1H NMR (400.132 MHz, DMSO) δ 0.23 (m, 2H), 0.43 (m, 2H), 1.03 (m, IH), 3.12 (t, 2H), 3.83 (s, 3H), 5.20 (s, 2H), 6.63 (d, IH), 7.32 (m, 2H), 8.12 (t, IH); MS m/z 292 [M+H]+. Intermediate 34: 4-amino-2-chloro-5-methoxy-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000156_0001
The title compound was prepared by an analogous method to the preparation of Intermediate 61, on a 3.06 mmol scale utilising 4-amino-2-chloro-5-methoxy-benzoic acid (Intermediate 62; 617 mg, 3.06 mmol) and l-methylpiperidin-4-amine (Fluorochem; 385 mg, 3.37 mmol), as an off-white solid (845 mg, 93%).
1H NMR (399.902 MHz, CDC13) δl.61 (m, 2H), 2.05 (m, 2H), 2.20 (m, 2H), 2.30 (s, 3H), 2.76 (m, 2H)5 3.88 (s, 3H), 4.03 (m, 3H), 6.57 (d, IH), 6.63 (s, IH), 7.34 (s, IH); MS m/z 298 [M+H]+.
Intermediate 35: 4-amino-2-fluoro-N-(l-methyI-4-piperidyl)benzamide
Figure imgf000156_0002
2-fluoro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 36; 1.62 g, 5.8 mmol), 10% Palladium on Carbon (160 mg) and Methanol (50 mL) were combined and stirred at 250C under Hydrogen at 5 bar pressure for 16 hours.. The catalyst was filtered off and the filtrate evaporated to give a brown solid which was triturated with 5% MeOH / DCM . The precipitate was collected by filtration and dried under vacuum to yield the title compound as a beige solid (560 mg, 39%). IH NMR (400.132 MHz, DMSO-D6) dl.74 (m, 2H), 1.99 (m, 2H), 2.76 (s, 3H), 3.09 (m, 2H), 3.42 (m, 2H), 3.97 (m, IH), 5.89 (s, 2H), 6.30 (m, IH), 6.39 (m, IH), 7.37 (m, IH), 7.67 (s, IH), 9.11 (s, IH); ); MS m/z 252 [M+H]+.
Intermediate 36:
2-fluoro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide
Figure imgf000157_0001
2-Fluoro-4-nitrobenzoic acid (Aldrich; 3 g, 16.21 mmol), 4-Amino-l-niethylpiperidine (Fluorochem; 2.03 g, 17.83 mmol), HATU (6.77 g, 17.83 mmol), DIPEA (8.5 mL, 48.63 mmol) and DMF (3 0 mL) were combined and stirred at ambient temperature for 18 hrs. Solvents evaporated and partitioned between DCM (200 mL) and water (100 mL). The aqueous phase was re-extracted with DCM (100 mL). The combined organic phases were dried (MgSO4) and evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0 - 5% 2M ammonia in MeOH / DCM then 5% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid (2.67 g, 59%)
1H NMR (400.132 MHz, DMSO-D6) δl.53 (m, 2H), 1.80 (m, 2H), 2.26 (m, 5H), 2.85 (m, 2H), 3.74 (m, IH), 7.72 (m, IH), 8.06 (m, IH), 8.12 (m, IH), 8.54 (d, IH); MS m/z 282
Intermediate 37: 4-amino-N-(l-ethyl-4-piperidyI)-3-methoxy-benzamide
Figure imgf000157_0002
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 18, on a 2 g scale utilising N-(l-ethyl-4-piperidyl)-3-methoxy-4- nitro-benzamide (Intermediate 38).
1HNMR (399.9 MHz, DMSO-dό) δ 0.99 - 1.02 (3H, t), 1.49 - 1.59 (2H, m), 1.75 (2H, d), 1.92 (2H, t), 2.32 (2H, q), 2.87 (2H, d), 3.68 - 3.76 (IH, m), 3.81 (3H, s), 5.19 (2H, s), 6.59 - 6.62 (IH, m), 7.28 - 7.30 (2H, m), 7.77 (IH, d); MS m/z 280 [M+H]+.
Intermediate 38:
N-( 1 -ethyl-4-piperidyl)-3 -methoxy-4-nitro-benzamide
Figure imgf000158_0001
The title compound was prepared by an analogous method to the preparation of Intermediate 19, on a 9.28 mmol scale utilising l-ethylpiperidin-4-amine (Fluorochem; 1.19 g, 9.28 mmol), as a brown solid (3.3 g, 100%) 1H NMR (399.9 MHz, DMSO-d6) δl.01 (3H, t), 1.56 - 1.63 (2H, m), 1.82 (2H, m), 1.92 - 1.98 (2H, m), 2.34 (2H, q), 2.89 (2H5 d), 3.75 - 3.79 (IH, m), 4.00 (3H, s), 7.54 - 7.57 (IH, m), 7.70 (IH5 d), 7.96 (IH, d), 8.49 (IH, d); MS m/z 308 [M+H]+.
Intermediate 39: T-amino-N-IClSjS^-P-methyl^-azabicyclofS.S.llnon-T-yllbenzoIl^Jdioxole^- carboxamide
Figure imgf000158_0002
N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]-7-nitro-benzo[l,3]dioxole-4-carboxamide (Intermediate 40; 408 mg, 1.17 mmol) and Palladium (10% on activated carbon) (52 mg, 0.05 mmol) in a mixture of Ethanol (10 niL) and DMF (4 mL) were stirred under an atmosphere of hydrogen at ambient temperature for 4 hours.
The reaction mixture evacuated and flushed with nitrogen (x3) and mixture diluted with more DMF (20 mL) and catalyst removed by filtration. The filtrate was treated with more Palladium (10% on activated carbon) (75 mg, ) and stirred under an atmosphere of hydrogen at ambient temperature for a further 4 hours. The reaction mixture was again evacuated and flushed with nitrogen (x 3) and the catalyst removed by filtration through celite. The filtrate was subjected to ion exchange chromatography, using an SCX-2 column (10 g). The desired product was eluted from the column using 2M NH3/MeOH and arnmoniacal fraction was evaporated to dryness to afford crude product as a dark yellow solid which was purified by flash silica chromatography, elution gradient 0 to 10% 2M ammonia/MeOH in DCM. Product containing fractions were evaporated to dryness to afford the title compound as a dark yellow solid (289 mg, 78 %). 1H NMR (400.132 MHz, DMSO) δ 0.87 - 0.93 (2H, m), 1.25 - 1.32 (2H, m), 1.38 - 1.46 (IH, m), 1.82 - 2.07 (3H, m), 2.19 - 2.26 (2H, m), 2.39 (3H, s), 2.95 - 2.97 (2H, m), 4.19 - 4.30 (IH, m), 5.50 (2H, s), 6.04 (2H, s), 6.29 (IH, d), 6.87 (IH, d), 7.09 (IH, d).; MS m/z 318 [M+H]+.
Intermediate 40:
N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]-7-nitro-benzo[l,3]dioxole-4- carboxamide
Figure imgf000159_0001
N,N-Diisopropylethylamine (0.830 mL, 4.77 mmol) was added to a suspension of 7- nitrobenzo[d][l,3]dioxole-4-carboxylic acid (WO2003082827; 411 mg, 1.95 mmol), in DCM (10 mL) The resulting solution was stirred at ambient temperature for 5 minutes before addition of a solution of endo-9-methyl-9-azabicyclo[3,3,l]-nonan-3-amine (350 mg, 2.27 mmol) in DCM (2 niL). HATU (960 mg, 2.52 mmol) was then added portionwise over 5 minutes and reaction mixture allowed to stir, under nitrogen, for 5 hours. The reaction mixture was washed with saturated Na2CO3(aq) (15 mL) and evaporated to afford a brown gum which was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, followed by a final flush with 10% 2M ammonia/methanol in DCM (~150 mL). Product containing fractions were combined and were evaporated to yield the title compound as a yellow solid (341 mg, 50%). 1H NMR (400.132 MHz, DMSO) δ 0.91 - 0.95 (2H, m), 1.37 - 1.47 (3H, m), 1.88 - 2.03 (3H, m), 2.20 - 2.28 (2H, m), 2.43 (3H, s), 2.97 - 3.04 (2H, m), 4.25 - 4.35 (IH, m), 6.43 (2H, s), 7.30 (IH, d), 7.63 (IH, d), 7.87 - 7.89 (IH, m); MS m/z 346 [M-H]-
Iiitermediate 41: 4-amino-3-chloro-N-(l-methyl-4-piperidyl)benzamide
Figure imgf000160_0001
3-chloro-N-(l-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 42; 1.8 g, 6 mmol) hydrogenated over 2 hours with agitation at 298K and pressure of 5 bar using a 5% Pt/C catalyst and EtOH (50 mL) solvent. The catalyst was filtered and the filtrate concentrated to give a yellow crystalline solid which was dissolved in DCM and purified by column chromatography (5% MeOH/DCM) to give the title compound as a pale yellow crystalline solid (1.62 g, 100%)
1H NMR (399.9 MHz, DMSO-d6) δl.53 - 1.60 (2H, m), 1.71 - 1.74 (2H, m), 1.90 - 1.95 (2H5 m), 2.16 (3H, s), 2.33 - 2.35 (IH, m), 2.67 - 2.69 (IH, m), 2.76 (2H, d), 3.66 - 3.70 (IH, m),
5.82 (2H, d), 6.78 (IH5 d), 7.56 - 7.58 (IH5 m), 7.76 (IH, d), 7.89 (IH5 d); MS m/z 268.14
[M+H]+. Intermediate 42: 3-chloro-N-(l-methyI-4-piperidyI)-4-nitro-benzamide
Figure imgf000161_0001
3-chloro-4-nitro-benzoyl chloride (Intermediate 43; 2.2 g, 10.00 mmol) was dissolved in DCM (20 niL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and 4-amino-l-methylpiperidine (Fluorochem; 1.14 g, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. A white precipitate resulted. The reaction mixture was washed with 2N NaOH, filtered and the filter cake washed with water and dried on a sinter over the weekend to give the title compound as a white solid (1.8Og, 60%) as a white solid. 1HNMR (399.9 MHz, DMSOd6) δl.53 - 1.63 (2H, m), 1.79 (2H, t), 1.92 - 1.99 (2H, m), 2.17 (3H, s), 2.78 (2H9 d), 3.70 - 3.77 (IH5 m), 7.99 - 8.02 (IH, m), 8.18 (2H, t), 8.60 (IH, d); MS m/z 298.2 [M+H]+.
Intermediate 43: 3-chloro-4-nitro-benzoyl chloride
Figure imgf000161_0002
3-Chloro-4-nitrobenzoic acid (Apin; Ig, 4.96 mmol) was suspended in toluene (10 mL) and thionyl chloride (1.1 mL, 14.88 mmol) added. The mixture was heated to 85°C for 45min Further thionyl chloride (1.1 mL) was added and the mixture heated at reflux for 0.5 hr. The reaction mixture was allowed to cool and stand overnight. The mixture was concentrated to give the title compound as a yellow liquid (1.15g, 100%). 1H NMR (399.9 MHz, CDCl3) 57.87 (IH, s), 8.07 - 8.10 (IH, m), 8.23 (IH, d); MS m/z 198.92 [M+H]+.
Intermediate 44; 4-amino-N-(l-ethyl-4-piperidyI)-2,5-difluoro-benzamide
Figure imgf000162_0001
The title compound was prepared by an analogous method to the preparation of Intermediate 58, on a 5.77 mmol scale utilising 4-amino-l-ethylpiperidine (Fluorochem; 815 mg, 6.35 mmol), as an orange solid (1.23 g, 75%) 1H NMR (399.902 MHz, CDC13) δl.09 (t, 3H), 1.57 (m, 2H), 2.04 (m, 2H), 2.14 (m, 2H), 2.42 (q, 2H), 2.86 (m, 2H), 4.02 (m, IH), 4.13 (s, 2H), 6.43 (m, IH), 6.51 (m, IH), 7.72 (m, lH); MS m/z 284 [M+H]+.
Intermediate 45:
4-amino-N-(4-dimethyIaminocyclohexyl)-2-fluoro-5-methoxy-benzamide
Figure imgf000162_0002
4-amino-2-fluoro-5-methoxy-benzoic acid (Intermediate 27; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 ml, 12.21 mmol) were stirred together in DMF (10 mL) for 10 minutes at ambient temperature, l-amino-4-dimethylaminocyclohexane (ABChem Inc.; 0.637 g, 4.48 mmol) in DMF (2 mL) was added and the reaction mixture stirred at ambient temperature overnight. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 (20 g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and the eluted with 2MNH3/MeOH. Product containing fractions were combined and evaporated to give a brown gum which was purified on a silica column eluting with 0-10% 2MNH3/MeOH/DCM to give a single unassigned isoform of the title compound as a pale 5 brown gum (250 mg, 20%)
1H NMR (400.132 MHz, DMSO-d6) δ 1.63 (m, 8H), 2.08 (m, IH), 2.18 (s, 6H), 3.77 (s, 3H), 3.91 (m, IH), 5.54 (bs, 2H), 6.40 (d, IH), 7.06 (d, IH), 7.24 (m, IH); MS m/z 310 [M+H]+.
A second unassigned isoform was also isolated and designated Intermediate 46 (394 mg, 10 31%)
Intermediate 46: 4-amino-N-(4-dimethylaminocyclohexyl)-2-fluoro-5-methoxy-benzamide
Figure imgf000163_0001
The title compound was obtained as a single unassigned isoform described above in the preparation of Intermediate 45 as a white solid (394 mg, 31%).
1H NMR (400.132 MHz, DMSO-d6) δ 1.28 (m, 4H), 1.85 (m, 4H), 2.11 (m, IH), 2.18 (s, 6H), 3.66 (m, IH), 3.77 (s, 3H), 5.53 (bs, 2H), 6.38 (d, IH), 7.04 (d, IH), 7.26 (m, IH); MS m/z 20 310 [M+H]+.
Intermediate 47: 4-amino~3-chloro-N-(2,2-dimethyI-3-pyrrolidin-l-yl-propyl)benzamide
25
Figure imgf000163_0002
A mixture of the 4-amino-3-chloro-benzoic acid (Fluorochem; 2.49 g, 14.5 mniol) and 2,2- dimetliyl-3-pyrrolidin-l-yl-propan-l -amine (Chemstep; 2.49 g, 15.95 mmol) were dissolved in DMF (50 mL), and to the solution was added DIPEA (5.1 rnL, 29.0 mmol).The reaction mixture was cooled with an ice-bath, and HATU (6.06 g, 15.95 mmol) added, portionwise. The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between Ethyl Acetate (100 mL), and saturated aqueous sodium carbonate solution (3 x 40 mL), washed with brine (3 x 40 mL), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated to give the crude product as an oily semi-solid, which was triturated with diethyl ether and filtered to yield the title compound as a pale yellow crystalline solid (850 mg, 19%) The mother-liquors from the trituration were purified on a silica column, pre-equilibrated ethyl acetate and eluting with 10% MeOH-DCM + 1%NH3. Product containing fractions were combined and evaporated to give the title compound as a viscous, yellow oil (1.72 g, 38%) 1H NMR (400.1MHz , CDC13) 6 1.00 (6H,s), 1.82-1.88 (4H,m), 2.56 (2H,s), 2.65-2.72 (4H,bs), 3.33-3.36 (2H,d), 4.30 (2H,s), 6.73-6.77 (lH,d), 7.55-7.60 (lH,dd), 7.65 (lH,s), 9.38 (lH,s). MS m/z 310 [M+H]+.
Intermediate 48: 4-amino-5-chloro-2-fluoro-N-[(3R)-l-methylpyrroIidin-3-yl]benzamide
Figure imgf000164_0001
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 49; 300 mg, 1.58 mmol), HATU (903 mg, 2.37 mmol) and (3R)- l-methylpyrrolidin-3 -amine di Hydrochloride (Intermediate 51; 325 mg, 2.37 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.2 mL, 7.12 mmol) added. The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a pale orange solid (333 mg,
10/ o, . Η NMR (399.9 MHz, DMSO-dό) δl.63 - 1.71 (IH5 m), 2.09 - 2.18 (IH5 m), 2.25 (3H5 s), 2.33 - 2.41 (2H5 m), 2.55 - 2.61 (IH5 m), 2.64 - 2.69 (IH, m), 4.30 - 4.35 (IH, m), 6.10 (2H5 s), 6.55 (IH5 d), 7.50 (IH5 d), 7.76 - 7.79 (IH5 m).
Intermediate 49:
4-amino-5-chloro-2-fluorobenzoic acid
Figure imgf000165_0001
4-Amino-5-chloro-2-fluorobenzoic acid tert-butyl ester (Intermediate 50; 3.0 g, 12.21 mmol) was dissolved in DCM (75 mL) and trifluoroacetic acid (25 niL) added. The mixture was stirred for 1 hour at room temperature and then concentrated to yield the title compound as a pale yellow solid (2.45 g, 100%).
1H NMR (399.9 MHz5 DMSOd6) 66.40 (2H5 s), 6.53 - 6.56 (IH, m), 7.67 (IH, d), 12.56 (IH, s).
Intermediate 50:
4-Amino-5-chloro-2-fluorobenzoic acid tert-butyl ester
Figure imgf000165_0002
4-Amino-2-fluorobenzoic acid tert-butyl ester (ABChem Inc.; 1 g, 4.73 mmol) in DMF (15 mL) was added dropwise to N-chlorosuccinimide (633 mg, 4.73 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into water (130 mL) and extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed with water, brine, dried (MgSO4) and concentrated. Column chromatography (5% ethyl acetate/isohexane) yielded the title compound as a pale yellow, crystalline solid (321 mg, 27.5%). 1H NMR (399.9 MHz, DMSOd6) δl.50 (9H5 s), 6.41 (2H, s), 6.54 (IH, d), 7.61 (IH, d) Intermediate 51: (3R)-l-methylpyrrolidin-3-amine di Hydrochloride
ry ■,N /N^ 2HCI tert-butyl N-[(3R)-l-methylpyrrolidin-3-yl]carbamate (Intermediate 185; 1.18 g, 5.67 mmol) was dissolved in 1,4-dioxane (10 mL) and 4M HCl in dioxane (10 niL) added. The mixture was stirred at room temperature for 1 hour and then concentrated to yield the title compound as a white hygroscopic solid (810 mg, 100%). 1H NMR (399.9 MHz, D2O) δ 2.19 - 2.29 (IH, m), 2.60 - 2.71 (IH, m), 3.10 (3H, M), 3.48 - 3.67 (3H, m), 3.85 - 3.93 (IH, m), 4.18 - 4.26 (IH, m).
Intermediate 52: 4-amiπo-5-chloro-N-(l-ethyl-4-piperidyl)-2-fluoro-benzamide
Figure imgf000166_0001
The title compound was prepared by an analogous method to the preparation of Intermediate 54, on a 2.64mol scale, utilising 4-amino-l-methylpiperidine (Fluorochem; 508 mg, 3.96 mmol) after purification on a silica column (gradient (3-4% ammonia in methanol/DCM), as a pale brown foam (647 mg, 82%).
1H NMR (399.9 MHz, DMSO-d6) δ 0.99 (3H, t), 1.46 - 1.55 (2H, m), 1.75 - 1.78 (2H, m), 1.92 - 1.97 (2H, m), 2.31 (2H, q), 2.81 (2H, d), 3.67 - 3.71 (IH, m), 6.09 (2H, s), 6.53 - 6.57 (IH, m), 7.48 (IH, d), 7.59 - 7.62 (IH, m); MS m/z 300 [M+H]+. Intermediate 53: 4-amino-5-chloro-N-(4-dimethylaminocyclohexyI)-2-fluoro-benzamide
Figure imgf000167_0001
The title compound was prepared by an analogous method to the preparation of Intermediate
54, on a 2.64mol scale, utilising l-amino-4-dimethylaminocyclohexane (ABChem Inc.; 472 mg, 3.31 mmol) after purification on a silica column (gradient (3-4% ammonia in methanol/DCM), as a pale brown foam (716 mg, 86%). 1R NMR (399.9 MHz, DMSO-d6) δl.19 - 1.35 (2H, m), 1.47 - 1.54 (2H, m), 1.62 - 1.91 (4H, m), 2.03 - 2.13 (IH, m), 2.17 (6H, s), 3.59 - 3.68 and 3.85 - 3.90 (both 0.5H, m), 6.08 (2H, s), 6.53 - 6.57 (IH, m), 7.47 - 7.49 (IH, m), 7.52 - 7.56 (IH, m); MS m/z 314 [M+H]+.
Intermediate 54: 4-amino-5-chloro-2-fluoro-N-(l -methyl-4-piperidyl)benzamide
Figure imgf000167_0002
4-amino-5-chloro-2-fluoiObenzoic acid (Intermediate 49; 500 mg, 2.64 mmol), 4-amino-l- methylpiperidine (ABCR; 452 mg, 3.96 mmol) and diisopropylethylamine (1.38 ml, 7.91 mmol) were stirred in DMF (5 mL) and HATU (1.50 g, 3.96 mmol) added. The reaction mixture was stirred for 3 hours at room temperature. The mixture was absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated to give a crystalline solid that was suspended in diethyl ether and filtered to yield the title compound as a pale brown solid (572 mg, 76%). 1H NMR (399.9 MHz, DMSO-dό) δ 1.47 - 1.58 (2H, m), 1.71 - 1.76 (2H, m), 1.95 (2H, t), 2.15 (3H, s), 2.69 - 2.72 (2H, m), 3.67 (IH, m), 6.09 (2H, s), 6.55 (IH, d), 7.49 (IH, d), 7.61 (IH, d); MS m/z 286 [M+H]+.
Intermediate 55:
4-amino-2,5-difluoro-N-[[l-(pyrroIidin-l-ylmethyl)cyclopropyl]methyl]benzamide
Figure imgf000168_0001
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 700 mg, 4.04 mmol), [1- (pyrrolidin-l-ylmethyl)cyclopropyl]methanamine (Intermediate 56; 655 mg, 4.25 mmol), HATU (1.69 g, 4.44 mmol) and DIPEA (2.1 mL, 12.12 mmol) were combined in DMF (10 mL) and stirred at room temperature for 2 hours. The reaction mixture divided into two portions and each loaded on to an SCX-2 column (20 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the residue taken up in DCM and purified on a silica column eluting with a 0 - 5% gradient of 2M ammonia in MeOH / DCM then 5% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to yield the title compound as an orange gum which solidified on standing to an orange solid (472 mg, 38%)
IH NMR (399.902 MHz, CDC13) dθ.37 (m, 2H), 0.55 (m, 2H), 1.75 (m, 4H), 2.50 (m, 6H), 3.42 (m, 2H), 4.08 (s, 2H), 6.43 (m, IH), 7.70 (m, IH), 8.53 (m, IH); MS m/z 310 [M+H]+.
Intermediate 56: [l-(pyrrolidin-l-ylmethyl)cyclopropyl]methanamine
Figure imgf000168_0002
To a solution of 1 -(pyrrolidine- l-carbonyl)cyclopropane-l-carboxamide (Intermediate 34;
5.0 g, 27.5 mmol) in anhydrous THF (150 rnL) was slowly added a 1 M anhydrous THF solution of Lithium Aluminium Hydride ( 138 mL, 138 mmol) controlling the reaction temperature at 400C with an ice / water bath.
The resultant clear solution was stirred overnight at room temperature under an inert gas flow to give a cloudy suspension.
Water (5.24 mL) was carefully added to the reaction mixture maintaining the reaction temperature at < 300C with an ice / water bath to give thick white slurry. 15% w/v aqueous Soium Hydroxide solution (5.24 mL) was carefully added followed by water (15.71 mL). The reaction was filtered and the filtrate evaporated to dryness to give the title compound (3.26 g,
77%)
Intermediate 57: l-(pyrrolidine-l-carbonyl)cyclopropane-l-carboxamide
Figure imgf000169_0001
To l-(aminocarbonyl)-l -cyclopropane carboxylic acid (Aldrich; 25 g, 193.6 mmol) in DCM (625 mL) was added HATU (73.61 g, 193.6 mmol) and the suspension stirred for 30 minutes.
Pyrrolidine (Aldrich; 24.25 mL) and Hunig's base (67 mL) was added and the reaction stirred at room temperature over the weekend.
The reaction was evaporated to dryness, DCM added and extracted with water (3x 150 mL).
The aqueous extracts were evaporated to dryness and the resultant material triturated with Ethyl acetate to give the title compound as a white solid (11.14 g, 32%) Intermediate 58: 4-amino-2,5-difluoro-N-[(3R)-l-methyIpyrroIidin-3-yI]benzamide
Figure imgf000170_0001
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 450 mg, 2.6 mmol), (3R)-I- methylpyrrolidin-3 -amine dihydrochloride (Intermediate 51; 473 mg, 2.73 mmol), HATU (1.08 g, 2.86 mmol) and DIPEA (2.25 mL, 13 mmol) were combined in DMF (10 mL) and stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in MeOH and added to an SCX-2 column (20 g), pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material dissolved in DCM and purified on a silica column eluting with 5% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to a yellow gum. Diethylether was added and re-evaporated and dried under high vacuum to yield the title compound as a yellow gum, which slowly crystallised to a cream solid (550 mg, 83%) 1H NMR (399.902 MHz, CDC13) δ 1.71 (m, IH), 2.26 - 2.42 (m, 5H), 2.64 (m, 2H), 2.86 (m, IH), 4.13 (s, 2H), 4.62 (m, IH), 6.43 (m, IH), 6.87 (m, IH), 7.70 (m, IH); MS m/z 256 [M+H]+.
Intermediate 59: 4-amino-2,5-difluoro-N-(2-pyrrolidin-l-ylethyl)benzamide
Figure imgf000170_0002
The title compound was prepared by an analogous method to the preparation of Intermediate 58, on a 5.77 mmol scale utilising 2-pyrrolidin-l-ylethanamine (Aldrich; 725 mg, 6.35 mmol), as a beige solid (648 mg, 42%)
IHNMR (399.902 MHz, CDC13) dl.78 (m, 4H), 2.56 (m, 4H), 2.69 (m, 2H), 3.55 (m, 2H), 4.12 (s, 2H), 6.43 (m, IH), 7.16 (m, IH), 7.72 (m, IH); MS m/z 270 [M+H]+.
Intermediate 60: 4-amino-2,5-difluoro-N-[(lS,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide
Figure imgf000171_0001
A mixture of the 4-amino-2,5-difluorobenzoic acid (Rarechem; 2.4 g, 13.87 mmol) and endo- 9-methyl-9-azabicyclo[3,3,l]-nonan-3-amine (Chempacific; 2.355 g, 15.26 mmol) was dissolved in DMF (150 mL), and to the solution was added DIPEA (5.3 mL, 27.74 mmol). The reaction was cooled on an ice-bath, and HATU( 5.805 g, 15.26 mmol) was added, portionwise. The reaction mixture was then stirred at ambient temperature for 18 hours, solvent evaporated, and the residue partitioned between ethyl acetate (200 mL), and saturated aqueous sodium carbonate solution (3 x 50 mL), washed with brine (3 x 50 mL), dried over anhydrous magnesium sulphate, filtered, and the solvent evaporated. The residue was purified on an SCX-2 column (50 g), developing and eluting with 1) water ; 2) MeOH ; and 3) 3.5M NH3 -MeOH. The solvent was evaporated to yield the title compound as a tan crystalline solid ( 2.58 g, 60%).
1H NMR (400.1MHz; CDCl3) δ 1.00-1.10 (2H,d), 1.23-1.33 (2h,dt), 1.48-1.58 (lH,m), 1.85- 2.03 (4H,d+m), 2.50 (3H,s), 2.44-2.56 (2H,m), 3.04-3.12 (2H,d), 4.20 (2H,s), 4.42-4.56 (lH,m), 6.33-6.50 (lH,m), 6.42-6.50 (lH,dd),7.70-7.77 (lH,dd). MS m/z 310 [M+H]+.
Intermediate 61: 4-amino-3-chloro-N-(l-ethyl-4-piperidyl)benzamide
Figure imgf000172_0001
To a mixture of 4-amino-3-chloro-benzoic acid (Fluorochem; 2.575 g, 15 mmol) and 1- ethylpiperidin-4-amine (Fluorochem; 2.12 g, 16.5 mmol) in DMF (50 mL), was added DIPEA (5.2 mL, 30 mmol).The mixture was cooled with an ice-bath. HATU (6.27g), added and the reaction mixture stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL), and Ethyl Acetate (4 x 50 mL). The organic extracts were washed with brine (2 x 75 ml), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated to give the crude product as a gum, which was triturated with ether to yield the title compound as a tan solid (3.54 g, 84%).
1H NMR (400.1, MHz DMSO-d6) δ 1.20-1.26 (3H,t), 1.65-1.85 (2H,bm), 1.92-2.10 (2H,bm), 2.90-3.20 (4H,m), 3.30 (3H,s), 3.40-3.60 (2H,bm), 3.90-4.05 (lH,m), 5.98 (2H,s), 6.77-6.81 (lH,d), 7.554-7.60(lH,dd), 7.88 (lH,s), 8.10 (lH,bs); MS m/z 282 [M+H]+.
Intermediate 62: 4-amino-2-chloro-5-methoxy-benzoic acid
Figure imgf000172_0002
2-chloro-5-methoxy-4-nitro-benzoic acid (Intermediate 63; 762 mg, 3.8 mmol) was dissolved in EtOH (20 mL) and a catalytic amount of 5% Pt on carbon added under an inert atmosphere. The solution was de-gassed and stirred under an atmosphere of hydrogen at room temperature overnight. The catalyst was filtered off and washed with EtOH and solvent evaporated and the resultant material dried under vacuum to yield the title compound as an off-white solid. (617 mg, 98%)
1H NMR (399.902 MHz, DMSO-d6) 53.72 (s, 3H), 5.65 (br s, 2H), 6.59 (s, IH), 7.21 (s, IH), 12.30 (br s, IH); MS m/z 201 [M+H]+.
Intermediate 63: 2-chloro-5-methoxy-4-nitro-benzoic acid
Figure imgf000173_0001
l-chloro-4-methoxy-2-methyl-5-nitro-benzene (APIN; 1 g, 4.96 mmol) was suspended in water (100 mL), potassium permanganate (3.14 g, 19.84 mmol) was added and the mixture diluted further with water (140 mL). The mixture was very slowed heated up to reflux over a 2 hour period and then stirred at reflux for 4 hours then allowed to cool to room temperature overnight with stirring. After 18 hours the mixture was reheated to 80 °C and filtered hot, the manganese filter cake was washed with boiling water (100 mL), then the aqueous filtrate was treated with a couple of drops of sodium metabisulfite solution and the permanganate colour was removed to give a yellow solution. The solution was acidified to pH 2 with concentrated hydrochloric acid and partially evaporated down to a volume of (200 mL) and extracted with EtOAc (2 x 100 mL). Combined organic extracts were washed with brine, dried (MgSO4) and evaporated to yield the title compound as a yellow solid. (752 mg, 65%). 1H NMR (399.902 MHz, DMSO-d6) 53.98 (s, 3H), 7.67 (s, IH), 8.14 (s, IH), 14.03 (br s, IH); MS m/z 229 [M-H]+. Intermediate 64: 4-amino-3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)benzamide
Figure imgf000174_0001
3-chloro-N-(3-dimethylamino-2,2-dimethyl-piOpyl)-4-nitro-benzamide (Intermediate 65; 2.29 g, 7.67 mmol), iron powder (2.45 g, 43.79 mmol) and ammonium chloride (781 mg, 14.60 mmol) were heated in ethanol (50 mL) and water (18 mL) at reflux for one hour. A few drops of acetic acid were added and heating continued for a further hour. The reaction mixture was cooled, filtered and the filtrate concentrated. This residue was partitioned between saturated NaHCO3 (aq.) and DCM. The organic phase was washed with brine, dried with MgSO4 and concentrated. Column chromatography gave the title compound as an orange crystalline solid. (850mg, 39%)
1H NMR (399.9 MHz, DMSOd6) δθ.86 (6H, s), 2.16 (2H, s), 2.26 (6H, s), 3.14 (2H, d), 5.83 (2H, s), 6.80 (IH5 d), 7.52 - 7.54 (IH, m), 7.72 (IH, d), 8.15 (IH, t); MS m/z 286.16 [M+H]+.
Intermediate 65; 3-chloro-N-(3-dimethyIamino-2,2-dimethyI-propyI)-4-nitro-benzamide
Figure imgf000174_0002
3-chloro-4-nitro-benzoyl chloride (Intermediate 43; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisoproρylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and N,N,2,2-tetramethyl-l,3-propanediamine (3.652 mL, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5h. The mixture was washed with brine, 2N NaOH (aq.), dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeOH/DCM) gave the title compound as a yellow oil (2.29g, 77%).
1H NMR (399.9 MHz, DMSOd6) δθ.89 (6H, s), 2.17 (2H, s), 2.26 (6H, s), 3.21 (2H, d), 7.96 - 7.98 (IH, m), 8.13 (IH5 d), 8.18 (IH, d), 8.73 (IH, t); MS m/z 314.21 [M+H]+.
Intermediate 66: 4-amino-3-chloro-N-(2-pyrrolidin-l-ylethyl)benzamide
Figure imgf000175_0001
The title compound was prepared by an analogous method to the preparation of Intermediate
61, on a 15 mmol scale utilising 2-pyrrolidin-l-ylethanamine (Aldrich; 1.885 g, 16.5 mmol), as a tan coloured solid (2.67 g, 66%).
1H NMR (400.1MHz, DMSO-d6) δ 1.80-2.05 (4H,m), 3.20-3.45 (6H,m), 3.48-3.58 (2H,q), 5.92 (2H,s), 6.78-6.82 (lH,d), 7.55-7.60 (lH,dd), 7.77 (lH,s), 8.30-8.40 (lH,t); MS m/z 268
[M+H]+.
Biological Assays for inhibition of PLK
The following assay was used to measure the effects of the compounds of the present invention as PIk kinase inhibitors.
In Vitro Plkl Enzyme Assay
Screening for inhibitors of PLKl kinase activity using the Caliper off-chip incubation mobility shift assay (Caliper LabChip LC3000) uses a microfluidic chip to measure the conversion of a fluorescent labelled peptide to a phosphorylated product by Plkl. The substrate peptide (FL-RRRAGALMDASFEEQ-CONH2) is supplied by CRB and the full- length Plkl protein supplied by Carna Biosciences.
Test compounds were prepared as 1OmM stock solutions in dimethyl sulphoxide (DMSO) and diluted into DMSO as required to give a range of final assay concentrations. Aliquots (2μl) of each compound dilution were dispensed into appropriate wells of a white 384-well flat bottom low volume assay plate (Greiner, Catalogue No. 784075). A 5μl aliquot of peptide mix (1.5μM peptide and llμM ATP) and a 5μl aliquot of enzyme mix (1OnM enzyme, ImM DTT and 5mM MgCl2) were added to each well. Both enzyme and peptide mixes were prepared in a kinase base buffer (5OmM MOPS, pH6.5 and 0.004% Triton x-100 in water). Assay plates were sealed and incubated at room temperature for 75minutes.
Reactions were stopped by addition of lOμl stop buffer (10OmM HEPES, pH7.5, 0.015% Brij-35 solution, 0.1% coating reagent #3, 4OmM EDTA and 5% DMSO in water) and analysed in separation buffer (10OmM HEPES, pH7.5, 0.015% Brij-35 solution, 0.1% coating reagent #3, 2OmM EDTA and 5% DMSO in water) using the LC3000. The fluorescent peptide and cleaved product in each well are separated by electrophoresis into two peaks and detected as a fluorescent signal revealing the extent of the reaction. The raw assay data were then analysed and Plkl enzyme inhibition for a given test compound is expressed as an IC50 value. The Example compounds of this invention were measured to have IC50 values as indicated.
Alternative In Vitro PIkI Enzyme Assay
The assay uses Scintillation Proximity Assay (SPA) technology (Antonsson et al., Analytical Biochemistry, 1999, 267: 294-299) to determine the ability of test compounds to inhibit phosphorylation by recombinant Plkl. The full-length Plkl protein is expressed in insect cells as an N-terminal 6His tag fusion and purified by standard Nickel chelate purification techniques using the His tag.
The amino terminal fragment of Cdc25C (encoding residues 1-165) is expressed in E.coli as a GST fusion and purified using the GST tag by standard purification techniques. Test compounds were prepared as 1OmM stock solutions in dimethylsulfoxide
(DMSO) and diluted into water as ' required to give a range of final assay concentrations. Aliquots (5μl) of each compound dilution were dispensed into a well of a 384-well flat bottom white polystyrene plate (Matrix, Catalogue No. 4316). A 35μl mixture of recombinant purified Plkl enzyme (12ng/well), purified GST-Cdc25C (150ng/well), adenosine triphosphate (ATP; 64nM), 33P-labelled adenosine triphosphate (33P-ATP; 60 nCi/well) in a buffer solution [comprising 5OmM HEPES pH7.5 buffer, 1OmM manganese chloride (MnCl2), ImM dithiothreitol (DTT), lmg/ml bovine serum albumin (BSA), lOOμM sodium vanadate (Na3VO4), lOOμM sodium fluoride (NaF) and 1OmM sodium glycerophosphate] was added and the reactions incubated at ambient temperature for 90 minutes. Reactions were stopped by addition of EDTA (HOmM) and the Cdc25C substrate captured via its GST tag to anti-GST antibody (Molecular Probes, Cat No A-5800) coated Protein A PVT SPA beads (Amersham Biosciences, Catalogue No. RPQOOl 9; 250μg/well) in 5OmM HEPES pH7.5 buffer containing 0.05% (w/v) sodium azide and incubated for up to 2 hours, followed by the addition of 20μl of 4M caesium chloride (final assay concentration of IM). Plates were then left in the dark overnight before counting on a Packard TopCount NXT.
Radiolabeled phosphorylated substrate is formed in situ as a result of Plkl mediated phosphorylation. The SPA beads contain a scintillant that can be stimulated to emit light. This stimulation only occurs when a radiolabeled phosphorylated substrate is bound to the surface of the coated SPA bead causing the emission of blue light that can be measured on a scintillation counter. Accordingly, the extent of Plkl mediated Cdc25C phosphorylation was assessed. The raw assay data were then analysed by non- linear regression analysis and Plkl enzyme inhibition for a given test compound is expressed as an IC50 value.
Cellular Assay
Chromosome condensation in mitosis is accompanied by phosphorylation of histone H3 on serine 10. Dephosphorylation begins in anaphase and ends at early telophase, thus histone H3 serine 10 phosphorylation acts as an excellent mitotic marker and is used to determine the ability of compounds of the present invention to block cells in mitosis. Cells of the human colon tumour cell line HT29 were seeded into 96 well black plates
(Costar, Catalogue No 3904) in phenol red free Dulbecco's Modified Eagles Medium (DMEM) supplemented with 10% (v/v) FCS and 1% (v/v) L-Glutamine and incubated overnight at 370C. Test compounds were solubilised in DMSO, diluted to give a range of final assay concentrations, added to cells and incubated for 24h at 370C. After 24 hours, cells were fixed in 3.7% (v/v) formaldehyde then permeabilised and blocked for 10 minutes in lOOμl 0.5% (v/v) Triton X-100, 1% (w/v) bovine serum albumin (BSA) in phosphate buffered saline (PBS). After washing with PBS5 50μl primary antibody (1:500 dilution of rabbit anti- phosphohistone H3 (Upstate Catalogue No 06-570) in 1% BSA, 0.05% Tween 20) was added to the cells that were left for 1 hour at room temperature. Cells were again washed with PBS and incubated with 50μl secondary antibody (1:1000 Alexa Fluor 488 goat anti-rabbit (Molecular Probes Cat No A-11008) and Hoechst (1:10000) diluted in PBS 0.05% (v/v) Tween 20 and left for 1 hour at room temperature in the dark. Cells were washed with PBS then covered with fresh PBS and stored at 40C until analysis. Images are acquired and analysed in an automated manner using the Cellomics ArrayScan II or VTi. In this assay both hoechst and phosphohistone H3 staining are measured. Hoechst staining generates a valid cell count while phosphohistone H3 staining determines the number of mitotic cells. Inhibition of PIk leads to an increase in the population of histone H3 SerlO positive cells, indicating inhibition of proliferation is brought about primarily by arrest of cells in the mitotic phase of the cell cycle. The raw assay data were analysed by non-linear regression analysis and used to determine an IC50 value for each compound. The Example compounds of this invention were measured to have IC50 values as indicated. For example, the compound of Example 1 was measured to have an IC50 of 0.056μM.

Claims

1. A compound of formula (I) :
Figure imgf000179_0001
(I) wherein
R1 represents represents hydrogen, -NH2, -OH, -CN, -C≡CH, -C(=O)NH2, C1-3alkyl, C-1-3alkylamino, C1-3alkylthio, C1-3alkyloxy, C1-3alkylcarbonyl, -CHO, or -SO2Me; R2 represents hydrogen, an optionally substituted C1-6alkyl group or an optionally substituted C3-6cycloalkyl group;
R3 represents hydrogen, an optionally substituted d-^alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-i2alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-12polycycloalkyl group, an optionally substituted C7-12polycycloalkenyl group, an optionally substituted C5_i2spirocycloalkyl 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 R2 and R3, together represent a saturated or unsaturated Ci-4alkyl bridge optionally comprising 1 heteroatom;
R4 each independently represent -CN, hydroxy, -NR6R7, halogen, an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted Q-salkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted Ci-6alkythio group, an optionally substituted C1-6alkylsulfoxo group or an optionally substituted
Ci-6alkylsulfonyl group, or when p is 2 and when each R4 is adjacent, both R4 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; Q is -Ln-R5 m, -C(=X)-Ln-R5 m -C(=X)-NRaRb, -(optionally substituted
Ci-3alkyl)g-NRa2Rb2, -S(O)2-NRa3Rb3, -NH-SO2-NRa4RM, -S(O)k-Ra5, -C(=X)-ORa6, -ORa7, -NH-C(=X)-Ra8, -NH~SO2-Ra9 or -(5- or 6-membered aromatic or heteroaromatic ring optionally comprising one or more heteroatoms selected from nitrogen, oxygen or sulphur)-Ln-R5 m; g is O or l; k is 0, 1 or 2;
Ra represents H or an optionally substituted C^alkyl group, and Rb represents H, an optionally substituted C1-6alkyl group, -Ln-R5 m, or Ra and Rb 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;
Ra2 represents H or an optionally substituted C1-6alkyl group, and Rb2 represents -Ln-R5 m, or R82 and Rb2 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; Ra3 represents H or an optionally substituted Chalky! group, and Rb3 represents
-Ln-R5 m, or Ra3 and Rb3 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; Ra3 represents H or an optionally substituted Ci-6alkyl group, and Rω represents -Ln-R5 m, or Ra3 and Rb3 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;
Ra5 represents -Ln-R5 m;
Ra6 represents ~Ln-R5 m; Ra7 represents -Ln-R5 m;
Ra8 represents -Ln-R5 m;
Ra9 represents -Ln-R5 m;
L represents a linker selected from optionally substituted C1-1OaIlCyI, optionally substituted C2.10alkenyl, optionally substituted C6-14aryl, optionally substituted -C2-4alkyl-C6-i4aryl, optionally substituted -C6-[4aryl-C1-4alkyl, optionally substituted
C3-i2cycloalkyl and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is O or 1; m is 1 or 2; R5 represents a group selected from among hydrogen, 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 and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group;
R8, R9 each independently represents hydrogen, an optionally substituted -C1-6alkyl, an optionally substituted -C1-4alkyl-C3-10cycloalkyl, an optionally substituted
-C3-iocycloalkyl, an optionally substituted -C6-i4aryl, an optionally substituted
Figure imgf000181_0001
an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted
-C1-4alkyloxycarbonyl, an optionally substituted -C6-14arylcarbonyl, an optionally substituted -C1-4alkylcarbonyl, an optionally substituted -Co-narylmethyloxycarbonyl, an optionally substituted -C6-i4arylsulfonyl, an optionally substituted
-Ci-4alkylsulfonyl or an optionally substituted -C6-14aryl-C1-4alkylsulfonyl; X is O, S or H2; and 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.
2. A compound according to Claim 1 wherein Q represents -C(=X)-NRaRb and X is O or H2.
3. A compound according to Claim 1 wherein the compound is a compound of formula (II):
Figure imgf000182_0001
(H) wherein
R2 represents hydrogen or an optionally substituted C^alkyl group; R3 represents hydrogen, an optionally substituted C1-12alkyl group, an optionally substituted C2-i2alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted C6-14aryl group, an optionally substituted C3-12cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C^upolycycloalkyl group, an optionally substituted C7-i2polycycloalkenyl group, an optionally substituted Cs-πspirocycloalkyl 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
R2 and R3 together represent a saturated or unsaturated C3-4alkyl bridge optionally comprising 1 heteroatom; R4 each independently represent -CN, hydroxy, -NR6R7, halogen, an optionally substituted Ci-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted C2-5alkenyloxy group, an optionally substituted C2-5alkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted Cι-6alkylsulfoxo group or an optionally substituted C1-6alkylsulfonyl group, or when p is 2 and when each R4 is adjacent, both R4 together with the aromatic ring atoms to which they are attached form a 4- to 7-niember unsaturated ring optionally comprising 1 or more heteroatoms; p is 0, 1 or 2;
L represents a linker selected from optionally substituted C1-10alkyl, optionally substituted C2-1oalkenyl, optionally substituted C6-i4aryl, optionally substituted -C2-4alkyl-C6-i4aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-12cycloalkyl, and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among optionally substituted morpholinyl, granatanyl, oxogranatanyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylrnorpholinyl, thiomorpholinyl, azacycloheptyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group; and R8, R9 each independently represents hydrogen, an optionally substituted C1-6alkyl, an optionally substituted -Ci_4alkyl-C3.iocycloalkyl, an optionally substituted
-C3-1ocycloalkyl, an optionally substituted -C6-14aryl, an optionally substituted -C1-4alkyl-C6-14aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted -C1-4alkyloxycarbonyl, an optionally substituted -C6- wary lcarbonyl, an optionally substituted -Ci-4alkylcarbonyl, an optionally substituted -Cό-warylmethyloxycarbonyl, an optionally substituted -C6-14arylsulfonyl, an optionally substituted
-Cj-4alkylsulfonyl and an optionally substituted C6-14aryl-Ci.4alkylsulfonyl, or pharmacologically acceptable salts thereof.
4. A compound according to Claim 1 wherein the compound is a compound of formula QIa):
Figure imgf000184_0001
(Ha) wherein
R2 represents hydrogen or an optionally substituted C^alkyl group; R3 represents hydrogen, an optionally substituted Ci.i2alkyl group, an optionally substituted C2-12alkenyl group, an optionally substituted C2-12alkynyl group, an optionally substituted Q-naryl group, an optionally substituted C3.i2cycloalkyl group, an optionally substituted C3-i2cycloalkenyl group, an optionally substituted C7-[2polycycloalkyl group, an optionally substituted Cγ.upolycycloalkenyl group, an optionally substituted C5-i2spirocycloalkyl 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
R2 and R3 together represent a saturated or unsaturated C3_4alkyl bridge optionally comprising 1 heteroatom;
R4a, R4b and R4c each independently represent hydrogen, -CN, hydroxy, -NR6R7, halogen, an optionally substituted Ci-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-5alkyloxy group, an optionally substituted C3-6cycloalkyloxy group, an optionally substituted
C2-5alkenyloxy group, an optionally substituted C2-salkynyloxy group, an optionally substituted C1-6alkythio group, an optionally substituted C1-6alkylsulfoxo group or an optionally substituted Ci-6alkylsulfonyl group, or R4a and R4b together with the carbon atoms to which they are attached form a 4- to 7-member unsaturated ring optionally comprising 1 or more heteroatoms;
L represents a linker selected from optionally substituted C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C6-i4aryl, optionally substituted -C2-4alkyl-C6-14aryl, optionally substituted -C6-14aryl-C1-4alkyl, optionally substituted C3-i2cycloalkyl, and optionally substituted heteroaryl comprising 1 or 2 nitrogen atoms; n is 0 or 1 ; m is 1 or 2;
R5 represents a group selected from among optionally substituted morpholinyl, granatanyl, oxogranatanyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, azacycloheptyl and -NR8R9;
R6, R7 each independently represents hydrogen or an optionally substituted C1-4alkyl group; and R8, R9 each independently represents hydrogen, an optionally substituted C1-6alkyl, an optionally substituted -Ci ^aUXyI-C3. locycloalkyl, an optionally substituted
-C3-iocycloalkyl, an optionally substituted -C6-14aryl, an optionally substituted -C1-4alkyl-C6-14aryl, an optionally substituted pyranyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted -C1-4alkyloxycarbonyl, an optionally substituted -C6-14arylcarbonyl, an optionally substituted -C1-4alkylcarbonyl, an optionally substituted -Cό-warylmethyloxycarbonyl, an optionally substituted -C6-14arylsulfonyl, an optionally substituted -CMalkylsulfonyl and an optionally substituted C^Haryl-Ci^alkylsulfonyl, or pharmacologically acceptable salts thereof.
5. A compound according to any one of Claims 1 to 3 wherein when p is I5 R4 represents methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine.
6. A compound according to any one of Claims 1 to 3 wherein when p is 2, each R4 may be the same or different and selected from methoxy, methyl, ethoxy, ethyl, propargyloxy, chlorine or fluorine.
7. A compound according to any one of Claims 1 to 3 wherein when p is 2 and when each R4 is adjacent, both R4 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.
8. A compound according to Claim 3 wherein R4b and R4c are hydrogen and R4a represents hydrogen, methoxy, methyl, ethoxy, chlorine or fluorine.
9. A compound according to Claim 3 wherein R4b is hydrogen, R4c is fluorine and R4a is selected from methoxy, chlorine or fluorine.
10. A compound according to Claim 3 wherein R4c is hydrogen and R4a and R4b together form a OCH2O bridge.
11. A compound according to any one of Claims 1 to 10 wherein R2 represents a methyl or ethyl group.
12. A compound according to any one of Claims 1 to 11 wherein R3 represents isopropyl, isobutyl, isopentyl, cyclopentyl, phenyl or cyclohexyl.
13. A compound according to any one of Claims 1 to 12 wherein when n is 1, L represents an optionally substituted C1-1OaIlCyI or C3-12cycloalkyl linker.
14. A compound according to Claim 13 wherein when n is 1, L represents -C(CH3VCH2- , -CH2-C(CH3)2-CH2- or a cyclohexyl linker.
15. A compound according to any one of Claims 1 to 12 wherein n is 0 and m is 1.
16. A compound according to any one of Claims 1 to 15 wherein m is 1 and R5 represents NR8R9 or a piperidinyl, morpholinyl, granatanyl, oxogranatanyl, pyrrolidinyl, sulphoxomorpholiny, piperazinyl, thiomorpholinyl or tropenyl each optionally substituted by one or more groups as defined for R8.
17. A compound according to Claim 16 wherein R8 represents methyl, ethyl or propyl, and R9 represents methyl, ethyl or propyl.
18. A process for preparing a compound of general formula (II),
Figure imgf000187_0001
(II) wherein R2-R5, m, n, p and L are as hereinbefore defined, comprising reacting a compound of general formula (III)
Figure imgf000188_0001
(III) wherein R2-R3, Rc and Rd are as hereinbefore defined and A is a leaving group, with an optionally substituted compound of general formula (IV):
Figure imgf000188_0002
(IV) wherein R4 is as hereinbefore defined; and R10 denotes OH, NH-Lm-R5 n, OMe, OEt, and, when R10 denotes OH, OMe or OEt, optionally after previous hydrolysis of the ester group -COR10, reacting with an amine of general formula (VI):
NH2 -Lm-R5 n (VI) wherein R5, L and m are as hereinbefore defined to give a compound of formula (II).
19. A pharmaceutical composition comprising a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one claims 1 to 17 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
20. A process for the preparation of a pharmaceutical composition as claimed in claim 19 which comprises mixing a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 17 with a pharmaceutically acceptable adjuvant, diluent or carrier.
21. A compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 17 for use in therapy.
22. Use of a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 17 in the manufacture of a medicament for use in the treatment of cancer.
23. Use of a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one claims 1 to 17 in the manufacture of a medicament for use in modulating polo-like kinas (PIk) activity.
24. A method of treating cancer which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), (II) or (Ha), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 17.
25. 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 claimed in any one claims 1 to 17.
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