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US20060270691A1 - Purine derivatives as purinergic receptor antagonists - Google Patents

Purine derivatives as purinergic receptor antagonists Download PDF

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US20060270691A1
US20060270691A1 US11/488,750 US48875006A US2006270691A1 US 20060270691 A1 US20060270691 A1 US 20060270691A1 US 48875006 A US48875006 A US 48875006A US 2006270691 A1 US2006270691 A1 US 2006270691A1
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purine
furyl
amine
alkyl
group
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US11/488,750
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Roger Gillespie
Joanne Lerpiniere
Claire Dawson
Suneel Gaur
Robert Pratt
Gemma Stratton
Scott Weiss
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Ligand UK Research Ltd
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Vernalis Research Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • the present invention relates to purine derivatives and their use in therapy.
  • the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial.
  • the invention relates in particular to blockade of adenosine receptors and particularly adenosine A 2A receptors, and to the treatment of movement disorders such as Parkinson's disease.
  • Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
  • Parkinson's disease There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson's disease are manifested.
  • L-dihydroxyphenylacetic acid L-DOPA
  • L-DOPA L-dihydroxyphenylacetic acid
  • Deprenyl® monoamine oxidase
  • dopamine receptor agonists e.g. bromocriptine and apomorphine
  • anticholinergics e.g. benztrophine, orphenadrine
  • Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when “on-off” symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients.
  • Blockade of A 2 adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson's disease (Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65).
  • the potential utility of adenosine A 2A receptor antagonists in the treatment of movement disorders such as Parkinson's Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320).
  • Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects.
  • the central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407-422).
  • This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5, 547-558).
  • Adenosine receptors represent a subclass (P 1 ) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors.
  • the main pharmacologically distinct adenosine receptor subtypes are known as A 1 , A 2A , A 2B (of high and low affinity) and A 3 (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156).
  • the adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128).
  • P 1 receptor-mediated agents The design of P 1 receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Williams, M. and Burnstock, G. Purinergic Approaches Exp. Ther . (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)
  • xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD).
  • ADHD attention-deficit hyperactivity disorder
  • Antagonism of adenosine receptors is thought to account for the majority of the behavioural effects of caffeine in humans and thus blockade of adenosine A 2A receptors may account for the observed effects of caffeine in ADHD patients. Therefore a selective A 2A receptor antagonist may provide an effective treatment for ADHD but without the unwanted side-effects associated with current therapy.
  • Adenosine receptors have been recognised to play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268). Recent evidence suggests that a substantial part of the actions of adenosine in regulating sleep is mediated through the adenosine A 2A receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA, 1996). Thus, a selective A 2A receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.
  • a 2A receptor antagonists may offer a novel therapy for the treatment of major depression and other affective disorders in patients.
  • adenosine A 2A receptors The pharmacology of adenosine A 2A receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372).
  • One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A 2 adenosine receptors is the evidence of a functional link between adenosine A 2A receptors to dopamine D 2 receptors in the CNS.
  • Some of the early studies e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A 2 receptors decreases the affinity of dopamine D 2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci.
  • adenosine A 2A antagonist therapy is that the underlying neurodegenerative disorder may also be treated.
  • the neuroprotective effect of adenosine A 2A antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N.Y. Acad. Sci. 1997, 825 (Neuroprotective Agents), 30-48).
  • blockade of A 2A receptor function confers neuroprotection against MPTP-induced neurotoxicity in mice (Chen, J-F., J. Neurosci. 2001, 21, RC143).
  • a 2A receptor antagonist may offer a novel treatment for conferring neuroprotection in neurodegenerative diseases such as Parkinson's disease.
  • Xanthine derivatives have been disclosed as adenosine A 2 receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A 2 receptors, such as Parkinson's disease (see, for example, EP-A-565377).
  • CSC 8-(3-chlorostyryl)caffeine
  • Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A 1 and A 2A receptors, has been studied clinically.
  • the patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W., J. Pharm. Pharmacol, 1994, 46, 515-517).
  • KF 17837 [(E)-8-(3′,4-dimethoxystyryl-1,3-dipropyl-7-methylxanthine] is a selective adenosine A 2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A 2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine.
  • KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A 2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A 2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268).
  • SAR structure activity relationship
  • New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A 2A Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71).
  • SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126-2133).
  • purine derivatives which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P 1 ) receptors, and in particular at the adenosine A 2A receptor.
  • Such compounds may therefore be useful for the treatment of disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A 2A receptors, may be beneficial.
  • such compounds may be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias.
  • Disorders of particular interest in the present invention include Parkinson's disease, Alzheimer's disease, spasticity, Huntington's chorea and Wilson's disease.
  • Such compounds may also be particularly suitable for the treatment of depression, cognitive or memory impairment including Alzheimer's disease, acute or chronic pain, ADHD, narcolepsy or for neuroprotection.
  • R 1 is selected from alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
  • R 2 is selected from N, O or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated carbon atom which is adjacent to one or two N, O or S-heteroatom(s), other than ortho,ortho-disubstituted heteroaryl groups;
  • R 3 is selected from H, alkyl, COR 8 , CONR 9 R 10 , CONR 8 NR 9 R 10 , CO 2 R 11 and SO 2 R 1 ;
  • R 4 , R 5 and R 6 are independently selected from H, alkyl and aryl or where R 5 and R 6 are in
  • alkyl means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted.
  • the alkyl group is preferably C 3 to C 12 , more preferably C 5 to C 10 , more preferably C 5 , C 6 or C 7 .
  • the alkyl group is preferably C 1 to C 10 , more preferably C 1 to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl.
  • alkyl as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.
  • lower alkyl means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • aryl means an aromatic group, such as phenyl or naphthyl (preferably phenyl), or a heteroaromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.
  • heteroaryl means an aromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.
  • non-aromatic heterocyclyl means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a cyclic amino group (including aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl) or a cyclic ether (including tetrahydrofuranyl).
  • a cyclic amino group including aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl
  • a cyclic ether including tetrahydrofuranyl
  • alkoxy means alkyl-O—.
  • aryloxy means aryl-O—.
  • halogen means a fluorine, chlorine, bromine or iodine radical.
  • ortho,ortho-disubstituted heteroaryl groups refers to heteroaryl groups which are substituted in both ortho positions of the heteroaryl group relative to the point of attachment of the heteroaryl group to the purine ring.
  • prodrug means any pharmaceutically acceptable prodrug of a compound of the present invention.
  • R 1 to R 120 is selected from alkyl, alkoxy and thioalkyl, in accordance with formula (I) as defined above, then that alkyl group, or the alkyl group of the alkoxy or thioalkyl group, may be substituted or unsubstituted.
  • R 1 to R 20 are selected from aryl, aryloxy and thioaryl, in accordance with formula (I) as defined above, then said aryl group, or the aryl group of the aryloxy or thioaryl group, may be substituted or unsubstituted.
  • R 5 and R 6 , or R 9 and R 10 , or R 8 and R 9 , or R 14 and R 15 are linked to form a heterocyclic group in accordance with formula (I) as defined above, then said heterocyclic ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include: carbon-containing groups such as
  • R 1 to R 20 is selected from aryl or from an aryl-containing group such as aryloxy or arylthio
  • preferred substituent group(s) are selected from halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO 2 , amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl, and particularly from unsubstituted alkyl, substituted alkyl (including alkoxyalkyl and aminoalkyl), halogen and amines.
  • any of R 1 to R 20 is directly substituted by an alkyl substituent group, or by an alkyl-containing substituent group (such as alkoxy or alkylcarbonylamino for example), then the alkyl moiety of the substituent group directly attached to any of R 1 to R 20 may be further substituted by the substituent groups hereinbefore described and particularly by halogen, hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and aryl.
  • any of R 1 to R 20 is directly substituted by an aryl substitutent group, or by an aryl-containing substituent group (such as aryloxy or arylaminocarbonylamino for example), then the aryl moiety of the substituent group directly attached to any of R 1 to R 20 may be further substituted by the substituent groups hereinbefore described and particularly by halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO 2 , amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl.
  • said aryl moiety is substituted by halogen, alkyl (including CF 3 ), hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and NO 2 .
  • said aryl moiety is substituted by unsubstituted all, substituted alkyl (particularly alkoxyalkyl and aminoalkyl), halogen and amines.
  • R 1 is selected from alkyl (including haloalkyl (such as CF 3 ), branched alkyl, cycloalkyl and arylalkyl), aryl (including heteroaryl), alkoxy, aryloxy, thioalkyl, thioaryl, halo, CN, NR 5 R 6 (including NH 2 ), NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 .
  • alkyl including haloalkyl (such as CF 3 ), branched alkyl, cycloalkyl and arylalkyl), aryl (including heteroaryl), alkoxy, aryloxy, thioalkyl, thioaryl, halo, CN, NR 5 R 6 (including NH 2 ), NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7
  • R 1 is selected from NR 5 R 6 (including NH 2 ), alkoxy, thioalkyl and alkyl.
  • R 1 is selected from NR 5 R 6 (including NH 2 ), and is preferably NH 2 .
  • R 1 is selected from alkyl, preferably R 1 is selected from C 1-6 alkyl, more preferably from saturated C 1-6 alkyl and more preferably from lower alkyl.
  • R 1 is selected from alkoxy and thioalkyl, preferably the alkyl moiety of said thioalkyl or alkoxy group is selected from C 1-6 alkyl, more preferably from saturated C 1-6 alkyl and more preferably from lower alkyl.
  • R 1 is selected from halo, preferably R 1 is selected from chloro.
  • R 1 is selected from NR 5 R 6 , preferably at least one and more preferably both of R 5 and R 6 are hydrogen.
  • R 1 is selected from NR 4 COR 5 , NR 4 CONR 5 , NR 4 CO 2 R 7 and R 4 SO 2 R 7 , and R 4 is selected from H and alkyl, and more preferably hydrogen.
  • R 2 is selected from furyl (including 2-furyl), thienyl (including 2-thienyl), pyridyl (including 2-pyridyl), thiazolyl (including 2- and 5-thiazolyl), pyrazolyl (including 3-pyrazolyl), triazolyl (including 4-triazolyl), pyrrolyl (including 2-pyrrolyl) and oxazolyl (including 5-oxazolyl).
  • R 2 is selected from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyrazolyl, 2-pyrrolyl, 4-triazolyl and 5-oxazolyl.
  • R 2 is selected from furyl, thienyl, pyridyl, thiazolyl and pyrazolyl, and particularly from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl and 3-pyrazolyl.
  • R 2 is selected from furyl, thienyl and pyridyl, preferably 2-furyl, 2-thienyl and 2-pyridyl, and more preferably from 2-furyl.
  • R 2 is substituted heteroaryl
  • substituent group(s) are not present in the ortho position relative to the point of attachment of the heteroaryl group to the purine moiety.
  • reference to ortho-substitution of the R 2 group means the ortho positions of the R 2 group relative to the point of attachment of R 2 to the pyrimidine moiety of formula (I).
  • R 2 is an unsubstituted heteroaryl group.
  • R 3 is selected from H, substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkynyl, branched and unbranched alkyl, and cyclic and acyclic alkyl), COR 8 , CONR 9 R 10 , CONR 8 NR 9 R 10 , CO 2 R 1 and SO 2 R 11 .
  • R 3 is selected from H, alkyl and CONR 9 R 11 .
  • R 3 is selected from H, substituted alkyl and CONR 9 R 10 .
  • R 3 is selected from alkyl (substituted or unsubstituted) and CONR 9 R 10 , preferably substituted alkyl and CONR 9 R 10 .
  • said substituted alkyl is preferably selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR 9 R 10 , and more preferably from arylalkyl (including heteroarylalkyl), and more preferably from arylmethyl (including heteroarylmethyl).
  • R 8 is preferably selected from alkyl (including cycloalkyl) and aryl (including heteroaryl), preferably from saturated C 1-6 alkyl (including cycloalkyl) and aryl.
  • R 9 and R 10 are selected from H, C 1-6 alkyl and aryl, and preferably from H, C 1-6 saturated alkyl (including cycloalkyl) and aryl, and more preferably from H, lower alkyl and aryl.
  • R 9 and R 10 is hydrogen.
  • R 9 or R 10 is aryl, it is preferred that said aryl is substituted or unsubstituted phenyl.
  • R 9 or R 10 is lower alkyl
  • said lower alkyl may be substituted by hydroxy, halo, alkoxy, dialkylamino, substituted or unsubstituted aryl, preferably by substituted or unsubstituted aryl (including heteroaryl), more preferably by substituted and unsubstituted phenyl, thienyl, furyl and pyridyl, and more preferably by substituted phenyl, thienyl, furyl and pyridyl.
  • R 3 is CONR 9 R 10 , R 9 is H and R 10 is selected from C 1-6 saturated alkyl, preferably saturated lower alkyl and preferably methyl, preferably substituted by substituted or unsubstituted aryl (including heteroaryl), more preferably substituted by phenyl, thienyl, furyl and pyridyl.
  • R 3 is selected from CO 2 R 11 , preferably R 11 is selected from C 1-6 alkyl, preferably saturated C 1-6 alkyl, preferably saturated C 1-6 alkyl, and more preferably lower alkyl, optionally substituted by one or more (preferably one) substituent group preferably selected from aryl.
  • R 3 is selected from SO 2 R 11 it is preferred that R 1 is selected from C 1-6 alkyl (including cycloalkyl and alkenyl) and aryl (including heteroaryl). Where R 3 is SO 2 R 11 and R 11 is aryl, the aryl group may be substituted or unsubstituted, preferably substituted, and preferably substituted by lower alkyl or halo groups.
  • R 3 is selected from alkyl
  • R 3 is selected from acyclic alkyl (substituted or unsubstituted).
  • R 3 is selected from substituted or unsubstituted C 1-6 alkyl (preferably acyclic, and including alkenyl and alkynyl), preferably from substituted or unsubstituted C 1-6 saturated alkyl and alkenyl (preferably acyclic), more preferably from substituted or unsubstituted C 1-6 saturated alkyl (preferably acyclic), preferably substituted or unsubstituted lower alkyl, more preferably from substituted or unsubstituted methyl, ethyl and propyl (n-propyl or isopropyl) groups, and more preferably from substituted or unsubstituted methyl.
  • R 3 is selected from substituted alkyl, preferably mono-substituted alkyl where said substituent(s) is/are represented by R 12 .
  • R 12 is selected from hydroxy, alkoxy, dialkylamino, NH 2 , aryloxy, CN, halo, cycloalkyl, aryl (including heteroaryl), non-aromatic heterocyclyl, COR 13 , CONR 14 R 15 , CONR 8 NR 9 R 10 , C( ⁇ NR 13 )NR 14 R 15 , NR 13 COR 14 , NR 13 CO 2 R 11 , trialkylsilyl and phthalimido, wherein R 13 , R 14 and R 15 are selected from hydrogen, alkyl and aryl, or where R 14 and R 15 are in an (NR 14 R 15 )group, R 14 and R 15 may be linked to form a heterocyclic ring.
  • R 12 is selected from aryl (including heteroaryl) and
  • R 14 and R 15 are selected from H, C 1-6 alkyl and aryl, preferably from H, C 1-6 saturated alkyl (including cycloalkyl and arylalkyl (including heteroaryl)) and aryl (including heteroaryl) and more preferably from H, lower alkyl and aryl.
  • R 14 and R 15 is hydrogen.
  • R 12 is CONR 14 R 15 and R 14 and/or R 15 are selected from alkyl substituted by one or more, preferably one, substituent group(s) selected from hydroxy, alkoxy and dialkylamino.
  • R 12 is selected from aryl (including heteroaryl), the aryl group may be unsubstituted or substituted, and is preferably substituted. In a preferred embodiment, R 12 is selected from mono-, di- or tri-substituted aryl (including heteroaryl) groups.
  • R 12 is preferably selected from mono or bicyclic heteroaryl groups, more preferably from pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, preferably 2-pyridyl), indolyl (including 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl), furyl (including 2-furyl and 3-furyl, preferably 2-furyl), thienyl (including 2-thienyl and 3-thienyl, preferably 2-thienyl), isoindolyl, indolinyl, isoxazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, quinolinyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, benzodioxo
  • R 12 is selected from phenyl, thienyl, furyl and pyridyl, more preferably from phenyl, 2-thienyl, 2-furyl and 2-pyridyl In a preferred embodiment, R 12 is phenyl.
  • R 12 is selected from mono-, di- or tri-substituted aryl (including heteroaryl) groups represented by the formula Ar(R 18 ) a (R 19 ) b (R 20 ) c wherein Ar is an aryl (including heteroaryl) group, preferably selected from the preferred aryl groups described above for R 12 ; wherein R 18 , R 19 and R 20 are substituent group(s), the same or different; and wherein a, b and c are 0 or 1 such that a+b+c ⁇ 1.
  • the substituent groups R 18 , R 19 and R 20 may be selected from any of the substituent groups described herein above.
  • R 18 , R 19 and R 20 are selected from NR 5 R 6 (including NH 2 , and NHR 5 ) alkyl (substituted or unsubstituted; preferably C 1-6 acyclic alkyl), alkoxy (including fluoroalkoxy), halogen (including F, Cl, Br and I), NO 2 , CN, hydroxy, NHOH, CHO, CONR 5 R 6 , CO 2 R 5 , N COR 5 (preferably NHCOR 5 ), NR 4 CO 2 R 7 (preferably NHCO 2 R 7 ), NR 4 SO 2 R 7 (preferably NHSO 2 R 7 ), OCO 2 R 7 and aryl (including heteroaryl).
  • NR 5 R 6 including NH 2 , and NHR 5 alkyl (substituted or unsubstituted; preferably C 1-6 acyclic alkyl), alkoxy (including fluoroalkoxy), halogen (including F, Cl, Br and I), NO 2 , CN,
  • R 18 , R 19 and R 20 are selected from NR 5 R 6 (including NH 2 and NHR 5 ), alkyl (substituted or unsubstituted; and preferably C 1-6 acyclic saturated alkyl) and halogen (preferably F or Cl, particularly F).
  • R 18 , R 19 and R 20 are selected from NR 5 (including NH 2 and NHR 5 , preferably NH 2 ) and alkyl (substituted or unsubstituted; preferably C 1-6 acyclic saturated alkyl).
  • R 18 , R 19 and R 20 are selected from substituted alkyl
  • said alkyl is preferably selected from alkoxyalkyl, hydroxyalkyl, aminoalkyl (including NH 2 -alkyl, mono-alkylaminoalkyl and di-alkylaminoalkyl), haloalkyl (particularly fluoroalkyl (including CF 3 )), cyanoalkyl, alkylthioalkyl, alkylcarboxyaminoalkyl, alkoxycarbonylaminoalkyl and alkylsulfonylamino, more preferably from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl (particularly fluoroalkyl (including CF 3 )) and most preferably from alkoxyalkyl and aminoalkyl.
  • R 12 is aryl, preferably phenyl
  • the substituent groups R 18 , R 19 and R 20 are selected from lower alkyl, hydroxy, lower alkoxy, amino (including NH 2 , mono and di-alkylamino), NO 2 , CN, amido, aminocarbonyl (including mono- and di-alkylaminocarbonyl), sulfonamido or halo group(s).
  • R 12 is aryl, preferably phenyl, substituted by NR 16 SO 2 R 17 wherein R 16 is selected from H, alkyl and aryl and preferably H, and R 17 is selected from alkyl and aryl, preferably from C 1-6 saturated alkyl and aryl (including heteroaryl). R 17 may be unsubstituted or substituted, for instance by alkyl or hydroxy.
  • R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 13 , R 14 and R 15 are independently selected from H, substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkenyl, branched and unbranched alkyl, and cyclic and acyclic alkyl) and substituted and unsubstituted aryl (including heteroaryl), or where R 5 and R 6 are in an (NR 5 R 6 ) group then R 5 and R 6 may be linked to form a heterocyclic group, or where R 9 and R 10 are in an (NR 9 R 10 ) group then R 9 and R 10 may be linked to form a heterocyclic group, or where R 8 , R 9 and R 10 are in a (CONR 8 NR 9 R 10 ) group, R 8 and R 9 may be linked to form a heterocyclic group, or where R 14 and R 15 are in an (NR 14 R 15 )group,
  • R 7 , R 11 and R 17 are independently selected from substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkenyl, branched and unbranched alkyl and cyclic and acyclic alkyl) and substituted and unsubstituted aryl (including heteroaryl).
  • R 4 , R 5 , R 6 , R 7 , R 13 and R 16 are independently selected from alkyl (substituted or unsubstituted), said alkyl group is preferably selected from C 1-6 alkyl, and preferably from C 1-6 saturated alkyl and C 1-6 alkenyl. In one embodiment, R 4 to R 7 , R 13 and R 16 are selected from C 1-6 saturated alkyl, preferably lower alkyl
  • R 4 , R 5 , R 6 , R 7 , R 13 and R 16 are independently selected from substituted alkyl (including saturated alkyl, alkenyl and alkynyl), the one or more substituent group(s) are preferably selected from cycloalkyl, substituted and unsubstituted aryl (including heteroaryl), non-aromatic heterocyclyl, hydroxy, alkoxy and dialkylamino.
  • heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated.
  • Said heterocyclic ring preferably is a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatoms preferably selected from N, O and S heteroatoms.
  • the compounds of formula (I) are selected from those compounds wherein R 1 is NH 2 , R 2 is 2-furyl and R 3 is arylalkyl (including heteroarylalkyl), particularly arylmethyl (including heteroarylmethyl).
  • the compounds of the present invention are selected from:
  • the compounds of the formula (I) may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.
  • the present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
  • a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A 2A receptors, may be beneficial comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
  • the disorder may be caused by the hyperfunctioning of the purine receptors.
  • the disorders of particular interest are those in which the blocking of purine receptors, partiucularly adenosine receptors and more particularly adenosine A 2A receptors, may be beneficial. These may include movement disorders such as Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson's disease (punch-drunk syndrome).
  • movement disorders such as Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson's disease (punch-drunk syndrome).
  • Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture.
  • the present invention may also be effective in treating Parkinson's with on-off phenomena; Parkinson's with freezing (end of dose deterioration); and Parkinson's with prominent dyskinesias.
  • the compounds of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA or a dopamine agonist, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • additional drugs useful in the treatment of movement disorders such as L-DOPA or a dopamine agonist
  • disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A 2A receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal degeneration, demyelinating disease (multiple sclerosis, disseminated sclerosis), Freidrich's ataxia, motoneurone disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (dia
  • a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
  • a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
  • the medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.
  • R 1 is selected from NR 5 R 6 (including NH 2 ), alkoxy, thioalkyl and alkyl, preferably wherein R 1 is selected from NR 5 R 6 , and more preferably wherein R 1 is NH 2 , and
  • R 3 is selected from alkyl and CONR 9 R 10 , preferably wherein R 3 is selected from substituted alkyl and CONR 9 R 10 , more preferably wherein R 3 is selected from substituted alkyl and CONR 9 R 10 wherein said substituted alkyl is selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR 9 R 10 .
  • R 1 is selected from NR 5 R 6 (including NH 2 ), alkoxy, thioalkyl and alkyl, preferably wherein R 1 is selected from NR 5 R 6 , and more preferably wherein R 1 is NH 2 , and
  • R 3 is selected from alkyl and CONR 9 R 10 , preferably wherein R 3 is selected from substituted alkyl and CONR 9 R 10 , more preferably wherein R 3 is selected from substituted alkyl and CONR 9 R 10 wherein said substituted alkyl is selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR 9 R 10 .
  • R 3 is alkyl (including arylalkyl, heteroarylalkyl and other substituted alkyl)
  • R 3 is alkyl (including arylalkyl, heteroarylalkyl and other substituted alkyl)
  • R 3 is alkyl (including arylalkyl, heteroarylalkyl and other substituted alkyl)
  • R 3 is alkyl (including arylalkyl, heteroarylalkyl and other substituted alkyl)
  • R 3 is alkyl (including arylalkyl, heteroarylalkyl and other substituted alkyl)
  • R 3 is alkyl substituted with R 12 wherein R 12 is CONR 14 R 15 or CONR 8 NR 9 R 10
  • R 3 is alkyl substituted with R 12 wherein R 12 is CO 2 R 13 by standard methods such as direct reaction with an appropriate amine or hydrazine or by initial hydrolysis of the ester group CO 2 R 13 to a carboxylic acid followed by reaction with an appropriate amine or hydrazine in the presence of a standard coupling reagent such as DCC.
  • R 3 is alkyl substituted with R 12 wherein R 12 is C( ⁇ NR 13 )NR 14 R 15 may be prepared from compounds of formula (1) where R 3 is alkyl substituted with R 12 wherein R 12 is CN by standard methods such as treatment with an appropriate amine in the presence of trimethylaluminium.
  • R 3 is alkyl substituted with R 12 wherein R 12 is NR 13 COR 14 , NR 13 CO 2 R 17 or NR 13 SO 2 R 17 may be prepared from compounds of formula (1) where R 3 is alkyl substituted with R 12 wherein R 12 is NHR 13 by standard methods such as treatment with an appropriate acid chloride (R 14 COCl), chloroformate (ClCO 2 R 17 ) or sulphonyl chloride (R 17 SO 2 Cl) in the presence of a suitable base such as triethyl amine.
  • R 14 COCl an appropriate acid chloride
  • ClCO 2 R 17 chloroformate
  • R 17 SO 2 Cl sulphonyl chloride
  • R 3 is alkyl substituted with R 12 wherein R 12 is NR 13 CONR 14 R 15
  • R 3 is alkyl substituted with R 12 wherein R 12 is NHR 13 by standard methods such as treatment with an appropriate isocyanate (R 14 NCO or R 15 NCO) or carbamoyl chloride (R 14 R 15 NCOCl).
  • R 3 is alkyl substituted with R 12 wherein R 12 is NHR 13
  • R 3 is alkyl substituted with R 12 wherein R 12 is NH 2 by standard methods such as alkylation or reductive alkylation.
  • Compounds of formula (1) where R 3 is alkyl substituted with R 12 wherein R 12 is NH 2 may be prepared from compounds of formula (1) where R 3 is alkyl substituted with R 12 wherein R 12 is phthalimide by standard methods such as treatment with hydrazine.
  • Compounds of formula (1) where R 3 is alkyl substituted with R 12 wherein R 12 is phthalimide may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate substituted alkyl halide in the presence of a suitable base such as sodium hydride.
  • R 3 is an ethyl group substituted in the D-position with an electron withdrawing group such as an ester, amide, ketone or nitrile group
  • an electron withdrawing group such as an ester, amide, ketone or nitrile group
  • compounds of formula (2) may be prepared from compounds of formula (2) by standard methods such as Michael addition with a suitable ⁇ , ⁇ -unsaturated ester, amide, ketone or nitrile. It will be appreciated by those skilled in the art that selection of an ⁇ , ⁇ -unsaturated ester, amide, ketone or nitrile which contained additional substituents would lead in an analogous way to compounds of formula (1) where R 3 is an ethyl group substituted in the ⁇ -position with an ester, amide, ketone or nitrile and additionally substituted elsewhere.
  • R 3 is COR 8 , CO 2 R 11 or SO 2 R 11
  • R 3 is COR 8
  • CO 2 R 11 or SO 2 R 11 may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate acid chloride (R 8 COCl), chloroformate (ClCO 2 R 11 ) or sulphonyl chloride (R 11 SO 2 Cl) in the presence of a suitable base such as triethylamine.
  • Compounds of formula (2) where R 1 is alkoxy, aryloxy, alkylthio, arylthio, CN or NR 5 R 6 may be prepared from compounds of formula (3) by standard methods such as nucleophilic displacement using an appropriate nucleophilic reagent such as an alcohol, thiol, cyanide or amine (HNR 5 R 6 ) in the presence of a suitable base if required.
  • an appropriate nucleophilic reagent such as an alcohol, thiol, cyanide or amine (HNR 5 R 6 ) in the presence of a suitable base if required.
  • Compounds of formula (3) may be prepared from the commercially available chloro compound of formula (4) by standard methods such as aryl or heteroaryl coupling reactions.
  • Suitable aryl or heteroaryl coupling reactions would include reaction with an appropriate aryl or heteroaryl trialkylstannane derivative, an aryl or heteroarylboronic acid or boronic ester derivative, or an aryl or heteroarylzinc halide derivative in the presence of a suitable catalyst such as a palladium complex.
  • R 1 is NR 4 CONR 5 R 6 , wherein R 4 is H
  • R 1 is NH 2
  • R 5 NCO or R 6 NCO isocyanate
  • R 5 R 6 NCOCl carbamoyl chloride
  • R 1 is NR 4 CONR 5 R 6 , wherein R 4 is alkyl or aryl
  • R 4 is alkyl or aryl
  • R 1 is NR 5 R 6 , wherein one of R 5 and R 6 is alkyl or aryl and the other is H, by standard methods as described above.
  • R 1 is NR 4 COR 5 , NR 4 CO 2 R 7 or NR 4 SO 2 R 7 , wherein R 4 is H
  • R 1 is NH 2 by standard methods such as treatment with an appropriate acid chloride (R 5 COCl), chloroformate (ClCO 2 R 7 ) or sulphonyl chloride (R 7 SO 2 Cl) in the presence of a suitable base.
  • R 1 is NR 4 COR 5 , NR 4 CO 2 R 7 or NR 4 SO 2 R 7 , wherein R 4 is alkyl or aryl
  • R 1 is NR 5 R 6 , wherein one of R 5 and R 6 is alkyl or aryl and the other is H, as described above.
  • R 1 is NH 2
  • R 1 is NR 5 R 6
  • one of R 5 and R 6 is a protecting group and the other is H by standard methods such as treatment with TFA or Amberlyst-15.
  • Suitable protecting groups would include 3,4-dimethoxybenzyl and THP.
  • Compounds of formula (1) where R 1 is alkyl may be prepared from compounds of formula (5) by standard methods such as reaction with a suitable reagent such as a trialkylaluminium reagent preferably in the presence of a suitable catalyst such as a palladium catalyst.
  • a suitable reagent such as a trialkylaluminium reagent preferably in the presence of a suitable catalyst such as a palladium catalyst.
  • Compounds of formula (7) are prepared from compounds of formula (8) by standard methods such as those described above.
  • compounds of formula (7) are prepared from compounds of formula (10) by standard methods such as those described above.
  • Compounds of formula (8) and formula (10) are prepared from the commercially available compound of formula (9) by standard methods such as those described above.
  • P is a protecting group
  • Compounds of formula (11) may be transformed into compounds of formula (8) by standard methods such as aryl coupling reactions as described above followed by removal of the protecting groups by standard methods such as treatment with Amberlyst-15.
  • Compounds of formula (11) are either known in the literature or may be prepared by methods analogous to those reported in the literature.
  • any of the groups R 1 to R 11 is an alkyl group or aryl group or where any of the groups R 1 to R 11 contains an alkyl or aryl substituent
  • the alkyl or aryl group may also be substituted. It will be appreciated by those skilled in the art that certain substituents on the alkyl or aryl groups mentioned above may be introduced directly as an integral part of the substituent R 1 to R 11 by using the synthetic methods described above. In other cases it may be advantageous to introduce certain substituents on the alkyl or aryl groups mentioned above by chemical transformation of other substituent groups.
  • alkyl or aryl group mentioned above contains an amino substituent this may be converted to an alkylamino or dialkylamino group by standard methods such as alkylation or reductive alkylation, or to an amide, carbamate, urea or sulphonamide by standard methods such as those described above.
  • alkyl or aryl group mentioned above contains a carboxylic ester substituent this may be converted to an amide or hydrazide derivative by standard methods such as reaction with an amine or hydrazine directly or in the presence of a catalyst such as Me 3 Al if required.
  • substituents such as an amino group or a carboxylic ester group may also be transformed by standard methods to a wide range of additional substituent groups.
  • a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or excipient.
  • compositions employed in the present invention comprise a compound of formula (I), or pharmaceutically acceptable salts or prodrugs thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
  • Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula (I).
  • oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
  • the most suitable route in any given case will depend on the severity of the condition being treated.
  • the most preferred route of administration is the oral route.
  • the compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous).
  • any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
  • the compounds of formula (I) may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.
  • compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the invention is illustrated with reference to the Examples set out in Table 1.
  • the syntheses of the Examples are performed using the general Synthetic Methods set out hereinafter.
  • the Method used for a given Example is noted in parentheses in column 1 of Table 1.
  • Table 2 includes the analytical data for the compounds.
  • the resulting solid was suspended in aqueous sodium bicarbonate, extracted with ether, the aqueous phase was acidified to pH 7 and the resulting solid filtered, suspended in methanol, treated with HCl in dioxane (4-M, 2 mL), diluted with ether and filtered to give the title compound (82 mg, 48%) as a yellow solid.
  • Retention time 5.82min (80:50) 75 C 43 IR ⁇ max (Nujol)/cm ⁇ 1 2924, 2854, 1636, 1599, 1569, 1466, 1357 and 756; NMR ⁇ H (400MHz, DMSO) 3.99(3H, s), 6.81(1H, dd, J 3.5, 1.7Hz), 7.85(1H, d, J 3.5Hz), 8.05(1H, m), 8.38(1H, s) and 13.3(1H, br s); M/Z 217(M+H) + ; Retention time: 0.81min (80:50) 77 G 79 mp >200° C.
  • Example K i (nM) Example 3 23 Example 13 12
  • Example 26 1
  • Example 36 7
  • Example 37 Example 38 1
  • Example 39 1
  • Example 45 2 Example 47 1
  • Example 52 5
  • Example 57 12 Example 68 9
  • Example 79 1 Example 80 5
  • Example 83 13 Example 92 6
  • Example 93 4 Example 106 1
  • Example 112 8 Example 118 3
  • Example 125 6 Example 126 7
  • Example 127 9 Example 141 36
  • Example 162 8 Example 185 7
  • Example 189 21 Example 192 24
  • Example 198 7 Example 201 2
  • Example 202 1
  • Example 208 6 Example 211 3
  • Example 212 35
  • Example 235 4 Example 240 7
  • Example 244 7 Example 259 11 Evaluation of Potential Anti-Parkinsonian Activity In Vivo Haloperidol-Induced Hypolocomotion Model
  • adenosine antagonists such as theophylline
  • dopamine antagonists such as haloperidol
  • rodents rodents
  • mice Female TO mice (25-30 g) obtained from TUCK, UK, are used for all experiments. Animals are housed in groups of 8 [cage size ⁇ 40 (width) ⁇ 40 (length) ⁇ 20 (height)cm] under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20 ⁇ 2° C.) and humidity (55 ⁇ 15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.
  • Liquid injectable haloperidol (1 ml Serenance ampoules from Baker Norton, Harlow, Essex, each containing haloperidol BP 5 mg, batch # P424) are diluted to a final concentration of 0.02 mg/ml using saline.
  • Test compounds are typically prepared as aqueous suspensions in 8% Tween. All compounds are administered intraperitoneally in a volume of 10 ml/kg.
  • mice 1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%.
  • Test substances are typically administered 5-60 minutes prior to testing.
  • the animals are then placed individually into clean, clear polycarbonate cages [20 (width) ⁇ 40 (length) ⁇ 20 (height) cm, with a flat perforated, Perspex lid].
  • Horizontal locomotor activity is determined by placing the cages within a frame containing a 3 ⁇ 6 array of photocells linked to a computer, which tabulates beam breaks. Mice are left undisturbed to explore for 1 hour, and the number of beams breaks made during this period serves as a record of locomotor activity which is compared with data for control animals for statistically significant differences.
  • Parkinson's disease is a progressive neurodegenerative disorder characterised by symptoms of muscle rigidity, tremor, paucity of movement (hypokinesia), and postural instability. It has been established for some time that the primary deficit in PD is a loss of dopaminergic neurones in the substantia nigra which project to the striatum, and indeed a substantial proportion of striatal dopamine is lost (ca 80-85%) before symptoms are observed. The loss of striatal dopamine results in abnormal activity of the basal ganglia, a series of nuclei which regulate smooth and well co-ordinated movement (Blandini F. et al., Glutamate and Parkinson's Disease. Mol. Neurobiol. 1996, 12, 73-94). The neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin 6-hydroxydopamine into brain regions containing either the cell bodies or axonal fibres of the nigrostriatal neurones.
  • mice Male Sprague-Dawley rats, obtained from Charles River, are used for all experiments. Animals are housed in groups of 5 under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20 ⁇ 2° C.) and humidity (55 ⁇ 15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.
  • 6-OHDA Ascorbic acid, desipramine, 6-OHDA and apomorphine (Sigma-Aldrich, Poole, UK).
  • 6-OHDA is freshly prepared as a solution in 0.2% ascorbate at a concentration of 4 mg/mL prior to surgery.
  • Desipramine is dissolved in warm saline, and administered in a volume of 1 ml/kg.
  • Apomorphine is dissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg.
  • Test compounds are suspended in 8% Tween and injected in a volume of 2 ml/kg.
  • mice 15 minutes prior to surgery, animals are given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to non-dopamine neurones.
  • Animals are then placed in an anaesthetic chamber and anaesthetised using a mixture of oxygen and isoflurane. Once unconscious, the animals are transferred to a stereotaxic frame, where anaesthesia is maintained through a mask. The top of the animal's head is shaved and sterilised using an iodine solution. Once dry, a 2 cm long incision is made along the midline of the scalp and the skin retracted and clipped back to expose the skull. A small hole is then drilled through the skill above the injection site.
  • desipramine 25 mg/kg
  • the injection cannula is slowly lowered to position above the right medial forebrain bundle at ⁇ 3.2 mm anterior posterior, ⁇ 1.5 mm medial lateral from bregma, and to a depth of 7.2 mm below the duramater. 2 minutes after lowing the cannula, 2 ⁇ L of 6-OHDA is infused at a rate of 0.5 ⁇ L/min over 4 minutes, yeilding a final dose of 8 ⁇ g. The cannula is then left in place for a further 5 minutes to facilitate diffusion before being slowly withdrawn. The skin is then sutured shut using Ethicon W501 Mersilk, and the animal removed from the strereotaxic frame and returned to its homecage. The rats are allowed 2 weeks to recover from surgery before behavioural testing.
  • Rotational behaviour is measured using an eight station rotameter system provided by Med Associates, San Diego, USA. Each station is comprised of a stainless steel bowl (45 cm diameter ⁇ 15 cm high) enclosed in a transparent Plexiglas cover running around the edge of the bowl, and extending to a height of 29 cm. To assess rotation, rats are placed in cloth jacket attached to a spring tether connected to optical rotameter positioned above the bowl, which assesses movement to the left or right either as partial (45°) or full (360°) rotations. All eight stations are interfaced to a computer that tabulated data.
  • rats are initially habituated to the apparatus for 15 minutes on four consecutive days. On the test day, rats are given an intraperitoneal injection of test compound 30 minutes prior to testing. Immediately prior to testing, animals are given a subcutaneous injection of a subthreshold dose of apomorphine, then placed in the harness and the number of rotations recorded for one hour. The total number of full contralatral rotations during the hour test period serves as an index of antiparkinsonian drug efficacy.

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Abstract

Use of a compound of formula (I) wherein R1 is selected from alkyl, aryl, alkoxy, aryloxy, 0thioalkyl, thioaryl, CN, halo, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7; R2 is selected from N, O or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated carbon atom which is adjacent to one or two N, O or S-heteroatom(s), other than ortho, ortho-disubstituted heteroaryl groups; R3 is selected from H, alkyl, COR8, CONR9R10, CONR8NR9R10, CO2R11 and SO2R11; R4, R5 and R6 are independently selected from H, alkyl and aryl or where R5 and R6 are in an (NR5R6) group then R5 and R6 may be linked to form a heterocyclic ring; R7 is selected from alkyl and aryl; R8, R9 and R10 are independently selected from H, alkyl and aryl, or R9 and R10 may be linked to form a heterocyclic ring, or where R8, R9 and R10 are in a (CONR8NR9R10) group, R8 and R9 may be linked to form a heterocyclic group; and R1 is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, in the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A2A receptors, may be beneficial, particularly wherein said disorder is a movement disorder such as Parkinson's disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject; compounds of formula (I) for use in therapy; and novel compounds of formula (I) per se.

Description

  • The present invention relates to purine derivatives and their use in therapy. In particular, the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to blockade of adenosine receptors and particularly adenosine A2A receptors, and to the treatment of movement disorders such as Parkinson's disease.
  • Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
  • There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson's disease are manifested.
  • Current strategies for the treatment of Parkinson's disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl®), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when “on-off” symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson's disease. In particular, effective treatments requiring less frequent dosing, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, are required.
  • Blockade of A2 adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson's disease (Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65). The potential utility of adenosine A2A receptor antagonists in the treatment of movement disorders such as Parkinson's Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320).
  • Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407-422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5, 547-558).
  • Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A1, A2A, A2B (of high and low affinity) and A3 (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128).
  • The design of P1 receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Williams, M. and Burnstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)
  • It has been speculated that xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD). A number of studies have demonstrated a beneficial effect of caffeine on controlling the symptoms of ADHD (Garfinkel, B. D. et al., Psychiatry, 1981, 26, 395-401). Antagonism of adenosine receptors is thought to account for the majority of the behavioural effects of caffeine in humans and thus blockade of adenosine A2A receptors may account for the observed effects of caffeine in ADHD patients. Therefore a selective A2A receptor antagonist may provide an effective treatment for ADHD but without the unwanted side-effects associated with current therapy.
  • Adenosine receptors have been recognised to play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268). Recent evidence suggests that a substantial part of the actions of adenosine in regulating sleep is mediated through the adenosine A2A receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA, 1996). Thus, a selective A2A receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.
  • It has recently been observed that patients with major depression demonstrate a blunted response to adenosine agonist-induced stimulation in platelets, suggesting that a dysregulation of A2A receptor function may occur during depression (Berk, M. et al, 2001, Eur. Neuropsychopharmacol. 11, 183-186). Experimental evidence in animal models has shown that blockade of A2A receptor function confers antidepressant activity (El Yacoubi, M et al. Br. J. Pharmacol. 2001, 134, 68-77). Thus, A2A receptor antagonists may offer a novel therapy for the treatment of major depression and other affective disorders in patients.
  • The pharmacology of adenosine A2A receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A2 adenosine receptors is the evidence of a functional link between adenosine A2A receptors to dopamine D2 receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7238-41) have been summarised in two more recent articles (Fuxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int. Symp.], 5th (1995), 499-507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci. 1997, 20, 482-487).
  • As a result of these investigations into the functional role of adenosine A2A receptors in the CNS, especially in vivo studies linking A2 receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 162-4; Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328, 135-141) investigations have been made into agents which selectively bind to adenosine A2A receptors as potentially effective treatments for Parkinson's disease.
  • While many of the potential drugs for treatment of Parkinson's disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A2A antagonist therapy is that the underlying neurodegenerative disorder may also be treated. The neuroprotective effect of adenosine A2A antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N.Y. Acad. Sci. 1997, 825 (Neuroprotective Agents), 30-48). In particular, compelling recent evidence suggests that blockade of A2A receptor function confers neuroprotection against MPTP-induced neurotoxicity in mice (Chen, J-F., J. Neurosci. 2001, 21, RC143). In addition, several recent studies have shown that consumption of dietary caffeine, a known adenosine A2A receptor antagonist, is associated with a reduced risk of Parkinson's disease in man (Ascherio, A. et al, Ann Neurol., 2001, 50, 56-63; Ross G W, et al., JAMA, 2000, 283, 2674-9). Thus, A2A receptor antagonists may offer a novel treatment for conferring neuroprotection in neurodegenerative diseases such as Parkinson's disease.
  • Xanthine derivatives have been disclosed as adenosine A2 receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A2 receptors, such as Parkinson's disease (see, for example, EP-A-565377).
  • One prominent xanthine-derived adenosine A2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141-144).
  • Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A1 and A2A receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophyilline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W., J. Pharm. Pharmacol, 1994, 46, 515-517).
  • KF 17837 [(E)-8-(3′,4-dimethoxystyryl-1,3-dipropyl-7-methylxanthine] is a selective adenosine A2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268). The structure activity relationship (SAR) of KF 17837 has been published (Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352). Recent data has also been provided on the A2A receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997, 23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998, 43(4), 507-513).
  • New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A2A Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126-2133).
  • The foregoing discussion indicates that a potentially effective treatment for movement disorders in humans would comprise agents which act as antagonists at adenosine A2A receptors.
  • It has now been found that purine derivatives, which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P1) receptors, and in particular at the adenosine A2A receptor. Such compounds may therefore be useful for the treatment of disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial. In particular such compounds may be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. Disorders of particular interest in the present invention include Parkinson's disease, Alzheimer's disease, spasticity, Huntington's chorea and Wilson's disease.
  • Such compounds may also be particularly suitable for the treatment of depression, cognitive or memory impairment including Alzheimer's disease, acute or chronic pain, ADHD, narcolepsy or for neuroprotection.
  • According to the present invention there is provided the use of a compound of formula (I):
    Figure US20060270691A1-20061130-C00001
    wherein
    R1 is selected from alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7;
    R2 is selected from N, O or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated carbon atom which is adjacent to one or two N, O or S-heteroatom(s), other than ortho,ortho-disubstituted heteroaryl groups;
    R3 is selected from H, alkyl, COR8, CONR9R10, CONR8NR9R10, CO2R11 and SO2R1;
    R4, R5 and R6 are independently selected from H, alkyl and aryl or where R5 and R6 are in an (NR5R6) group then R5 and R6 may be linked to form a heterocyclic group;
    R7 is selected from alkyl and aryl;
    R8, R9 and R10 are independently selected from H, alkyl and aryl, or R9 and R10 may be linked to form a heterocyclic group, or where R8, R9 and R10 are in a (CONR8NR9R10) group, R8 and R9 may be linked to form a heterocyclic group, and
    R11 is selected from alkyl and aryl,
    or a pharmaceutically acceptable salt thereof or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A2A receptors, may be beneficial.
  • As used herein, the term “alkyl” means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10, more preferably C5, C6 or C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl. It will be appreciated therefore that the term “alkyl” as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.
  • As used herein, the term “lower alkyl” means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • As used herein, the term “aryl” means an aromatic group, such as phenyl or naphthyl (preferably phenyl), or a heteroaromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.
  • As used herein, the term “heteroaryl” means an aromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.
  • As used herein, the term “non-aromatic heterocyclyl” means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a cyclic amino group (including aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl) or a cyclic ether (including tetrahydrofuranyl).
  • As used herein, the term “alkoxy” means alkyl-O—. As used herein, the term “aryloxy” means aryl-O—.
  • As used herein, the term “halogen” means a fluorine, chlorine, bromine or iodine radical.
  • As used herein, the term “ortho,ortho-disubstituted heteroaryl groups” refers to heteroaryl groups which are substituted in both ortho positions of the heteroaryl group relative to the point of attachment of the heteroaryl group to the purine ring.
  • As used herein, the term “prodrug” means any pharmaceutically acceptable prodrug of a compound of the present invention.
  • Where any of R1 to R120 is selected from alkyl, alkoxy and thioalkyl, in accordance with formula (I) as defined above, then that alkyl group, or the alkyl group of the alkoxy or thioalkyl group, may be substituted or unsubstituted. Where any of R1 to R20 are selected from aryl, aryloxy and thioaryl, in accordance with formula (I) as defined above, then said aryl group, or the aryl group of the aryloxy or thioaryl group, may be substituted or unsubstituted. Where R5 and R6, or R9 and R10, or R8 and R9, or R14 and R15, are linked to form a heterocyclic group in accordance with formula (I) as defined above, then said heterocyclic ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include: carbon-containing groups such as
      • alkyl,
      • aryl, (e.g. substituted and unsubstituted phenyl, including (alkyl)phenyl, (alkoxy)phenyl and halophenyl),
      • arylalkyl; (e.g. substituted and unsubstituted benzyl, including alkylbenzyl);
        halogen atoms and halogen containing groups such as
      • haloalkyl (e.g. trifluoromethyl),
      • haloaryl (e.g. chlorophenyl);
        oxygen containing groups such as
      • alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl, (aryl)(hydroxy)alkyl),
      • ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, alkoxyaryl, aryloxyaryl),
      • aldehydes (e.g. carboxaldehyde),
      • ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl, arylalkylcarbonyl, arylalkylcarbonylalkyl, arylalkylcarbonylaryl)
      • acids (e.g. carboxy, carboxyalkyl, carboxyaryl),
      • acid derivatives such as esters
        • (e.g. alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides
        • (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, cyclicaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl or arylalkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl or arylalkylcarbonylaminoalkyl), carbamates
        • (eg. alkoxycarbonylamino, aryloxycarbonylamino, arylalkyloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy or arylalkylaminocarbonyloxy) and ureas
        • (eg. mono- or di-alkylaminocarbonylamino, arylaminocarbonylamino or arylalkylaminocarbonylamino);
          nitrogen containing groups such as
      • amines (e.g. amino, mono- or dialkylamino, cyclicamino, arylamino, aminoalkyl, mono- or dialkylaminoalkyl), azides,
      • nitriles (e.g. cyano, cyanoalkyl),
      • nitro;
      • sulfonamides (e.g. aminosulfonyl, mono- or di-alkylaminosulfonyl, mono- or di-arylaminosulfonyl, alkyl- or aryl-sulfonylamino, alkyl- or aryl-sulfonyl(alkyl)amino, alkyl- or aryl-sulfonyl(aryl)amino)
        sulfur containing groups such as
      • thiols, thioethers, sulfoxides, and sulfones
        • (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
          heterocyclic groups containing one or more, preferably one, heteroatom,
      • (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl); and
        silicon-containing groups such as
      • silanes (e.g. trialkylsilyl).
  • Where any of R1 to R20 is selected from aryl or from an aryl-containing group such as aryloxy or arylthio, preferred substituent group(s) are selected from halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO2, amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl, and particularly from unsubstituted alkyl, substituted alkyl (including alkoxyalkyl and aminoalkyl), halogen and amines.
  • In one embodiment, where any of R1 to R20 is directly substituted by an alkyl substituent group, or by an alkyl-containing substituent group (such as alkoxy or alkylcarbonylamino for example), then the alkyl moiety of the substituent group directly attached to any of R1 to R20 may be further substituted by the substituent groups hereinbefore described and particularly by halogen, hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and aryl.
  • In a further embodiment, where any of R1 to R20 is directly substituted by an aryl substitutent group, or by an aryl-containing substituent group (such as aryloxy or arylaminocarbonylamino for example), then the aryl moiety of the substituent group directly attached to any of R1 to R20 may be further substituted by the substituent groups hereinbefore described and particularly by halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO2, amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl. In a further embodiment, said aryl moiety is substituted by halogen, alkyl (including CF3), hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and NO2. In a further embodiment, said aryl moiety is substituted by unsubstituted all, substituted alkyl (particularly alkoxyalkyl and aminoalkyl), halogen and amines.
  • The terms “directly substituted” and “directly attached”, as used herein, mean that the substituent group is bound directly to any of R1 to R20 without any intervening divalent atoms or groups.
  • In the compounds of formula (I), R1 is selected from alkyl (including haloalkyl (such as CF3), branched alkyl, cycloalkyl and arylalkyl), aryl (including heteroaryl), alkoxy, aryloxy, thioalkyl, thioaryl, halo, CN, NR5R6 (including NH2), NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7.
  • In a preferred embodiment, R1 is selected from NR5R6 (including NH2), alkoxy, thioalkyl and alkyl.
  • In a particularly preferred embodiment, R1 is selected from NR5R6 (including NH2), and is preferably NH2.
  • Where R1 is selected from alkyl, preferably R1 is selected from C1-6 alkyl, more preferably from saturated C1-6 alkyl and more preferably from lower alkyl.
  • Where R1 is selected from alkoxy and thioalkyl, preferably the alkyl moiety of said thioalkyl or alkoxy group is selected from C1-6 alkyl, more preferably from saturated C1-6 alkyl and more preferably from lower alkyl.
  • Where R1 is selected from halo, preferably R1 is selected from chloro.
  • Where R1 is selected from NR5R6, preferably at least one and more preferably both of R5 and R6 are hydrogen.
  • In one embodiment, R1 is selected from NR4COR5, NR4CONR5, NR4CO2R7 and R4SO2R7, and R4 is selected from H and alkyl, and more preferably hydrogen.
  • In a preferred embodiment, R2 is selected from furyl (including 2-furyl), thienyl (including 2-thienyl), pyridyl (including 2-pyridyl), thiazolyl (including 2- and 5-thiazolyl), pyrazolyl (including 3-pyrazolyl), triazolyl (including 4-triazolyl), pyrrolyl (including 2-pyrrolyl) and oxazolyl (including 5-oxazolyl). In a further embodiment, R2 is selected from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyrazolyl, 2-pyrrolyl, 4-triazolyl and 5-oxazolyl. In a further preferred embodiment, R2 is selected from furyl, thienyl, pyridyl, thiazolyl and pyrazolyl, and particularly from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl and 3-pyrazolyl. In a further embodiment, R2 is selected from furyl, thienyl and pyridyl, preferably 2-furyl, 2-thienyl and 2-pyridyl, and more preferably from 2-furyl.
  • In the compounds of formula (I), where R2 is substituted heteroaryl, it is preferred that the substituent group(s) are not present in the ortho position relative to the point of attachment of the heteroaryl group to the purine moiety. As used herein, reference to ortho-substitution of the R2 group means the ortho positions of the R2 group relative to the point of attachment of R2 to the pyrimidine moiety of formula (I).
  • In a preferred embodiment, R2 is an unsubstituted heteroaryl group.
  • In the compounds of formula (I), R3 is selected from H, substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkynyl, branched and unbranched alkyl, and cyclic and acyclic alkyl), COR8, CONR9R10, CONR8NR9R10, CO2R1 and SO2R11.
  • In a preferred embodiment, R3 is selected from H, alkyl and CONR9R11.
  • In a particularly preferred embodiment, R3 is selected from H, substituted alkyl and CONR9R10. In an alternative embodiment, R3 is selected from alkyl (substituted or unsubstituted) and CONR9R10, preferably substituted alkyl and CONR9R10. Wherein R3 is substituted alkyl, said substituted alkyl is preferably selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR9R10, and more preferably from arylalkyl (including heteroarylalkyl), and more preferably from arylmethyl (including heteroarylmethyl).
  • Where R3 is selected from COR8, R8 is preferably selected from alkyl (including cycloalkyl) and aryl (including heteroaryl), preferably from saturated C1-6 alkyl (including cycloalkyl) and aryl.
  • Where R3 is selected from CONR9R10, it is preferred that R9 and R10 are selected from H, C1-6 alkyl and aryl, and preferably from H, C1-6 saturated alkyl (including cycloalkyl) and aryl, and more preferably from H, lower alkyl and aryl. Preferably one of R9 and R10 is hydrogen. Where R9 or R10 is aryl, it is preferred that said aryl is substituted or unsubstituted phenyl. Where R9 or R10 is lower alkyl, said lower alkyl may be substituted by hydroxy, halo, alkoxy, dialkylamino, substituted or unsubstituted aryl, preferably by substituted or unsubstituted aryl (including heteroaryl), more preferably by substituted and unsubstituted phenyl, thienyl, furyl and pyridyl, and more preferably by substituted phenyl, thienyl, furyl and pyridyl.
  • In a preferred embodiment, R3 is CONR9R10, R9 is H and R10 is selected from C1-6 saturated alkyl, preferably saturated lower alkyl and preferably methyl, preferably substituted by substituted or unsubstituted aryl (including heteroaryl), more preferably substituted by phenyl, thienyl, furyl and pyridyl.
  • Where R3 is selected from CO2R11, preferably R11 is selected from C1-6 alkyl, preferably saturated C1-6 alkyl, preferably saturated C1-6 alkyl, and more preferably lower alkyl, optionally substituted by one or more (preferably one) substituent group preferably selected from aryl.
  • Where R3 is selected from SO2R11 it is preferred that R1 is selected from C1-6 alkyl (including cycloalkyl and alkenyl) and aryl (including heteroaryl). Where R3 is SO2R11 and R11 is aryl, the aryl group may be substituted or unsubstituted, preferably substituted, and preferably substituted by lower alkyl or halo groups.
  • Where R3 is selected from alkyl, in one embodiment R3 is selected from acyclic alkyl (substituted or unsubstituted). In a further embodiment, R3 is selected from substituted or unsubstituted C1-6 alkyl (preferably acyclic, and including alkenyl and alkynyl), preferably from substituted or unsubstituted C1-6 saturated alkyl and alkenyl (preferably acyclic), more preferably from substituted or unsubstituted C1-6 saturated alkyl (preferably acyclic), preferably substituted or unsubstituted lower alkyl, more preferably from substituted or unsubstituted methyl, ethyl and propyl (n-propyl or isopropyl) groups, and more preferably from substituted or unsubstituted methyl.
  • In a preferred embodiment, R3 is selected from substituted alkyl, preferably mono-substituted alkyl where said substituent(s) is/are represented by R12. Preferably, R12 is selected from hydroxy, alkoxy, dialkylamino, NH2, aryloxy, CN, halo, cycloalkyl, aryl (including heteroaryl), non-aromatic heterocyclyl, COR13, CONR14R15, CONR8NR9R10, C(═NR13)NR14R15, NR13COR14, NR13CO2R11, trialkylsilyl and phthalimido, wherein R13, R14 and R15 are selected from hydrogen, alkyl and aryl, or where R14 and R15 are in an (NR14R15)group, R14 and R15 may be linked to form a heterocyclic ring. Preferably, R12 is selected from aryl (including heteroaryl) and CONR14R15, and preferably from aryl (including heteroaryl).
  • Where R12 is CONR14R15, it is preferred that R14 and R15 are selected from H, C1-6 alkyl and aryl, preferably from H, C1-6 saturated alkyl (including cycloalkyl and arylalkyl (including heteroaryl)) and aryl (including heteroaryl) and more preferably from H, lower alkyl and aryl. Preferably one of R14 and R15 is hydrogen.
  • In one embodiment, R12 is CONR14R15 and R14 and/or R15 are selected from alkyl substituted by one or more, preferably one, substituent group(s) selected from hydroxy, alkoxy and dialkylamino.
  • Where R12 is selected from aryl (including heteroaryl), the aryl group may be unsubstituted or substituted, and is preferably substituted. In a preferred embodiment, R12 is selected from mono-, di- or tri-substituted aryl (including heteroaryl) groups. Where R12 is heteroaryl, R12 is preferably selected from mono or bicyclic heteroaryl groups, more preferably from pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, preferably 2-pyridyl), indolyl (including 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl), furyl (including 2-furyl and 3-furyl, preferably 2-furyl), thienyl (including 2-thienyl and 3-thienyl, preferably 2-thienyl), isoindolyl, indolinyl, isoxazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, quinolinyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, benzodioxolyl and dihydrobenzofuranyl, more preferably from pyridyl (preferably 2-pyridyl), indolyl, furyl (preferably 2-furyl) and thienyl (preferably 2-thienyl), and most preferably from pyridyl (preferably 2-pyridyl), furyl (preferably 2-furyl) and thienyl (preferably 2-thienyl). Preferably, R12 is selected from phenyl, thienyl, furyl and pyridyl, more preferably from phenyl, 2-thienyl, 2-furyl and 2-pyridyl In a preferred embodiment, R12 is phenyl.
  • In one embodiment, R12 is selected from mono-, di- or tri-substituted aryl (including heteroaryl) groups represented by the formula Ar(R18)a(R19)b(R20)c wherein Ar is an aryl (including heteroaryl) group, preferably selected from the preferred aryl groups described above for R12; wherein R18, R19 and R20 are substituent group(s), the same or different; and wherein a, b and c are 0 or 1 such that a+b+c≧1.
  • The substituent groups R18, R19 and R20 may be selected from any of the substituent groups described herein above.
  • In a preferred embodiment, R18, R19 and R20 are selected from NR5R6 (including NH2, and NHR5) alkyl (substituted or unsubstituted; preferably C1-6 acyclic alkyl), alkoxy (including fluoroalkoxy), halogen (including F, Cl, Br and I), NO2, CN, hydroxy, NHOH, CHO, CONR5R6, CO2R5, N COR5 (preferably NHCOR5), NR4CO2R7 (preferably NHCO2R7), NR4SO2R7 (preferably NHSO2R7), OCO2R7 and aryl (including heteroaryl).
  • In a more preferred embodiment, R18, R19 and R20 are selected from NR5R6 (including NH2 and NHR5), alkyl (substituted or unsubstituted; and preferably C1-6 acyclic saturated alkyl) and halogen (preferably F or Cl, particularly F).
  • In a particularly preferred embodiment, R18, R19 and R20 are selected from NR5 (including NH2 and NHR5, preferably NH2) and alkyl (substituted or unsubstituted; preferably C1-6 acyclic saturated alkyl).
  • Where R18, R19 and R20 are selected from substituted alkyl, said alkyl is preferably selected from alkoxyalkyl, hydroxyalkyl, aminoalkyl (including NH2-alkyl, mono-alkylaminoalkyl and di-alkylaminoalkyl), haloalkyl (particularly fluoroalkyl (including CF3)), cyanoalkyl, alkylthioalkyl, alkylcarboxyaminoalkyl, alkoxycarbonylaminoalkyl and alkylsulfonylamino, more preferably from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl (particularly fluoroalkyl (including CF3)) and most preferably from alkoxyalkyl and aminoalkyl.
  • In one embodiment, particularly where R12 is aryl, preferably phenyl, the substituent groups R18, R19 and R20 are selected from lower alkyl, hydroxy, lower alkoxy, amino (including NH2, mono and di-alkylamino), NO2, CN, amido, aminocarbonyl (including mono- and di-alkylaminocarbonyl), sulfonamido or halo group(s). In a further embodiment R12 is aryl, preferably phenyl, substituted by NR16SO2R17 wherein R16 is selected from H, alkyl and aryl and preferably H, and R17 is selected from alkyl and aryl, preferably from C1-6 saturated alkyl and aryl (including heteroaryl). R17 may be unsubstituted or substituted, for instance by alkyl or hydroxy.
  • In the compounds of formula (I) R4, R5, R6, R8, R9, R10, R13, R14 and R15 are independently selected from H, substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkenyl, branched and unbranched alkyl, and cyclic and acyclic alkyl) and substituted and unsubstituted aryl (including heteroaryl), or where R5 and R6 are in an (NR5R6) group then R5 and R6 may be linked to form a heterocyclic group, or where R9 and R10 are in an (NR9R10) group then R9 and R10 may be linked to form a heterocyclic group, or where R8, R9 and R10 are in a (CONR8NR9R10) group, R8 and R9 may be linked to form a heterocyclic group, or where R14 and R15 are in an (NR14R15)group, R14 and R15 may be linked to form a heterocyclic group. Preferably, R14, R13 and R16 are independently selected from H and alkyl.
  • In the compounds of formula (I), R7, R11 and R17 are independently selected from substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkenyl, branched and unbranched alkyl and cyclic and acyclic alkyl) and substituted and unsubstituted aryl (including heteroaryl).
  • Where R4, R5, R6, R7, R13 and R16 are independently selected from alkyl (substituted or unsubstituted), said alkyl group is preferably selected from C1-6 alkyl, and preferably from C1-6 saturated alkyl and C1-6 alkenyl. In one embodiment, R4 to R7, R13 and R16 are selected from C1-6 saturated alkyl, preferably lower alkyl
  • Where R4, R5, R6, R7, R13 and R16 are independently selected from substituted alkyl (including saturated alkyl, alkenyl and alkynyl), the one or more substituent group(s) are preferably selected from cycloalkyl, substituted and unsubstituted aryl (including heteroaryl), non-aromatic heterocyclyl, hydroxy, alkoxy and dialkylamino.
  • Where R5 and R6, or R9 and R10, or R8 and R9, or R14 and R15, in accordance with the definitions herein, are linked to form a heterocyclic ring, said heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated. Said heterocyclic ring preferably is a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatoms preferably selected from N, O and S heteroatoms.
  • In a particularly preferred embodiment of the invention, the compounds of formula (I) are selected from those compounds wherein R1 is NH2, R2 is 2-furyl and R3 is arylalkyl (including heteroarylalkyl), particularly arylmethyl (including heteroarylmethyl).
  • In a particularly preferred embodiment of the invention, the compounds of the present invention are selected from:
    • N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine;
    • 6-(2-furyl)-1H-purine-2-amine;
    • 6-(2-Furyl)-2-methylthio-1H-purine;
    • 2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-carboxamide;
    • 2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide;
    • 2-Amino-6-(2-furyl)-N-(4-methoxybenzyl)-9H-purine-9-carboxamide;
    • 2-Amino-6-(2-furyl)-N-(4-methylbenzyl)-9H-purine-9-carboxamide;
    • 2-Amino-N-(2-chlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
    • (1S)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-purine-9-carboxamide;
    • 2-Amino-6-(2-furyl)-N-(3-methylbenzyl)-9H-purine-9-carboxamide;
    • 2-Amino-6-(2-furyl)-N-n-pentyl-9H-purine-9-carboxamide;
    • 6-(2-Furyl)-9-(1-phenyl-1-propene-3-yl)-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(3-phenylpropyl)-9H-purine-2-amine;
    • 2-Amino-N-(4-fluorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
    • 2-Amino-N-(3,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
    • 6-(2-Furyl)-9-(4-isopropylbenzyl)-9H-purine-2-amine;
    • 2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-carboxamide;
    • 2-Amino-N-(2,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
    • Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate;
    • N-Benzyl-2-methoxy-6-(2-furyl)-9H-purine-9-carboxamide;
    • 2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-carboxamide;
    • 9-(3-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(3-methylbenzyl)-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-amine;
    • 2-Amino-N-(3-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide;
    • 9-(2-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(4-trifluoromethylbenzyl)-9H-purine-2-amine;
    • 9-(4-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(2-phenylethenyl)sulphonyl-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(3-(3-pyridyl)propyl)-9H-purine-2-amine;
    • 9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine;
    • 2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-carboxamide;
    • 2-Amino-6-(2-furyl)-N-(2-thienylmethyl)-9H-purine-9-carboxamide;
    • 9-(4-Methylbenzyl)-6-(5-methyl-2-furyl)-9H-purine-2-amine;
    • 9-(2,6-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(6-methyl-2-pyridyl)methyl-9H-purine-2-amine;
    • 6-(2-Furyl)-9-(2-(1-methyl-1H-imidazol-4-ylsulphonylamino)benzyl)-9H-purine-2-amine;
    • 9-(5-Chloro-2-thienylmethyl)-6-(2-furyl)-9H-purine-2-amine;
    • 9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-purine-2-amine; and
    • 9-(2-Fluoro-5-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine.
  • Where chiral the compounds of the formula (I) may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.
  • The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
  • According to a further aspect of the present invention there is provided a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial, the method comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
  • The disorder may be caused by the hyperfunctioning of the purine receptors.
  • The disorders of particular interest are those in which the blocking of purine receptors, partiucularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial. These may include movement disorders such as Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson's disease (punch-drunk syndrome).
  • Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture. The present invention may also be effective in treating Parkinson's with on-off phenomena; Parkinson's with freezing (end of dose deterioration); and Parkinson's with prominent dyskinesias.
  • The compounds of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA or a dopamine agonist, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • Other disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal degeneration, demyelinating disease (multiple sclerosis, disseminated sclerosis), Freidrich's ataxia, motoneurone disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (diabetic neuropathy, tabes dorsalis, drug-induced neuropathy, vitamin deficiency), systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy, spasticity; schizophrenia and related pyshoses; cognitive disorders including dementia, Alzheimers Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body dementia, senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome, dementia pugilans; attention disorders such as attention-deficit hyperactivity disorder (ADHD), attention deficit disorder, minimal brain dysfunction, brain-injured child syndrome, hyperkinetic reaction childhood, and hyperactive child syndrome; central nervous system injury including traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injury, raised intracranial pressure, cerebral oedema, hydrocephalus, spinal cord injury; cerebral ischaemia including transient ischaemic attack, stroke (thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke, lacunar stroke) subarachnoid haemorrhage, cerebral vasospasm, neuroprotection for stroke, peri-natal asphyxia, drowning, cardiac arrest, subdural haematoma; myocardial ischaemia; muscle ischaemia; sleep disorders such as hypersomnia and narcolepsy; eye disorders such as retinal ischaemia-reperfusion injury and diabetic neuropathy; cardiovascular disorders such as claudication and hypotension; and diabetes and its complications.
  • According to a further aspect of the present invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of movement disorders in a subject.
  • According to a further aspect of the invention there is provided a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
  • According to a further aspect of the invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.
  • According to a further aspect of the invention there is provided a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
  • The medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.
  • According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
      • (i) compounds wherein R1 is halogen or aryl and R3 is benzyl, and preferably other than compounds wherein R1 is halogen or aryl; and
      • (ii) compounds wherein R3 is H, R1 is NH2 and R2 is thienyl, preferably other than compounds wherein R3 is H and R1 is NH2, and preferably other than compounds wherein R3 is H.
  • According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
      • (i) compounds wherein R1 is halogen or aryl and R3 is benzyl, and preferably other than compounds wherein R1 is halogen or aryl; and
      • (ii) compounds wherein R3 is H, R1 is NH2 and R2 is thienyl, preferably other than compounds wherein R3 is H and R2 is thienyl, and preferably other than compounds wherein R2 is thienyl.
  • In an alternative embodiment, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R1 is selected from NR5R6 (including NH2), alkoxy, thioalkyl and alkyl, preferably wherein R1 is selected from NR5R6, and more preferably wherein R1 is NH2, and
  • R3 is selected from alkyl and CONR9R10, preferably wherein R3 is selected from substituted alkyl and CONR9R10, more preferably wherein R3 is selected from substituted alkyl and CONR9R10 wherein said substituted alkyl is selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR9R10.
  • According to a further aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, per se, other than:
      • (i) compounds wherein R1 is halogen or aryl and R3 is benzyl, and preferably other than compounds wherein R1 is halogen or aryl; and
      • (ii) compounds wherein R3 is H, R1 is NH2 and R2 is thienyl, preferably other than compounds wherein R3 is H and R1 is NH2, and preferably other than compounds wherein R3 is H.
  • According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, per se, other than:
      • (i) compounds wherein R1 is halogen or aryl and R3 is benzyl, and preferably other than compounds wherein R1 is halogen or aryl; and
      • (ii) compounds wherein R3 is H, R1 is NH2 and R2 is thienyl, preferably other than compounds wherein R3 is H and R2 is thienyl, and preferably other than compounds wherein R2 is thienyl.
  • In an alternative embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, per se, wherein:
  • R1 is selected from NR5R6 (including NH2), alkoxy, thioalkyl and alkyl, preferably wherein R1 is selected from NR5R6, and more preferably wherein R1 is NH2, and
  • R3 is selected from alkyl and CONR9R10, preferably wherein R3 is selected from substituted alkyl and CONR9R10, more preferably wherein R3 is selected from substituted alkyl and CONR9R10 wherein said substituted alkyl is selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR9R10.
  • According to a further aspect of the invention, there is provided a method of preparing the novel compounds of the present invention. Compounds of formula (I) may be prepared according to conventional synthetic methods, such as set out in Reaction Scheme 1.
    Figure US20060270691A1-20061130-C00002
  • Compounds of formula (1) where R3 is alkyl (including arylalkyl, heteroarylalkyl and other substituted alkyl) may be prepared from a compound of formula (2) by standard methods such as reaction with an appropriate alkyl halide, or substituted alkyl halide in the presence of a suitable base such as sodium hydride.
  • Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is CONR14R15 or CONR8NR9R10 may be prepared from compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is CO2R13 by standard methods such as direct reaction with an appropriate amine or hydrazine or by initial hydrolysis of the ester group CO2R13 to a carboxylic acid followed by reaction with an appropriate amine or hydrazine in the presence of a standard coupling reagent such as DCC.
  • Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is C(═NR13)NR14R15 may be prepared from compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is CN by standard methods such as treatment with an appropriate amine in the presence of trimethylaluminium.
  • Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is CO2R13 or CN may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate substituted alkyl halide in the presence of a suitable base such as sodium hydride.
  • Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is NR13COR14, NR13CO2R17 or NR13SO2R17 may be prepared from compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is NHR13 by standard methods such as treatment with an appropriate acid chloride (R14COCl), chloroformate (ClCO2R17) or sulphonyl chloride (R17SO2Cl) in the presence of a suitable base such as triethyl amine.
  • Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is NR13CONR14R15 may be prepared from compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is NHR13 by standard methods such as treatment with an appropriate isocyanate (R14NCO or R15NCO) or carbamoyl chloride (R14R15NCOCl).
  • Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is NHR13 may be prepared from compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is NH2 by standard methods such as alkylation or reductive alkylation.
  • Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is NH2 may be prepared from compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is phthalimide by standard methods such as treatment with hydrazine. Compounds of formula (1) where R3 is alkyl substituted with R12 wherein R12 is phthalimide may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate substituted alkyl halide in the presence of a suitable base such as sodium hydride.
  • Compounds of formula (1) where R3 is an ethyl group substituted in the D-position with an electron withdrawing group such as an ester, amide, ketone or nitrile group may be prepared from compounds of formula (2) by standard methods such as Michael addition with a suitable α,β-unsaturated ester, amide, ketone or nitrile. It will be appreciated by those skilled in the art that selection of an α,β-unsaturated ester, amide, ketone or nitrile which contained additional substituents would lead in an analogous way to compounds of formula (1) where R3 is an ethyl group substituted in the β-position with an ester, amide, ketone or nitrile and additionally substituted elsewhere.
  • Compounds of formula (1) where R3 is CONR9R10 or CONR8NR9R10 may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate isocyanate (R9NCO or R10NCO) or carbamoyl chloride (R9R10NCOCl, or R8R9NR10NCOCl).
  • Compounds of formula (1) where R3 is COR8, CO2R11 or SO2R11 may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate acid chloride (R8COCl), chloroformate (ClCO2R11) or sulphonyl chloride (R11SO2Cl) in the presence of a suitable base such as triethylamine.
  • Compounds of formula (2) where R1 is alkoxy, aryloxy, alkylthio, arylthio, CN or NR5R6 may be prepared from compounds of formula (3) by standard methods such as nucleophilic displacement using an appropriate nucleophilic reagent such as an alcohol, thiol, cyanide or amine (HNR5R6) in the presence of a suitable base if required.
  • Compounds of formula (3) may be prepared from the commercially available chloro compound of formula (4) by standard methods such as aryl or heteroaryl coupling reactions. Suitable aryl or heteroaryl coupling reactions would include reaction with an appropriate aryl or heteroaryl trialkylstannane derivative, an aryl or heteroarylboronic acid or boronic ester derivative, or an aryl or heteroarylzinc halide derivative in the presence of a suitable catalyst such as a palladium complex.
  • Compounds of formula (1) where R1 is NR4CONR5R6, wherein R4 is H, may be prepared from compounds of formula (1) where R1 is NH2, by standard methods such as treatment with an appropriate isocyanate (R5NCO or R6NCO) or carbamoyl chloride (R5R6NCOCl).
  • Compounds of formula (1) where R1 is NR4CONR5R6, wherein R4 is alkyl or aryl, may be prepared from compounds of formula (1) where R1 is NR5R6, wherein one of R5 and R6 is alkyl or aryl and the other is H, by standard methods as described above.
  • Compounds of formula (1) where R1 is NR4COR5, NR4CO2R7 or NR4SO2R7, wherein R4 is H, may be prepared from compounds of formula (1) where R1 is NH2 by standard methods such as treatment with an appropriate acid chloride (R5COCl), chloroformate (ClCO2R7) or sulphonyl chloride (R7SO2Cl) in the presence of a suitable base. Compounds of formula (1) where R1 is NR4COR5, NR4CO2R7 or NR4SO2R7, wherein R4 is alkyl or aryl, may be prepared from compounds of formula (1) where R1 is NR5R6, wherein one of R5 and R6 is alkyl or aryl and the other is H, as described above.
  • Compounds of formula (1) where R1 is NH2 may be prepared from compounds of formula (1) where R1 is NR5R6, wherein one of R5 and R6 is a protecting group and the other is H by standard methods such as treatment with TFA or Amberlyst-15. Suitable protecting groups would include 3,4-dimethoxybenzyl and THP.
  • Alternatively it may be advantageous to prepare compounds of formula (1) from compounds of formula (5) by standard methods such as nucleophilic displacement reactions as described above. Compounds of formula (5) are prepared either from compounds of formula (3) or from compounds of formula (6) by standard methods as described above. Compounds of formula (6) are prepared from compounds of formula (4) by standard methods as described above.
  • Compounds of formula (1) where R1 is alkyl may be prepared from compounds of formula (5) by standard methods such as reaction with a suitable reagent such as a trialkylaluminium reagent preferably in the presence of a suitable catalyst such as a palladium catalyst.
  • Compounds of formula (1) where R1 is aryl may be prepared from compounds of formula (5) by standard methods such as aryl coupling reaction as described above.
  • Alternatively compounds of formula (1) where R1 is NH2 may be prepared by standard methods such as those illustrated in Reaction Scheme 2.
    Figure US20060270691A1-20061130-C00003
  • Compounds of formula (7) are prepared from compounds of formula (8) by standard methods such as those described above. Alternatively compounds of formula (7) are prepared from compounds of formula (10) by standard methods such as those described above. Compounds of formula (8) and formula (10) are prepared from the commercially available compound of formula (9) by standard methods such as those described above. In certain cases it may be advantageous to prepare compounds of formula (8) from compounds of formula (11) where P is a protecting group, for example THP. Compounds of formula (11) may be transformed into compounds of formula (8) by standard methods such as aryl coupling reactions as described above followed by removal of the protecting groups by standard methods such as treatment with Amberlyst-15. Compounds of formula (11) are either known in the literature or may be prepared by methods analogous to those reported in the literature.
  • Alternatively compounds of formula (I) where R1 is alkyl or aryl are prepared by standard methods such as those illustrated in Reaction Scheme 3.
    Figure US20060270691A1-20061130-C00004
  • Compounds of formula (1) where R1 is alkyl or aryl are prepared from compounds of formula (2) where R1 is alkyl or aryl by standard methods such as those described above. Alternatively compounds of formula (1) where R1 is alkyl or aryl are prepared from compounds of formula (12) where R1 is alkyl or aryl by standard methods such as those described above. Compounds of formula (2) where R1 is alkyl or aryl and compounds of formula (12) where R1 is alkyl or aryl are prepared from compounds of formula. (13) by standard methods such as those described above. Compounds of formula (13) where R1 is alkyl or aryl are either known in the literature or may be prepared by methods analogous to those reported in the literature.
  • In the compounds of the present invention, where any of the groups R1 to R11 is an alkyl group or aryl group or where any of the groups R1 to R11 contains an alkyl or aryl substituent, the alkyl or aryl group may also be substituted. It will be appreciated by those skilled in the art that certain substituents on the alkyl or aryl groups mentioned above may be introduced directly as an integral part of the substituent R1 to R11 by using the synthetic methods described above. In other cases it may be advantageous to introduce certain substituents on the alkyl or aryl groups mentioned above by chemical transformation of other substituent groups. For example where the alkyl or aryl group mentioned above contains an amino substituent this may be converted to an alkylamino or dialkylamino group by standard methods such as alkylation or reductive alkylation, or to an amide, carbamate, urea or sulphonamide by standard methods such as those described above. Additionally, for example, where the alkyl or aryl group mentioned above contains a carboxylic ester substituent this may be converted to an amide or hydrazide derivative by standard methods such as reaction with an amine or hydrazine directly or in the presence of a catalyst such as Me3Al if required. It will be appreciated by those skilled in the art that substituents such as an amino group or a carboxylic ester group may also be transformed by standard methods to a wide range of additional substituent groups.
  • According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or excipient.
  • The pharmaceutical compositions employed in the present invention comprise a compound of formula (I), or pharmaceutically acceptable salts or prodrugs thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art. The term, “pharmaceutically acceptable salts”, refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
  • Where the compounds of formula (I) are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula (I). For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
  • Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
  • In addition to the common dosage forms set out above, the compounds of formula (I) may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.
  • Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practised without departing from the purpose and interest of this invention.
    • EXAMPLES Synthetic Examples
  • The invention is illustrated with reference to the Examples set out in Table 1. The syntheses of the Examples are performed using the general Synthetic Methods set out hereinafter. The Method used for a given Example is noted in parentheses in column 1 of Table 1. Table 2 includes the analytical data for the compounds.
    TABLE 1
    Ex-
    ample Structure Compound Name
    1 (A)
    Figure US20060270691A1-20061130-C00005
         		2-Chloro-6-(2-furyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine
    2 (B)
    Figure US20060270691A1-20061130-C00006
         		N,N-Dimethyl-6-(2-furyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine
    3 (C)
    Figure US20060270691A1-20061130-C00007
         		N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine
    4 (B)
    Figure US20060270691A1-20061130-C00008
         		6-(2-Furyl)-N-(2-hydroxyethyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine
    5 (C)
    Figure US20060270691A1-20061130-C00009
         		N-(2-Hydroxyethyl)-6-(2-furyl)-1H-purine-2-amine
    6 (S)
    Figure US20060270691A1-20061130-C00010
         		2-Chloro-9-cyclopentyl-6-(2-furyl)-9H-purine
    7 (A)
    Figure US20060270691A1-20061130-C00011
         		tert-Butyl 2-chloro-6-(2-furyl)-9H-purine-9-carboxylate
    8 (A)
    Figure US20060270691A1-20061130-C00012
         		2-Chloro-6-(2-furyl)-1H-purine
    9 (B)
    Figure US20060270691A1-20061130-C00013
         		(2R)-1-(6-(2-Furyl)-1H-purine-2-yl)-2-pyrrolidinemethanol
    10 (B)
    Figure US20060270691A1-20061130-C00014
         		N-(3,4-Dimethoxybenzyl)-6-(2-furyl)-1H-purine-2-amine
    11 (D)
    Figure US20060270691A1-20061130-C00015
         		6-(2-Furyl)-1H-purine-2-amine
    12 (E)
    Figure US20060270691A1-20061130-C00016
         		tert-Butyl 6-(2-furyl)-2-methylthio-9H-purine-9-carboxylate
    13 (F)
    Figure US20060270691A1-20061130-C00017
         		6-(2-Furyl)-2-methylthio-1H-purine
    14 (A)
    Figure US20060270691A1-20061130-C00018
         		tert-Butyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate
    15 (B)
    Figure US20060270691A1-20061130-C00019
         		N-Allyl-6-(2-furyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine
    16 (B)
    Figure US20060270691A1-20061130-C00020
         		6-(2-Furyl)-N-methyl-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine
    17 (C)
    Figure US20060270691A1-20061130-C00021
         		N-Allyl-6-(2-furyl)-1H-purine-2-amine
    18 (C)
    Figure US20060270691A1-20061130-C00022
         		6-(2-Furyl)-N-methyl-1H-purine-2-amine
    19 (A)
    Figure US20060270691A1-20061130-C00023
         		2-Amino-N-cylcohexyl-6-(2-furyl)-9H-purine-9-carboxamide
    20 (A)
    Figure US20060270691A1-20061130-C00024
         		2-Methylpropyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate
    21 (A)
    Figure US20060270691A1-20061130-C00025
         		2-Amino-N-tert-butyl-6-(2-furyl)-9H-purine-9-carboxamide
    22 (A)
    Figure US20060270691A1-20061130-C00026
         		Phenyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate
    23 (A)
    Figure US20060270691A1-20061130-C00027
         		N-(6-(2-Furyl)-1H-purine-2-yl)-N′-phenylurea
    24 (A)
    Figure US20060270691A1-20061130-C00028
         		2-Amino-N-ethyl-6-(2-furyl)-9H-purine-9-carboxamide
    25 (A)
    Figure US20060270691A1-20061130-C00029
         		2-Amino-6-(2-furyl)-N-phenyl-9H-purine-9-carboxamide
    26 (G)
    Figure US20060270691A1-20061130-C00030
         		2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-carboxamide
    27 (H)
    Figure US20060270691A1-20061130-C00031
         		9-(4-tert-Butylphenylsulphonyl)-6-(2-furyl)-9H-pur- ine-2-amine
    28 (H)
    Figure US20060270691A1-20061130-C00032
         		9-Cyclohexylcarbonyl-6-(2-furyl)-9H-purine-2-amine
    29 (I)
    Figure US20060270691A1-20061130-C00033
         		6-(2-Furyl)-9-(1-pyrrolidinylcarbonyl)-9H-purine-2-amine
    30 (G)
    Figure US20060270691A1-20061130-C00034
         		2-Amino-6-(2-furyl)-N-isopropyl-9H-purine-9-carboxamide
    31 (A)
    Figure US20060270691A1-20061130-C00035
         		2-Chloro-N-cyclohexyl-6-(2-furyl)-9H-purine-9-carboxamide
    33 (H)
    Figure US20060270691A1-20061130-C00036
         		6-(2-Furyl)-9-(3-methylbutyryl)-9H-purine-2-amine
    34 (H)
    Figure US20060270691A1-20061130-C00037
         		9-Acetyl-6-(2-furyl)-9H-purine-2-amine
    35 (G)
    Figure US20060270691A1-20061130-C00038
         		N-Benzyl-6-(2-furyl)-2-methylthio-9H-purine-9-carboxamide
    36 (G)
    Figure US20060270691A1-20061130-C00039
         		2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide
    37 (G)
    Figure US20060270691A1-20061130-C00040
         		2-Amino-6-(2-furyl)-N-(4-methoxybenzyl)-9H-pur- ine-9-carboxamide
    38 (G)
    Figure US20060270691A1-20061130-C00041
         		2-Amino-6-(2-furyl)-N-(4-methylbenzyl)-9H-purine-9-carboxamide
    39 (G)
    Figure US20060270691A1-20061130-C00042
         		2-Amino-N-(2-chlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide
    40 (G)
    Figure US20060270691A1-20061130-C00043
         		2-Amino-6-(2-furyl)-N-(1-naphthyl)-9H-purine-9-carboxamide
    41 (G)
    Figure US20060270691A1-20061130-C00044
         		2-Amino-6-(2-furyl)-N-n-heptyl-9H-purine-9-carboxamide
    42 (G)
    Figure US20060270691A1-20061130-C00045
         		2-Amino-6-(2-furyl)-N-(2-methylphenyl)-9H-purine-9-carboxamide
    43 (G)
    Figure US20060270691A1-20061130-C00046
         		2-Amino-6-(2-furyl)-N-(3-methylphenyl)-9H-purine-9-carboxamide
    44 (G)
    Figure US20060270691A1-20061130-C00047
         		2-Amino-N-(2-chlorophenyl)-6-(2-furyl)-9H-purine-9-carboxamide
    45 (G)
    Figure US20060270691A1-20061130-C00048
         		(1S)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-pur- ine-9-carboxamide
    46 (G)
    Figure US20060270691A1-20061130-C00049
         		(1R)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-pur- ine-9-carboxamide
    47 (G)
    Figure US20060270691A1-20061130-C00050
         		2-Amino-6-(2-furyl)-N-(3-methylbenzyl)-9H-purine-9-carboxamide
    48 (G)
    Figure US20060270691A1-20061130-C00051
         		2-Amino-6-(2-furyl)-N-(4-methylphenyl)-9H-purine-9-carboxamide
    49 (G)
    Figure US20060270691A1-20061130-C00052
         		2-Amino-6-(2-furyl)-N-(2-methoxyphenyl)-9H-pur- ine-9-carboxamide
    50 (G)
    Figure US20060270691A1-20061130-C00053
         		2-Amino-6-(2-furyl)-N-(4-methoxyphenyl)-9H-pur- ine-9-carboxamide
    51 (G)
    Figure US20060270691A1-20061130-C00054
         		2-Amino-N-(4-chlorophenyl)-6-(2-furyl)-9H-purine-9-carboxamide
    52 (G)
    Figure US20060270691A1-20061130-C00055
         		2-Amino-6-(2-furyl)-N-n-pentyl-9H-purine-9-carboxamide
    53 (G)
    Figure US20060270691A1-20061130-C00056
         		2-Amino-N-n-dodecyl-6-(2-furyl)-9H-purine-9-carboxamide
    54 (K)
    Figure US20060270691A1-20061130-C00057
         		9-(2-Cyclohexylethyl)-6-(2-furyl)-9H-purine-2-amine
    55 (G)
    Figure US20060270691A1-20061130-C00058
         		N-Benzyl-2-dimethylamino-6-(2-furyl)-9H-purine-9-carboxamide
    56 (H)
    Figure US20060270691A1-20061130-C00059
         		N,N-Dimethyl-6-(2-furyl)-9-(4-methyl- phenylsulphonyl)-9H-purine-2-amine
    57 (K)
    Figure US20060270691A1-20061130-C00060
         		6-(2-Furyl)-9-(1-phenyl-1-propene-3-yl)-9H-purine-2-amine
    58 (K)
    Figure US20060270691A1-20061130-C00061
         		9-(But-2-ene-4-yl)-6-(2-furyl)-9H-purine-2-amine
    59 (K)
    Figure US20060270691A1-20061130-C00062
         		9-n-Butyl-6-(2-furyl)-9H-purine-2-amine
    60 (K)
    Figure US20060270691A1-20061130-C00063
         		9-Cyclopentyl-6-(2-furyl)-9H-purine-2-amine
    61 (K)
    Figure US20060270691A1-20061130-C00064
         		6-(2-Furyl)-9-isopropyl-9H-purine-2-amine
    62 (K)
    Figure US20060270691A1-20061130-C00065
         		6-(2-Furyl)-9-(4-phenylbutyl)-9H-purine-2-amine
    63 (K)
    Figure US20060270691A1-20061130-C00066
         		9-(2-Benzyloxyethyl)-6-(2-furyl)-9H-purine-2-amine
    64 (K)
    Figure US20060270691A1-20061130-C00067
         		6-(2-Furyl)-9-(3-methylbutyl)-9H-purine-2-amine
    65 (K)
    Figure US20060270691A1-20061130-C00068
         		6-(2-Furyl)-9-(2-methyl-2-buten-4-yl)-9H-purine-2-amine
    66 (K)
    Figure US20060270691A1-20061130-C00069
         		9-Benzyl-6-(2-furyl)-9H-purine-2-amine
    67 (K)
    Figure US20060270691A1-20061130-C00070
         		9-(4-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    68 (K)
    Figure US20060270691A1-20061130-C00071
         		6-(2-Furyl)-9-(3-phenylpropyl)-9H-purine-2-amine
    69 (X)
    Figure US20060270691A1-20061130-C00072
         		Ethyl 2-amino-6-(2-furyl)-9H-purine-9-acetate
    70 (L)
    Figure US20060270691A1-20061130-C00073
         		Isopropyl 2-dimethylamino-6-(2-furyl)-9H-purine-9-acetate
    71 (B)
    Figure US20060270691A1-20061130-C00074
         		Ethyl 2-dimethylamino-6-(2-furyl)-9H-purine-9-acetate
    72 (A)
    Figure US20060270691A1-20061130-C00075
         		Ethyl 2,6-bis(2-furyl)-9H-purine-9-acetate
    73 (M)
    Figure US20060270691A1-20061130-C00076
         		2-Amino-6-(2-furyl)-9H-purine-9-acetic acid
    74 (N)
    Figure US20060270691A1-20061130-C00077
         		6-(2-Furyl)-2-methoxy-9-(2-tri- methylsilylethoxymethyl)-9H-purine
    75 (C)
    Figure US20060270691A1-20061130-C00078
         		6-(2-Furyl)-2-methoxy-1H-purine
    76 (O)
    Figure US20060270691A1-20061130-C00079
         		6-(2-Thienyl)-1H-purine-2-amine
    77 (G)
    Figure US20060270691A1-20061130-C00080
         		2-Amino-N-benzyl-6-(2-thienyl)-9H-purine-9-carboxamide
    78 (A)
    Figure US20060270691A1-20061130-C00081
         		tert-Butyl 2-amino-6-(2-thienyl)-9H-purine-9-carboxylate
    79 (G)
    Figure US20060270691A1-20061130-C00082
         		2-Amino-N-(4-fluorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide
    80 (G)
    Figure US20060270691A1-20061130-C00083
         		2-Amino-N-(3,4-dichlorobenzyl)-6-(2-furyl)-9H-pur- ine-9-carboxamide
    81 (K)
    Figure US20060270691A1-20061130-C00084
         		6-(2-Furyl)-9-(2-phenylethyl)-9H-purine-2-amine
    82 (K)
    Figure US20060270691A1-20061130-C00085
         		9-(1-(4-Fluorophenyl)ethyl)-6-(2-furyl)-9H-purine-2-amine
    83 (K)
    Figure US20060270691A1-20061130-C00086
         		6-(2-Furyl)-9-(4-isopropylbenzyl)-9H-purine-2-amine
    84 (K)
    Figure US20060270691A1-20061130-C00087
         		9-(3,4-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    85 (P)
    Figure US20060270691A1-20061130-C00088
         		2-Amino-6-(2-furyl)-N-phenyl-9H-purine-9-acetamide
    86 (Q)
    Figure US20060270691A1-20061130-C00089
         		2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetamide
    87 (Q)
    Figure US20060270691A1-20061130-C00090
         		2-Amino-6-(2-furyl)-9H-purine-9-acetamide
    88 (Q)
    Figure US20060270691A1-20061130-C00091
         		6-(2-Furyl)-9-(2-oxo-2-(1-pyrrolidinyl)ethyl)-9H-pur- ine-2-amine
    89 (Q)
    Figure US20060270691A1-20061130-C00092
         		2-Amino-6-(2-furyl)-N-methyl-9H-purine-9-acetamide
    90 (R)
    Figure US20060270691A1-20061130-C00093
         		6-(5-Methyl-[1,2,4]-oxadiazol-3-yl)-1H-purine-2-amine
    91 (G)
    Figure US20060270691A1-20061130-C00094
         		2-Amino-N-benzyl-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-9H-pur- ine-9-carboxamide
    92 (G)
    Figure US20060270691A1-20061130-C00095
         		2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-carboxamide
    93 (G)
    Figure US20060270691A1-20061130-C00096
         		2-Amino-N-(2,4-dichlorobenzyl)-6-(2-furyl)-9H-pur- ine-9-carboxamide
    94 (G)
    Figure US20060270691A1-20061130-C00097
         		(1RS)-2-Amino-6-(2-furyl)-N-(1-(1-naphthyl)ethyl)-9H-pur- ine-9-carboxamide
    95 (G)
    Figure US20060270691A1-20061130-C00098
         		2-Amino-6-(2-furyl)-N-(2-(3-isopropenylphenyl)-2-pro- pyl)-9H-purine-9-carboxamide
    96 (Q)
    Figure US20060270691A1-20061130-C00099
         		2-Amino-6-(2-furyl)-N-(2-hydroxyethyl)-9H-purine-9-acetamide
    97 (Q)
    Figure US20060270691A1-20061130-C00100
         		6-(2-Furyl)-9-(2-oxo-2-(4-methyl-1-pipe- razinyl)ethyl)-9H-purine-2-amine
    98 (G)
    Figure US20060270691A1-20061130-C00101
         		2-Amino-N-(2-chloroethyl)-6-(2-furyl)-9H-purine-9-carboxamide
    99 (G)
    Figure US20060270691A1-20061130-C00102
         		2-Amino-N-(3-chloropropyl)-6-(2-furyl)-9H-purine-9-carboxamide
    100 (G)
    Figure US20060270691A1-20061130-C00103
         		Ethyl 3-(2-Amino-6-(2-furyl)-9H-purine-9-yl)carbonyl- aminopropionate
    101 (G)
    Figure US20060270691A1-20061130-C00104
         		Ethyl 2-(2-Amino-6-(2-furyl)-9H-purine-9-yl)carbonyl- amino-3-phenylpropionate
    102 (S)
    Figure US20060270691A1-20061130-C00105
         		6-(2-Furyl)-9-(2-(2-pyridyl)ethyl)-9H-purine-2-amine
    103 (S)
    Figure US20060270691A1-20061130-C00106
         		6-(2-Furyl)-9-(2-(1-piperazinyl)ethyl)-9H-purine-2-amine
    104 (S)
    Figure US20060270691A1-20061130-C00107
         		6-(2-Furyl)-9-(2-(1-piperidinyl)ethyl)-9H-purine-2-amine
    105 (S)
    Figure US20060270691A1-20061130-C00108
         		6-(2-Furyl)-9-(2-(1-pyrrolidinyl)ethyl)-9H-purine-2-amine
    106 (T)
    Figure US20060270691A1-20061130-C00109
         		Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate
    112 (G)
    Figure US20060270691A1-20061130-C00110
         		N-Benzyl-2-methoxy-6-(2-furyl)-9H-purine-9-carboxamide
    113 (S)
    Figure US20060270691A1-20061130-C00111
         		9-(2-(4-Chlorophenyl)ethyl)-6-(2-furyl)-9H-purine-2-amine
    114 (S)
    Figure US20060270691A1-20061130-C00112
         		9-(2-(4-Dimethylaminophenyl)ethyl)-6-(2-furyl)-9H-pur- ine-2-amine
    115 (S)
    Figure US20060270691A1-20061130-C00113
         		6-(2-Furyl)-9-(2-phenoxyethyl)-9H-purine-2-amine
    116 (S)
    Figure US20060270691A1-20061130-C00114
         		9-Cyclohexylmethyl-6-(2-furyl)-9H-purine-2-amine
    117 (S)
    Figure US20060270691A1-20061130-C00115
         		9-(3-Cyclohexylpropyl)-6-(2-furyl)-9H-purine-2-amine
    118 (I)
    Figure US20060270691A1-20061130-C00116
         		2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-carboxamide
    119 (Q)
    Figure US20060270691A1-20061130-C00117
         		2-Amino-6-(2-furyl)-N-(2-pyridylmethyl)-9H-pur- ine-9-acetamide
    120 (O)
    Figure US20060270691A1-20061130-C00118
         		6-(Benzofuran-2-yl)-1H-purine-2-amine
    122 (Q)
    Figure US20060270691A1-20061130-C00119
         		2-Amino-6-(2-furyl)-N-(2-pyridyl)-9H-purine-9-acetamide
    123 (Q)
    Figure US20060270691A1-20061130-C00120
         		2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-acetamide
    124 (Q)
    Figure US20060270691A1-20061130-C00121
         		2-Amino-6-(2-furyl)-N-n-propyl-9H-purine-9-acetamide
    125 (S)
    Figure US20060270691A1-20061130-C00122
         		9-(3-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    126 (S)
    Figure US20060270691A1-20061130-C00123
         		6-(2-Furyl)-9-(3-methylbenzyl)-9H-purine-2-amine
    127 (S)
    Figure US20060270691A1-20061130-C00124
         		6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-amine
    128 (G)
    Figure US20060270691A1-20061130-C00125
         		2-Amino-6-(benzofuran-2-yl)-N-benzyl-9H-purine-9-carboxamide
    129 (O)
    Figure US20060270691A1-20061130-C00126
         		6-(5-Chloro-2-thienyl)-1H-purine-2-amine
    130 (G)
    Figure US20060270691A1-20061130-C00127
         		2-Amino-N-benzyl-6-(5-chloro-2-thienyl)-9H-pur- ine-9-carboxamide
    131 (I)
    Figure US20060270691A1-20061130-C00128
         		6-(2-Furyl)-9-(1,2,3,4-tetrahydroisoquinolin-2-yl- carbonyl)-9H-purine-2-amine
    132 (I)
    Figure US20060270691A1-20061130-C00129
         		6-(2-Furyl)-9-(1-indolinylcarbonyl)-9H-purine-2-amine
    133 (A)
    Figure US20060270691A1-20061130-C00130
         		6-(1-Methyl-1H-pyrrol-2-yl)-1H-purine-2-amine
    134 (G)
    Figure US20060270691A1-20061130-C00131
         		2-Amino-N-benzyl-6-(1-methyl-1H-pyrrol-2-yl)-9H-pur- ine-9-carboxamide
    137 (Y)
    Figure US20060270691A1-20061130-C00132
         		6-(5-Thiazolyl)-1H-purine-2-amine
    139 (G)
    Figure US20060270691A1-20061130-C00133
         		2-Amino-N-benzyl-6-(5-thiazolyl)-9H-purine-9-carboxamide
    140 (Q)
    Figure US20060270691A1-20061130-C00134
         		2-Amino-6-(2-furyl)-N-(2-methylphenyl)-9H-purine-9-acetamide
    141 (Q)
    Figure US20060270691A1-20061130-C00135
         		2-Amino-N-(3-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide
    142 (Q)
    Figure US20060270691A1-20061130-C00136
         		2-Amino-6-(2-furyl)-N-(4-pyridyl)-9H-purine-9-acetamide
    143 (Q)
    Figure US20060270691A1-20061130-C00137
         		2-Amino-6-(2-furyl)-N-(3-pyridyl)-9H-purine-9-acetamide
    144 (Q)
    Figure US20060270691A1-20061130-C00138
         		2-Amino-N-(4-chlorobenzyl)-6-(2-furyl)-9H-purine-9-acetamide
    145 (Q)
    Figure US20060270691A1-20061130-C00139
         		2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-acetamide
    146 (S)
    Figure US20060270691A1-20061130-C00140
         		6-(2-Furyl)-9-(2-(4-pyridyl)ethyl)-9H-purine-2-amine
    147 (S)
    Figure US20060270691A1-20061130-C00141
         		6-(2-Furyl)-9-(2-(4-morpholinyl)ethyl)-9H-purine-2-amine
    148 (S)
    Figure US20060270691A1-20061130-C00142
         		6-(2-Furyl)-9-(3-pyridylmethyl)-9H-purine-2-amine
    150 (A)
    Figure US20060270691A1-20061130-C00143
         		6-(3-Methyl-2-thienyl)-1H-purine-2-amine
    151 (AA)
    Figure US20060270691A1-20061130-C00144
         		Methyl 3-(2-amino-6-(2-furyl)-9H-purine-9-yl)pro- pionate
    152 (M)
    Figure US20060270691A1-20061130-C00145
         		3-(2-Amino-6-(2-furyl)-9H-purine-9-yl)propionic acid
    153 (AB)
    Figure US20060270691A1-20061130-C00146
         		6-(2-Furyl)-2-methyl-1H-purine
    154 (G)
    Figure US20060270691A1-20061130-C00147
         		N-Benzyl-6-(2-furyl)-2-methyl-9H-purine-9-carboxamide
    155 (H)
    Figure US20060270691A1-20061130-C00148
         		6-(2-Furyl)-9-isopropylsulphonyl-9H-purine-2-amine
    156 (AC)
    Figure US20060270691A1-20061130-C00149
         		2-Chloro-6-(2-furyl)-9-(4-methylbenzyl)-9H-purine
    157 (AC)
    Figure US20060270691A1-20061130-C00150
         		9-(2-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    158 (AC)
    Figure US20060270691A1-20061130-C00151
         		6-(2-Furyl)-9-(3-nitrobenzyl)-9H-purine-2-amine
    159 (AC)
    Figure US20060270691A1-20061130-C00152
         		6-(2-Furyl)-9-(4-trifluoromethylbenzyl)-9H-purine-2-amine
    160 (H)
    Figure US20060270691A1-20061130-C00153
         		6-(2-Furyl)-9-(3-nitrophenyl)sulphonyl-9H-purine-2-amine
    161 (H)
    Figure US20060270691A1-20061130-C00154
         		9-(2-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine
    162 (H)
    Figure US20060270691A1-20061130-C00155
         		9-(4-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine
    163 (H)
    Figure US20060270691A1-20061130-C00156
         		9-(4-Fluorophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine
    164 (H)
    Figure US20060270691A1-20061130-C00157
         		6-(2-Furyl)-9-methanesulphonyl-9H-purine-2-amine
    165 (H)
    Figure US20060270691A1-20061130-C00158
         		9-Butanesulphonyl-6-(2-furyl)-9H-purine-2-amine
    166 (H)
    Figure US20060270691A1-20061130-C00159
         		6-(2-Furyl)-9-(8-quinolinesulphonyl)-9H-purine-2-amine
    167 (H)
    Figure US20060270691A1-20061130-C00160
         		9-(3,5-Dimethylisoxazole-4-yl)sulphonyl-6-(2-fur- yl)-9H-purine-2-amine
    168 (H)
    Figure US20060270691A1-20061130-C00161
         		6-(2-Furyl)-9-(5-(2-pyridyl)-2-thienyl)sulphonyl-9H-pur- ine-2-amine
    169 (Q)
    Figure US20060270691A1-20061130-C00162
         		2-Amino-6-(2-furyl)-N-(4-methoxy-2-meth- ylphenyl)-9H-purine-9-acetamide
    170 (Q)
    Figure US20060270691A1-20061130-C00163
         		2-Amino-N-(2,4-dimethylphenyl)-6-(2-furyl)-9H-pur- ine-9-acetamide
    171 (I)
    Figure US20060270691A1-20061130-C00164
         		N-Benzyl-N,2-dimethyl-6-(2-furyl)-9H-purine-9-carboxamide
    172 (AC)
    Figure US20060270691A1-20061130-C00165
         		6-(2-Furyl)-9-(4-nitrobenzyl)-9H-purine-2-amine
    173 (AH)
    Figure US20060270691A1-20061130-C00166
         		6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-carbonitrile
    174 (X)
    Figure US20060270691A1-20061130-C00167
         		6-(2-Furyl)-9-(2-phthalimidoethyl)-9H-purine-2-amine
    175 (Q)
    Figure US20060270691A1-20061130-C00168
         		2-Amino-N-(4-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide
    176 (Q)
    Figure US20060270691A1-20061130-C00169
         		2-Amino-N-(3,4-dichlorophenyl)-6-(2-furyl)-9H-pur- ine-9-acetamide
    177 (AC)
    Figure US20060270691A1-20061130-C00170
         		9-(3-Cyanobenzyl)-6-(2-furyl)-9H-purine-2-amine
    178 (AC)
    Figure US20060270691A1-20061130-C00171
         		9-(2-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    179 (H)
    Figure US20060270691A1-20061130-C00172
         		N-(5-(2-Amino-6-(2-furyl)-9H-purine-9-yl- sulphonyl)-2-thienylmethyl)-4-chlorobenzamide
    180 (H)
    Figure US20060270691A1-20061130-C00173
         		9-(2,1,3-Benzoxadiazol-4-yl)sulphonyl-6-(2-furyl)-9H-pur- ine-2-amine
    181 (H)
    Figure US20060270691A1-20061130-C00174
         		Mehtyl 3-(2-amino-6-(2-furyl)-9H-purine-9-sul- phonyl)thiophene-2-carboxylate
    182 (H)
    Figure US20060270691A1-20061130-C00175
         		6-(2-Furyl)-9-(5-(isoxazol-3-yl)-2-thienyl)sulphonyl-9H-pur- ine-2-amine
    183 (H)
    Figure US20060270691A1-20061130-C00176
         		6-(2-Furyl)-9-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sul- phonyl-9H-purine-2-amine
    184 (H)
    Figure US20060270691A1-20061130-C00177
         		9-(4-Acetylphenylsulphonyl)-6-(2-furyl)-9H-purine-2-amine
    185 (H)
    Figure US20060270691A1-20061130-C00178
         		6-(2-Furyl)-9-(2-phenylethenyl)sulphonyl-9H-pur- ine-2-amine
    186 (H)
    Figure US20060270691A1-20061130-C00179
         		9-Ethanesulphonyl-6-(2-furyl)-9H-purine-2-amine
    187 (S)
    Figure US20060270691A1-20061130-C00180
         		6-(2-Furyl)-9-(2-pyridylmethyl)-9H-purine-2-amine
    188 (S)
    Figure US20060270691A1-20061130-C00181
         		6-(2-Furyl)-9-(4-pyridylmethyl)-9H-purine-2-amine
    189 (S)
    Figure US20060270691A1-20061130-C00182
         		6-(2-Furyl)-9-(3-(3-pyridyl)propyl)-9H-purine-2-amine
    190 (S)
    Figure US20060270691A1-20061130-C00183
         		6-(2-Furyl)-9-(3-(4-pyridyl)propyl)-9H-purine-2-amine
    191 (G)
    Figure US20060270691A1-20061130-C00184
         		2-Amino-N-(1-(4-bromophenyl)ethyl)-6-(2-furyl)-9H-pur- ine-9-carboxamide
    192 (AD)
    Figure US20060270691A1-20061130-C00185
         		9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine
    193 (AC)
    Figure US20060270691A1-20061130-C00186
         		Methyl 3-(2-amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoate
    194 (AC)
    Figure US20060270691A1-20061130-C00187
         		9-(4-Cyanobenzyl)-6-(2-furyl)-9H-purine-2-amine
    195 (Y)
    Figure US20060270691A1-20061130-C00188
         		6-(5-Methyl-2-furyl)-1H-purine-2-amine
    196 (H)
    Figure US20060270691A1-20061130-C00189
         		9-n-Decanesulphonyl-6-(2-furyl)-9H-purine-2-amine
    197 (AC)
    Figure US20060270691A1-20061130-C00190
         		6-(2-Furyl)-9-(2-nitrobenzyl)-9H-purine-2-amine
    198 (AC)
    Figure US20060270691A1-20061130-C00191
         		6-(2-Furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine
    199 (M)
    Figure US20060270691A1-20061130-C00192
         		3-(2-Amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoic acid
    200 (B)
    Figure US20060270691A1-20061130-C00193
         		N,N-Dimethyl-6-(2-furyl)-9-(4-methylbenzyl)-9H-pur- ine-2-amine
    201 (G)
    Figure US20060270691A1-20061130-C00194
         		2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-carboxamide
    202 (G)
    Figure US20060270691A1-20061130-C00195
         		2-Amino-6-(2-furyl)-N-(2-thienylmethyl)-9H-pur- ine-9-carboxamide
    203 (AC)
    Figure US20060270691A1-20061130-C00196
         		9-(3-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    204 (G)
    Figure US20060270691A1-20061130-C00197
         		2-Amino-N-benzyl-6-(5-methyl-2-furyl)-9H-purine-9-car- boxamide
    205 (AF)
    Figure US20060270691A1-20061130-C00198
         		9-(3-Acetamidobenzyl)-6-(2-furyl)-9H-purine-2-amine
    206 (AC)
    Figure US20060270691A1-20061130-C00199
         		6-(2-Furyl)-9-(4-methanesulphonylbenzyl)-9H-pur- ine-2-amine
    207 (AD)
    Figure US20060270691A1-20061130-C00200
         		9-(2-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine
    208 (AC)
    Figure US20060270691A1-20061130-C00201
         		9-(4-Methylbenzyl)-6-(5-methyl-2-furyl)-9H-purine-2-amine
    209 (Y)
    Figure US20060270691A1-20061130-C00202
         		6-(1-Methyl-1H-imidazol-5-yl)-1H-purine-2-amine
    210 (AF)
    Figure US20060270691A1-20061130-C00203
         		6-(2-Furyl)-9-(2-methanesulphonylaminobenzyl)-9H-pur- ine-2-amine
    211 (AC)
    Figure US20060270691A1-20061130-C00204
         		9-(2,6-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    212 (S)
    Figure US20060270691A1-20061130-C00205
         		6-(2-Furyl)-9-(6-methyl-2-pyridyl)methyl-9H-pur- ine-2-amine
    213 (S)
    Figure US20060270691A1-20061130-C00206
         		6-(2-Furyl)-9-(3-furylmethyl)-9H-purine-2-amine
    214 (H)
    Figure US20060270691A1-20061130-C00207
         		9-Benzylsulphonyl-6-(2-furyl)-9H-purine-2-amine
    215 (AC)
    Figure US20060270691A1-20061130-C00208
         		Methyl 4-(2-amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoate
    216 (M)
    Figure US20060270691A1-20061130-C00209
         		4-(2-Amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoic acid
    217 (AF)
    Figure US20060270691A1-20061130-C00210
         		6-(2-Furyl)-9-(3-methanesulphonylaminobenzyl)-9H-pur- ine-2-amine
    218 (Q)
    Figure US20060270691A1-20061130-C00211
         		2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-acetamide
    219 (AC)
    Figure US20060270691A1-20061130-C00212
         		9-(3,5-Dimethoxybenzyl)-6-(2-furyl)-9H-purine-2-amine
    220 (AF)
    Figure US20060270691A1-20061130-C00213
         		9-(2-Acetamidobenzyl)-6-(2-furyl)-9H-purine-2-amine
    221 (AG)
    Figure US20060270691A1-20061130-C00214
         		6-(2-Furyl)-9-(3-hydroxybenzyl)-9H-purine-2-amine
    222 (S)
    Figure US20060270691A1-20061130-C00215
         		N-(2-(2-Amino-6-(2-furyl)-9H-purine-9-yl)ethyl)-4-py- ridinecarboxamide
    223 (S)
    Figure US20060270691A1-20061130-C00216
         		6-(2-Furyl)-9-(3-thienylmethyl)-9H-purine-2-amine
    224 (S)
    Figure US20060270691A1-20061130-C00217
         		9-(1-Benzyl-1H-imidazol-2-ylmethyl)-6-(2-furyl)-9H-pur- ine-2-amine
    225 (AD)
    Figure US20060270691A1-20061130-C00218
         		9-(4-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine
    226 (P)
    Figure US20060270691A1-20061130-C00219
         		3-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N-benzyl- benzamide
    227 (P)
    Figure US20060270691A1-20061130-C00220
         		4-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N-benzyl- benzamide
    228 (H)
    Figure US20060270691A1-20061130-C00221
         		6-(2-Furyl)-9-(4-methylphenylsulphonyl)-9H-purine-2-amine
    229 (AC)
    Figure US20060270691A1-20061130-C00222
         		9-(3,5-Dimethylisoxazol-4-ylmethyl)-6-(2-furyl)-9H-pur- ine-2-amine
    230 (P)
    Figure US20060270691A1-20061130-C00223
         		3-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N,N-di- methylbenzamide
    231 (Q)
    Figure US20060270691A1-20061130-C00224
         		2-Amino-6-(2-furyl)-N-(3-methoxyphenyl)-9H-pur- ine-9-acetamide
    232 (AF)
    Figure US20060270691A1-20061130-C00225
         		6-(2-Furyl)-9-(4-methanesulphonylaminobenzyl)-9H-pur- ine-2-amine
    233 (P)
    Figure US20060270691A1-20061130-C00226
         		4-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N,N-di- methylbenzamide
    234 (AF)
    Figure US20060270691A1-20061130-C00227
         		N-(2-(2-Amino-6-(2-furyl)-9H-purine-9-yl- methyl)phenyl)cyclopropanecarboxamide
    235 (AF)
    Figure US20060270691A1-20061130-C00228
         		6-(2-Furyl)-9-(2-(1-methyl-1H-imidazol-4-yl- sulphonylamino)benzyl)-9H-purine-2-amine
    236 (Q)
    Figure US20060270691A1-20061130-C00229
         		2-Amino-6-(2-furyl)-N-(2-methoxybenzyl)-9H-pur- ine-9-acetamide
    237 (Q)
    Figure US20060270691A1-20061130-C00230
         		2-Amino-N-(2-fluorobenzyl)-6-(2-furyl)-9H-purine-9-acetamide
    238 (AF)
    Figure US20060270691A1-20061130-C00231
         		6-(2-Furyl)-9-(2-(2-thienylsulphonylamino)benzyl)-9H-pur- ine-2-amine
    239 (AF)
    Figure US20060270691A1-20061130-C00232
         		6-(2-Furyl)-9-(2-(3,5-dimethylisoxazol-4-yl- sulphonylamino)benzyl)-9H-purine-2-amine
    240 (AC)
    Figure US20060270691A1-20061130-C00233
         		9-(5-Chloro-2-thienylmethyl)-6-(2-furyl)-9H-purine-2-amine
    241 (Z)
    Figure US20060270691A1-20061130-C00234
         		6-(5-Methyl-2-pyridinyl)-1H-purine-2-amine
    242 (AF)
    Figure US20060270691A1-20061130-C00235
         		N-(6-(2-Furyl)-9-(2-(2-methylpropanamido)benzyl)-9H-pur- ine-2-yl)-2-methylpropanamide
    243 (AC)
    Figure US20060270691A1-20061130-C00236
         		9-(2-Fluorobenzyl)-6-(5-methyl-2-pyridinyl)-9H-pur- ine-2-amine
    244 (AJ)
    Figure US20060270691A1-20061130-C00237
         		9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-pur- ine-2-amine
    245 (AK)
    Figure US20060270691A1-20061130-C00238
         		2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetimid- amide
    246 (Q)
    Figure US20060270691A1-20061130-C00239
         		2-Amino-6-(2-furyl)-N-(1-methylpropyl)-9H-purine-9-acetamide
    247 (Q)
    Figure US20060270691A1-20061130-C00240
         		2-Amino-N-ethyl-6-(2-furyl)-9H-purine-9-acetamide
    248 (Q)
    Figure US20060270691A1-20061130-C00241
         		N-Allyl-2-amino-6-(2-furyl)-9H-purine-9-acetamide
    249 (Q)
    Figure US20060270691A1-20061130-C00242
         		2-Amino-N-(3,4-difluorophenyl)-6-(2-furyl)-9H-pur- ine-9-acetamide
    250 (AF)
    Figure US20060270691A1-20061130-C00243
         		6-(2-Furyl)-9-(3-(3,5-dimethylisoxazol-4-yl- sulphonylamino)benzyl)-9H-purine-2-amine
    251 (AL)
    Figure US20060270691A1-20061130-C00244
         		(2S)-9-(2-Amino-1-propyl)-6-(2-furyl)-9H-purine-2-amine
    252 (Q)
    Figure US20060270691A1-20061130-C00245
         		2-Amino-N-(2-dimethylaminoethyl)-6-(2-furyl)-9H-pur- ine-9-acetamide
    253 (AC)
    Figure US20060270691A1-20061130-C00246
         		9-(4-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine
    254 (AL)
    Figure US20060270691A1-20061130-C00247
         		(2R)-9-(2-Amino-1-propyl)-6-(2-furyl)-9H-purine-2-amine
    255 (X)
    Figure US20060270691A1-20061130-C00248
         		9-(2-(Butoxycarbonylamino)ethyl)-6-(2-furyl)-9H-pur- ine-2-amine
    256 (AC)
    Figure US20060270691A1-20061130-C00249
         		N,9-Bis(4-methylbenzyl)-6-(2-furyl)-9H-purine-2-amine
    257 (F)
    Figure US20060270691A1-20061130-C00250
         		9-(2-Aminoethyl)-6-(2-furyl)-9H-purine-2-amine
    258 (AC)
    Figure US20060270691A1-20061130-C00251
         		6-(2-Furyl)-N,N,9-tris(4-methylbenzyl)-9H-purine-2-amine
    259 (AC)
    Figure US20060270691A1-20061130-C00252
         		9-(2-Fluoro-5-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine
    260 (AG)
    Figure US20060270691A1-20061130-C00253
         		6-(2-Furyl)-9-(4-hydroxybenzyl)-9H-purine-2-amine
    261 (AC)
    Figure US20060270691A1-20061130-C00254
         		6-(2-Furyl)-9-(4-methoxybenzyl)-9H-purine-2-amine
    262 (AM)
    Figure US20060270691A1-20061130-C00255
         		9-(2-Fluorobenzyl)-6-(1H-pyrazol-3-yl)-9H-purine-2-amine
    263 (AM)
    Figure US20060270691A1-20061130-C00256
         		9-(2-Fluorobenzyl)-6-(1H-triazol-3-yl)-9H-purine-2-amine
    264 (AM)
    Figure US20060270691A1-20061130-C00257
         		9-(3-Aminobenzyl)-6-(1H-pyrazol-3-yl)-9H-purine-2-amine
    265 (AO)
    Figure US20060270691A1-20061130-C00258
         		9-(3-Aminobenzyl)-6-(5-methyl-1H-pyrazol-3-yl)-1H-pur- ine-2-amine
    266 (AC)
    Figure US20060270691A1-20061130-C00259
         		9-(3-Methoxybenzyl)-6-(5-methyl-2-furyl)-9H-pur- ine-2-amine
    267 (AC)
    Figure US20060270691A1-20061130-C00260
         		9-(2-Fluorobenzyl)-6-(thiazol-5-yl)-9H-purine-2-amine
    268 (AC)
    Figure US20060270691A1-20061130-C00261
         		9-(6-Allyloxymethyl-2-pyridyl)-6-(2-furyl)-9H-pur- ine-2-amine
    269 (AC)
    Figure US20060270691A1-20061130-C00262
         		9-(3-Methyl-4-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine
    270 (AC)
    Figure US20060270691A1-20061130-C00263
         		tert-butyl 4-(2-amino-6-(2-furyl)-1H-purine-9-yl- methyl)indole-1-carboxylate
    271 (AQ)
    Figure US20060270691A1-20061130-C00264
         		6-(2-Furyl)-9-(4-indolylmethyl)-9H-purine-2-amine
    272 (AQ)
    Figure US20060270691A1-20061130-C00265
         		6-(2-Furyl)-9-(5-indolylmethyl)-9H-purine-2-amine
    273 (AC)
    Figure US20060270691A1-20061130-C00266
         		tert-butyl 5-(2-amino-6-(2-furyl)-1H-purine-9-yl- methyl)indole-1-carboxylate

    Method A
    • 2-Chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (Example 1)
  • A solution of 2,6-dichloro-9-(2-trimethylsilylethoxymethyl)-9H-purine (957 mg, 3 mmol) in DMF (2.5 mL) was treated with PdCl2(PPh3)2 (105 mg, 0.15 mmol) and 2-(tributylstannyl)furan (944 μL, 3 mmol), stirred at room temperature for 16 h, diluted with EtOAc, washed with water, dried (MgSO4) and concentrated in vacuo, purified by chromatography [SiO2; EtOAc:Heptane, (1:2)] and the resulting cream solid recrystallised (heptane) to give the title compound (738 mg, 70%) as a white solid.
  • Method B
    • N,N-Dimethyl-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine-2-amine (Example 2)
  • A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (488 mg, 1.4 mmol) in isopropanol (5 mL) was treated with 40% dimethylamine in water (1 mL), refluxed for 2 h, concentrated in vacuo and purified by chromatography [SiO2; EtOAc Heptane, (1:1)] to give the title compound (431 mg, 86%) as a white solid.
  • Method C
    • N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine (Example 3)
  • A solution of N,N-dimethyl-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine-2-amine (200 mg, 0.56 mmol) in TB (5 mL) was treated with tetra-n butylammonium fluoride (1-M in THF, 0.67 mL, 0.67 mmol), refluxed for 4 h, cooled, poured into water and extracted with EtOAc. The combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; EtOAc) to give the title compound (98 mg, 76%) as a pale yellow solid.
  • Method D
    • 6-(2-Furyl)-1H-purine-2-amine (Example 11)
  • A solution of N-(3,4-dimethoxybenzyl)-6-(2-furyl)-1H-purine-2-amine (194 mg, 0.55 mmol) in TPA (1 mL) was heated at 60° C. for 30 min, poured into water, extracted with EtOAc and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; 5% MeOH in EtOAc). The resulting yellow solid was dissolved in MeOH, treated with HCl (1-M in Et2O) and filtered to give the title compound (75 mg, 57%) as a yellow solid.
  • Method E
    • tert-Butyl 6-(2-furyl)-2-thiomethoxy-9H-purine-9-carboxylate (Example 12)
  • A solution of tert-butyl 2-chloro-6-(2-furyl)-9H-purine-9-carboxylate (320 mg, 1 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was treated with NaSMe (140 mg, 2 mmol), heated at 110° C. for 48 h, cooled, poured into water, extracted with CHCl3 and the combined organic phase dried (MgSO4) and concentrated in vacuo. The resulting crude intermediate was dissolved in THF (2 mL), treated with di-tert-butyl dicarbonate (218 mg, 1 mmol), Et3N (139 μL, 1 mmol) and a catalytic amount of DMAP, stirred for 1 h, poured into water, extracted with CHCl3 and the combined organic phase dried MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Eleptane:EtOAc (4:1)] to give the title compound (106 mg, 32%) as a cream solid.
  • Method F
    • 6-(2-Furyl)-2-thiomethoxy-1H-purine (Example 13)
  • A solution of tert-butyl 6-(2-furyl)-2-thiomethoxy-9H-purine-9-carboxylate (75 mg, 0.23 mmol) in dioxan (0.5 mL) was treated with HCl in dioxan (4-M, 0.5 mL, 2 mmol), stirred at room temperature for 30 min, poured into sat. NaHCO3, extracted with EtOAc and the combined organic phase dried (MgSO4), concentrated in vacuo and the resulting cream solid triturated with EtOAc and filtered to give the title compound (46 mg, 86%) as a cream solid.
  • Method G
    • 2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide (Example 36)
  • A solution of 6-(2-furyl)-1H-purine-2-amine (0.050 g, 0.25 mmol) and DMAP (5 mg, 0.03 mmol) in anhydrous DMF (1 mL) was treated with n-butylisocyanate (0.029 g, 0.30 mmol), shaken at 65° C. for 1 h, poured onto ice-cold water (10 mL), cooled at 0° C. for 15 min and the resulting precipitate filtered and dried in vacuo over P2O5 to give the title compound (74 mg, 100%) as a white solid.
  • Method H
    • 9-(4-tert-Butylphenylsulphonyl)-(2-furyl)-9H-purine-2-amine (Example 27)
  • A solution of 6-(2-furyl)-1H-purine-2-amine (100 mg, 0.5 mmol) in THF (2 mL) and DMF (0.5 mL) was treated with 4-tert-butylbenzenesulphonyl chloride (116 mg, 0.5 mmol) and Et3N (69 μL, 0.6 mmol), heated at 60° C. for 2 h, cooled, diluted with water and the resulting solid filtered and washed with EtOAc to give the title compound (106 mg, 53%) as a cream solid.
  • Method I
    • 6-(2-Furyl)-9-(1-pyrrolidinylcarbonyl)-9H-purine-2-amine (Example 29)
  • A solution of pyrrolidine (50 mL, 0.6 mmol) in toluene (2 mL) was treated with a solution of phosgene in toluene (0.31 mL, 1.93-M, 0.6 mmol), heated at 80° C. for 30 mins, cooled and concentrated in vacuo. The residue was dissolved in THF (2 mL) and added to a solution of 6-(2-furyl)-1H-purine-2-amine (100 mg, 0.5 mmol) and Et3N (83 mL, 0.6 mmol) in DMF (0.5 mL), stirred at 60° C. for 16 h, poured into water and extracted with EtOAc. The combined organic phase was dried (MgSO4), concentrated in vacuo and the resulting solid triturated with EtOAc/heptane and filtered to give the title compound (92 mg, 62%) as a cream solid.
  • Method K
    • 9-(2-Cyclohexylethyl)-6-(2-furyl)-9H-purine-2-amine (Example 54)
  • A solution of 6-(2-furyl)-1H-purine-2-amine (25 mg, 0.12 mmol) in anhydrous DMF (0.5 mL) and anhydrous THF (2 mL) was treated with triphenylphosphine polystyrene (65 mg, 0.25 mmol) and 2-cyclohexylethanol (35 mg, 0.25 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.058 g, 0.25 mmol), shaken at room temperature for 16 h, filtered and concentrated in vacuo. The resulting oil was dissolved in CH2Cl2 (2 mL) and TFA (1 mL), shaken for 2 h and concentrated in vacuo. The resulting oil was dissolved in CH2Cl2 (3 mL), shaken with 1-M aq HCl (1 mL) for 15 min and the organic phase concentrated in vacuo and purified by chromatography (SiO2; EtOAc) to give the title compound (22 mg, 57%) as a yellow solid.
  • Method L
    • Isopropyl 2-dimethylamino-6-(2-furyl)-9H-purine-9-acetate (Example 70)
  • A solution of ethyl 2-chloro-6-(2-furyl)-9H-purine-9-acetate (100 mg, 0.33 mol) in isopropanol (1 mL) was treated with 40% dimethylamine in water, refluxed for 2 h, cooled, poured into water, extracted with EtOAc and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Heptane:EtOAc, (1:1)] to give the title compound (20 mg, 19%) as a white solid.
  • Method M
    • 2-Amino-6-(2-furyl)-9H-purine-9-acetic acid (Example 73)
  • A solution of ethyl 2-amino-6-(2-furyl)-9H-purine-9-acetate (200 mg, 0.69 mmol) in MeOH (3 mL) was treated with aq NaOH (2-M, 0.5 mL, 1 mmol), refluxed for 10 min, cooled, diluted with water, acidified with aq HCl (1-M) and the resulting solid filtered, washed with water and dried to give the title compound (129 mg, 72%) as a yellow solid.
  • Method N
    • 6-(2-Furyl)-2-methoxy-9-(2-trimethylsilylethoxymethyl)-9H-purine (Example 74)
  • A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (0.35 g, 1.0 mmol) and sodium methoxide (60 mg, 1.1 mmol) in methanol (5 mL) was refluxed for 23 h, cooled, concentrated in vacuo and the resulting solid treated with water, acidified to pH 4 with acetic acid, extracted with EtOAc, dried (Na2SO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc:heptane (1:1)]to give the title compound (232 mg, 67%) as a pale yellow solid.
  • Method O
    • 6-(5-Chloro-2-thienyl)-1H-purine-2-amine (Example 129)
  • A solution of N,9-bis(tetrahydropyran-2-yl)-6-chloro-9H-purine-2-amine (1.01 g, 3.0 mmol) and Pd(PPh3)4 (250 mg, 10 mol %) in THF (20 mL) was treated with 5-chloro-2-thiopheneboronic acid (536 mg, 3.3 mmol) and saturated aq NaHCO3 (10 mL), refluxed for 1 h, diluted with H2O, extracted with EtOAc and the organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane:EtOAc (2:1)] to give the coupled product as a pale-yellow syrup. This material was dissolved in MeOH (20 mL) and stirred vigorously at 50° C. with Amberlyst-15 resin for 1 hr. The resin was filtered off, washed once with MeOH, and then re-suspended in fresh MeOH (20 mL), treated with NH3 solution (2-M in MeOH, 2.0 mL), stirred vigorously at 50° C. for 1 h, filtered, the resin washed twice with MeOH, and the filtrate concentrated in vacuo to give the title compound (230 mg, 36%) as a yellow solid.
  • Method P
    • 2-Amino-6-(2-furyl)-N-phenyl-9H-purine-9-acetamide (Example 85)
  • A solution of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DCM (2 mL) was treated with EDCI (96 mg, 0.5 mmol) and aniline (45 μL, 0.5 mmol), stirred at room temperature for 3 days, diluted with DCM, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; 1% MeOH in EtOAc) to give the title compound (51 mg, 31%) as a white solid.
  • Method Q
    • 2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetamide (Example 86)
  • A suspension of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DMF (2 μL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with benzylamine (55 μL, 0.5 mmol), stirred at room temperature for 2 h, diluted with water, filtered and dried to give the title compound (115 mg, 66%) as a white solid.
  • Method R
    • 6-(5-Methyl-[1,2,4]-oxadiazol-3-yl)-1H-purine-2-amine (Example 90)
  • A mixture of hydroxylamine hydrochloride (847 mg, 12.2 mmol) and potassium hydroxide (855 mg, 15.3 mmol) in EtOH was refluxed for 30 min, cooled, filtered to remove solid potassium chloride, treated with 9-(2-tetrahydropyranyl)-2-(2-tetrahydropyranylamino)-9H-purine-6-carbonitrile (1.0 g, 3.05 mmol), refluxed for 1 h, concentrated in vacuo and the residue triturated with Et2O to give a pale yellow solid (1.12 g). A portion (600 mg) of this material was stirred with N,N-dimethylacetamide dimethylacetal at 100° C. for 1 h, concentrated in vacuo and purified by chromatography (SiO2; EtOAc) to give a pale yellow syrup (212 mg). This material was dissolved in MeOH and stirred vigorously at 50° C. with Amberlyst-15 resin for 1 hr and the resin filtered off and washed once with MeOH. The resin was then re-suspended in fresh MeOH, treated with a solution of NH3 in MeOH (2-M, 2 mL), stirred vigorously at 60° C. for 1 h, filtered, washed twice with MeOH, and the filtrate concentrated in vacuo to give the title compound (73 mg, 21%) as a pale grey solid.
  • Method S
    • 6-(2-Furyl)-9-(2-(2-pyridyl)ethyl)-9H-purine-2-amine (Example 102)
  • A mixture of 6-(2-furyl)-1H-purine-2-amine (50 mg, 0.25 mmol) and triphenylphosphine polystyrene (0.21 g, 0.62 mmol) in anhydrous DMF (0.5 mL) and anhydrous THE (2 mL) was treated with 2-(2-hydroxyethyl)pyridine (61 mg, 0.50 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.115 g, 0.50 mmol), shaken for 16 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2-MeOH (100:5)] to give the title compound (36 mg, 47%) as an off-white solid.
  • Method T
    • Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate (Example 106)
  • A solution of 6-(2-furyl)-1H-purine-2-amine (0.201 g, 1.0 mmol), benzyl chloroformate (0.20 mL, 1.1 mmol), triethylamine (0.21 mL, 1.5 mmol) and DMAP (15 mg) in DMF (10 mL) was stirred at room temperature for 4 h, poured into cold water, cooled for 30 min at 5° C. and the resulting solid filtered and dried at 40° C. to give the title compound (0.327 g, 98%) as a cream solid.
    • Method X Ethyl 2,6-dichloro-9H-purine-9-acetate
  • An ice-cold solution of 2,6-dichloro-1H-purine (1.89 g, 10 mmol) in THF (10 mL) was treated with NaH (60% in oil, 440 mg, 11 mmol), stirred at 0° C. for 30 min, treated with ethyl bromoacetate (1.22 mL, 11 mmol), stirred at room temperature for 2 h, poured into sat. NaHCO3, extracted with EtOAc and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Heptane:EtOAc (2:1)] to give the title compound (1.46 g, 53%) as a white solid: IR νmax (Nujol)/cm−1 3106, 2985, 2955, 2924, 2854, 1734, 1598, 1557, 1374, 1341, 1298, 1156 and 884; NMR δH (400 MHz, CDCl3) 1.31 (3H, t, J 7.0 Hz), 4.29 (2H, q, J 7.0 Hz), 5.01 (2H, s), 8.17 (1H, s).
  • Method Y
    • 6-(5-Methyl-2-furyl)-1H-purine-2-amine (Example 195)
  • A solution of N,9-bis(tetrahydropyran-2-yl)-4-chloro-9H-purine-2-amine (338 mg, 1 mmol), 5-methyl-2-(tributylstannyl)furan and Pd(PPh3)2C2 (70 mg) in DMF was heated at 80° C. for 5 h, cooled, diluted with H2O, extracted with EtOAc and the organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane:EtOAc (6:1)] to give the coupled product. This material was dissolved in MeOH (20 mL), stirred vigorously at 50° C. with Amberlyst-15 resin for 1 h then the resin was filtered off and washed once with MeOH. The resin was then re-suspended in fresh MeOH (20 mL), treated with NH3 solution (2-M in MeOH, 1.0 mL) stirred vigorously at 50° C. for 1 h, filtered, washed twice with MeOH, and the filtrate concentrated in vacuo to give the title compound (45 mg, 21%) as a pale-yellow solid.
  • Method Z
    • 6-(5-Methyl-2-pyridinyl)-1H-purine-2-amine (Example 241)
  • A stirred solution of 5-methyl-2-pyridylzinc bromide (0.5 M, 8 mL, 4 mmol) was treated with Pd(PPh3)4 (250 mg) and N,9-bis(tetrahydropyran-2-yl)-4-chloro-9H-purine-2-amine (676 mg, 2 mmol), refluxed for 1 h, cooled, diluted with H2O, extracted with EtOAc, the extracts dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane:EtOAc (1:2), then EtOAc] to give the coupled product (498 mg). A portion of this material (100 mg) was suspended in MeOH, treated with a solution of HCl (4-M in dioxan, 0.5 mL), stirred for 17 h, diluted with Et2O and filtered to afford the title compound (37 mg, 35%) as a yellow solid.
  • Method AA
    • Methyl 3-(2-amino-6-(2-furyl)-9H-purine-9-yl)propionate (Example 151)
  • A solution of 6-(2-furyl)-1H-purine-2-amine (0.70 g, 3.48 mmol) and K2CO3 (0.48 g, 3.48 mmol) in DMF (20 mL) was treated with methyl acrylate (3.3 g, 38.3 mmol), stirred for 40 h, diluted with EtOAc, filtered to remove polymeric acrylate, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2:EtOAc-heptane, (4:1)] to give the title compound (114 mg, 11%) as a white solid.
  • Method AB
    • 6-(2-Furyl)-2-methyl-1H-purine (Example 153)
  • A solution of 2-chloro-6-(2-furyl)-1H-purine (1.1 g, 5.0 mmol) and Pd(PPh3)4 (0.58 g, 0.5 mmol) in 1,2-dichloroethane (50 mL) at room temperature was treated dropwise with trimethylaluminium (3.3 mL, 2.0 M hexane), refluxed for 16 h, treated with water (100 mL) then EtOAc (100 mL), stirred for 60 h and filtered through glass microfibre paper. The organic phase was separated, dried (MgSO4), concentrated in vacuo and the resulting solid recrystallised from 90% ethanol to give the title compound (0.30 g, 30%) as a pale brown solid.
  • Method AC
    • 6-(2-Furyl)-9-(3-nitrobenzyl)-9H-purine-2-amine (Example 158)
  • An ice-cold solution of 6-(2-furyl)-1H-purine-2-amine (201 mg, 1 mmol) in DMF (6 mL) was treated with NaH (44 mg, 1.1 mmol), stirred for 30 min, treated with 3-nitrobenzyl bromide (238 mg, 1.1 mmol), stirred at room temperature for 3 h, treated with water and the resulting solid filtered, suspended in methanol, stirred for 30 min, and filtered to give the title compound (201 mg, 60%) as a yellow solid.
  • Method AD
    • 9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine (Example 192)
  • A solution of 6-(2-furyl)-9-(3-nitrobenzyl)-9H-purine-2-amine (400 mg, 1.12 mmol) in EtOH (10 mL) at 50° C. was treated with a solution of SnCl2.2H2O (808 mg, 3.58 mmol) in conc.HCl (1.8 ml, 21.42 mmol), stirred for 1.5 h, cooled, basified to pH 10 (1-M NaOH) and the resulting solid was filtered, suspended in methanol, treated with HCl in dioxane (4-M, 2 mL), diluted with diethyl ether and filtered to give the title compound (90 mg, 22%) as a yellow solid.
  • Method AF
    • 9-(3-Acetamidobenzyl)-6-(2-furyl)-9H-purine-2-amine (Example 205)
  • An ice-cold solution of 9-(3-aminobenzyl)-6-(2-furyl)-9H-purine-2-amine (145 mg, 0.48 mmol) in pyridine (3 mL) was treated with acetyl chloride (38 μL, 0.53 mmol), stirred for 1 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:Hexane:EtOAc (1:3) to EtOAc:MeOH (99:1)) to give the title compound (71 mg, 43%) as a yellow solid.
  • Method AG
    • 6-(2-Furyl)-9-(3-hydroxybenzyl)-9H-purine-2-amine (Example 221)
  • An ice-cold solution of 6-(2-furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine (160 mg, 0.5 mmol) in DCM (3 mL) was treated with BBr3 (1 mL, 1-M in DCM 1 mmol), stirred at 0° C. for 3 h, treated with more BBr3 (2 mL, 1-M in DCM, 2 mmol), stirred for 16 h, treated with NH4Cl solution, extracted with EtOAc, dried (MgSO4), concentrated in vacuo, triturated with ether and filtered. The resulting solid was suspended in aqueous sodium bicarbonate, extracted with ether, the aqueous phase was acidified to pH 7 and the resulting solid filtered, suspended in methanol, treated with HCl in dioxane (4-M, 2 mL), diluted with ether and filtered to give the title compound (82 mg, 48%) as a yellow solid.
  • Method AH
    • 6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-carbonitrile (Example 173)
  • A solution of 2-chloro-6-(2-furyl)-9-(4-methylbenzyl)-9H-purine (0.10 g, 0.31 mmol) and Et4NCN (0.10 g, 0.62 mmol) in acetonitrile (10 mL) was treated with DABCO (0.07 g, 0.62 mmol), stirred for 48 h, concentrated in vacuo, dissolved in chloroform (50 mL), washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (56 mg, 57%) as a pale green solid.
  • Method AI
    • 2-Amino-9-(2-fluorobenzyl)-9H-purine-6-thiocarboxamide
  • A suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-carbonitrile (680 mg, 1.85 mmol) in isopropanol (50 mL) was treated with H2S gas for 15 min, then treated with Et3N (0.51 mL, 3.7 mmol), heated at 50° C. for 1 h, concentrated in vacuo, diluted with Et2O and filtered to give the title compound (757 mg, 100%) as a yellow solid; NMR δH (400 MHz, DMSO) 5.36 (2H, s), 6.66 (2H, br s), 7.06-7.43 (4H, m), 8.15 (1H, s), 9.81 (1H, br s) and 10.22 (1H, br s).
  • Method AJ
    • 9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-purine-2-amine (Example 244)
  • A stirred suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-thiocarboxamide (200 mg, 0.5 mmol) and chloroacetone (1 mL) in isopropanol (5 mL) was heated at 80° C. for 2 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (26 mg, 12%) as a yellow solid.
  • Method AK
    • 2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetimidamide (Example 245)
  • A solution of 2-amino-6-(2-furyl)-9H-purine-9-acetonitrile (0.24 g, 1.0 mmol) in dry toluene (5 mL) under argon was treated with N-benzylmethylchloroaluminium amide in toluene (1.2-M, 5 mL, 6.0 mmol), heated to 80° C. for 3 h, stirred at room temperature for 16 h, poured into a slurry of SiO2 (5 g) and CHCl3 (25 mL) and stirred for 5 min. The slurry was filtered, the filtrate concentrated in vacuo and the resulting solid purified by chromatography [SiO2; CH2Cl2-MeOH—NHOH (100:10:1)] to give the title compound (0.16 g, 46%) as a white solid.
  • Method AL
    • (2S)-9-(2-Amino-1-propyl)-6-(2-furyl)-9H-purine-2-amine (Example 251)
  • A solution of the 6-(2-furyl)-1H-purine-2-amine (0.1 g, 0.5 mmol) in DMSO was treated with fleshly ground KOH (112 mg, 2 mmol), shaken for 10 min, treated with N-butoxycarbonyl-L-alaninol mesylate (316 mg, 3 mmol), shaken at 40° C. for a further 17 h, treated with di-tert-butyl dicarbonate (655 mg, 3 mmol), shaken for a further 30 min, diluted with H2O, extracted with EtOAc and the extracts dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; (EtOAc)]. The resulting gelatinous solid was dissolved in MeOH (3 mL), treated with HCl solution (4-M in dioxan, 0.5 mL), stirred for 17 h, diluted with Et2O and filtered to give the title compound (67 mg, 45%) as a yellow solid.
  • Method AM
    • 9-(2-fluorobenzyl)-6-(1H-pyrazol-3-yl)-9H-purine-2-amine (Example 262)
  • A mixture of 1-(2-trimethylsilylethoxymethyl)-1H-pyrazole-5-boronic acid, Pd(PPh3)4 and saturated aqueous NaHCO3 in THF was refluxed with vigorous stirring for 1 h, cooled, diluted with EtOAc, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (2:1)] to give the coupled product. This material was dissolved in MeOH (2 mL), treated with HCl solution (4-M in dioxan, 2 mL), stirred for 17 h, diluted with Et2O and filtered to give the title compound (161 mg, 46%) as a cream solid.
  • Method AO
    • 9-(3-Aminobenzyl)-6-(5-methyl-1H-pyrazol-3-yl)-1H-purine-2-amine (Example 265)
  • A mixture of 6-chloro-9-(3-nitrobenzyl)-1H-purine-2-amine (304 mg, 1 mmol), 1-((2-trimethylsilylethoxy)methyl)-1H-pyrazole-5-boronic acid (2.4 mmol), Pd(PPh3)4 (110 mg, 10 mol %) and saturated NaHCO3 (5 mL) in THF (20 mL) was refluxed for 3 h, treated with more Pd(PPh3)4 (50 mg, 5 mol %) and refluxed for a further 17 h. The mixture was diluted with H2O (50 mL), extracted with EtOAc (2×25 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (1:2)] to afford a brown gum. This material was treated with MeOH (10 mL) and 10% Pd/C, stirred under an atmosphere of hydrogen for 30 min, filtered through a pad of Celite and concentrated in vacuo. The resulting gum was dissolved in MeOH (5 mL), treated with HCl solution (4-M in dioxane, 1 mL), stirred for 17 h and the filtered to give the title compound (25 mg, 7%) as a grey solid.
  • Method AP
    • 2-Allyloxymethyl-6-bromomethylpyridine
  • A solution of 6-allyloxymethylpyridine-2-methanol (1.56 g, 8.72 mmol) and triphenylphosphine (2.74 g, 10.5 mmol) in dichloromethane (40 mL) at 0° C. was treated portionwise with CBr4 (4.34 g, 13.1 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1)] to give the title compound (1.99 g, 94%) as a colourless oil: NMR H (400 MHz, CDCl3) 7.71 (1H, t, J 7.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 6.03-5.93 (1H, m), 5.37-5.32 (1H, m), 5.26-5.22 (1H, m), 4.64 (2H, s), 4.54 (2H, s) and 4.14-4.12 (2H, m).
  • Method AQ
    • 6-(2-Furyl)-9-(5-indolylmethyl)-1H-purine-2-amine (Example 272)
  • A solution of tert-butyl 5-(2-amino-6-(2-furyl)-1N-purine-9-ylmethyl)indole-1-carboxylate (352 mg, 0.82 mmol) in MeOH (3 mL) was treated with NaOMe (221 mg, 4.1 mmol), refluxed for 17 h, diluted with water (10 mL) and filtered to give the title compound (168 mg, 62%) as a brown powder.
  • Method AR
    • tert-Butyl 5-bromomethylindole-1-carboxylate
  • A solution of tert-butyl 5-methylindole-1-carboxylate (2.07 g, 9.0 mmol) in CCl4 (50 mL) was treated with N-bromosuccinimide (1.60 g, 9.0 mmol) and benzoyl peroxide (75% in H2O, 276 mg, 9.0 mmol), refluxed for 3 h, concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (20:1)] to give the title compound (1.67 g, 60%) as an orange oil: NMR δH (400 MHz, CDCl3) 8.11 (1H, br d, J 8.5 Hz), 6.72 (1H, d, J 3.5 Hz), 7.59 (1H, d, J 1.5 Hz), 7.35 (1H, dd, J 8.5, 1.5 Hz), 6.54 (1H, d, J 4.0 Hz), 4.64 (2H, s) and 1.67 (9H, s).
  • Method AS
    • 6-Allyloxymethyl-2-pyridinemethanol
  • A solution of 2,6-pyridinedimethanol (5.0 g, 35.9 mmol) in DMF (30 mL) at 0° C. was treated with sodium hydride (1.44 g, 35.9 mmol), stirred for 30 min, treated with allyl bromide (3.42 ml, 39.5 mmol), stirred for 16 h at room temperature, poured into water (150 mL), extracted with EtOAc (3×30 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1 to 1:1)] to give the title compound (1.56 g, 24%) as a colourless oil: NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 6.04-5.93 (1H, m), 5.38-5.21 (2H, m), 4.74 (2H, d, J 5.0 Hz), 4.65 (2H, s), 4.15-4.09 (2H, m) and 3.76 (1H, t, J 5.0 Hz).
  • The following intermediates were synthesised by the methods described above.
    • 6-Chloro-9-(3-nitrobenzyl)-1H-purine-2-anine
  • This was prepared from 6-chloro-1H-purine-2-amine by method AC: NMR δH (400 MHz, DMSO) 8.82 (1H, s), 8.20-8.13 (2H, m), 7.73-7.61 (2H, m), 6.94 (2H, br s) and 5.45 (2H, s).
    • 6-Chloro-9-(3-methoxybenzyl)-1H-purine-2-amine
  • This was prepared from 6-chloro-1H-purine-2-amine by method AC: NMR δH (400 MHz, DMSO) 8.22 (1H, s), 7.25 (1H, t, J 7.5 Hz), 6.91 (2H, br s), 6.89-6.84 (2H, m), 6.79 (1H, d, J 7.5 Hz), 5.25 (2×, s) and 3.72 (3H, s).
    • 6-Chloro-9-(2-fluorobenzyl)-1H-purine-2-amine
  • This was prepared from 6-chloro-1H-purine-2-amine by method AC: IR (Nujol)/cm−1 3488, 3379, 2926, 1569, 1568, 1465, 1378, 918 and 756; NMR δH (400 MHz, DMSO) 8.17 (1H, s), 7.43-7.33 (1H, m), 7.29-7.21 (1H, m), 7.20-7.07 (2H, m), 6.91 (2H, br s) and 5.35 (2H, s).
    • 2,6-Dichloro-9-(2-trimethylsilylethoxymethyl)-9H-purine
  • This was prepared from 2,6-dichloro-1H-purine by method X to give the title compound (1.77 g, 78%) as a pale yellow oil; NMR H (400 M, CDCl3) 0.00 (9H, s), 0.94 (2H, t, J 8.3 Hz), 3.63 (2H, t, J 8.3 Hz), 5.63 (2H, s) and 8.25 (1H, s).
    • tert-Butyl 2-amino-6-chloro-9H-purine-9-carboxylate
  • This was prepared from 6-chloro-1H-purine-2-amine and di-tert-butyl dicarbonate by method G to give title compound (862 mg, 64%) as a white solid; mp>350° C.; IR νmax (Nujol)/cm−1 3521, 3304, 3193, 3129, 2955, 2925, 2854, 1772, 1730, 1632, 1561, 1511, 1367, 1308 and 1155; NMR δH (400 MHz, DMSO) 1.58 (9H, s), 7.06 (2H, s), 8.36 (1H, s). Anal. Calcd for C10H12ClN5O2: C, 44.54; H, 4.48; N, 25.96. Found: C, 44.27; H, 4.54; N, 25.88.
    • Isobutyl 2-amino-6-chloro-9H-purine-9-carboxylate
  • This was prepared from 6-chloro-1H-purine-2-amine by method T to give the title compound (528 mg, 98%) as a white solid; IR νmax (Nujol)/cm−1 3519, 3310, 3201, 3124, 2955, 2925, 2854, 1778, 1624, 1560, 1469, 1367, 1301 and 1186; NMR δH (400 MHz, CDCl3) 1.07 (6H, d, J 7.0 Hz), 2.10-2.25 (1H, m), 4.29 (2H, d, J 6.6 Hz), 5.48 (2H, s) and 8.25 (1H, s).
    • 2-Amino-N-tert-butyl-6-chloro-9H-purine-9-carboxamide
  • This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (286 mg, 53%) as a white solid; IR νmax (Nujol)/cm−1 3501, 3299, 3190, 3156, 2993, 2955, 2924, 2854, 1742, 1627, 1563, 1506 and 1369; NMR δH (400 MHz, CDCl3) 1.46 (9H, s), 7.40 (1H, s), 8.45 (1H, s) and 8.57 (1H, s).
    • Phenyl 2-amino-6-chloro-9H-purine-9-carboxylate
  • This was prepared from 6-chloro-1H-purine-2-amine by method T to give the crude title compound (625 mg, 100%) as a white solid.
    • 2-Amino-6-chloro-N-phenyl-9H-purine-9-carboxamide
  • This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (424 mg, 73%) as a white solid; IR νmax (Nujol)/cm−1 3506, 3333, 3292, 3191, 3140, 2925, 2854, 1740, 1653, 1637, 1562, 1481 and 1367; NMR δH (400 MHz, DMSO) 7.20 (1H, m), 7.44-7.50 (2H, m), 7.61 (2H, s), 7.75-7.81 (2H, m), 8.60 (1H, s), 10.86 (1H, s).
    • 2-Amino-6-chloro-N-ethyl-9H-purine-9-carboxamide
  • This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (449 mg, 93%) as a white solid; IR νmax (Nujol)/cm−1 3404, 3324, 3304, 3222, 3125, 2925, 2854, 1730, 1646, 1614, 1547, 1514, 1484, 1460, 1370 and 1228; NMR δH (400 MHz, DMSO) 1.25 (3H, t, J 7.0 Hz), 3.37-3.46 (2×, m), 7.37 (2H, s), 8.47 (1×, s), 8.64 (1H, t, J 5.5 Hz).
    • 2-Amino-6-chloro-N-cyclohexyl-9H-purine-9-carboxamide
  • This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (1.66 g, 53%) as a white solid; NMR δH (400 MHz, CDCl3) 1.29-1.41 (1H, m), 1.42-1.54 (4H, m), 1.60-1.70 (1H, m), 1.74-1.86 (2H, m), 2.00-2.10 (2H, m), 3.88-4.00 (1H, m), 8.13 (1H, d, J 6.7 Hz) and 8.81 (1H, s).
    • 2-Amino-9-(2-fluorobenzyl)-9H-purine-6-carbonitrile
  • This was prepared from 6-chloro-9-(2-fluorobenzyl)-9H-purine-2-amine by method AH to give the title compound (450 mg, 84%) as a cream solid; NMR δH (400 MHz, DMSO) 5.39 (2H, s), 7.12 (2H, br s), 7.1207.45 (4H, m) and 8.41 (1H, s).
  • Table 2—Analytical Data
  • HPLC is carried out using the following conditions: Column. Waters Xterra RP 18 (50×4.6 mm); Particle size 5 μM; Mobile phase MeOH:10 mM aq NH4OAc (pH 7 buffer); Gradient 50:50 isocratic for 1 min. then linear gradient 50:50 to 80:20 over 5 min. then 80:20 isocratic for 3 mL/min.; Flow rate 2.0 mL/min.; Detection wavelength λ=230 nM. Retention times are provided in Table 2.
  • Alternatively HPLC is carried out using the following conditions: Column. Supelcosil ABZ+ (170×4.6 mm), particle size 5 μM, mobile phase MeOH: 10 mM aq NH4OAc (80:20), (80:50), (70:30), (60:40) or (50:20) (specified in Table 2), flow rate 1.0 mL/min., detection wavelength λ=230 nM. Retention times and mobile phase ratio are provided in
    TABLE 2
    Example Method Yield(%) Data
    1 A 70 mp 105.8-106.2° C.; IR νmax(Nujol)/cm−1 3552, 3146, 3892, 3082, 2954, 2924,
    2854, 1589, 1566, 1484, 1370, 1319, 1250, 1219 1162, 1095 and 841; NMR
    δH(400MHz, CDCl3) 0.0(9H, s), 0.97(2H, t, J 8.3Hz), 3.66(2H, t, J 8.3Hz),
    5.66(2H, s), 6.69-6.73(1H, m), 7.82(1H, s), 7.92(1H, d, J 3.5Hz) and 8.24(1H, s);
    Anal. Calcd for C15H19ClN4O2Si: C, 51.35; H, 5.46; N, 15.96. Found: C, 51.39; H,
    5.45; N, 15.97.
    2 B 86 mp 81.5-82.2° C.; IR νmax(Nujol)/cm−1 3142, 3109, 2927, 2854, 1601, 1585,
    1560, 1465, 1397, 1372 and 1106; NMR δH(400MHz, DMSO) −0.04(9H, s),
    0.95(2H, t, J 8.3Hz), 3.29(6H, s), 3.64(2H, t, J 8.3Hz), 5.51(2H, s),
    6.60-6.63(1H, m), 7.67(1H, d, J 2.5Hz); 7.73-7.74(1H, m) and 7.87(1H, s); Anal.
    Calcd for C17H25N5O2Si: C, 56.80; H, 7.01; N, 19.47. Found: C, 56.40; H, 6.98; N,
    19.27.
    3 C 76 IR νmax(Nujol)/cm−1 3132, 3105, 2924, 2854, 1631, 1588, 1563, 1538, 1466,
    1401, 1364, 832 and 780; NMR δH(400MHz, DMSO) 3.21(6H, s),
    6.74-6.80(1H, m), 7.77(1H, d, J 2.9Hz), 8.00(1H, s), 8.11(1H, s), 12.76(1H, s); Anal.
    Calcd for C11H11N5O.0.1 H2O: C, 57.18; H, 4.89; N, 30.31. Found: C, 57.14; H,
    4.81; N, 30.26.
    4 B 60 mp 125.9-126.4° C.; IR νmax(Nujol)/cm−1 3376, 3327, 2955, 2924, 2854, 1605,
    1588, 1537, 1462, 1410, 1367, 1356, 1248, 1094 and 835; NMR δH(400MHz,
    CDCl3) −0.03(9H, s), 0.94(2H, t, J 8.3Hz), 1.21(1H, d, J 6.5Hz), 3.61(2H, t, J
    8.3Hz), 3.69(2H, q, 5.6Hz), 3.90(2H, q, J 4.8Hz), 5.49(2H, s),
    5.56-5.64(1H, m), 6.62-6.66(1H, m), 7.72(1H, d, J 5.6Hz) and 7.79(1H, d, J 3.5Hz).
    5 C 86 mp 227.1-228.1° C.; IR νmax(Nujol)/cm−1 3428, 3113, 2924, 2854, 1626, 1588,
    1576, 1541, 1485, 1457, 1404 and 1371; NMR δH(400MHz, DMSO) 3.41(2H,
    q, J 6.0Hz), 3.53-3.62(2H, m), 4.67-4.76(1H, s), 6.74-6.79(1H, m),
    6.81-6.94(1H, s), 7.69-7.78(1H, s), 7.98(1H, s), 8.05-8.15(1H, s) and
    12.68-12.81(1H, s).
    7 A 48 mp >305° C. dec.; IR νmax(Nujol)/cm−1 3130, 3111, 2925, 2854, 1776, 1755, 1596,
    1558, 1467, 1373, 1302, 1288, 1153 and 1135; NMR δH(400MHz, CDCl3)
    1.71(9H, s), 6.63-6.72(1H, m), 7.78-7.81(1H, m), 7.90(1H, d J 3.5Hz) and
    8.50(1H, s); Anal. Calcd for C14H13ClN4O3: C, 52.43; H, 4.09; N, 17.46. Found: C,
    52.68; H, 4.08; N, 17.50.
    8 A 61 mp >303° C. dec.; IR νmax(Nujol)/cm−1 3101, 3042, 2927, 2854, 1628, 1556, 1448,
    1364, 1283, 1166, 1023, 921, 837 and 752; NMR δH(400MHz, DMSO)
    6.84-6.91(1H, m), 7.73-7.93(1H, s), 8.13(1H, s), 8.65-8.75(1H, s) and
    13.71-13.84(1H, s); Anal. Calcd for C9H5ClN4O: C, 49.00; H, 2.28; N, 25.38. Found: C,
    48.78; H, 2.54; N, 25.10.
    9 B 64 mp 130.9-131.5° C.; IR νmax(Nujol)/cm−1 3526, 3218, 3111, 3070, 2924, 2855,
    2733, 1629, 1600, 1560, 1518, 1463, 1375 and 835; NMR δH(400MHz, DMSO)
    1.85-2.08(4H, m), 3.42-3.66(3H, m), 3.67-3.78(1H, m), 4.15-4.25(1H, s),
    4.81-5.09(1H, s), 6.76-6.80(1H, m), 7.73-7.79(1H, s), 8.01(1H, s),
    8.09-8.16(1H, s) and 12.78-12.87(1H, s); Anal. Calcd for C14H15N5O2: C, 56.27; H,
    5.57; N, 23.44. Found: C, 56.35; H, 5.52; N, 23.18.
    10 B 50 mp >206.5-207.4° C.; IR νmax(Nujol)/cm−1 3389, 3121, 2924, 2854, 1620, 1590,
    1570 1539, 1515, 1465 and 1026; NMR δH(400MHz, DMSO) 3.71(3H, s),
    3.73(3H, s), 4.49(2H, d, J 5.9Hz), 6.77(1H, s), 6.82-6.94(2H, m), 7.06(1H, s),
    7.41-7.56(1H, s), 7.76(1H, s), 7.98(1H, s), 8.08(1H, s) and 12.72(1H, s);
    Anal. Calcd for C14H15N5O2.0.5 H2O: C, 59.99; H, 5.03; N, 19.43. Found: C,
    59.81; H, 4.75; N, 19.07.
    11 D 57 mp >230° C. dec.; IR νmax(Nujol)/cm−1 3370, 3134, 3085, 2924, 2854, 2481, 1674,
    1616 and 1465; NMR δH(400MHz, DMSO) 6.91-6.97(1H, m), 7.91(1H, s),
    8.25(1H, s) and 8.71(1H, s); M/Z 202(M+H)+.
    12 E 32 mp 112.0-113.0° C.; IR νmax(Nujol)/cm−1 3113, 2925, 2854, 1775, 1749, 1596,
    1460, 1374, 1303, 1139 and 762; NMR δH(400MHz, CDCl3) 1.72(9H, s),
    2.68(3H, s), 6.63-6.68(1H, m), 7.77(1H, s), 7.82(1H, d, J 3.6Hz) and 8.44(1H, s).
    13 F 86 mp 239.5-239.9° C.; IR νmax(Nujol)/cm−1 3371, 3044, 2924, 2854, 2703, 1624,
    1606, 1584, 1563, 1465, 1307 and 843; NMR δH(400MHz, DMSO) 2.61(3H, s),
    3.93-5.45(2H, s), 6.80-6.86(1H, m), 7.79(1H, d, J 3.6Hz), 8.07-8.09(1H,
    m) and 8.53(1H, s); Anal. Calcd for C10H8N4O5.0.25 HCl.0.5 H2O: C, 48.26;
    H, 3.71; N, 22.14. Found: C, 47.97; H, 3.72; N, 22.38.
    14 A 69 mp 143.2-144.1° C.; IR νmax(Nujol)/cm−1 3512, 3394, 3324, 3215, 2955, 2925,
    2854, 1769, 1749, 1639, 1587, 1565, 1372, 1298 and 1143; NMR δH(400MHz,
    CDCl3) 1.68(9H, s), 5.38(2H, s), 6.62-6.66(1H, m), 7.71-7.73(1H, m),
    7.82(1H, d, J 3.6Hz) and 8.17(1H, s); Anal. Calcd for C14H15N5O3: C, 55.81; H, 5.02;
    N, 23.23. Found: C, 55.73; H, 5.06; N, 22.84.
    15 B 45 mp 185.5-186° C.; IR νmax(Nujol)/cm−1 3307, 3141, 3077, 2954, 2924, 2854,
    1604, 1542, 1460, 1368, 1247 and 1093; NMR δH(400MHz, CDCl3) 0.00(9H,
    s), 0.97(2H, t, J 8.3Hz), 3.66(2H, t, J 8.3Hz), 4.19(2H, t, J 5.8Hz),
    5.15-5.20(1H, m), 5.30-5.37(1H, m), 5.54(2H, s), 5.96-6.09(1H, m), 6.63-6.69(1H,
    m), 7.74-7.76(1H, m), 7.81(1H, d, J 3.5Hz) and 7.92(1H, s); Anal. Calcd for
    C18H25N5O2Si: C, 58.19; H, 6.78; N, 18.84. Found: C, 58.14; H, 6.80; N, 18.73.
    16 B 82 mp 160.1-160.8° C.; IR νmax(Nujol)/cm−1 3312, 3143, 3095, 2924, 2854, 1605,
    1580, 1552, 1467, 1396, 1367, 1249 and 1092; NMR δH(400MHz, CDCl3)
    0.00(9H, s), 0.99(2H, t, J 8.3Hz), 3.11(3H, d, J 5.0Hz), 3.68(2H, t, J 8.3Hz),
    5.21-5.29(1H, s), 5.56(2H, s), 6.64-6.69(1H, m), 7.74(1H, s), 7.81(1H, d, 2.9Hz)
    and 7.91(1H, s); Anal. Calcd for C16H23N5O2Si.0.2 H2O: C, 55.05; H, 6.76;
    N, 20.06. Found: C, 55.03; H, 6.60; N, 20.12.
    17 C 58 mp 158.7-160.1° C.; IR νmax(Nujol)/cm−1 3397, 3528, 3084, 2924, 2854, 1626,
    1592, 1536 and 1460; NMR δH(400MHz, DMSO) 3.99(2H, t, J 4.9Hz),
    5.06(1H, d, J 10.2Hz), 5.21(1H, d, J 18.9Hz), 5.91-6.03(1H, m), 6.72-6.79(1H,
    m), 7.12-7.20(1H, s), 7.76(1H, d, J 3.0Hz), 7.97(1H, s) and 8.08(1H, s).
    18 C 81 mp 235-236° C. dec.; IR νmax(Nujol)/cm−1 3311, 3102, 2924, 2854, 1630, 1587,
    1555, 1460, 1400 and 1370; NMR δH(400MHz, DMSO) 2.87(3H, d, J 4.8Hz),
    6.74-6.78(1H, m), 6.90-7.01(1H, s), 7.76(1H, d, J 3.5Hz), 7.96(1H, s) and
    8.07(1H, s).
    19 A 41 mp 177.6-178.2° C.; IR νmax(Nujol)/cm−1 3511, 3406, 3289, 3254, 3164, 3132,
    2924, 2854, 1723, 1636, 1600, 1588, 1549, 1467 and 1403; NMR δH(400MHz,
    DMSO) 1.23-1.34(1H, m), 1.36-1.54(4H, m), 1.58-1.68(1H, m),
    1.73-1.81(2H, m), 1.94-2.06(2H, m), 3.73-3.84(1H, m), 6.75-6.81(1H, m),
    6.91(1H, s), 7.76(1H, d, J 2.6Hz), 7.99(1H, s), 8.44(1H, s) and 8.80(1H, d, J 7.5Hz).
    20 A 24 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3368, 3323, 3217, 3140, 3128, 2956, 2925,
    2855, 1750, 1641, 1590, 1565, 1468, 1400, 1371, 1274 and 995; NMR δH(400MHz,
    DMSO) 1.04(6H, d, J 6.3Hz), 2.03-2.19(1H, m), 4.23(2H, d, J 7.0Hz),
    6.77-6.81(1H, m), 6.85(2H, s), 7.74(1H, d, J 3.6Hz), 8.01(1H, s) and
    8.46(1H, s); Anal. Calcd for C14H15N5O3: C, 55.81; H, 5.02; N, 23.23. Found: C,
    55.84; H, 5.08; N, 23.24.
    21 A 73 mp 295° C. dec.; IR νmax(Nujol)/cm−1 3517, 3310, 3269, 3190, 3127, 3082, 2924,
    2854, 1734, 1644, 1627, 1603, 1561, 1468 and 1369; NMR δH(400MHz, CDCl3)
    1.52(9H, s), 5.14(2H, s), 6.62-6.70(1H, m), 7.72-7.74(1H, m), 7.86(1H, d, J
    3.5Hz), 8.47(1H, s) and 8.59(1H, s); Anal. Calcd for C14H16N6O2: C, 55.99; H,
    5.37; N, 27.97. Found: C, 55.78; H, 5.35; N, 27.79.
    22 A 75 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3499, 3298, 3179, 3117, 2924, 2854, 1790,
    1635, 1589, 1373, 1302 and 1193; NMR δH(400MHz, DMSO) 6.78-6.82(1H,
    m), 6.96(2H, s), 7.37-7.44(1H, m), 7.44-7.50(2H, m), 7.50-7.59(2H, m),
    7.75-7.77(2H, m), 8.02-8.03(1H, m) and 8.65(1H, s); Anal. Calcd for
    C16H11N5O3.0.25 H2O: C, 58.99; H, 3.56; N, 21.50. Found: C, 58.79; H, 3.32; N,
    21.82.
    23 A 26 mp >330° C. dec.; IR νmax(Nujol)/cm−1 2924, 2854, 1678, 1613, 1597, 1568, 1355,
    1288 and 751; NMR δH(400MHz, DMSO) 6.88-6.93(1H, m), 7.09(1H, t, J 7.4Hz),
    7.41(2H, t, J 8.1Hz), 7.75(1H, d, J 8.0Hz), 7.92(1H, s), 8.24(1H, s),
    8.48(1H, s), 10.02(1H, s), 12.35(1H, s) and 13.42(1H, s); Anal. Calcd for
    C16H12N6O2: C, 60.00; H, 3.78; N, 26.22. Found: C, 59.60; H, 3.75; N, 26.01; M/Z
    321(M+H)+.
    24 A 74 mp >280° C. dec.; IR νmax(Nujol)/cm−1 3510, 3292, 3161, 3112, 3053, 2955, 2925,
    2854, 1749, 1725, 1645, 1603, 1591, 1567, 1468, 1401, 1372 and 748; NMR
    δH(400MHz, DMSO) 1.26(3H, t, J 7.2Hz), 3.38-3.49(2H, m), 6.78-6.83(1H,
    m), 7.05(2H, s), 7.77(1H, d, J 3.5Hz), 8.02-8.04(1H, s), 8.48(1H, s) and
    8.86(1H, t, J 5.5Hz); Anal. Calcd for C12H12N6O2: C, 52.94; H, 4.44; N, 30.85. Found:
    C, 52.94; H, 4.59; N, 30.65.
    25 A 21 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3392, 3315, 3193, 3135, 3114, 2924, 2854,
    1728, 1641, 1601, 1557, 1509, 1479, 1468, 1405, 1377, 1270, 1240 and 763;
    NMR δH(400MHz, DMSO) 6.80-6.85(1H, m), 7.23(1H, t, J 7.4Hz),
    7.31(2H, s), 7.48(2H, t, J 8.0Hz), 7.78-7.85(3H, m), 8.04-8.07(1H, m), 8.60(1H,
    s) and 11.13(1H, s); Anal. Calcd for C16H12N6O2.0.5 H2O: C, 58.36; H, 3.98; N,
    25.52. Found: C, 58.38; H, 3.70; N, 25.61.
    26 G 84 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3515, 3279, 3187, 3131, 2924, 2854, 1725,
    1631, 1600, 1552, 1465, 1400 and 1373; NMR δH(400MHz, DMSO) 4.66(2H,
    d, J 6.2Hz), 6.79-6.83(1H, m), 7.06(2H, s), 7.29-7.45(5H, m), 7.78(1H, d, J
    3.5Hz), 8.03(1H, s), 8.53(1H, s) and 9.34(1H, t, J 6.2Hz); Anal. Calcd for
    C17H14N6O2.0.1 H2O: C, 60.74; H, 4.26; N, 25.00. Found: C, 60.94; H, 4.25; N,
    24.67.
    27 H 53 mp 238.7-239.2° C.; IR νmax(Nujol)/cm−1 3500, 3343, 3221, 3135, 3064, 2925,
    2854, 1628, 1593, 1566, 1478, 1383, 1349, 1146 and 1065; NMR δH(400MHz,
    DMSO) 1.29(9H, s), 6.65-6.79(1H, m), 7.05(2H, s), 7.69(1H, d, J 3.5Hz),
    7.73(2H, d, J 9.1Hz), 7.98-8.01(1H, m), 8.19(2H, d, J 8.6Hz) and 8.53(1H,
    s); Anal. Calcd for C19H19N5O3S.0.1 H2O: C, 57.16; H, 4.85; N, 17.54. Found: C,
    57.04; H, 4.86; N, 17.22.
    28 H 65 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3497, 3283, 3158, 3129, 2931, 2854, 1720,
    1627, 1593, 1467, 1392, 1360, 1259, 1180 and 746; NMR δH(400MHz, DMSO)
    1.23-1.35(1H, m), 1.39-1.58(4H, m), 1.69-1.82(3H, m), 1.95-2.04(2H,
    m), 3.94-4.03(1H, m), 6.77-6.80(1H, m), 6.91(2H, m), 7.74(1H, d, J 3.5Hz),
    7.99-8.09(1H, m) and 8.56(1H, s).
    29 I 62 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3414, 3312, 3206, 3137, 3118, 2922, 2854,
    1681, 1629, 1588, 1565, 1464, 1403, 1368 and 1194; NMR δH(400MHz, DMSO)
    1.82-2.01(4H, m), 3.49-3.63(4H, m), 6.76-6.80(1H, m), 6.81(2H, s),
    7.72-7.77(1H, m), 8.06(1H, s) and 8.31(1H, s).
    30 G 92 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3550, 3378, 3309, 3242, 3139, 3054, 2924,
    2854, 1715, 1640, 1603, 1588, 1543, 1465 and 1377; NMR δH(400MHz, DMSO)
    1.32(6H, d, J 6.6Hz), 3.98-4.10(1H, m), 6.78-6.81(1H, m), 7.08(2H, s),
    7.76(1H, d, J 3.5Hz), 8.01-8.04(1H, m), 8.47(1H, s) and 8.79(1H, d, J 7.4Hz);
    Anal. Calcd for C13H14N6O2.0.9 H2O: C, 51.62; H, 5.26; N, 27.78. Found:
    C, 51.80; H, 5.04; N, 27.51.
    31 A 38 mp 177.4-177.8° C.; IR νmax(Nujol)/cm−1 3304, 3126, 3106, 2926, 2854, 1726,
    1597, 1567, 1548, 1465, 1377 and 768; NMR δH(400MHz, DMSO)
    1.29-1.41(1H, m), 1.44-1.53(4H, m), 1.60-1.69(1H, m), 1.75-1.85(2H, m),
    2.00-2.10(2H, m), 3.89-4.00(1H, m), 6.67-6.72(1H, m), 7.80-7.82(1H, m) and
    7.94(1H, d, J 3.5Hz).
    33 H 17 mp 175.4-176.1° C.; IR νmax(Nujol)/cm−1 3497, 3294, 3173, 3122, 2924, 2854,
    1729, 1623, 1595, 1463, 1392, 1376 and 1359; NMR δH(400MHz, CDCl3)
    1.09(6H, d, 6.5Hz), 2.27-2.42(1H, m), 3.24(2H, d, J 6.3Hz), 5.16(1H, s),
    6.62-6.66(1H, m), 7.70-7.73(1H, m), 7.82(1H, d, J 3.5Hz) and 8.48(1H, s); Anal.
    Calcd for C14H15N5O2: C, 58.94; H, 5.30; N, 24.54. Found: C, 58.84; H, 5.30; N,
    24.19.
    34 H 14 mp >300° C. dec.; NMR δH(400MHz, CDCl3) 2.94(3H, s), 5.21(2H, s),
    6.62-6.69(1H, m), 7.72(1H, s), 7.83(1H, d, J 3.6Hz) and 8.48(1H, s).
    35 G 82 mp 175.5° C.; IR νmax(Nujol)/cm−1 3282, 3131, 3116, 3033, 2924, 2854, 1735,
    1587, 1576, 1538, 1478, 1462, 1375, 1294 and 1201; NMR δH(400MHz, CDCl3)
    2.35(3H, s), 4.69(2H, d, J 5.5Hz), 6.63-6.67(1H, m), 7.33-7.44(5H, m),
    7.77-7.78(1H, m), 7.84(1H, d, J 3.4Hz), 8.65(1H, s) and 8.96-9.03(1H, s);
    Anal. Calcd for C18H15N5O2S: C, 59.17; H, 4.14; N, 19.16. Found: C, 59.00; H,
    4.14; N, 18.95.
    36 G 100 IR νmax(Nujol)/cm−1 3399, 3317, 3204, 1717, 1643, 1603, 1557, 1510, 1403, 1268
    and 1232; NMR δH(400MHz, DMSO) 0.94(3H, t, J, 7.3Hz), 1.39(2H, sextet, J
    7.4Hz), 1.61(2H, quintet, J 7.3Hz), 3.38(2H, q, J 6.5Hz), 6.78(1H, dd, J 1.5,
    3.5Hz), 7.02(2H, br s), 7.74(1H, dd, J 1.0, 3.5Hz), 8.00(1H, dd, J 1.0, 1.5Hz),
    8.46(1H, s) and 8.83(1H, t, J 5.4Hz); Retention time: 4.12min
    37 G 100 NMR δH(400MHz, DMSO) 3.74(3H, s), 4.55(2H, d, J 5.9Hz), 6.78(1H, dd, J
    1.5, 3.5Hz), 6.93(2H, d, J 8.5Hz), 7.01(2H, br s), 7.33(2H, d, J 8.5Hz),
    7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, m), 8.49(1H, s) and 9.23(1H, t, J 6.3Hz);
    Retention time: 4.62min
    38 G 97 NMR δH(400MHz, DMSO) 2.29(3H, s), 4.58(2H, d, J 6.1Hz), 6.78(1H, dd, J
    1.5, 3.5Hz), 7.01(2H, br s), 7.17(2H, d, J 8.0Hz), 7.29(2H, d, J 8.0Hz),
    7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.50(1H, s) and 9.26(1H, t, J
    6.3Hz); Retention time: 5.55min
    39 G 100 NMR δH(400MHz, DMSO) 4.69(2H, d, J 6.6Hz), 6.79(1H, dd, J 1.5, 3.5Hz),
    7.00(2H, br s), 7.36(2H, m), 7.51(2H, m), 7.76(1H, dd, J 1.0, 3.5Hz), 8.02(1H,
    m), 8.50(1H, s) and 9.41(1H, t, J 6.4Hz); Retention time: 5.63min
    40 G 96 NMR δH(400MHz, DMSO) 6.77(1H, dd, J 1.5, 3.5Hz), 7.00(2H, br s),
    7.42-7.68(7H, m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.22(1H,
    s) and 9.21(1H, s); Retention time: 6.94min; (80:50).
    41 G 70 NMR δH(400MHz, DMSO) 0.86(3H, t, J 6.8Hz), 1.22-1.39(10H, m),
    3.37(2H, q, J 6.7Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.02(2H, br s), 7.74(1H, dd, J 1.0,
    3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.46(1H, s) and 8.84(1H, t, J 5.7Hz);
    Retention time: 6.96min
    42 G 100 NMR δH(400MHz, DMSO) 2.44(3H, s), 6.81(1H, dd, J 2.0, 3.5Hz), 7.10(2H,
    br s), 7.16(2H, m), 7.29(1H, m), 7.34(1H, m), 7.78(1H, m), 8.03(1H, m),
    8.60(1H, s) and 10.64(1H, s); Retention time: 3.82min
    43 G 90 NMR δH(400MHz, DMSO) 2.37(3H, s), 6.80(1H, dd, J 1.5, 3.5Hz), 7.02(1H,
    m), 7.32(3H, m), 7.61(2H, m), 7.77(1H, br d, J 3.5Hz), 8.03(1H, d, J 1.0Hz),
    8.57(1H, s) and 11.05(1H, s); Retention time: 6.54min
    44 G 91 NMR δH(400MHz, DMSO) 6.81(1H, dd, J 1.5, 3.5Hz), 7.03(2H, br s),
    7.07(1H, m), 7.27(1H, m), 7.46(1H, m), 7.79(1H, dd, J 1.0, 3.5Hz), 8.04(1H, m),
    8.27(1H, m), 8.62(1H, s) and 11.12(1H, s); Retention time: 6.65min
    45 G 87 NMR δH(400MHz, DMSO) 1.60(3H, d, J 7.0Hz), 5.11(1H, quintet, J 7.2Hz),
    6.78(1H, dd, J 1.5, 3.5Hz), 7.13(2H, br s), 7.29(1H, m), 7.38(2H, m), 7.45(2H,
    m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.02(1H, m), 8.45(1H, s) and 9.34(1H, d, J 8.0Hz);
    Retention time: 5.11min
    46 G 91 NMR δH(400MHz, DMSO) 1.60(3H, d, J 7.0Hz), 5.12(1H, quintet, J 7.1Hz),
    6.79(1H, dd, J 1.5, 3.5Hz), 7.13(2H, br s), 7.29(1H, m), 7.38(2H, m), 7.46(2H,
    m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.44(1H, s) and
    9.34(1H, d, J 8.0Hz); Retention time: 5.14min
    47 G 96 NMR δH(400MHz, DMSO) 2.30(3H, s), 4.59(2H, d, J 6.2Hz), 6.79(1H, dd, J
    2.0, 3.5Hz), 7.02(2H, br s), 7.09(1H, m), 7.20(2H, m), 7.26(1H, m), 7.75(1H,
    br d, J 3.5Hz), 8.01(1H, m), 8.50(1H, s) and 9.28(1H, d, J 6.1Hz); Retention
    time: 5.63min
    48 G 89 NMR δH(400MHz, DMSO) 2.32(3H, s), 6.80(1H, dd, J 2.0, 3.5Hz), 7.25(2H,
    d, J 8.0Hz), 7.28(2H, br s), 7.68(2H, d, J 8.0Hz), 7.77(1H, br d, J 3.1Hz),
    8.03(1H, m), 8.57(1H, s) and 11.02(1H, s); Retention time: 6.66min
    49 G 100 NMR δH(400MHz, DMSO) 3.99(3H, s), 6.80(1H, dd, J 1.5, 3.5Hz), 6.89(2H,
    br s), 7.01(1H, m), 7.17(2H, m), 7.79(1H, dd, J 1.0, 3.5Hz), 8.04(1H, m),
    8.16(1H, m), 8.60(1H, s) and 10.98(1H, s); Retention time: 6.28min
    50 G 77 NMR δH(400MHz, DMSO) 3.78(3H, s), 6.80(1H, dd, J 1.5, 3.5Hz), 7.02(2H,
    d, J 9.1Hz), 7.26(2H, br s), 7.69(2H, d, J 9.0Hz), 7.77(1H, dd, J 1.0, 3.5Hz),
    8.03(1H, dd, J 1.0, 1.5Hz), 8.56(1H, s) and 10.93(1H, s); Retention time: 5.70min
    51 G 100 NMR δH(400MHz, DMSO) 6.38(2H, br s), 6.80(1H, dd, J 2.0, 3.5Hz),
    7.52(2H, d, J 9.0Hz), 7.77(1H, br d, J 3.5Hz), 7.84(2H, m, J 9.0Hz), 8.03(1H, m),
    8.58(1H, s) and 11.21(1H, s); Retention time: 7.19min
    52 G 62 NMR δH(400MHz, DMSO) 0.90(3H, t, J 7.1Hz), 1.35(4H, m), 1.63(2H,
    quintet, J 7.2Hz), 3.37(2H, q, J 6.7Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.02(2H,
    br s), 7.74(1H, dd, J 0.5, 3.5Hz), 8.01(1H, m), 8.46(1H, s) and 8.84(1H, t, J 5.8Hz);
    Retention time: 5.27min
    53 G 81 NMR δH(400MHz, DMSO) 0.83(3H, t, J 6.8Hz), 1.19-1.38(18H, m),
    1.62(2H, quintet, J 7.0Hz), 3.37(2H, q, J 6.4Hz), 6.78(1H, dd, J 1.5, 3.5Hz),
    7.02(2H, br s), 7.75(1H, dd, J 0.5, 3.5Hz), 8.01(1H, m), 8.46(1H, s) and 8.84(1H, t,
    J 5.9Hz); Retention time: 10.76min
    54 K 57 IR νmax(Nujol)/cm−1 3431, 3384, 3334, 3220, 3122, 1665, 1648, 1587, 1564,
    1302, 1210 and 1130; NMR δH(400MHz, CDCl3) 1.01(2H, m), 1.17-1.32(4H,
    m), 1.66-1.82(7H, m), 4.14(2H, t, J 7.5Hz), 6.32(2H, br s), 6.69(1H, m),
    7.81(1H, m), 7.89(1H, m) and 7.99(1H, m); M/Z 312(M+H)+; Retention time: 5.09min
    55 G 63 IR νmax(Nujol)/cm−1 3320, 3218, 3109, 3029, 2926, 2854, 1734, 1601, 1587, 1550,
    1464 and 1375; NMR δH(400MHz, DMSO) 3.31(6H, s), 4.66(2H, d, J 5.5Hz),
    6.80-6.82(1H, m), 7.30-7.36(1H, m), 7.38-7.43(2H, m), 7.44-7.50(2H, m),
    7.80(1H, d, J 3.5Hz), 8.05-8.07(1H, m), 8.53(1H, s) and 9.11(1H, t, J 5.0Hz);
    Anal. Calcd for C19H18N6O2.0.25 H2O: C, 62.20; H, 5.08; N, 22.91. Found:
    C, 62.42; H, 5.01; N, 22.58.
    56 H 86 mp 212.6-213° C.; IR νmax(Nujol)/cm−1 3138, 2925, 2854, 1601, 1555, 1463,
    1372, 1352, 1183, 670 and 584; NMR δH(400MHz, DMSO) 2.41(3H, s),
    3.21(6H, s), 6.76-6.80(1H, m), 7.53(2H, d, J 7.9Hz), 7.72(1H, d, J 3.5Hz),
    8.02-8.04(1H, m), 8.12-8.16(2H, m) and 8.54(1H, s); Anal. Calcd for C18H17N5O3S:
    C, 56.39; H, 4.47; N, 18.26. Found: C, 56.20; H, 4.48; N, 18.23.
    57 K 21 NMR δH(4.00MHz, CDCl3) 4.89(2H, dd, J 1.5, 6.0Hz), 5.09(2H, br s),
    6.37(1H, dt, J 6.0, 16.0Hz), 6.59(1H, dt, J 1.5, 16.0Hz), 6.64(1H, dd, J 1.5, 3.5Hz),
    7.28-7.38(5H, m), 7.72(1H, dd, J 1.0, 1.5Hz), 7.82(1H, dd, J 1.0, 3.5Hz) and
    7.84(1H, s); M/Z 318(M+H)+; Retention time: 3.82min
    58 K 18 NMR δH(400MHz, CDCl3) 1.74(3H, m), 4.65(2H, m), 5.06(2H, br s),
    5.71(2H, m), 6.63(1H, dd, J 1.5, 3.5Hz), 7.71(1H, dd, J 1.0, 1.5Hz), 7.78(1H, s)
    and 7.80(1H, dd, J 1.0, 3.5Hz); M/Z 256(M+H)+; Retention time: 1.19min
    59 K 40 M/Z 258(M+H)+; Retention time: 1.40min
    60 K 20 M/Z 270(M+H)+; Retention time: 1.43min
    61 K 18 M/Z 244(M+H)+; Retention time: 0.87min
    62 K 34 NMR δH(400MHz, CDCl3) 1.68(2H, quintet, J 7.5Hz), 1.92(2H, quintet, J 7.5Hz),
    2.67(2H, t, J 7.5Hz), 4.12(2H, t, J 7.1Hz), 5.63(2H, br s), 6.67(1H, br s),
    7.12-7.30(5H, m), 7.77(2H, m) and 7.89(1H, m); Retention time: 4.60min
    63 K 43 NMR δH(400MHz, CDCl3) 3.79(2H, t, J 5.0Hz), 4.30(2H, t, J 4.8Hz),
    4.51(2H, s), 6.17(2H, br s), 6.69(1H, dd, J 1.5, 3.5Hz), 7.20-7.32(5H, m),
    7.80(1H, m), 7.98(1H, m) and 8.00(1H, s); Retention time: 1.88min
    64 K 19 NMR δH(400MHz, CDCl3) 0.99(6H, d, J 6.5Hz), 1.62(1H, septet, J 6.6Hz),
    1.78(2H, q, J 7.4Hz), 4.13(2H, t, J 7.2Hz), 5.15(2H, br s), 6.63(1H, m),
    7.71(1H, m) and 7.80(2H, m); Retention time: 2.21min
    65 K 31 NMR δH(400MHz, CDCl3) 1.82(6H, d, J 6.6Hz), 4.68(2H, d, J 7.0Hz),
    5.41(1H, t, J 7.0Hz), 6.24(2H, br s), 6.69(1H, m), 7.80(1H, m), 7.87(1H, m) and
    7.98(1H, m); Retention time: 1.82min
    66 K 22 NMR δH(400MHz, CDCl3) 5.29(2H, s), 5.85(2H, br s), 6.63(1H, m),
    7.33-7.46(4H, m), 7.57-7.72(3H, m) and 8.22(1H, s); Retention time: 1.87min
    67 K 21 NMR δH(400MHz, CDCl3) 5.27(2H, s), 5.97(2H, br s), 6.55(1H, m),
    7.29-7.60(6H, m) and 8.21(1H, s); Retention time: 3.93min
    68 K 23 NMR δH(400MHz, CDCl3) 2.26(2H, quintet, J 7.2Hz), 2.71(2H, t, J 7.4Hz),
    4.14(2H, t, J 7.3Hz), 6.72(1H, m), 6.83(2H, br s), 7.15-7.33(5H, m),
    7.86(1H, m), 7.92(1H, m) and 8.06(1H, m); Retention time: 3.48min
    69 X 55 mp 184.3-184.5° C.; IR νmax(Nujol)/cm−1 3458, 3316, 3200, 3069, 2955, 2924,
    2854, 1749, 1728, 1631, 1606, 1592, 1462 and 1210; NMR δH(400MHz, DMSO)
    1.24(3H, t, J 7.1Hz), 4.19(2H, q, J 7.1Hz), 5.01(2H, s), 6.61(2H, s),
    6.75-6.79(1H, m), 7.75(1H, d, J 2.5Hz), 7.98(1H, s) and 8.11(1H, s); Anal. Calcd
    for C18H17N5O3S: C, 56.39; H, 4.47; N, 18.26. Found: C, 56.20; H, 4.48; N, 18.23.
    70 L 19 IR νmax(Nujol)/cm−1 3139, 3109, 2924, 2854, 1740, 1610, 1583, 1561, 1547, 1403,
    1235 and 1114; NMR δH(400MHz, DMSO) 1.25(6H, d, J 6.1Hz), 3.21(6H, s),
    5.00(2H, s), 6.77-6.80(1H, m), 7.76(1H, d, J 3.5Hz), 7.99-8.03(1H, m) and
    8.14(1H, s); Anal. Calcd for C18H17N5O3S: C, 56.39; H, 4.47; N, 18.26. Found: C,
    56.20; H, 4.48; N, 18.23.
    71 B 47 mp 180.6-181.8° C.; IR νmax(Nujol)/cm−1 3387, 3139, 3116, 2925, 2854, 1744,
    1611, 1588, 1559, 1464, 1401, 1376, 1220, 1008 and 764; NMR δH(400MHz,
    CDCl3) 1.28(3H, t, J 7.0Hz), 4.26(2H, q, J 7.0Hz), 4.86(2H, s),
    6.58-6.62(1H, m), 7.65-7.67(1H, m), 7.71-7.73(1H, m) and 7.79(1H, s); Anal. Calcd
    for C15H17N5O3: C, 57.14; H, 5.43; N, 22.20. Found: C, 56.88; H, 5.43; N, 22.05.
    72 A 12 mp 314° C.; IR νmax(Nujol)/cm−1 3142, 3106, 3064, 2924, 2854, 1736, 1587, 1567,
    1487, 1402, 1347, 1230 and 768; NMR δH(400MHz, CDCl3) 1.31(3H, t, J 7.0Hz),
    4.30(2H, q, J 7.0Hz), 5.10(2H, s), 6.56-6.59(1H, m), 6.66-6.68(1H,
    m), 7.40(1H, d, J 3.7Hz), 7.64-7.65(1H, m), 7.79-7.81(1H, m), 7.89(1H, d,
    J 3.5Hz) and 8.15(1H, s); Anal. Calcd for C17H14N4O4: C, 60.35; H, 4.17; N,
    16.56. Found: C, 59.91; H, 4.25; N, 16.36.
    73 M 72 mp >300° C. dec.; IR νmax(Nujol)/cm−1 3320, 3129, 3107, 2924, 2854, 2776, 1908,
    1690, 1636, 1597, 1465, 1383, 1312, 782, 768, 686 and 676; NMR δH(400MHz,
    DMSO) 4.90(2H, s), 6.60(2H, s), 6.75-6.79(1H, m), 7.73-7.75(1H, m),
    7.97-7.98(1H, s), 8.11(1H, s), 13.02-13.48(1H, s); Anal. Calcd for C11H9N5O3: C,
    50.97; H, 3.50; N, 27.00. Found: C, 50.75; H, 3.53; N, 26.80.
    74 N 67 mp 79.6° C. dec; IR νmax(Nujol)/cm−1 3094, 2924, 2855, 1600, 1466, 1380, 1248,
    1092 and 839; NMR δH(400MHz, CDCl3) −0.04(9H, s), 0.95(2H, m), 3.65(2H,
    m), 4.10(3H, s), 5.60(2H, s), 6.65(1H, dd, J 3.5, 1.7Hz), 7.78(2H, m) and
    8.08(1H, s). Retention time: 5.82min (80:50)
    75 C 43 IR νmax(Nujol)/cm−1 2924, 2854, 1636, 1599, 1569, 1466, 1357 and 756; NMR
    δH(400MHz, DMSO) 3.99(3H, s), 6.81(1H, dd, J 3.5, 1.7Hz), 7.85(1H, d, J 3.5Hz),
    8.05(1H, m), 8.38(1H, s) and 13.3(1H, br s); M/Z 217(M+H)+; Retention
    time: 0.81min (80:50)
    77 G 79 mp >200° C. dec; IR νmax(Nujol)/cm−1 3458, 3360, 2925, 1721, 1611, 1549, 1465,
    1386, 1046 and 702; NMR δH(400MHz, DMSO) 4.64(2H, d, J 6.5Hz),
    6.97(2H, br s), 7.23-7.44(6H, m), 7.88(1H, dd, J 5.0, 1.5Hz) 8.53(1H, s) 8.55(1H,
    dd, J 3.5, 1.0Hz) and 9.33(1H, br t, J 6.0Hz); Retention time: 6.08min
    78 A 5 mp >250° C. dec; IR νmax(Nujol)/cm−1 3332, 3215, 3144, 2925, 1741, 1651, 1576,
    1378, 1292, 1143, 993 and 713; NMR δH(400MHz, DMSO) 1.69(9H, s),
    5.22(2H, br. s), 7.22(1H, dd, J 5.0, 3.5Hz), 7.57(1H, dd, J 5.0, 1.0Hz), 8.10(1H, s)
    and 8.58(1H, dd, J 4.5, 1.5Hz); Retention time: 3.95min
    79 G 59 NMR δH(400MHz, DMSO) 4.61(2H, d, J 5.9Hz), 6.78(1H, dd, J 1.5, 3.5Hz),
    7.01(2H, br s), 7.22(2H, m), 7.45(2H, m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H,
    dd, J 1.0, 1.5Hz), 8.50(1H, s) and 9.31(1H, t, J 6.2Hz); Retention time: 5.07min
    80 G 100 NMR δH(400MHz, DMSO) 4.63(2H, d, J 6.1Hz), 6.78(1H, dd, J 1.5, 3.5Hz),
    6.99(2H, br s), 7.41(1H, dd, J 2.0, 8.5Hz), 7.63(1H, d, J 8.5Hz), 7.69(1H, d, J
    2.0Hz), 7.75(1H, br d, J 3.5Hz), 8.01(1H, m), 8.49(1H, s) and 9.35(1H, t, J 6.1Hz);
    Retention time: 7.12min
    81 K 66 NMR δH(400MHz, CDCl3) 3.16(2H, t, J 7.0Hz), 4.35(2H, t, J 7.0Hz),
    5.05(2H, br s), 6.62(1H, m), 7.09(2H, m), 7.22-7.31(3H, m), 7.40(1H, s),
    7.70(1H, m) and 7.76(1H, m); Retention time: 2.13min
    82 K 10 NMR δH(400MHz, CDCl3) 1.95(3H, d, J 7.0Hz), 5.03(2H, br s), 5.81(1H, q, J
    7.0Hz), 6.63(1H, dd, J 1.5, 3.5Hz), 7.04(2H, m), 7.30(2H, m), 7.71(1H, m),
    7.75(1H, m) and 7.79(1H, m); Retention time: 2.94min
    83 K 48 NMR δH(400MHz, CDCl3) 1.23(6H, d, J 6.6Hz), 2.89(1H, septet, J 6.9Hz),
    5.06(2H, br s), 5.25(2H, s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.21(4H, s), 7.71(1H,
    dd, J 1.0, 1.5Hz), 7.74(1H, s) and 7.79(1H, br d, J 3.5Hz); Retention time: 5.23min
    84 K 12 NMR δH(400MHz, CDCl3) 5.06(2H, br s), 5.19(2H, s), 6.64(1H, dd, J 1.5, 3.5Hz),
    6.99-7.16(3H, m), 7.72(1H, m), 7.75(1H, s) and 7.80(1H, br d, J 3.5Hz);
    Retention time: 3.22min
    85 P 31 mp 289.1-289.7° C.; IR νmax(Nujol)/cm−1 3499, 3477, 3314, 3264, 3199, 3139,
    3076, 2926, 2854, 1673, 1662, 1634, 1606, 1590, 1467 and 750; NMR δH(400MHz,
    DMSO) 5.03(2H, s), 6.55(2H, s), 6.76-6.79(1H, m), 7.09(1H, t, J 7.5Hz,)
    7.34(2H, t, J 8.1Hz), 7.60(2H, d, J 7.6Hz), 7.76(1H, d, J 4.0Hz),
    7.97-7.99(1H, s), 8.12(1H, s) and 10.43(1H, s); Anal. Calcd for C17H14N6O2.0.4
    H2O: C, 59.78; H, 4.37; N, 24.61. Found: C, 59.92; H, 4.08; N, 24.36.
    86 Q 66 mp 287.2-287.8° C.; IR νmax(Nujol)/cm−1 3479, 3464, 3279, 3182, 3076, 2924,
    2854, 1656, 1631, 1608, 1539, 1567 and 1464; NMR δH(400MHz, DMSO)
    4.34(2H, d, J 5.9Hz), 4.86(2H, s), 6.53(2H, s), 6.75-6.78(1H, m), 7.24-7.39(5H,
    m), 7.75(1H, d, J 3.0Hz), 7.97(1H, s), 8.09(1H, s) and 8.72(1H, t, J 5.8Hz).
    87 Q 100 mp 321.5-321.6° C.; IR νmax(Nujol)/cm−1 3379, 3296, 3220, 2924, 2854, 1689,
    1662, 1593, 1463 and 1378; NMR δH(400MHz, DMSO) 4.75(2H, s), 6.53(2H,
    s), 6.74-6.78(1H, m), 7.29(1H, s), 7.69(1H, s), 7.74(1H, d, J 2.5Hz),
    7.96-7.98(1H, m) and 8.05(1H, s).
    88 Q 74 mp 283.6-283.7° C.; IR νmax(Nujol)/cm−1 3368, 3332, 3215, 3098, 2925, 2854,
    1648, 1585, 1566, 1467, 1408 and 1298; NMR δH(400MHz, DMSO) 1.83(2H,
    quin, J 6.8Hz), 1.98(2H, quin, J 6.8Hz), 3.34(2H, t, J 6.8Hz), 3.57(2H, t, J 6.8Hz),
    4.97(2H, s), 6.52(2H, s), 6.75-6.78(1H, m), 7.75(1H, d, J 2.5Hz),
    7.96-7.99(1H, m) and 8.01(1H, s); Anal. Calcd for C15H16N6O2.0.5 H2O: C, 56.07; H,
    5.33; N, 26.15. Found: C, 56.26; H, 5.08; N, 26.13.
    89 Q 67 mp 290.2-291.6° C.; IR νmax(Nujol)/cm−1 3558, 3471, 3324, 3113, 2924, 2854,
    1664, 1626, 1598 and 1460; NMR δH(400MHz, DMSO) 2.64(3H, d, J 4.5Hz),
    4.76(2H, s), 6.53(2H, s), 6.75-6.78(1H, m), 7.74(1H, d, J 3.2Hz),
    7.96-7.98(1H, m), 8.06(1H, s) and 8.09-8.15(1H, m).
    90 R 21 mp >200° C. dec; IR νmax(Nujol)/cm−1 3499, 3394, 2925, 1628, 1598, 1455, 1378,
    1249, 950, 878 and 628; NMR δH(400MHz, DMSO) 2.73(3H, s), 6.58(1H, br
    s), 8.24(1H, br s) and 12.76(1H, br s); M/Z 217(M+H)+; Retention time: 0.6min
    91 G 72 mp >250° C. dec; IR νmax(Nujol)/cm−1 3505, 3255, 3089, 2925, 1735, 1622, 1465,
    1278, 887 and 725; NMR δH(400MHz, DMSO) 2.73(3H, s) 4.65(2H, d, J 6.0Hz),
    7.18-7.45(5H, m), 8.56(1H, s) and 9.22(1H, br t, J 6.0Hz); Retention
    time: 1.99min
    92 G 89 NMR δH(400MHz, DMSO) 2.96(2H, t, J 7.2Hz), 3.63(2H, q, J 6.9Hz),
    6.78(1H, dd, J 1.9, 3.5Hz), 6.94(2H, br s), 7.17-7.30(5H, m), 7.74(1H, br d, J 3.5Hz),
    8.01(1H, dd, J 1.0, 1.5Hz), 8.46(1H, s) and 8.92(1H, t, J 5.5Hz);
    Retention time: 4.89min
    93 G 100 NMR δH(400MHz, DMSO) 4.66(2H, d, J 6.1Hz), 6.79(1H, dd, J 1.5, 3.5Hz),
    7.00(2H, br s), 7.44(1H, m), 7.54(1H, m), 7.66(1H, m), 7.75(1H, dd, J 1.0, 3.5Hz),
    8.01(1H, dd, J 1.0, 1.5Hz), 8.49(1H, s) and 9.40(1H, t, J 6.1Hz);
    Retention time: 7.06min
    94 G 100 NMR δH(400MHz, DMSO) 1.74(3H, d, J 7.0Hz), 5.92(1H, quintet, J 7.0Hz),
    6.79(1H, dd, J 1.5, 3.5Hz), 7.16(2H, br s), 7.47-7.68(5H, m), 7.76(1H, dd, J
    1.0, 3.5Hz), 7.79-7.99(2H, m), 8.02(1H, dd, J 1.0, 1.5Hz), 8.45(1H, s) and
    9.52(1H, t, J 8.2Hz); Retention time: 7.12min
    95 G 85 NMR δH(400MHz, DMSO) 1.81(6H, s), 2.09(3H, s), 5.08(1H, m), 5.38(1H,
    m), 6.79(1H, dd, J 1.5, 3.5Hz), 7.09(2H, br s), 7.37(3H, m), 7.56(1H, m),
    7.76(1H, dd, J 1.0, 3.5Hz), 8.02(1H, dd, J 1.0, 1.5Hz), 8.39(1H, s) and 9.33(1H, t, J
    5.8Hz); Retention time: 7.14min
    96 Q 84 mp >250° C. dec.; IR νmax(Nujol)/cm−1 3462, 3279, 3212, 3097, 2924, 2854, 1660,
    1591 and 1465; NMR δH(400MHz, DMSO) 3.13-3.24(2H, m),
    3.41-3.49(2H, m), 4.73(1H, s), 4.79(2H, s), 6.53(2H, s), 6.74-6.79(1H, m), 7.74(1H, d,
    J 2.6Hz), 7.97(1H, s), 8.05(1H, s) and 8.24-8.34(1H, m).
    97 Q 52 mp >270° C. dec.; IR νmax(Nujol)/cm−1 3386, 3327, 3214, 3087, 2924, 2854, 1668,
    1640, 1585, 1565, 1466, 1408 and 1376; NMR δH(400MHz, DMSO) 2.24(3H,
    s), 2.29-2.35(2H, m), 2.39-2.46(2H, m), 3.44-3.51(2H, m), 3.54-3.61(2H,
    m), 5.08(2H, s), 6.52(2H, s), 6.75-6.79(1H, m), 7.74(1H, d, J 3.7Hz),
    7.97(1H, s) and 8.01(1H, s).
    98 G 39 NMR δH(400MHz, DMSO) 3.74(2H, q, J 5.9Hz), 3.85(2H, t, J 6.0Hz),
    6.78(1H, dd, J 1.5, 3.5Hz), 6.99(2H, br s), 7.75(1H, dd, J 1.0, 3.5Hz), 8.02(1H, dd,
    J 1.0, 1.5Hz), 8.49(1H, s) and 9.12(1H, t, J 5.8Hz); Retention time: 2.16min
    99 G 80 NMR δH(400MHz, DMSO) 2.10(2H, quintet, J 6.7Hz), 3.52(2H, q, J 6.5Hz),
    3.77(2H, t, J 6.5Hz), 6.78(1H, dd, J 2.0, 3.5Hz), 7.02(2H, br s), 7.74(1H, dd, J
    1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 2.0Hz), 8.47(1H, s) and 8.90(1H, t, J 5.7Hz);
    Retention time: 3.08min
    100 G 70 NMR δH(400MHz, DMSO) 1.18(3H, t, J 6.9Hz), 2.70(2H, t, J 6.7Hz),
    3.61(2H, q, J 6.5Hz), 4.10(2H, t, J 7.2Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 6.96(2H, br
    s), 7.74(1H, br d, J 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.47(1H, s) and
    8.98(1H, t, J 5.8Hz); Retention time: 2.19min
    101 G 46 NMR δH(400MHz, DMSO) 1.17(3H, t, J 7.0Hz), 3.19(1H, dd, J 8.5, 14.0Hz),
    3.29(1H, dd, J 6.0, 14.0Hz), 4.15(2H, q, J 7.0Hz), 4.70(1H, m), 6.78(1H, dd, J
    1.5, 3.5Hz), 7.03(2H, br s), 7.15-7.39(5H, m), 7.74(1H, dd, J 1.0, 3.5Hz),
    8.02(1H, dd, J 1.0, 2.0Hz), 8.43(1H, s) and 9.23(1H, d, J 6.9Hz).
    102 S 47 NMR δH(400MHz, CDCl3) 3.34(2H, t, J 6.6Hz), 4.60(2H, t, J 6.7Hz),
    5.05(2H, br s), 6.61(1H, dd, J 1.5, 3.5Hz), 6.98(1H, d, J 7.5Hz), 7.15(1H, m),
    7.53(1H, m), 7.53(1H, s), 7.69(1H, m), 7.74(1H, dd, J 1.0, 3.5Hz) and 8.60(1H, m);
    Retention time: 0.76min
    103 S 44 NMR δH(400MHz, DMSO) 3.36-3.42(10H, m), 4.49(2H, m), 6.90(1H, dd, J
    1.5, 3.5Hz), 7.91(1H, br d, J 3.5Hz), 8.18(1H, m), 8.52(1H, s) and 9.62(2H, br
    s); Retention time: 0.80min, (50:20)
    104 S 66 NMR δH(400MHz, CDCl3) 1.44(2H, m), 1.57(4H, m), 2.45(4H, m), 2.69(2H,
    t, J 6.0Hz), 4.18(2H, t, J 6.0Hz), 5.02(2H, br s), 6.63(1H, m), 7.71(1H, m),
    7.79(1H, m) and 7.99(1H, s); M/Z 313(M+H)+; Retention time: 3.69min,
    (50:20)
    105 S 53 NMR δH(400MHz, CDCl3) 1.78(4H, m), 2.58(4H, m), 2.90(2H, t, J 6.3Hz),
    4.22(2H, t, J 6.2Hz), 5.03(2H, br s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.71(1H, m),
    7.79(1H, br d, J 3.5Hz) and 7.93(1H, s); Retention time: 1.50min, (50:20)
    106 T 98 mp 161.7° C. dec; NMR δH(400MHz, CDCl3) 5.36(2H, br s), 5.52(2H, s),
    6.64(1H, dd, J 3.5, 1.7Hz), 7.35-7.75(5H, m), 7.72(1H, nm), 7.81(1H, m) and
    8.26(1H, s); Retention time: 3.95min (80:50)
    112 G 35 mp 139.3° C.; NMR δH(400MHz, CDCl3) 3.99(3H, s), 4.70-4.71(2H, s,
    rotamers), 6.67(1H, dd, J 3.5, 1.7Hz), 7.27-7.44(5H, m), 7.79(1H, m),
    7.84(1H, m), 8.66(1H, s) and 8.95(1H, br); Retention time: 5.13min (80:50)
    113 S 37 NMR δH(400MHz, CDCl3) 3.14(2H, t, J 6.8Hz), 4.33(2H, t, J 7.0Hz),
    5.06(2H, br s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.02(2H, d, J 8.1Hz), 7.25(2H, m),
    7.41(1H, s), 7.72(1H, m) and 7.76(1H, br d, J 3.5Hz); Retention time: 4.02min
    114 S 64 NMR δH(400MHz, CDCl3) 2.91(6H, s), 3.04(2H, t, J 6.8Hz), 4.29(2H, t, J 6.8Hz),
    5.05(2H, br s), 6.62(1H, dd, J 2.0, 3.5Hz), 6.65(2H, d, J 8.6Hz), 6.95(2H,
    d, J 8.7Hz), 7.40(1H, s), 7.70(1H, dd, J 1.0, 1.5Hz) and 7.76(1H, dd, J 1.0, 3.5Hz);
    Retention time: 2.58min
    115 S 15 NMR δH(400MHz, CDCl3) 4.30(2H, t, J 5.0Hz), 4.52(2H, t, J 5.0Hz),
    5.08(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 6.87(2H, m), 6.96(1H, m), 7.27(2H, m),
    7.71(1H, m), 7.80(1H, br d, J 3.5Hz) and 7.79(1H, s); Retention time: 2.37min
    116 S 66 NMR δH(400MHz, CDCl3) 1.01(2H, m), 1.21(4H, m), 1.69(4H, m), 1.89(1H,
    m), 3.39(2H, d, J 7.8Hz), 5.04(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.71(1H,
    m), 7.74(1H, s) and 7.79(1H, br d, J 3.5Hz); Retention time: 3.78min
    117 S 84 NMR δH(400MHz, CDCl3) 0.87(2H, m), 1.09-1.27(6H, m), 1.61-1.72(5H,
    m), 1.88(2H, quintet, J 7.0Hz), 4.08(2H, t, J 7.1Hz), 5.04(2H, br s), 6.64(1H,
    dd, J 2.0, 3.5Hz), 7.72(1H, dd, J 1.0, 2.0Hz), 7.78(1H, s) and 7.79(1H, dd, J
    1.0, 3.5Hz); Retention time: 6.06min
    118 I 20 NMR δH(400MHz, CDCl3) 3.04(3H, s), 4.72(2H, br s), 5.18(2H, br s),
    6.64(1H, dd, J 3.5, 1.7Hz), 7.29-7.42(5H, m), 7.72(1H, m), 7.83(1H, m), 8.10(1H,
    s); M/Z 349(M+H)+; Retention time: 1.66min (80:50)
    119 Q 85 mp 238.3-238.4° C.; IR νmax(Nujol)/cm−1 3444, 3325, 3181, 3083, 2925, 2855,
    1651, 1696, 1591, 1567, 1523, 1467, 1414, 1376, 1355, 1300, 1182, 1017 and
    754; NMR δH(400MHz, DMSO) 4.41(2H, d, J 5.4Hz), 4.88(2H, s), 6.53(2H,
    s), 6.72-6.77(1H, m), 7.25-7.31(1H, m), 7.36(2H, d, J 8.0Hz), 7.72(1H, d, J
    3.6Hz), 7.75-7.81(1H, m), 7.94(1H, s), 8.08(1H, s), 8.51(1H, d, J 4.5Hz) and
    8.80(1H, t, J 5.8Hz).
    120 O 12 mp 310.0-310.3° C.; IR νmax(Nujol)/cm−1 3322, 2925, 1636, 1586, 1464, 1378,
    1297, 1026, 734 and 630; NMR δH(400MHz, DMSO) 6.53(2H, br s), 7.34(1H,
    t, J 7.5Hz), 7.45(1H, t, J 8.0Hz), 7.72(1H, d, J 8.5Hz), 7.83(1H, d, J 7.5Hz),
    8.17(1H, br s), 8.21(1H, br s) and 12.78(1H, br s); Retention time: 1.48min
    122 Q 46 mp 242.5-243.6° C.; IR νmax(Nujol)/cm−1 3485, 3442, 3312, 3203, 3072, 2924,
    2854, 1697, 1652, 1633, 1605, 1580, 1462, 1442, 1412 and 1303; NMR δH(400MHz,
    DMSO) 5.07(2H, s), 6.53(2H, s), 6.73-6.77(1H, m), 7.09-7.14(1H,
    m), 7.73(1H, d, J 2.8Hz), 7.77(1H, t, J 7.0Hz), 7.90-8.04(2H, m), 8.08(1H,
    s), 8.35(1H, d, J 4.0Hz) and 10.96(1H, s).
    123 Q 57 mp 247.3-247.4° C.; IR νmax(Nujol)/cm−1 3500, 3308, 3187, 3092, 3022, 2924,
    2854, 1656, 1636, 1609, 1590, 1567 and 1466; NMR δH(400MHz, DMSO)
    2.72(2H, t, J 7.3Hz), 3.24-3.35(2H, m), 4.73(2H, s), 6.49(2H, s), 6.71-6.77(1H,
    m), 7.15-7.23(3H, m), 7.25-7.32(2H, m), 7.71(2H, d, J 3.5Hz),
    7.93-7.95(1H, m), 8.01(1H, s) and 8.29(1H, t, J 5.5Hz).
    124 Q 46 mp 258.7-260.1° C.; IR νmax(Nujol)/cm−1 3487, 3470, 3293, 3172, 3098, 2925,
    2854, 1659, 1629, 1605, 1594, 1568, 1461 and 1409; NMR δH(400MHz, DMSO)
    0.86(3H, t, J 7.6Hz), 1.39-1.48(2H, m), 3.05(2H, q, J 6.5Hz), 4.75(2H, s),
    6.49(2H, s), 6.72-6.77(1H, m), 7.72(1H, d, J 3.5Hz), 7.93-7.96(1H, m),
    8.04(1H, s) and 8.19(1H, t, J 5.5Hz).
    125 S 12 NMR δH(400MHz, CDCl3) 5.07(2H, br s), 5.27(2H, s), 6.64(1H, dd, J 1.5, 3.5Hz),
    7.14(1H, m), 7.25-7.30(3H, m), 7.72(1H, m), 7.76(1H, s) and 7.80(1H,
    dd, J 1.0, 3.5Hz); Retention time: 2.66min
    126 S 33 NMR δH(400MHz, CDCl3) 2.32(3H, s), 5.07(2H, br s), 5.25(2H, s), 6.63(1H,
    dd, J 2.0, 3.5Hz), 7.06(2H, m), 7.13(1H, d, J 7.6Hz), 7.23(1H, d, J 7.6Hz),
    7.71(1H, m), 7.74(1H, s) and 7.79(1H, dd, J 1.0, 3.5Hz); Retention time: 2.12min
    127 S 17 NMR δH(400MHz, CDCl3) 2.34(3H, s), 5.06(2H, br s), 5.24(2H, s), 6.63(1H,
    dd, J 2.0, 3.5Hz), 7.16(4H, m), 7.71(1H, dd, J 1.0, 2.0Hz), 7.73(1H, s) and
    7.79(1H, dd, J 1.0, 3.5Hz); Retention time: 2.21min
    128 G 53 mp >250° C. dec; IR νmax(Nujol)/cm−1 3296, 3181, 2925, 1717, 1629, 1467, 1390,
    1228 and 754; NMR δH(400MHz, DMSO) 4.66(2H, d, J 6.0Hz), 7.18(2H, br
    s), 7.21-7.51(7H, m), 7.74(1H, d, J 8.0Hz), 7.87(1H d, J 7.5Hz), 8.25(1H, s),
    8.59(1H, s) and 9.30(1H, br t, J 6.0Hz); Retention time: 6.85min
    129 O 36 mp >250° C. dec; IR νmax(Nujol)/cm−1 3492, 3331, 3196, 2924, 1618, 1569, 1442,
    1377, 1301, 1180, 1030 and 784; NMR δH(400MHz, DMSO) 6.39(2H, br s),
    7.27(1H, d, J 4.0Hz), 8.12(1H, s), 8.33(1H, d, J 4.0Hz) and 12.68(1H, br s);
    Retention time: 2.74min
    130 G 67 mp 194-195° C. dec; IR νmax(Nujol)/cm−1 3460, 3360, 2923, 1722, 1608, 1465,
    1386, 1218, 1013 and 792; NMR δH(400MHz, DMSO) 4.64(2H, d, J 6.0Hz),
    7.02(2H, br s), 7.25-7.44(6H, m), 8.35(1H, d, J 4.0Hz) and 9.28(1H, t, J 6.0Hz);
    Retention time: 7.81min
    131 I 17 IR νmax(Nujol)/cm−1 4332, 4258, 3421, 3299, 3193, 3105, 2924, 2854, 1682, 1631,
    1596, 1465, 1376, 747; NMR δH(400MHz, CDCl3) 3.09(2H, m), 3.86(2H, br
    m), 4.80(2H, br m), 5.10(2H, s), 6.66(1H, dd, J 3.5, 1.7Hz), 7.18-7.25(4H,
    m), 7.74(1H, m), 7.85(1H, m) and 8.12(1H, s); Retention time: 2.25min (80:50)
    132 I 81 IR νmax(Nujol)/cm−1 4331, 3293, 3164, 2924, 2854, 1694, 1638, 1467, 746; NMR
    δH(400MHz, CDCl3) 3.23(2H, m), 4.33(2H, m), 5.13(2H, s), 6.67(1H, dd, J
    3.5, 1.7Hz), 7.10-7.31(4H, m), 7.74(1H, m), 7.74(1H, m), 7.86(1H, m) and
    8.16(1H, s); M/Z 369(M+Na)+; Retention time: 2.80min (80:50)
    133 A 11 mp >240° C. dec; IR νmax(Nujol)/cm−1 3465, 3321, 2925, 1619, 1567, 1460, 1384,
    1304, 1056, 832 and 740; NMR δH(400MHz, DMSO) 4.11(3H, s), 6.15(3H, m),
    6.98(1H, t, J 2.0Hz), 7.60(1H, br s), 7.96(1H, s) and 12.43(1H, br s); Retention
    time: 1.67min
    134 G 68 mp >230° C. dec; IR νmax(Nujol)/cm−1 3465, 3364, 2924, 1722, 1609, 1549, 1462,
    1062 and 732; NMR δH(400MHz, DMSO) 4.12(3H, s), 4.67(2H, d, J 6.0Hz),
    6.20(1H, dd, J 4.0, 2.5Hz), 6.80(2H, br s), 7.08(1H, t, J 2.0Hz),
    7.25-7.33(1H, m), 7.34-7.43(4H, m), 7.68(1H, dd, J 4.0, 2.0Hz), 8.41(1H, s) and
    9.43(1H, t, J 6.0Hz); Retention time: 5.26min
    137 Y 39 mp 300° C. (dec); IR νmax(Nujol)/cm−1 3423, 3313, 2924, 1622, 1580, 1464, 1389,
    1305, 1114, 888 and 633; NMR δH(400MHz, DMSO) 6.46(2H, br s), 8.15(1H,
    s), 9.11(1H, s), 9.27(1H, s) and 12.72(1H, br s); Retention time: 1.24min
    139 G 76 mp 188° C.; IR νmax(Nujol)/cm−1 3313, 3195, 2924, 1718, 1629, 1558, 1467, 1392,
    1254, 890, 792 and 702; NMR δH(400MHz, DMSO) 4.65(2H, d, J 6.5Hz),
    7.09(2H, br s), 7.25-7.32(1H, m), 7.34-7.44(4H, m), 8.59(1H, s), 9.11(1H, s),
    9.27(1H, t, J 6.5Hz) and 9.35(1H, s); Retention time: 4.34min
    140 Q 80 Mp 299.2-299.3° C.; IR νmax(Nujol)/cm−1 3483, 3259, 3187, 2923, 2854, 1661,
    1631, 1603, 1570, 1537, 1462, 1416 and 1378; NMR δH(400MHz, DMSO)
    9.69(1H, br s), 8.11(1H, s), 7.95(1H, s), 7.73(1H, d, J 3.3Hz), 7.43(1H, d, J 7.6Hz),
    7.23-7.07(3H, m), 6.75(1H, dd, J 3.3, 1.7Hz), 6.49(2H, br s), 5.04(2H, s)
    and 2.25(3H, s); Anal. Calcd for C18H16N6O2.0.8 H2O: C, 59.59; H, 4.89; N,
    20.17. Found: C, 59.43; H, 4.60; N, 20.27.
    141 Q 60 Mp 278° C. (dec); IR νmax(Nujol)/cm−1 3480, 3257, 3179, 2924, 2854, 1678, 1661,
    1627, 1592, 1545, 1463 and 1415; NMR δH(400MHz, DMSO) 10.59(1H, br s),
    8.10(1H, s), 7.95(1H, s), 7.76-7.73(2H, m), 7.45(1H, d, J 9.2Hz), 7.36(1H, t,
    J 8.0Hz), 7.13(1H, m), 6.75(1H, dd, J 3.6, 2.0Hz), 6.50(2H, s) and 5.01(2H,
    s); Anal. Calcd for C17H13ClN6O2.0.25 H2O: C, 54.70; H, 3.65; N, 23.51. Found:
    C, 54.53; H, 3.50; N, 23.50.
    142 Q 20 Mp 281.3-283.2° C.; IR νmax(Nujol)/cm−1 3185, 2923, 2854, 1704, 1638, 1591,
    1571, 1541, 1464, 1416, 1377 and 1297; NMR δH(400MHz, DMSO) 10.80(1H,
    br s), 8.45(2H, d, J 5.6Hz), 8.10(1H, s), 7.95(1H, s), 7.73(1H, d, J 3.2Hz),
    7.54(2H, d, J 6.4Hz), 6.75(1H, dd, J 3.2, 1.6Hz), 6.51(2H, br s) and 5.05(2H, s).
    143 Q 63 Mp 285.6-286.4° C.; IR νmax(Nujol)/cm−1 3472, 3176, 2924, 2854, 1698, 1640,
    1591, 1560, 1460, 1415, 1377 and 1297; NMR δH(400MHz, DMSO) 10.63(1H,
    br s), 8.74(1H, d, J 2.4Hz), 8.29(1H, d, J 3.6Hz), 8.11(1H, s), 8.00(1H, m),
    7.95(1H, s), 7.74(1H, d, J 3.2Hz), 7.36(1H, dd, J 8.4, 4.8Hz), 6.75(1H, dd, J
    3.2, 1.6Hz), 6.51(2H, br s) and 5.04(2H, s); Anal. Calcd for C16H13N7O2.2.2
    H2O: C, 51.25; H, 4.68; N, 26.15. Found: C, 51.33; H, 4.51; N, 26.18.
    144 Q 51 Mp 277° C. (dec); IR νmax(Nujol)/cm−1 3486, 3272, 3181, 2924, 2854, 1650, 1633,
    1594, 1555, 1492, 1463, 1412 and 1377; NMR δH(400MHz, DMSO) 8.70(1H,
    br t, J 6.0Hz), 8.07(1H, s), 7.94(1H, s), 7.72(1H, d, J 3.2Hz), 7.42-7.30(4H,
    m), 6.74(1H, dd, J 3.2, 1.6Hz), 6.50(2H, br s), 4.84(2H, s) and 4.30(2H, d, J
    5.6Hz).
    145 Q 64 Mp 224.0-224.1° C.; IR νmax(Nujol)/cm−1 3476, 3317, 3196, 3072, 2924, 2854,
    1654, 1628, 1607, 1592, 1570, 1515, 1490, 1458, 1413, 1360, 1304 and 1292;
    NMR δH(400MHz, DMSO) 8.04(1H, s), 7.94(1H, d, J 1.0Hz), 7.73(1H, d, J
    2.9Hz), 7.48-7.25(5H, m), 6.75(1H, dd, J 3.4, 1.8Hz), 6.48(2H, br s),
    5.13(2H, s), 4.53(2H, s) and 3.07(3H, s).
    146 S 16 NMR δH(400MHz, CDCl3) 3.19(2H, t, J 7.0Hz), 4.38(2H, t, J 7.0Hz)
    5.08(2H, br s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.04(2H, dd, J 1.5, 4.5Hz), 7.49(1H, s),
    7.72(1H, dd, J 1.0, 2.5Hz), 7.78(1H, dd, J 1.5, 3.5Hz) and 8.52(2H, dd, J 1.5,
    4.5Hz); Retention time: 2.71min, (50:20).
    147 S 9 NMR δH(400MHz, CDCl3) 2.52(4H, t, J 4.7Hz), 2.76(2H, t, J 6.0Hz),
    3.69(4H, t, J 4.7Hz), 4.10(2H, t, J 6.0Hz), 5.04(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz),
    7.71(1H, dd, J 1.0, 1.5Hz), 7.79(1H, dd, J 1.0, 3.5Hz) and 7.94(1H, s);
    Retention time: 1.96min, (50:20).
    148 S 17 NMR δH(400MHz, CDCl3) 5.06(2H, br s), 5.31(2H, s), 6.63(1H, dd, J 2.0, 3.5Hz),
    7.28(1H, m), 7.60(1H, m), 7.72(1H, dd, J 1.0, 2.5Hz), 7.77(1H, s),
    7.80(1H, dd, J 1.0, 3.5Hz), 8.59(1H, dd, J 1.5, 5.0Hz) and 8.67(1H, d, J 2.5Hz);
    Retention time: 2.51min, (50:20).
    150 A 10 mp 247-248° C.; NMR δH(400MHz, DMSO) 2.66(3H, s), 6.28(2H, br s),
    7.03(1H, d, J 5.0Hz), 7.63(1H, d, J 5.0Hz), 8.03(1H, s) and 12.57(1H, br s);
    Retention time: 2.91min
    151 AA 11 IR νmax(Nujol)/cm−1 3317, 3194, 2923, 2854, 1732, 1456; NMR δH(400MHz,
    CDCl3) 2.92(2H, t, J 6.4Hz), 3.67(3H, s), 4.40(2H, t, J 6.4Hz), 5.30(2H, br s),
    6.62(1H, dd, J 1.6, 3.4Hz), 7.70(1H, dd, J 0.7, 1.6Hz), 7.79(1H, dd, J 0.7, 3.4Hz
    and 7.87(1H, s).
    152 M 99 IR νmax(Nujol)/cm−1 3500-2800 br, 2923, 2855, 1715, 1644, 1588, 1520, 1465,
    1412 and 1378; NMR δH(400MHz, DMSO) 8.07(1H, s), 7.94(1H, m), 7.70(1H,
    m), 6.73(1H, dd, J 3.5, 1.5Hz), 6.55(2H, br s), 4.25(2H, t) and 2.85(2H, t, J 6.5Hz);
    M/Z 274(M+H)+.
    153 AB 30 Mp. 342° C. dec.; IR νmax(Nujol)/cm−1 2925, 2855, 1587, 1463, 1377, 846; NMR
    δH(400MHz, DMSO) 2.68(3H, s), 6.78(1H, m), 7.80(1H, m), 8.00(1H, m),
    8.40(1H, m) and 13.32(1H, br).
    154 G 46 Mp 152° C. (dec); IR νmax(Nujol)/cm−1 3273, 3109, 2920, 2854, 1727, 1600, 1588,
    1551, 1481, 1455, 1401 and 1374; NMR δH(400MHz, DMSO) 9.26(1H, t, J 5.9Hz),
    8.92(1H, s), 8.09(1H, m), 7.85(1H, m), 7.30-7.50(5H, m), 6.84(1H, dd, J
    3.5, 1.5Hz), 4.68(2H, d, J 5.9Hz) and 2.76(3H, s); Retention time 5.38min.
    (80:50)
    155 H NMR δH(400MHz, CDCl3) 8.25(1H, s), 8.09(1H, d, J 6.8Hz), 7.84(1H, d, J
    3.6Hz), 6.66(1H, dd, J 3.6, 1.6Hz), 5.15(2H, br s), 4.07(1H, m) and 1.44(6H,
    d, J 6.8Hz).
    156 AC 6 IR νmax (Nujol)/cm−1 2923, 2854, 1588, 1564, 1486, 1462, 1376, 1352, 1309 and
    1236; NMR δH(400MHz, CDCl3) 7.96(1H, s), 7.88(1H, m), 7.75(1H, m),
    7.20(4H, m), 6.50(1H, m), 5.35(2H, s) and 2.35(3H, s).
    157 AC NMR δH(400MHz, DMSO) 5.38(2H, s), 6.56(2H, br s), 6.75(1H, dd, J 1.5, 3.5Hz),
    7.10(1H, m), 7.16(1H, m), 7.25(1H, m), 7.37(1H, m), 7.72(1H, d, J 3.5Hz),
    7.95(1H, dd, J 1.0, 2.0Hz) and 8.15(1H, s); Retention time: 1.58min,
    (80:50).
    158 AC 60 mp 284.5-285.3° C.; IR νmax(Nujol)/cm−1 3319, 3195, 3139, 3091, 1641, 1590,
    1557, 1530, 1463, 1377 and 1349; NMR δH(400MHz, DMSO) 5.47(2H, s),
    6.58(2H, s), 6.72-6.78(1H, m), 7.65(1H, dt, J 7.5, 1.0Hz), 7.69-7.76(2H, m),
    7.95(1H, t, J 1.0Hz), 8.15-8.16(1H, m), 8.17(1H, s), 8.26(1H, s); Anal. Calcd for
    C16H12N6O3.0.35 H2O: C, 56.09; H, 3.74; N, 24.53. Found: C, 56.10; H, 3.72; N,
    24.40.
    159 AC 46 mp 212.8-212.9° C.; NMR δH(400MHz, DMSO) 5.43(2H, s), 6.57(2H, s),
    6.73-6.78(1H, m), 7.45(2H, d, J 8.0Hz), 7.70-7.75(3H, m), 7.95-7.97(1H, m),
    8.24(1H, s); Anal. Calcd for C17H12N5OF3.0.1 H2O: C, 56.54; H, 3.41; N, 19.39.
    Found: C, 56.65; H, 3.62; N, 19.01.
    160 H 95 NMR δH(400MHz, DMSO) 6.76(1H, dd, J 2.0, 3.5Hz), 7.05(2H, br s),
    7.67(1H, d, J 3.5Hz), 7.99(2H, m), 8.56(1H, s), 8.62(1H, dd, J 1.5, 8.0Hz),
    8.72(1H, d, J 8.0Hz) and 8.89(1H, t, J 2.0Hz); Retention time: 4.15min, (80:50).
    161 H 55 IR νmax(Nujol)/cm−1 3493, 3405, 3309, 3192, 2924, 2854, 1624, 1586, 1565, 1467
    and 1351; NMR δH(400MHz, DMSO) 6.77(1H, dd, J 2.0, 3.5Hz), 6.86(2H, br,
    s), 7.70(1H, d, J 3.5Hz), 7.72-7.76(2H, m), 7.90(1H, dd, J 2.0, 7.0Hz),
    8.00(1H, d, J 1.5Hz), 8.39(1H, dd, J 2.5, 7.5Hz) and 8.62(1H, s); Retention time
    4.54min, (80:50).
    162 H 69 IR νmax(Nujol)/cm−1 3503, 3324, 3202, 3115, 2924, 2854, 1634, 1587, 1569,
    1467, 1392 and 1350; NMR δH(400MHz, DMSO) 6.76(1H, dd, J 2.0, 3.5Hz),
    7.04(2H, br s), 7.67(1H, dd, J 0.5, 3.5Hz), 7.92(2H, d, J 8.5Hz), 7.98(1H, dd,
    J 1.0, 2.0Hz), 8.17(2H, d, J 9.0Hz) and 8.50(1H, s); Retention time 2.01min,
    (80:50).
    163 H 36 IR νmax(Nujol)/cm−1 3505, 3327, 3206, 2924, 2854, 1634, 1593, 1567, 1480,
    1465, 1384 and 1348; NMR δH(400MHz, DMSO) 6.76(1H, dd, J 1.5, 3.5Hz),
    7.04(2H, br s), 7.54(2H, t, J 9.0Hz), 7.67(1H, dd, J 0.5, 3.5Hz), 7.98(1H, dd, J
    1.0, 2.0Hz), 8.34(1H, dd, J 5.0, 9.0Hz) and 8.50(1H, s); Retention time 3.89min,
    (80:50).
    164 H 29 IR νmax(Nujol)/cm−1 3484, 3301, 3184, 3107, 2924, 2854, 1661, 1633, 1588,
    1465, 1376, 1356 and 1166; NMR δH(400MHz, DMSO) 3.78(3H, s), 6.78(1H,
    dd, J 2.0 3.5Hz), 7.05(2H, br s), 7.72(1H, m), 8.01(1H, m) and 8.31(1H, s);
    Retention time 3.22min, (80:50).
    165 H 34 NMR δH(400MHz, DMSO) 0.84(3H, t, J 7.2Hz), 1.36(2H, sextet, J 7.2Hz),
    1.65(2H, m), 3.93(2H, m), 6.78(1H, dd, J 2.0, 3.5Hz), 7.05(2H, br s), 7.73(1H,
    dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz) and 8.32(1H, s); Retention time
    2.27(80:50).
    166 H 55 NMR δH(400MHz, DMSO) 6.74(1H, dd, J 1.5, 3.5Hz), 6.76(2H, br s),
    7.66(2H, m), 7.92(1H, t, J 8.0Hz), 7.95(1H, dd, J 1.0, 2.0Hz), 8.48(1H, dd, J 1.5,
    8.0Hz), 8.55(1H, dd, J 1.5, 8.5Hz), 8.72(1H, dd, J 1.5, 7.5Hz), 8.75(1H, s) and
    8.95(1H, dd, J 1.5, 4.5Hz); Retention time 3.29min, (80:50).
    167 H 26 NMR δH(400MHz, DMSO) 2.38(3H, s), 2.87(3H, s), 6.77(1H, dd, J 1.5 3.5Hz),
    6.97(2H, br s), 7.70(1H, dd, J 1.0, 3.5Hz), 8.00(1H, dd, J 1.0, 1.5Hz) and
    8.57(1H, s); Retention time: 3.70min, (80:50).
    168 H 58 NMR δH(400MHz, DMSO) 6.76(1H, dd, J 1.5, 3.5Hz), 7.43(1H, ddd, J 1.0,
    5.0, 7.5Hz), 7.68(1H, dd, J 1.0, 3.5Hz), 7.93(1H, dt, J 1.5, 7.5Hz), 7.97(1H, d,
    J 4.5Hz), 7.99(1H, dd, J 1.0, 1.5Hz), 8.09(1H, dt, J 1.0, 8.0Hz), 8.24(1H, d, J
    4.0Hz), 8.52(1H, s) and 8.59(1H, ddd, J 1.0, 5.0, 5.5Hz); Retention time 5.71min,
    (80:50).
    169 Q Mp 287.1-288.2° C.; IR νmax(Nujol)/cm−1 3200, 2920, 2854, 1666, 1651, 1591,
    1568, 1538, 1503, 1453, 1416, 1378, 1282 and 1233; NMR δH(400MHz, DMSO)
    9.60(1H, br s), 8.11(1H, s), 7.96(1H, s), 7.73(1H, d, J 3.2Hz), 7.25(1H, d, J
    8.4Hz), 6.80(1H, d, J 2.8Hz), 6.76-6.71(2H, m), 6.52(2H, br s), 5.00(2H, s),
    3.71(3H, s) and 2.20(3H, s).
    170 Q NMR δH(400MHz, DMSO) 9.63(1H, br s), 8.11(1H, s), 7.95(1H, s), 7.73(1H,
    s), 7.28(1H, d, J 8.0Hz), 7.03(1H, s), 6.97(1H, m), 6.75(1H, s), 6.52(2H, br s),
    5.02(2H, s), 2.24(3H, s) and 2.20(3H, s).
    171 I 57 Mp 134.6° C.; NMR δH(400MHz, DMSO) 8.35(1H, s), 7.88(1H, m), 7.65(1H,
    m), 7.30-7.40(5H, m), 6.67(1H, dd, J 3.5, 1.5Hz), 4.75(2H, br m), 3.09(3H,
    br m) and 2.86(3H, s); Retention time 2.56min (80:50)
    172 AC 28 mp 245.6-246.0° C.; IR νmax(Nujol)/cm−1 3393, 3318, 3189, 3091, 1794, 1740,
    1646, 1592, 1519, 1466, 1408, 1342 and 1310; NMR δH(400MHz, DMSO)
    5.49(2H, s), 6.58(2H, s), 6.74-6.79(1H, m), 7.47-7.51(2H, m), 7.75(1H, dd, J 3.5Hz,
    1.0Hz), 7.96-7.98(1H, m), 8.19-8.24(2H, m) and 8.26(1H, s).
    173 AH 57 Mp. 196.5° C. dec.; IR νmax(Nujol)/cm−1 2923, 2852, 2243, 1596, 1463, 1378,
    1144; NMR δH(400MHz, CDCl3) 2.35(3H, s), 5.42(2H, s), 6.69(1H, dd J 1.8,
    3.5Hz), 7.19(2H, m), 7.25(2H, m), 7.82(1H, m), 7.90(1H, m) and 8.19(1H, br
    s).
    174 X 43 Mp 160° C. (dec); IR νmax(Nujol)/cm−1 3347, 2924, 2854, 1771, 1718, 1607, 1593,
    1562, 1460, 1403 and 1378; NMR δH(400MHz, DMSO) 8.07(1H, s), 7.93(1H,
    d, J 2.0Hz), 7.80(4H, s), 7.67(1H, d, J 4.0Hz), 6.72(1H, dd, J 3.5, 2.0Hz),
    6.19(2H, br s), 4.37-4.30(2H, m), 4.04-3.96(2H, m) and 3.30(3H, s).
    175 Q NMR δH(400MHz, DMSO) 10.55(1H, br s), 8.10(1H, s), 7.96(1H, s), 7.74(1H,
    s), 7.60(2H, m), 7.39(2H, m), 6.76(1H, s), 6.53(2H, br s) and 5.01(2H, s).
    176 Q NMR δH(400MHz, DMSO) 10.72(1H, br s), 8.10(1H, s), 7.96(1H, s), 7.94(1H,
    s), 7.74(1H, s), 7.59(1H, d, J 8.8Hz), 7.49(1H, d, J 8.4Hz), 6.76(1H, s),
    6.54(2H, s) and 5.02(2H, s).
    177 AC 50 mp 302.5-304.8° C.; IR νmax(Nujol)/cm−1 3356, 3314, 3198, 2232, 1636, 1618,
    1591, 1557, 1515 and 1463; NMR δH(400MHz, DMSO) 5.38(2H, s), 6.58(2H,
    s), 6.73-6.78(1H, m), 7.54-7.61(2H, m), 7.73(1H, d, J 3.5Hz),
    7.76-7.80(2H, m), 7.94-7.96(1H, m), 8.23(1H, s); Anal. Calcd for C17H12N6O.0.4 H2O:
    C, 63.11; H, 3.99; N, 25.98. Found: C, 63.18; H, 3.92; N, 26.02.
    178 AC 32 IR νmax(Nujol)/cm−1 1644, 1584, 1463, 1408 and 1377; NMR δH(400MHz,
    DMSO) 5.44(3H, s), 6.92-6.95(1H, m), 7.03-7.06(1H, m), 7.32(1H, dt, J 7.5Hz,
    1.5Hz), 7.39(1H, dt, J 7.5Hz, 1.5Hz), 7.55(1H, dd, J 8.0Hz, 1.0Hz),
    7.98(1H, d, J 3.5Hz), 8.23(1H, s) and 8.51(1H, s).
    179 H 38 NMR δH(400MHz, DMSO) 4.67(2H, d, J 5.5Hz), 6.76(1H, dd, J 1.5, 3.5Hz),
    7.05(2H, br s), 7.23(1H, d, J 4.0Hz), 7.55(2H, d, J 8.5Hz), 7.67(1H, d, J 3.5Hz),
    7.87(1H, d, J 8.5Hz), 7.99(1H, dd, J 1.0 1.5Hz), 8.10(1H, d, J 4.5Hz),
    8.48(1H, s) and 9.34(1H, t, J 6.0Hz); Retention time 5.38min, (80:50).
    180 H 34 NMR δH(400MHz, DMSO) 6.75(1H, dd, J 2.0, 3.5Hz), 6.95(2H, br s),
    7.66(1H, dd, J 1.0, 3.5Hz), 7.89(1H, dd, J 7.0, 9.0Hz), 7.97(1H, dd, J 1.0, 1.5Hz),
    8.55(1H, dd, J 1.0, 9.0Hz) and 8.64(2H, t, J 3.5Hz); Retention time 3.82min,
    (80:50).
    181 H IR νmax(Nujol)/cm−1 3480, 3317, 3203, 2923, 2854, 1723, 1626, 1588, 1566,
    1466, 1378, 1350 and 1268; NMR δH(400MHz, DMSO) 3.83(3H, s), 6.77(1H,
    dd, J 1.5, 3.5Hz), 6.89(2H, br s), 7.70(1H, dd, J 1.5, 3.5Hz), 7.80(1H, d, J 5.5Hz),
    7.99(1H, dd, J 0.5, 1.5Hz), 8.12(1H, d, J 5.0Hz) and 8.49(1H, s);
    Retention time 2.71min, (80:50).
    182 H 61 NMR δH(400MHz, DMSO) 4.39(2H, br s), 6.77(1H, dd, J 1.5, 3.5Hz),
    7.20(1H, d, J 2.0Hz), 7.69(1H, dd, J 1.0, 3.5Hz), 7.87(1H, d, J 4.0Hz), 8.01(1H,
    dd, J 1.0, 1.5Hz), 8.29(1H, d, J 4.0Hz), 8.54(1H, s) and 8.76(1H, d, J 2.0Hz);
    Retention time 4.72min, (80:50).
    183 H IR νmax(Nujol)/cm−1 3424, 3323, 3208, 2924, 2854, 1634, 1586, 1565, 1502,
    1464, 1378 and 1352; NMR δH(400MHz, DMSO) 2.56(3H, s), 3.75(3H, s),
    6.76(1H, dd, J 1.5, 3.5Hz), 6.88(2H, br s), 7.69(1H, dd, J 1.0, 3.5Hz),
    7.99(1H, dd, J 0.5, 2.0Hz) and 8.49(1H, s); Retention time 2.98min, (80:50).
    184 H 47 NMR δH(400MHz, DMSO) 2.62(3H, s), 6.76(1H, dd, J 1.5, 0.5Hz), 7.06(2H,
    br s), 7.68(1H, dd, J 1.0, 3.5Hz), 7.99(1H, dd, J 1.0, 1.5Hz), 8.18(2H, d, J 8.5Hz),
    8.38(2H, d, J 8.5Hz) and 8.54(1H, s); Retention time 3.27min, (80:50).
    185 H 59 IR νmax(Nujol)/cm−1 3493, 3334, 2924, 2854, 1627, 1591, 1565, 1469, 1378,
    1346, 1156 and 1145; NMR δH(400MHz, DMSO) 6.76(1H, dd, J 1.5, 3.5Hz),
    6.98(2H, br s), 7.46-7.53(3H, m), 7.70(1H, dd, J 1.0, 3.5Hz), 7.73(1H, d, J
    15.5Hz), 7.81(2H, dd, J 1.5, 8.5Hz), 7.99(1H, dd, J 1.0, 2.0Hz), 8.06(1H, J
    15.5Hz) and 8.39(1H, s); Retention time 4.77min, (80:50).
    186 H 18 NMR δH(400MHz, DMSO) 1.25(3H, t, J 7.5Hz), 3.92(2H, q, J 7.5Hz),
    6.78(1H, dd, J 1.5, 3.5Hz), 7.05(2H, br s), 7.73(1H, d, J 3.5Hz), 8.01(1H, dd, J 1.0,
    2.0Hz) and 8.32(1H, s); Retention time 1.0, (80:50).
    187 S 34 NMR δH(400MHz, CDCl3) 5.10(2H, br s), 5.42(2H, s), 6.64(1H, dd, J 1.5, 3.5Hz),
    7.20(1H, d, J 8.0Hz), 7.23(1H, m), 7.65(1H, dt, J 2.0, 7.5Hz), 7.71(1H,
    m), 7.82(1H, d, J 4.0Hz), 7.96(1H, s) and 8.58(1H, m); Retention time 2.66min,
    (50:20).
    188 S 30 IR νmax(Nujol)/cm−1 3315, 3190, 2924, 1586, 1567, 1513, 1462, 1408 and 1377;
    NMR δH(400MHz, CDCl3) 1.75(2H, br s), 5.11(2H, br s), 6.65(1H, dd, J 1.5,
    2.5Hz), 7.12(2H, dd, J 1.0, 4.5Hz), 7.73(1H, dd, J 1.0, 2.0Hz), 7.78(1H, s),
    7.83(1H, dd, J 1.0, 3.5Hz), and 8.60(2H, dd, J 1.5, 4.5Hz); Retention time 2.27min,
    (50:20).
    189 S 43 IR νmax(Nujol)/cm−1 3501, 3303, 3176, 3150, 2933, 2855, 1640, 1604, 1587,
    1568, 1515, 1466, 1411 and 1378; NMR δH(400MHz, CDCl3) 2.26(2H, quintet,
    J 7.5Hz), 2.69(2H, t, J 7.5Hz), 4.16(2H, t, J 7.0Hz), 5.12(2H, br s), 6.64(1H,
    dd, J 1.5, 3.5Hz), 7.24(1H, ddd, J 1.0, 5.0, 8.0Hz), 7.51(1H, dt, J 2.0, 8.0, 8.1Hz),
    7.74(1H, dd, J 1.0, 2.0Hz), 7.76(1H, s), 7.80(1H, dd, J 1.0, 3.5Hz),
    8.48(1H, dd, J 1.5, 5.0Hz) and 8.51(1H, d, J 2.0Hz); Retention time 4.15min,
    (50:20).
    190 S 31 NMR δH(400MHz, CDCl3) 2.26(2h, quintet, J 7.5Hz), 2.68(2H, t, J 7.5Hz),
    4.16(2H, t, J 7.0Hz), 5.08(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.12(2H, dd, J
    1.5, 4.5Hz), 7.72(1H, dd, J 1.0, 1.5Hz), 7.75(1H, s), 7.80(1H, dd, J 1.0, 3.5Hz)
    and 8.52(2H, dd, J 1.5, 4.5Hz); Retention time 3.95min, (50:20).
    191 G 39 NMR δH(400MHz, DMSO) 1.58(3H, d, J 7.0Hz), 5.09(1H, m), 6.78(1H, dd, J
    1.5, 3.5Hz), 7.13(2H, br s), 7.42(2H, d, J 8.5Hz), 7.57(2H, d, J 8.5Hz),
    7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 2.0Hz), 8.44(1H, s) and 1.33(1H, d,
    J 7.5Hz); Retention time 6.28min, (80:50).
    192 AD 22 IR νmax(Nujol)/cm−1 3404, 3347, 3137, 3089, 1661, 1647, 1628, 1535, 1517,
    1466, 1420 and 1377; NMR δH(400MHz, DMSO) 3.51-4.43(6H, s), 5.37(2H,
    s), 6.84-6.86(1H, m), 7.03(1H, s), 7.16(2H, t, J 10.0Hz), 7.40(1H, t, J 7.5Hz),
    7.86(1H, d, J 3.0Hz), 8.10(1H, s) and 8.42(1H, s).
    193 AC 36 mp 216.5-216.6° C.; IR νmax(Nujol)/cm−1 3483, 3298, 3186, 3096, 1721, 1624,
    1595, 1514, 1489, 1456, 1409, 1379, 1287 and 1202; NMR δH(400MHz, DMSO)
    3.83(3H, s), 5.40(2H, s), 6.74-6.76(1H, m), 7.49-7.58(2H, m),
    7.72-7.74(1H, m), 7.85-7.91(2H, m), 7.96(1H, t, J 1.0Hz) and 8.25(1H, s); Anal. Calcd
    for C18H15N5O3: C, 61.89; H, 4.33; N, 20.55. Found: C, 61.77; H, 4.38; N, 19.96.
    194 AC 45 IR νmax(Nujol)/cm−1 3309, 3089, 2231, 1645, 1517, 1466, 1410, 1378 and 1304;
    NMR δH(400MHz, DMSO) 5.45(2H, s), 6.85-6.90(1H, m), 7.45(2H, d, J 8.5Hz),
    7.84(2H, d, J 8.5Hz), 7.88(1H, d, J 3.5Hz), 8.15(1H, s) and 8.48(1H, s).
    195 Y 21 mp >190° C. (dec); IR νmax(Nujol)/cm−1 3492, 3302, 3085, 2918, 1629, 1580,
    1456, 1031, 817 and 627; NMR δH(400MHz, DMSO) 2.40(3H, s),
    6.42-6.31(3H, m), 7.66(1H, d, J 3.0Hz), 8.02(1H, s) and 12.54(1H, br s); Retention time
    (80:50) 0.65min
    196 H 27 NMR δH(400MHz, DMSO) 0.82(3H, t, J 7.5Hz), 1.15-1.30(6H, m), 1.66(2H,
    quintet, J 7.5Hz), 3.92(2H, t, J 7.5Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.05(2H, br
    s), 7.72(1H, d, J 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz) and 8.32(1H, s); Retention
    time 7.72(80:50).
    197 AC 74 mp 290.6-290.7° C.; NMR δH(400MHz, DMSO) 5.69(2H, s), 6.58(2H, s),
    6.75-6.79(1H, m), 6.87(1H, d, J 7.5Hz), 7.60(1H, t, J 7.5Hz), 7.68(1H, d, J 3.5Hz),
    7.97(1H, s) and 8.14-8.20(2H, m).
    198 AC 17 mp 19.7-201.5° C.; NMR δH(400MHz, DMSO) 3.72(3H, s), 5.28(2H, s),
    6.56(2H, s), 6.73-6.76(1H, m), 6.79-6.91(3H, m), 7.25(1H, t, J 7.5Hz), 7.72(1H,
    dd, J 3.5Hz, 1.0Hz), 7.94-7.96(1H, m) and 8.20(1H, s).
    199 M 77 mp 294.0-294.3° C.; NMR δH(400MHz, DMSO) 5.40(2H, s), 5.75(1H, s),
    6.57(2H, s), 6.74-6.77(1H, m), 7.45-7.56(2H, m), 7.74(1H, dd, J 3.5, 1.0Hz),
    7.80-7.83(1H, m), 7.86(1H, dt, J 7.5, 1.5Hz), 7.95-7.97(1H, m), 8.25(1H, s)
    and 12.83-13.12(1H, s).
    201 G 62 Mp. 350° C. dec.; NMR δH(400MHz, CDCl3) 4.62(2H, m), 6.45(2H, m),
    6.80(1H, m), 7.05(1H, br s), 7.63(1H, m), 7.77(1H, m), 8.03(1H, m), 8.50(1H, s)
    and 9.20(1H, m).
    202 G 20 Mp 296.3° C.; IR νmax(Nujol)/cm−1 3291, 3167, 3119, 2927, 1715, 1633, 1596,
    1567, 1401 and 1376; NMR δH(400MHz, DMSO) 9.32(1H, t, J 6.0Hz),
    8.46(1H, s), 8.05(1H, m), 7.75(1H, m), 7.45(1H, m), 7.15(1H, m), 7.00(3H, m),
    6.78(1H, m) and 4.79(2H, d, J 6.0Hz); Retention time 3.52min (80:50)
    203 AC 20 mp 218.2-218.5° C.; IR νmax(Nujol)/cm−1 3335, 3201, 1654, 1586, 1520, 1470
    and 1412; NMR δH(400MHz, DMSO) 5.35(2H, s), 6.57(2H, s),
    6.74-6.77(1H, m), 7.07-7.17(3H, m), 7.36-7.44(1H, m), 7.73(1H, d, J 3.5Hz),
    7.96(1H, s) and 8.22(1H, s).
    204 G 50 Mp 160° C. (dec); IR νmax(Nujol)/cm−1 3540, 3300, 3188, 3123, 2920, 2854, 1708,
    1628, 1603, 1584, 1561, 1461, 1395 and 1377; NMR δH(400MHz, DMSO)
    9.33(1H, br t, J 6.5Hz), 8.47(1H, s), 7.70(1H, d, J 3.5Hz), 7.44-7.33(4H, m),
    7.32-7.25(1H, m), 7.00(2H, br s), 6.42(1H, dd, J 3.5, 1.0Hz), 4.63(2H, d, J 6.5Hz)
    and 2.42(3H, s).
    205 AF 43 IR νmax(Nujol)/cm−1 3516, 3294, 3170, 3144, 3075, 1655, 1629, 1589, 1540,
    1464, 1410 and 1368; NMR δH(400MHz, DMSO) 1.98(3H, s), 5.30(2H, s),
    6.55(2H, s), 6.74-6.77(1H, m), 6.92(1H, d, J 8.5Hz), 7.23-7.31(2H, m),
    7.54(1H, d, J 8.0Hz), 7.72-7.75(1H, m), 7.95-7.96(1H, m), 8.18(1H, s) and
    9.88(1H, s).
    206 AC 19 mp 201.9-203.0° C.; NMR δH(400MHz, DMSO) 3.18(3H, s), 5.45(2H, s),
    6.57(2H, s), 6.47-6.77(1H, m), 7.48(2H, d, J 8.5Hz), 7.74(1H, d, J 3.5Hz),
    7.90(2H, d, J 8.5Hz), 7.95-7.97(1H, m) and 8.25(1H, s).
    207 AD 34 IR νmax(Nujol)/cm−1 3314, 1644, 1464, 1378, 1311, 1256 and 1117; NMR δH(400MHz,
    DMSO) 5.31(2H, s), 6.84-6.89(1H, m), 6.91-7.01(1H, m), 7.14(2H, t,
    J 7.5Hz), 7.24(1H, t, J 7.0Hz), 7.87(1H, d, J 3.5Hz), 8.14(1H, s), 8.47(1H, s).
    208 AC 34 Mp 210-220° C. (dec); NMR δH(400MHz, DMSO) 7.77(1H, d, J 3.0Hz),
    7.69(1H, s), 7.19-7.12(4H, m), 6.26-6.22(1H, m), 5.22(2H, s), 5.04(2H, br s),
    2.49(3H, s) and 2.33(2H, s).
    209 Y 58 Mp 300° C. (dec); NMR δH(400MHz, DMSO) 8.24(1H, s), 8.02(1H, s),
    7.82(1H, s), 6.31(2H, br s) and 4.11(3H, s).
    210 AF 16 mp 254.7-255.3° C.; NMR δH(400MHz, DMSO) 3.12(3H, s), 5.42(2H, s),
    6.53(2H, s), 6.74-6.77(1H, m), 6.96(1H, d, J 7.0Hz), 7.21(1H, dt, J 7.5Hz, 1.0Hz),
    7.34(1H, dt, J 7.0Hz, 1.5Hz), 7.39-7.43(1H, m), 7.74(1H, dd, J 3.5Hz,
    1.0Hz), 7.96-7.97(1H, m), 8.17(1H, s).
    211 AC 53 IR νmax(Nujol)/cm−1 3325, 3194, 1650, 1589, 1519, 1467, 1411, 1377, 1305 and
    1016; NMR δH(400MHz, DMSO) 5.37(2H, s), 6.51(2H, s), 6.72-6.75(1H,
    m), 7.15(2H, t, J 8.0Hz), 7.43-7.52(1H, m), 7.69(1H, dd, J 3.5Hz, 1.0Hz),
    7.93-7.95(1H, m) and 8.05(1H, s).
    212 S 43 NMR δH(400MHz, CDCl3) 2.55(3H, s), 5.08(2H, br s), 5.37(2H, s), 6.63(1H,
    dd, J 1.5, 3.5Hz), 6.93(1H, d, J 7.8Hz), 7.07(1H, d, J 7.8Hz), 7.52(1H, t, J 7.5Hz),
    7.71(1H, dd, J 1.0, 1.5Hz), 7.81(1H, dd, J 1.0, 3.5Hz) and 7.98(1H, s);
    Retention time 4.68min, (50:20).
    213 S 11 NMR δH(400MHz, CDCl3) 5.05(2H, br s), 5.14(2H, s), 6.38(1H, dd, J 1.0, 2.0Hz),
    6.63(1H, dd, J 2.0, 3.0Hz), 7.41(1H, dd, J 1.5, 2.0Hz), 7.48(1H, dd, J 1.0,
    2.0Hz), 7.71(1H, dd, J 1.0, 2.0Hz), 7.76(1H, s) and 7.79(1H, dd, J 1.0, 3.5Hz);
    Retention time 0.88min, (80:50).
    214 H 17 NMR δH(400MHz, DMSO) 5.27(2H, s), 6.78(1H, dd, J 1.5, 3.5Hz),
    7.12-7.18(3H, m), 7.33-7.38(2H, m), 7.68(1H, dd, J 1.0, 3.5Hz), 7.96(1H, s) and
    8.04(1H, dd, J 1.0, 1.5Hz); Retention time 2.16min, (80:50).
    215 AC 56 mp 219.5-219.7° C.; NMR δH(400MHz, DMSO) 3.86(3H, s), 5.42(2H, s),
    6.57(2H, s), 6.74-6.77(1H, m), 7.36(2H, d, J 8.0Hz), 7.74(1H, d, J 3.0Hz),
    7.91-7.98(3H, m) and 8.23(1H, s).
    216 M 98 mp 301.1-302.1° C.; NMR δH(400MHz, DMSO) 5.42(2H, s) 6.80-6.84(1H,
    m), 7.36(2H, d, J 8.5Hz), 7.82(1H, d, J 3.0Hz), 7.93(2H, d, J 8.0Hz),
    8.06(1H, s) and 8.38(1H, s).
    217 AF 95 mp 171.2-171.3° C.; NMR δH(400MHz, DMSO) 5.42(2H, s), 6.80-6.84(1H,
    m), 7.36(2H, d, J 8.5Hz), 7.82(1H, d, J 3.0Hz), 7.89-7.94(2H, m), 8.06(1H,
    s) and 8.38(1H, s).
    218 Q 52 mp 276.4-276.9° C.; NMR δH(400MHz, DMSO) 4.31(2H, d, J 5.5Hz),
    4.81(2H, s), 6.29(1H, d, J 3.5Hz), 6.41(1H, m), 6.52(2H, s), 6.74-6.76(1H, m),
    7.59-7.61(1H, m), 7.73(1H, d, J 3.0Hz), 7.95(1H, s), 8.06(1H, s) and
    8.72(1H, t, J 5.5Hz).
    219 AC 45 mp 205.3-205.4° C.; IR νmax(Nujol)/cm−1 3571, 3384, 3328, 3215, 3081, 1645,
    1394, 1523, 1480, 1466, 1409, 1364 and 1312; NMR δH(400MHz, DMSO)
    3.69(6H, s), 5.22(2H, s), 6.41-6.46(2H, m), 6.56(2H, s), 6.73-6.76(1H, m),
    7.72(1H, d, J 2.5Hz), 7.95(1H, d, J 1.0Hz) and 8.19(1H, s).
    220 AF 10 NMR δH(400MHz, DMSO) 2.12(3H, s), 5.27(2H, s), 6.55(2H, s),
    6.74-6.77(1H, m), 6.90(1H, d, J 7.0Hz), 7.13(1H, t, J 7.5Hz), 7.28(1H, dt, J 7.5Hz, 1.0Hz),
    7.36-7.41(1H, m), 7.73(1H, d, J 3.5Hz), 7.95-7.97(1H, m), 8.10(1H, s)
    and 9.69(1H, s); Retention time 0.87min (80:20)
    221 AG 48 IR νmax(Nujol)/cm−1 4328, 1643, 1463, 1410, 1378 and 1284; NMR δH(400MHz,
    DMSO) 5.27(2H, s), 6.66(1H, t, J 1.5Hz), 6.68-6.74(2H, m), 6.90-6.96(1H,
    m), 7.15(1H, t, J 7.5Hz), 7.97(1H, d, J 3.5Hz), 8.23(1H, s) and 8.59(1H, s).
    222 S 4 NMR δH(400MHz, CD, OD) 3.83(2H, t, J 5.6Hz), 4.43(2H, t, J 5.6Hz),
    6.69(1H, dd, J 1.5, 3.5Hz), 7.63(2H, dd, J 1.5, 4.5Hz), 7.66(1H dd, J 1.0, 3.5Hz),
    7.82(1H, dd, J 1.0, 2.0Hz), 8.06(1H, s) and 8.63(2H, dd, J 2.0, 4.5Hz).
    223 S 9 IR νmax(Nujol)/cm−1 3336, 3204, 3090, 2923, 2854, 1651, 1588, 1567, 1519,
    1468, 1408, 1376 and 1302; NMR δH(400MHz, CDCl3) 5.07(2H, br s),
    5.29(2H, s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.04(1H, dd, J 1.5, 5.0Hz), 7.22(1H, dd, J
    1.0, 3.0Hz), 7.33(1H, dd, J 3.0, 5.0Hz), 7.71(1H, dd, J 1.0, 1.5Hz), 7.75(1H, s)
    and 7.80(1H, dd, J 1.0, 3.5Hz); Retention time 1.47min, (80:50).
    224 S 15 NMR δH(400MHz, CDCl3) 5.01(2H, br s), 5.24(2H, s), 5.33(2H, s), 6.62(1H,
    dd, J 2.0, 3.5Hz), 6.85(2H, dd, J 1.5, 8.0Hz), 6.93(1H, d, J 1.5Hz), 7.10(1H, d,
    J 1.5Hz), 7.12-7.21(3H, m), 7.69(1H, dd, J 1.0, 1.5Hz), 7.73(1H, dd, J 1.0,
    3.5Hz) and 7.82(1H, s); Retention time 1.07min, (80:50).
    225 AD 86 IR νmax(Nujol)/cm−1 4330, 4259, 1642, 1579, 1513, 1464 and 1378; NMR δH(400MHz,
    DMSO) 5.34(2H, s), 6.84-6.87(1H, m), 7.25(2H, d, J 8.5Hz), 7.35(2H,
    d, J 8.5Hz), 7.88(1H, d, J 3.5Hz), 8.12(1H, s) and 8.45(1H, s).
    226 P 92 mp 243.2-243.8° C.; IR νmax(Nujol)/cm−1 3481, 3266, 3190, 1639, 1626, 1544,
    1514, 1463, 1409 and 1378; NMR δH(400MHz, DMSO) 4.47(2H, d, J 6.0Hz),
    5.37(2H, s), 6.54(2H, s), 6.75(1H, s), 7.19-7.25(1H, m), 7.26-7.33(4H, m),
    7.37-7.49(2H, m), 7.73(1H, d, J 2.5Hz), 7.79-7.83(2H, m), 7.95(1H, s),
    8.22(1H, s) and 8.99-9.05(1H, m).
    227 P 47 mp 170.0-171.9° C.; IR νmax(Nujol)/cm−1 3474, 3286, 3179, 1634, 1591, 1548,
    1462, 1408, 1377 and 1308; NMR δH(400MHz, DMSO) 4.46(2H, d, J 6.0Hz),
    5.38(2H, s), 6.56(2H, s), 6.73-6.77(1H, m), 7.19-7.26(1H, m),
    7.28-7.36(5H, m), 7.73(1H, d, J 3.0Hz), 7.86(2H, d, J 8.5Hz), 7.96(1H, s), 8.23(1H, s)
    and 8.96(1H, t, J 6.0Hz); Anal. Calcd for C24H20N6O2.1.0 H2O: C, 65.15; H,
    5.01; N, 18.99. Found: C, 65.51; H, 4.66; N, 18.63.
    228 H 54 IR νmax(Nujol)/cm−1 3504, 3299, 3184, 3138, 1630, 1596, 1468, 1376 and 1353;
    NMR δH(400MHz, DMSO) 2.39(3H, s), 6.76(1H, s), 7.01(2H, s), 7.50(2H, d,
    J 7.0Hz), 7.67(1H, s), 7.98(1H, s), 8.13(2H, d, J 7.0Hz), 8.49(1H, s); Anal.
    calcd for C16H13N5O3S.0.8 H2O: C, 51.97; H 3.98; N, 18.94. Found: C, 52.21; H,
    3.79; N, 18.60. M/Z 355(M+H)+.
    229 AC 40 mp 282.4-282.6° C.; NMR δH(400MHz, DMSO) 2.19(3H, s), 2.49(3H, s),
    5.08(2H, s), 6.53(2H, s), 6.73-6.75(1H, m), 6.70(1H, d, J 2.5Hz), 7.94(1H, s) and
    8.16(1H, s).
    230 P 3 IR νmax(Nujol)/cm−1 3390, 3325, 3215, 1640, 1586, 1518, 1467, 1410 and 1379;
    NMR δH(400MHz, DMSO) 2.85(3H, s), 2.95(3H, s), 5.35(2H, s), 6.57(2H, s),
    6.73-6.76(1H, m), 7.29-7.35(3H, m), 7.41(1H, t, J 7.0Hz), 7.73(1H, d, J 3.5Hz),
    7.94-7.97(1H, m) and 8.23(1H, s).
    231 Q 45 mp 278.5-280.4° C.; IR νmax(Nujol)/cm−1 3458, 3273, 3185, 1679, 1604, 1551,
    1495, 1466 and 1378; NMR δH(400MHz, DMSO) 3.71(3H, s), 5.00(2H, s),
    6.53(2H, s), 6.65(1H, dd, J 8.0Hz, 2.0Hz), 6.74-6.77(1H, m), 7.11(1H, d, J
    8.0Hz), 7.23(1H, t, J 8.5Hz), 7.28(1H, t, J 2.0Hz), 7.74(1H, d, J 4.0Hz),
    7.95-7.96(1H, m), 8.10(1H, s) and 10.41(1H, s); Anal. calcd for C18H16N6O3.0.7
    H2O: C, 57.35; H, 4.65; N, 22.29. Found: C, 57.27; H, 4.30; N, 22.29.
    232 AF 10 IR νmax(Nujol)/cm−1 3466, 3331, 3210, 1705, 1634, 1591, 1515, 1465, 1408,
    1378, 1331, 1225 and 1152; NMR δH(400MHz, DMSO) 2.95(3H, s), 5.26(2H,
    s), 6.55(2H, s), 6.73-6.76(1H, m), 7.17(2H, d, J 8.5Hz), 7.27(2H, d, J 8.5Hz),
    7.72(1H, d, J 3.0Hz), 7.95(1H, d, J 1.0Hz), 8.18(1H, s) and 9.73(1H, s).
    233 P 45 mp 223.1-226.9° C.; NMR δH(400MHz, DMSO) 2.87(3H, s), 2.94(3H, s),
    5.36(2H, s), 6.57(2H, s), 6.73-6.77(1H, m), 7.30(2H, d, J 8.5Hz), 7.37(2H, d, J
    3.5Hz), 7.73(1H, d, J 3.5Hz), 7.94-7.97(1H, m) and 8.20-8.24(1H, m);
    Anal. calcd for C19H18N6O2.1.2 H2O: C, 59.43; H, 5.35; N, 21.89. Found: C,
    59.70; H, 5.16; N, 21.50.
    234 AF 8 NMR δH(400MHz, DMSO) 0.83(4H, d, J 6.0Hz), 5.28(2H, s), 6.54(2H, s),
    6.74-6.77(1H, m), 6.85(1H, d, J 7.5Hz), 7.12(1H, t, J 7.5Hz), 7.27(1H, t, J
    7.5Hz), 7.42(1H, d, J 3.5Hz), 7.74(1H, d, J 3.5Hz), 7.94-7.98(1H, m),
    8.10(1H, s) and 9.93(1H, s); Anal. calcd for C20H18N6O2.0.8 H2O: C, 61.78; H, 5.08;
    N, 21.61. Found: C, 61.92; H, 4.81; N, 21.60.
    235 AF 48 mp 253.1-257.1° C.; NMR δH(400MHz, DMSO) 3.68(3H, s), 5.36(2H, s),
    6.59(2H, s), 6.72-6.80(1H, m), 6.97(1H, d, J 7.5Hz), 7.08-7.15(1H, m),
    7.19-7.23(2H, m), 7.74(1H, d, J 3.5Hz), 7.77(1H, s), 7.84(1H, s), 7.97(1H, s),
    8.08(1H, s) and 10.42(1H, s).
    236 Q 54 mp 279.9-281.0° C.; NMR δH(400MHz, DMSO) 3.83(3H, s), 4.30(2H, d, J 4.5Hz),
    4.82(2H, s), 6.23(2H, s), 6.72(1H, s), 6.88-7.00(2H, m), 7.24(1H, s),
    7.70(1H, s), 7.89(1H, s), 8.03(1H, s) and 8.32(1H, s).
    237 Q 60 mp 291.9-292.1° C.; NMR δH(400MHz, DMSO) 4.35(2H, s), 4.83(2H, s),
    6.52(2H, s), 6.74(1H, s), 7.13-7.23(2H, m), 7.27-7.43(2H, m), 7.72(1H, s),
    7.95(1H, s), 8.06(1H, s) and 8.71(1H, s).
    238 AF 52 mp 265.6-266.0° C.; NMR δH(400MHz, DMSO) 5.27(2H, s), 6.56(2H, s),
    6.76(1H, s), 6.94(2H, t, J 6.5Hz), 7.13-7.28(3H, m); 7.51-7.55(1H, m),
    7.72-7.76(1H, m), 7.95-8.00(2H, m), 8.03(1H, s) and 10.39(1H, s); Anal. calcd for
    C20H16N6O3S2.1.0 H2O: C, 51.05; H, 3.86; N, 17.86. Found: C, 50.72; H, 3.48;
    N, 17.98.
    239 AF 50 mp 251.4-253.1° C.; NMR δH(400MHz, DMSO) 2.13(3H, s), 2.31(3H, s),
    5.37(2H, s), 6.52(2H, s), 6.74-6.77(1H, m), 6.90-6.94(1H, m), 6.99-7.03(1H,
    m), 7.25-7.32(2H, m), 7.74(1H, d, J 3.5Hz), 7.97(1H, s), 8.08(1H, s) and
    10.28(1H, s).
    240 AC 19 mp 210.9-211.5° C.; NMR δH(400MHz, DMSO) 5.42(2H, s), 6.61(2H, s),
    6.72-6.78(1H, m), 6.99-7.03(2H, m), 7.71(1H, d, J 3.5Hz), 7.95(1H, t, J 1.0Hz)
    and 8.19(1H, s); Anal. Calcd for C14H10ClN5OS: C, 50.68; H, 3.04; N, 21.10.
    Found: C, 50.57; H, 3.15; N, 21.11. M/Z 332(M+H)+.
    241 Z 35 mp 246.2-248.0° C.; IR νmax(Nujol)/cm−1 3410, 3325, 2924, 1689, 1463, 1377,
    1289, 654 and 620; NMR δH(400MHz, DMSO) 2.49(3H, s), 7.76(1H, br s),
    8.02(1H, d, J 8.5Hz), 8.76(1H, s), 8.81(1H, d, J 7.5Hz) and 8.87(1H, s);
    Retention time(20/50): 1.89min
    242 AF 42 IR νmax(Nujol)/cm−1 4330, 4259, 3239, 1716, 1665, 1597, 1518, 1464, 1404 and
    1378; NMR δH(400MHz, DMSO) 1.11(3H, s), 1.12(3H, s), 1.15(3H, s),
    1.16(3H, s), 5.36(2H, s), 6.79-6.83(1H, m), 7.16-7.22(1H, m), 7.22-7.26(1H,
    m), 7.30(2H, d, J 3.5Hz), 7.36-7.40(1H, m), 7.84(1H, d, J 3.0Hz), 8.05(1H,
    s), 8.56(1H, s), 9.71(1H, s), 10.71(1H, s).
    243 AC 33 Mp 299.8° C.; IR νmax(Nujol)/cm−1 3470, 3356, 2922, 2854, 1621, 1607, 1592,
    1567, 1492, 1462 and 1377; NMR δH(400MHz, DMSO) 9.20-7.85(3H, br m),
    7.46-7.36(1H, m), 7.33-7.16(3H, m), 7.11(2H, br s), 5.48(2H, s) and
    2.45(3H, s).
    244 AJ 12 mp 259.2° C.; NMR δH(400MHz, DMSO) 3.29(3H, s), 5.40(2H, s), 6.69(2H, br
    s), 7.06-7.20(2H, m), 7.21-7.31(1H, m), 7.33-7.42(1H, m), 7.56(1H, s) and
    8.23(1H, s); Retention time(80:50): 2.15min
    245 AK 46 IR νmax(Nujol)/cm−1 3643, 3464, 3263, 3099, 1636, 1601, 1567, 1413, 1311, 1221
    and 1170; NMR δH(400MHz, DMSO) 4.17(2H, br s), 4.76(2H, s), 6.52(2H, br
    s), 6.74(1H, dd, J 1.5, 3.5Hz), 7.15-7.24(5H, m), 7.72(1H, dd, J 1.0, 3.5Hz),
    7.94(1H, dd, J 1.0, 1.5Hz) and 8.08(1H, s); Retention time: 0.70min.
    246 Q 42 IR νmax(Nujol)/cm−1 3486, 3281, 3182, 3075, 1657, 1605, 1563, 1460, 1409 and
    1377; NMR δH(400MHz, DMSO) 0.85(3H, t, J 7.5Hz), 1.05(3H, d, J 6.5Hz),
    1.37-1.46(2H, m), 3.63-3.72(1H, m), 4.74(2H, s), 6.48(2H, s), 6.75(1H, s),
    7.72(1H, d, J 2.5Hz), 7.95(1H, s) and 8.02-8.09(2H, m).
    247 Q 13 NMR δH(400MHz, DMSO) 1.05(3H, t, J 7.0Hz), 3.07-3.16(2H, m),
    4.74(2H, s), 6.50(2H, s), 6.74-6.76(1H, m), 7.72(1H, dd, J 3.5Hz, 1.0Hz),
    7.94-7.95(1H, m), 8.04(1H, s) and 8.20(1H, t, J 5.0Hz); Anal. calcd for C13H14N6O2.
    0.35 H2O: C, 53.36; H, 5.06; N, 28.72. Found: C, 53.39; H, 5.03; N, 28.38.
    248 Q 42 NMR δH(400MHz, DMSO) 3.70-3.77(2H, m), 4.80(2H, s), 5.10(1H, d, J 9.5Hz),
    5.21(1H, d, J 17.0Hz), 5.75-5.88(1H, m), 6.50(2H, s), 6.75(1H, s),
    7.72(1H, d, J 2.5Hz), 7.95(1H, s), 8.05(1H, s) and 8.39(1H, t, J 5.0Hz); Anal. calcd
    for C14H14N6O2.0.7 H2O: C, 54.08; H, 4.99; N, 27.03. Found: C, 53.96; H, 4.64;
    N, 26.78.
    249 Q 43 NMR δH(400MHz, DMSO) 5.01(2H, s), 6.54(2H, s), 6.76(1H, s),
    7.27-7.33(1H, m), 7.36-7.45(1H, m), 7.70-7.77(2H, m), 7.96(1H, s), 8.10(1H, s) and
    10.66(1H, s); Anal. calcd for C17H12N6O2F2.1.8 H2O: C, 50.70; H, 3.90; N,
    20.87. Found: C, 50.87; H, 3.75; N, 20.58.
    250 AF 54 IR νmax(Nujol)/cm−1 3552, 3397, 3336, 3224, 1644, 1589, 1567, 1464, 1409,
    1377, 1331 and 1300; NMR δH(400MHz, DMSO) 2.15(3H, s), 2.35(3H, s),
    5.28(2H, s), 6.74-6.77(1H, m), 6.92(1H, s), 6.97(1H, d, J 8.0Hz), 7.04(1H, d,
    J 7.5Hz), 7.28(1H, t, J 8.0Hz) 7.74(1H, d, J 3.0Hz), 7.96(1H, s), 8.14(1H, s)
    and 10.46(1H, s).
    251 AL 45 mp 247-252° C.; IR νmax(Nujol)/cm−1 3328, 2922, 1661, 1586, 1464, 1378 and
    767; NMR δH(400MHz, DMSO) 1.28(3H, d, J 6.5Hz), 3.74-3.87(1H, m),
    4.30(1H, dd, J 14, 5.5Hz), 4.43(1H, dd, J 14, 7.5Hz), 6.91-6.95(1H, m),
    7.99(1H, d, J 3.5Hz), 8.23(1H, s) and 8.46-8.60(4H, m); Retention time(50:20):
    0.81min
    252 Q 44 IR νmax(Nujol)/cm−1 3480, 3275, 3189, 3086, 1660, 1608, 1568, 1462, 1414, 1378
    and 1359; NMR δH(400MHz, DMSO) 2.20(6H, s), 2.37(2H, t, J 6.0Hz),
    3.21(2H, q, J 6.0Hz), 4.76(2H, s), 6.50(2H, s), 6.73-6.77(1H, m), 7.72(1H, d, J
    3.0Hz), 7.95(1H, s), 8.04(1H, s), 8.19(1H, t, J 5.0Hz); Anal. calcd for
    C15H19N7O2.0.6 H2O: C, 52.96; H, 5.99; N, 28.82. Found: C, 52.84; H, 5.83; N,
    28.58.
    253 AC 42 IR νmax(Nujol)/cm−1 2923, 1651, 1463; NMR δH(400MHz, DMSO) 8.37(1H, s),
    8.07-8.06(1H, m), 7.81-7.79(1H, m), 7.40-7.35(2H, m), 7.21-7.16(2H, m),
    6.83-6.81(1H, m) and 5.32(2H, s).
    254 AL 37 IR νmax(Nujol)/cm−1 3500-2500 br, 2923, 2853, 1659, 1585, 1463 and 1378;
    NMR δH(400MHz, DMSO) 8.52(1H, s), 8.48(2H, br s), 8.21(1H, s), 7.96(1H,
    d, J 3.5Hz), 6.91(1H, d, J 3.5Hz), 4.42(1H, dd, J 14.5, 7.5Hz), 4.29(1H, dd, J
    14.5, 5.5Hz), 3.88-3.73(1H, m) and 2.33(2H, s).
    255 X 32 Mp 181.6-181.7° C.; NMR δH(400MHz, DMSO) 7.98-7.95(1H, m),
    7.95-7.93(1H, m), 7.71(1H, d, J 3.5Hz), 7.00-6.94(1H, br m), 6.74(1H, dd, J 3.5,
    2.0Hz), 6.49(2H, br s), 4.10(2H, br t, J 5.5Hz), 3.34(2H, br q, J 6.0Hz) and
    1.33(9H, s).
    256 AC 12 IR νmax(Nujol)/cm−1 3318, 2922, 2854, 1604, 1588, 1538, 1456, 1406, 1377, 1356
    and 1308; NMR δH(400MHz, DMSO) 8.20(1H, s), 7.97-7.94(1H, m),
    7.70(1H, d, J 3.5Hz), 7.25(2H, d, J 8.0Hz), 7.18(2H, d, J 8.0Hz), 7.06(4H, d, J 8.0Hz),
    6.76-6.71(1H, m), 5.21(2H, s), 4.50(2H, br d, J 6.0Hz), 2.26(3H, s) and
    2.25(3H, s).
    257 F 99 Mp 190° C. (dec); IR νmax(Nujol)/cm−1 3379, 2923, 2854, 1679, 1649, 1626, 1600,
    1585, 1462 and 1377; NMR δH(400MHz, DMSO) 8.49(1H, s), 8.39-8.25(3H,
    m), 8.19(1H, s), 7.93(1H, d, J 3.5Hz), 6.90(1H, dd, J 3.5, 1.5Hz), 4.42(2H, t, J
    6.0Hz) and 3.41-3.31(2H, m).
    258 AC 2 NMR δH(400MHz, DMSO) 7.74(1H, s), 7.71(1H, s), 7.57(1H, d, J 3.5Hz),
    7.22(5H, d, J 7.5Hz), 7.15-7.01(7H, m), 6.57(1H, dd, J 3.5, 1.5Hz), 5.17(2H,
    s), 4.93(4H, br s), 2.33(6H, s) and 2.31(3H, s).
    259 AC 29 IR νmax(Nujol)/cm−1 3324, 3189, 3085, 1649, 1587, 1568, 1527, 1463, 1411, 1377
    and 1347; NMR δH(400MHz, DMSO) 5.48(2H, s), 6.58(2H, s),
    6.73-6.77(1H, m), 7.57(1H, t, J 9.5Hz), 7.72(1H, d, J 2.5Hz), 7.96(1H, s),
    8.06-8.10(1H, m), 8.21(1H, s) and 8.26-8.31(1H, m).
    260 AG 55 IR νmax(Nujol)/cm−1 2924, 2854, 1587, 1516, 1462; NMR δH(400MHz, DMSO)
    9.44(1H, s), 8.17(1H, s), 7.96-7.95(1H, m), 7.73-7.72(1H, m), 7.15(2H, d, J
    8.5Hz), 6.76-6.74(1H, m), 6.72(2H, d, J 8.5Hz), 6.60(2H, br s) and 5.17(2H,
    s).
    261 AC 70 IR νmax(Nujol)/cm−1 3290, 2922, 2854, 1644, 1514, 1464; NMR δH(400MHz,
    DMSO) 8.17(1H, s), 7.95-7.94(1H, m), 7.72-7.70(1H, m), 7.26(2H, d, J 8.5Hz),
    6.90(2H, d, J 8.5Hz), 6.75-6.73(1H, m), 6.54(2H, br s), 5.23(2H, s) and
    3.72(3H, s).
    262 AM 46 Mp 257-259° C.; IR νmax(Nujol)/cm−1 3326, 3147, 3111, 1654, 1640, 1615, 1587,
    1461, 1415 and 1376; NMR δH(400MHz, DMSO) 8.62(1H, s), 8.10(1H, d, J 2.0Hz),
    7.48(1H, d, J 2.5Hz), 7.45-7.36(1H, m), 7.31-7.24(2H, m),
    7.23-7.16(1H, m) and 5.43(1H, s).
    263 AM 28 NMR δH(400MHz, DMSO) 5.65(2H, s), 7.18-7.31(2H, m), 7.36-7.45(1H,
    m), 7.55-7.62(1H, m), 8.64(1H, s), 8.87(1H, s) and 9.58(2H, s); Retention
    time: 0.98min (80:50)
    264 AM 76 IR νmax(Nujol)/cm−1 3500-2500 br, 2921, 1650, 1609, 1584, 1526, 1462, 1415
    and 1377; NMR δH(400MHz, DMSO) 8.75(1H, s), 8.14(1H, d, J 2.0Hz),
    7.51(1H, d, J 2.5Hz), 7.43(1H, t, J 8.0Hz), 7.29-7.20(3H, m) and 5.43(2H, s).
    265 AO 7 IR νmax(DR)/cm−1 3311, 2919, 1646, 1463, 1378, 999 and 738; NMR δH(400MHz,
    DMSO) 8.74(1H, s), 7.69-7.59(1H, m), 7.58-7.51(1H, m), 7.48(1H, t,
    J 7.5Hz), 7.34-7.24(4H, m), 5.42(2H, s) and 2.40(3H, s).
    266 AC 26 NMR δH(400MHz, DMSO) 8.16(1H, s), 7.67(1H, d, J 3.5Hz), 7.25(1H, t, J
    8.0Hz), 6.91-6.83(2H, m), 6.81(1H, d, J 7.5Hz), 6.54(2H, br s), 6.38(1H, d, J
    3.5Hz), 5.26(2H, s), 3.72(3H, s) and 2.40(3H, s).
    267 AC 38 mp 190.5-190.6° C.; IR νmax(DR)/cm−1 3502, 3306, 3192, 3089, 2710, 1766, 1633
    and 1228; NMR δH(400MHz, DMSO) 9.29(1H, s), 9.12(1H, s), 8.24(1H, s),
    7.43-7.33(1H, m), 7.28-7.21(1H, m), 7.20-7.10(2H, m), 6.61(2H, br s) and
    5.40(2H, s).
    268 AC 37 mp 183.0-183.1° C.; IR νmax(DR)/cm−1 3328, 3209, 3091, 2855, 1598, 1519,
    1466; NMR δH(400MHz, DMSO) 8.21(1H, s), 7.96-7.95(1H, m),
    7.80-7.76(1H, m), 7.75-7.74(1H, m), 7.35(1H, d, J 7.5Hz), 7.00(1H, d, J 7.5Hz),
    6.76-6.75(1H, m), 6.53(2H, br s), 5.97-5.87(1H, m), 5.41(2H, s), 5.31-5.25(1H,
    m), 5.18-5.14(1H, m), 4.50(2H, s) and 4.05-4.03(2H, m); Anal. Calcd for
    C19H18N6O2.0.1 H2O: C, 62.66; H, 5.04; N, 23.08. Found: C, 62.45; H, 4.98; N,
    22.91.
    269 AC 75 IR νmax(Nujol)/cm−1 3332, 3204, 2923, 1648, 1588, 1515, 1464, 1342, 1166, 1010,
    842 and 738; NMR δH(400MHz, DMSO) 5.40(2H, s), 6.57(2H, s),
    6.75-6.76(1H, m), 7.26(1H, dd, J 8.5, 1.5Hz), 7.38-7.41(1H, m), 7.74(1H, d, J 3.5Hz),
    7.94-7.98(2H, m) and 8.24(1H, s); Anal. calcd for C17H14N6O3.0.5 H2O: C,
    56.82; H, 4.21; N, 23.39. Found: C, 57.07; H, 4.13; N, 22.99.
    270 AC 29 mp 190.4-190.5° C.; IR νmax(Nujol)/cm−1 3457, 3311, 2923, 1724, 1586, 1456,
    1348, 1129, 849, 757, 523 and 516; NMR δH(400MHz, DMSO) 8.15(1H, s),
    8.02(1H, d, J 8.5Hz), 7.97-7.94(1H, m), 7.72(2H, t, J 3.5Hz), 7.29(1H, t, J
    7.5Hz), 7.04(1H, d, J 7.0Hz), 6.95(1H, d, J 4.0Hz), 6.75-6.72(1H, m),
    6.57(2H, s), 5.56(2H, s) and 1.64(9H, s).
    271 AQ 69 mp 305.4-306.8° C.; IR νmax(Nujol)/cm−1 3324, 3209, 2923, 1639, 1592, 1465,
    1411, 1303, 1166, 1015, 851 and 750; NMR δH(400MHz, DMSO) 11.21(1H, s),
    8.10(1H, s), 7.96-7.94(1H, m), 7.71(1H, d, J 4.0Hz), 7.35(2H, t, J 3.0Hz),
    7.03(1H, t, 7.5Hz), 6.78(1H, d, J 8.0Hz), 6.75-6.72(1H, m), 6.56(3H, s) and
    5.53(2H, s).
    272 AQ 62 IR νmax(DR)/cm−1 3482, 3201, 1595, 1461, 1208, 1141, 1100, 1023, 949, 887,
    840, 793, 738, 655, 595 and 505; NMR δH(400MHz, DMSO) 11.08(1H, s),
    8.17(1H, s), 7.95-7.93(1H, m), 7.71(1H, d, J 4.0Hz), 7.48(1H, s), 7.35-7.32(2H,
    m), 7.09(1H, d, J 8.0Hz), 6.75-6.73(1H, m), 6.54(2H, s), 6.39(1H, s) and
    5.34(2H, s).
    273 AC 82 NMR δH(400MHz, DMSO) 8.29(1H, s), 8.07(1H, s), 7.81(1H, d, J 8.5Hz),
    7.57(2H, d, J 4.0Hz), 7.51(1H, d, J 3.5Hz), 7.39(1H, s), 6.79-6.76(1H, m),
    6.66(1H, s), 6.52(1H, s), 6.44(1H, d, J 3.5Hz), 5.50(2H, s) and 1.59(9H, d, J
    7.5Hz).

    Adenosine Receptor Binding
    Binding Affinities at hA2A Receptors
  • The compounds were examined in an assay measuring in vitro binding to human adenosine A2A receptors by determining the displacement of the adenosine A2A receptor selective radioligand [3H]-CGS 21680 using standard techniques. The results are summarised in Table 3.
    TABLE 3
    Example Ki (nM)
    Example 3 23
    Example 13 12
    Example 26 1
    Example 36 7
    Example 37 4
    Example 38 1
    Example 39 1
    Example 45 2
    Example 47 1
    Example 52 5
    Example 57 12
    Example 68 9
    Example 79 1
    Example 80 5
    Example 83 13
    Example 92 6
    Example 93 4
    Example 106 1
    Example 112 8
    Example 118 3
    Example 125 6
    Example 126 7
    Example 127 9
    Example 141 36
    Example 157 4
    Example 159 10
    Example 162 8
    Example 185 7
    Example 189 21
    Example 192 24
    Example 198 7
    Example 201 2
    Example 202 1
    Example 208 6
    Example 211 3
    Example 212 35
    Example 235 4
    Example 240 7
    Example 244 7
    Example 259 11

    Evaluation of Potential Anti-Parkinsonian Activity In Vivo
    Haloperidol-Induced Hypolocomotion Model
  • It has previously been demonstrated that adenosine antagonists, such as theophylline, can reverse the behavioural depressant effects of dopamine antagonists, such as haloperidol, in rodents (Mandhane S. N. et al., Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats. Eur. J. Pharmacol. 1997, 328, 135-141). This approach is also considered a valid method for screening drugs with potential antiparkinsonian effects. Thus, the ability of novel adenosine antagonists to block haloperidol-induced deficits in locomotor activity in mice can be used to assess both in vivo and potential antiparkinsonian efficacy.
  • Method
  • Female TO mice (25-30 g) obtained from TUCK, UK, are used for all experiments. Animals are housed in groups of 8 [cage size−40 (width)×40 (length)×20 (height)cm] under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.
  • Drugs
  • Liquid injectable haloperidol (1 ml Serenance ampoules from Baker Norton, Harlow, Essex, each containing haloperidol BP 5 mg, batch # P424) are diluted to a final concentration of 0.02 mg/ml using saline. Test compounds are typically prepared as aqueous suspensions in 8% Tween. All compounds are administered intraperitoneally in a volume of 10 ml/kg.
  • Procedure
  • 1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%. Test substances are typically administered 5-60 minutes prior to testing. The animals are then placed individually into clean, clear polycarbonate cages [20 (width)×40 (length)×20 (height) cm, with a flat perforated, Perspex lid]. Horizontal locomotor activity is determined by placing the cages within a frame containing a 3×6 array of photocells linked to a computer, which tabulates beam breaks. Mice are left undisturbed to explore for 1 hour, and the number of beams breaks made during this period serves as a record of locomotor activity which is compared with data for control animals for statistically significant differences.
  • 6-OHDA Model
  • Parkinson's disease is a progressive neurodegenerative disorder characterised by symptoms of muscle rigidity, tremor, paucity of movement (hypokinesia), and postural instability. It has been established for some time that the primary deficit in PD is a loss of dopaminergic neurones in the substantia nigra which project to the striatum, and indeed a substantial proportion of striatal dopamine is lost (ca 80-85%) before symptoms are observed. The loss of striatal dopamine results in abnormal activity of the basal ganglia, a series of nuclei which regulate smooth and well co-ordinated movement (Blandini F. et al., Glutamate and Parkinson's Disease. Mol. Neurobiol. 1996, 12, 73-94). The neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin 6-hydroxydopamine into brain regions containing either the cell bodies or axonal fibres of the nigrostriatal neurones.
  • By unilaterally lesioning the nigrostriatal pathway on only one-side of the brain, a behavioural asymmetry in movement inhibition is observed. Although unilaterally-lesioned animals are still mobile and capable of self maintenance, the remaining dopamine-sensitive neurones on the lesioned side become supersenstive to stimulation. This is demonstrated by the observation that following systemic administration of dopamine agonists, such as apomorphine, animals show a pronounced rotation in a direction contralateral to the side of lesioning. The ability of compounds to induce contralateral rotations in 6-OHDA lesioned rats has proven to be a sensitive model to predict drug efficacy in the treatment of Parkinson's Disease.
  • Animals
  • Male Sprague-Dawley rats, obtained from Charles River, are used for all experiments. Animals are housed in groups of 5 under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.
  • Drugs
  • Ascorbic acid, desipramine, 6-OHDA and apomorphine (Sigma-Aldrich, Poole, UK). 6-OHDA is freshly prepared as a solution in 0.2% ascorbate at a concentration of 4 mg/mL prior to surgery. Desipramine is dissolved in warm saline, and administered in a volume of 1 ml/kg. Apomorphine is dissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg. Test compounds are suspended in 8% Tween and injected in a volume of 2 ml/kg.
  • Surgery
  • 15 minutes prior to surgery, animals are given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to non-dopamine neurones. Animals are then placed in an anaesthetic chamber and anaesthetised using a mixture of oxygen and isoflurane. Once unconscious, the animals are transferred to a stereotaxic frame, where anaesthesia is maintained through a mask. The top of the animal's head is shaved and sterilised using an iodine solution. Once dry, a 2 cm long incision is made along the midline of the scalp and the skin retracted and clipped back to expose the skull. A small hole is then drilled through the skill above the injection site. In order to lesion the nigrostriatal pathway, the injection cannula is slowly lowered to position above the right medial forebrain bundle at −3.2 mm anterior posterior, −1.5 mm medial lateral from bregma, and to a depth of 7.2 mm below the duramater. 2 minutes after lowing the cannula, 2 μL of 6-OHDA is infused at a rate of 0.5 μL/min over 4 minutes, yeilding a final dose of 8 μg. The cannula is then left in place for a further 5 minutes to facilitate diffusion before being slowly withdrawn. The skin is then sutured shut using Ethicon W501 Mersilk, and the animal removed from the strereotaxic frame and returned to its homecage. The rats are allowed 2 weeks to recover from surgery before behavioural testing.
  • Apparatus
  • Rotational behaviour is measured using an eight station rotameter system provided by Med Associates, San Diego, USA. Each station is comprised of a stainless steel bowl (45 cm diameter×15 cm high) enclosed in a transparent Plexiglas cover running around the edge of the bowl, and extending to a height of 29 cm. To assess rotation, rats are placed in cloth jacket attached to a spring tether connected to optical rotameter positioned above the bowl, which assesses movement to the left or right either as partial (45°) or full (360°) rotations. All eight stations are interfaced to a computer that tabulated data.
  • Procedure
  • To reduce stress during drug testing, rats are initially habituated to the apparatus for 15 minutes on four consecutive days. On the test day, rats are given an intraperitoneal injection of test compound 30 minutes prior to testing. Immediately prior to testing, animals are given a subcutaneous injection of a subthreshold dose of apomorphine, then placed in the harness and the number of rotations recorded for one hour. The total number of full contralatral rotations during the hour test period serves as an index of antiparkinsonian drug efficacy.

Claims (21)

1. A method of treating a disorder selected from a group consisting of:
(i) movement disorders;
(ii) acute and chronic pain;
(iii) affective disorders;
(iv) central and peripheral nervous system degenerative disorders;
(v) schizophrenia and related psychoses;
(vi) cognitive disorders;
(vii) attention disorders;
(viii) central nervous system injury;
(ix) cerebral ischaemia;
(x) myocardial ischaemia;
(xi) muscle ischaemia;
(xii) sleep disorders;
(xiii) eye disorders selected from retinal ischaemia-reperfusion injury and diabetic neuropathy;
(xiv) cardiovascular disorders; and
(xv) diabetes and its complications;
the method comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):
Figure US20060270691A1-20061130-C00267
wherein
R1 is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7, and NR4SO2R7;
R2 is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety;
R3 is selected from the group consisting of H, alkyl, COR8, CONR9R10, CONR8NR9R10, CO2R11, and SO2R11;
R4, R5, and R6 are independently selected from the group consisting of H, alkyl, and aryl, or where R5 and R6 are in an (NR5R6) group then R5 and R6 may be linked to form a heterocyclic ring;
R7 is alkyl or aryl;
R8, R9, and R10 are independently selected from the group consisting of H, alkyl, and aryl, or R9 and R10 may be linked to form a heterocyclic ring, or where R8, R9, and R10 are in a (CONR8NR9R10) group, R8 and R9 may be linked to form a heterocyclic group; and
R11 is alkyl or aryl,
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein said disorder is a movement disorder.
3. The method of claim 2, wherein the movement disorder is Parkinson's disease.
4. The method of claim 3 for treatment of drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning, or post-traumatic Parkinson's disease.
5. The method of claim 2, wherein the movement disorder is selected from the group consisting of progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, and other disorders of the basal ganglia which result in dyskinesias.
6. The method of claim 1, wherein the compound of formula (I) is administered in combination with one or more additional drugs useful in the treatment of movement disorders.
7. The method of claim 6, wherein the components are in the same formulation.
8. The method of claim 6, wherein the components are in separate formulations for administration simultaneously or sequentially.
9. The method of claim 6, wherein said one or more additional drugs useful in the treatment of movement disorders are drugs useful in the treatment of Parkinson's disease.
10. The method of claim 6, wherein the one or more additional drugs is L-DOPA or a dopamine agonist.
11. The method of claim 1, wherein said disorder is selected from the group consisting of depression, cognitive impairment, memory impairment, acute pain, chronic pain, ADHD, and narcolepsy.
12. The method of claim 11, wherein said cognitive or memory impairment disorder is Alzheimer's disease.
13. The method of claim 1, wherein the subject is human.
14. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of:
N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine;
6-(2-Furyl)-1H-purine-2-amine;
6-(2-Furyl)-2-methylthio-1H-purine;
2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-carboxamide;
2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide;
2-Amino-6-(2-furyl)-N-(4-methoxybenzyl)-9H-purine-9-carboxamide;
2-Amino-6-(2-furyl)-N-(4-methylbenzyl)-9H-purine-9-carboxamide;
2-Amino-N-(2-chlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
(1S)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-purine-9-carboxamide;
2-Amino-6-(2-furyl)-N-(3-methylbenzyl)-9H-purine-9-carboxamide;
2-Amino-6-(2-furyl)-N-n-pentyl-9H-purine-9-carboxamide;
6-(2-Furyl)-9-(1-phenyl-1-propene-3-yl)-9H-purine-2-amine;
6-(2-Furyl)-9-(3-phenylpropyl)-9H-purine-2-amine;
2-Amino-N-(4-fluorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
2-Amino-N-(3,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
6-(2-Furyl)-9-(4-isopropylbenzyl)-9H-purine-2-amine;
2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-carboxamide;
2-Amino-N-(2,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;
Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate;
N-Benzyl-2-methoxy-6-(2-furyl)-9H-purine-9-carboxamide;
2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-carboxamide;
9-(3-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine;
6-(2-Furyl)-9-(3-methylbenzyl)-9H-purine-2-amine;
6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-amine;
2-Amino-N-(3-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide;
9-(2-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine;
6-(2-Furyl)-9-(4-trifluoromethylbenzyl)-9H-purine-2-amine;
9-(4-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine;
6-(2-Furyl)-9-(2-phenylethenyl)sulphonyl-9H-purine-2-amine;
6-(2-Furyl)-9-(3-(3-pyridyl)propyl)-9H-purine-2-amine;
9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine;
6-(2-Furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine;
2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-carboxamide;
2-Amino-6-(2-furyl)-N-(2-thienylmethyl)-9H-purine-9-carboxamide;
9-(4-Methylbenzyl)-6-(5-methyl-2-furyl)-9H-purine-2-amine;
9-(2,6-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine;
6-(2-Furyl)-9-(6-methyl-2-pyridyl)methyl-9H-purine-2-amine;
6-(2-Furyl)-9-(2-(1-methyl-1H-imidazol-4-ylsulphonylamino)benzyl)-9H-purine-2-amine;
9-(5-Chloro-2-thienylmethyl)-6-(2-furyl)-9H-purine-2-amine;
9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-purine-2-amine; and
9-(2-Fluoro-5-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine.
15. A method of neuroprotection comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):
Figure US20060270691A1-20061130-C00268
wherein
R1 is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7, and NR4SO2R7;
R2 is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety;
R3 is selected from the group consisting of H, alkyl, COR8, CONR9R10, CONR8NR9R10, CO2R11, and SO2R11;
R4, R5, and R6 are independently selected from the group consisting of H, alkyl, and aryl, or where R5 and R6 are in an (NR5R6) group then R5 and R6 may be linked to form a heterocyclic ring;
R7 is alkyl or aryl;
R8, R9, and R10 are independently selected from the group consisting of H, alkyl, and aryl, or R9 and R10 may be linked to form a heterocyclic ring, or where R8, R9, and R10 are in a (CONR8NR9R10) group, R8 and R9 may be linked to form a heterocyclic group; and
R11 is alkyl or aryl,
or a pharmaceutically acceptable salt thereof.
16. The method of claim 15, wherein said method is for neuroprotection in a subject suffering from or at risk from a neurodegenerative disorder.
17. The method of claim 16, wherein said neurodegenerative disorder is a movement disorder.
18. The method of claim 17, wherein said movement disorder is selected from the group consisting of Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning, post traumatic Parkinson's disease, progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, and other disorders of the basal ganglia which result in dyskinesias.
19. The method of claim 15, wherein the subject is human.
20. A method of treating a disorder in which the blocking of adenosine A2A receptors is beneficial selected from the group consisting of:
(i) movement disorders;
(ii) acute and chronic pain;
(iii) affective disorders;
(iv) central and peripheral nervous system degenerative disorders;
(v) schizophrenia and related psychoses;
(vi) cognitive disorders;
(vii) attention disorders;
(viii) central nervous system injury;
(ix) cerebral ischaemia;
(x) myocardial ischaemia;
(xi) muscle ischaemia;
(xii) sleep disorders;
(xiii) eye disorders selected from retinal ischaemia-reperfusion injury and diabetic neuropathy;
(xiv) cardiovascular disorders; and
(xv) diabetes and its complications;
the method comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):
Figure US20060270691A1-20061130-C00269
wherein
R1 is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7, and NR4SO2R7;
R2 is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety;
R3 is selected from the group consisting of H, alkyl, COR8, CONR9R10, CONR8NR9R10, CO2R11, and SO2R1;
R4, R5, and R6 are independently selected from the group consisting of H, alkyl, and aryl, or where R5 and R6 are in an (NR5R6) group then R5 and R6 may be linked to form a heterocyclic ring;
R7 is alkyl or aryl;
R8, R9, and R10 are independently selected from the group consisting of H, alkyl, and aryl, or R9 and R10 may be linked to form a heterocyclic ring, or where R8, R9, and R10 are in a (CONR8NR9R10) group, R8 and R9 may be linked to form a heterocyclic group; and
R11 is alkyl or aryl,
or a pharmaceutically acceptable salt thereof.
21. The method of claim 20, wherein the disorder is caused by hyperfunctioning of the adenosine receptors.
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