Thieno(3,2-d)pyrimidines and furano(3,2-d)pyimidines and their use as purinergic receptor antagonists

[0001] The present invention relates to thieno(3,2-d)pyrimidines and furano(3,2-d)pyrimidines 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.

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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).

[0006] 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).

[0007] 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).

[0008] 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 Approachies Exp. Ther. (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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, 723841) 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).

[0013] 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.

[0014] 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 MTP-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.

[0015] 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).

[0016] One prominent xanthine-derived adenosine A2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141-144).

[0017] 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 theophylline 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).

[0018] 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 KE 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).

[0019] 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]pyriridine) 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.

[0020] It has now been found that thieno(3,2-d)pyrimidines and furano(3,2-d)pyrimidines, 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 include Parkinson's disease, Alzheimer's disease, spasticity, Huntington's chorea and Wilson's disease.

[0021] 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.

[0022] According to the present invention there is provided a compound of formula (I):

[0023] wherein

[0024] X is S or O;

[0025] R1 is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR5, CO2R5, CONR6R7, CONR5NR6R7, NR6R7, NR5CONR6R7, NR5COR6, NR5CO2R8, and NR5SO2R8;

[0026] R2 is selected from aryl attached via an unsaturated carbon atom;

[0027] R3 is selected from H, alkyl, hydroxy, alkoxy, halogen, CN and NO2;

[0028] R4 is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO2, COR5, CO2R5, CONR6R7, CONR5NR6R7, NR6R7, NR5CONR6R7, NR5COR6, NR5CO2R8 and NR5SO2R8;

[0029] R5, R6 and R7 are independently selected from H, alkyl and aryl, or where R6 and R7 are in an (NR6R7) group, R6 and R7 may be linked to form a heterocyclic group, or where R5, R6 and R7 are in a (CONR5NR6R7) group, R5 and R6 may be linked to form a heterocyclic group; and

[0030] R8 is selected from alkyl and aryl,

[0031] or a pharmaceutically acceptable salt thereof or prodrug thereof.

[0032] 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.

[0033] As used herein, the term “lower alkyl” means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).

[0034] 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 or pyrimidinyl.

[0035] 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 or pyrimidinyl.

[0036] As used herein, the term “alkoxy” means alkyl-O—. As used herein, the term “aryloxy” means aryl-O—.

[0037] As used herein, the term “halogen” means a fluorine, chlorine, bromine or iodine radical.

[0038] As used herein, the term “ortho,ortho-disubstituted aryl groups” refers to aryl groups which are substituted in both ortho positions of the aryl group relative to the point of attachment of the aryl group to the pyrimidine ring.

[0039] As used herein, the term “prodrug” means any pharmaceutically acceptable prodrug of a compound of the present invention.

[0040] Where any of R1 to R13 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 R13 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 R6 and R7, or R12 and R13, or R5 and R12 are linked to form a heterocyclic group, the heterocyclic group may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:

[0041] carbon-containing groups such as

[0042] alkyl,

[0043] aryl, (e.g. substituted and unsubstituted phenyl (including alkylphenyl, alkoxyphenyl and halophenyl),

[0044] arylalkyl; (e.g. substituted and unsubstituted benzyl);

[0045] halogen atoms and halogen containing groups such as

[0046] haloalkyl (e.g. trifluoromethyl),

[0047] haloaryl (e.g. chlorophenyl);

[0048] oxygen containing groups such as

[0049] alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl, (aryl)(hydroxy)alkyl),

[0050] ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, alkoxyaryl, aryloxyaryl),

[0051] aldehydes (e.g. carboxaldehyde),

[0052] ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl, arylalkylcarbonyl, arylalkylcarbonylalkyl, arylalkylcarbonylaryl)

[0053] acids (e.g. carboxy, carboxyalkyl, carboxyaryl),

[0054] acid derivatives such as esters

[0055] (e.g. alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides

[0056] (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, cyclicaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl or arylalkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino or arylalkylcarbonylamino), carbamates

[0057] (eg. alkoxycarbonylamino, aryloxycarbonylamino, arylalkyloxycarbonylamino, aminocarbonyloxy, monoor di-alkylaminocarbonyloxy, arylaminocarbonyloxy or arylalkylaminocarbonyloxy) and ureas

[0058] (eg. mono- or di-alkylaminocarbonylamino, arylaminocarbonylamino or arylalkylaminocarbonylamino);

[0059] nitrogen containing groups such as

[0060] amines (e.g. amino, mono- or dialkylamino, cyclicamino, arylamino, aminoalkyl, mono- or dialkylaminoalkyl),

[0061] azides,

[0062] nitriles (e.g. cyano, cyanoalkyl),

[0063] nitro,

[0064] 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);

[0065] sulfur containing groups such as

[0066] thiols, thioethers, sulfoxides, and sulfones

[0067] (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);

[0068] heterocyclic groups containing one or more, preferably one, heteroatom,

[0069] (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

[0070] silicon-containing groups-such as

[0071] silanes (e.g. trialkylsilyl).

[0072] In one embodiment, where any of R1 to R13 is directly substituted by an alkyl substituent group, or by an alkyl-containing substituent group (such as alkoxy, alkoxyalkyl or alkylcarbonylamino for example), then the alkyl moiety of the substituent group directly attached to any of R1 to R13 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.

[0073] In a further embodiment, where any of R1 to R13 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 R13 may be further substituted by the substituent groups hereinbefore described and particularly by halogen, alkyl (including CF3), hydroxy, alkoxy, CN, amines (including amino, mono- and dialkyl amino) and NO2.

[0074] The terms “directly substituted” and “directly attached”, as used herein, mean that the substituent group is bound directly to any of R1 to R13 without any intervening divalent atoms or groups.

[0075] In the compounds of formula (I), it is preferred that X is S.

[0076] In the compounds of formula (I), R1 is selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), aryl (including heteroaryl), hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR5, CO2R5, CONR6R7, CONR5NR6R7, NR6R7 (including NH2, monoalkyl amino and dialkylamino), NR5CONR6R7, NR5COR6, NR5CO2R8 and NR5SO2R8.

[0077] It is preferred that R1 is selected from alkyl, alkoxy, thioalkyl, NR6R7 and NR5COR6, and preferably from alkyl and NR6R7. In one embodiment, R1 is selected from NH2.

[0078] Where R1 is selected from alkyl, alkoxy and alkylthio, then said alkyl group or the alkyl group of the alkoxy or alkylthio is preferably selected from C1-6 alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), preferably saturated C1-6 alkyl, and more preferably lower alkyl. In a preferred embodiment, R1 is selected from substituted alkyl, particularly haloalkyl (including CF3) and arylalkyl (including heteroarylalkyl).

[0079] In one embodiment, R1 is selected from CONR5NR6R7, NR5CONR6R7, NR5COR6, NR5CO2R8 and NR5SO2R8, and R5 is H or alkyl, and preferably H.

[0080] In one embodiment, R1 is selected from NR6R7 wherein R6 is preferably selected from H and alkyl (preferably H), and R7 is a substituted alkyl group represented by (CR9R10)nR11, wherein R9 and R10 are independently selected from H, alkyl and aryl (preferably from H and alkyl, and more preferably from H), n is selected from 1 to 6 (preferably from 2 to 4, more preferably 2), and R11 is selected from aryl (including heteroaryl), COR5, CO2R5, CONR12R13, CONR5NR12R13, NR12R13 (including NH2, monoalkyl amino and dialkylamino), NR5CONR12R13, NR5COR12, NR5CO2R8 and NR5SO2R8 (and preferably from aryl heteroaryl), NR12R13 (including NH2, monoalkyl amino and dialkylamino), NR5CONR12R13, NR5COR12, NR5CO2R8 and NR5SO2R8), wherein R5 and R8 are as hereinbefore defined and wherein R12 and R13 are independently selected from H, alkyl and aryl, or where R12 and R13 are in an (NR12R13) group, R12 and R13 may be linked to form a heterocyclic group, or where R5, R12 and R13 are in a (CONR5NR12R13) group, R5 and R12 may be linked to form a heterocyclic group.

[0081] In the compounds of formula (I), R2 is substituted or unsubstituted aryl (including heteroaryl) attached via an unsaturated carbon atom. Preferably, the aryl group is a 5- or 6-membered monocyclic aryl group.

[0082] Preferably, R2 is a heteroaryl group, and preferably a heteroaryl group which is attached to the pyrimidine ring of formula (I) such that a heteroatom is adjacent to the unsaturated carbon atom attached to said pyrimidine ring. Preferably, R2 is an N, O or S-containing heteroaryl group. R2 may contain one or more heteroatom(s) selected from N, O and S.

[0083] It is preferred that the aryl (including heteroaryl) group of R2 is not ortho,ortho-disubstituted. Preferably, the aryl (including heteroaryl) group of R2 is not substituted at either ortho position. 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).

[0084] 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 preferred embodiment, R2 is selected from furyl, thienyl, pyridyl and thiazolyl, and preferably from 2-furyl, 2-thienyl, 2-thiazolyl and 2-pyridyl.

[0085] In a particularly preferred embodiment, R2 is selected from 2-thiazolyl, optionally substituted, particularly by methyl.

[0086] In the compounds of formula (I), R3 is selected from H, alkyl (including haloalkyl (particularly CF3)), hydroxy, alkoxy (including OCF3), halogen, CN and NO2. Preferably, R3 is selected from H, CF3, hydroxy, alkoxy, halogen, CN and NO2, and preferably R3 is H.

[0087] In the embodiment where R3 is selected from alkyl or alkoxy, then said alkyl group or the alkyl group of said alkoxy is preferably C1-6 alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), preferably saturated C1-6 alkyl, and more preferably lower alkyl. In a preferred embodiment of compounds wherein R3 is selected from alkyl, R3 is haloalkyl (particularly CF3).

[0088] In the compounds of formula (I), R4 is selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), aryl (including heteroaryl), hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO2, COR5, CO2R5, CONR6R7, CONR5NR6R7, NR6R7 (including NH2), NR5CONR6R7, NR5COR6, NR5CO2R8 and NR5SO2R8.

[0089] Where R4 is selected from alkyl, preferably R4 is C1-6 alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), preferably saturated C1-6 alkyl, and more preferably lower alkyl. In one embodiment, R4 is selected from substituted alkyl, wherein the substituent groups are selected from halogen, susbtituted and unsubstituted aryl (including heteroaryl), cycloalkyl, non-aromatic heterocyclyl, CO2R5, CONR6R7, CONR5NR6R7 and C(═NR5)NR6R7, preferably aryl (including heteroaryl) and CONR6R7, more preferably aryl (including heteroaryl). In an alternative embodiment, R4 is selected from substituted alkyl, particularly haloalkyl (including CF3) and arylalkyl (including heteroarylalkyl). In an alternative embodiment, R4 is selected from unsubstituted C1-6 alkyl (preferably saturated C1-6 alkyl).

[0090] In one embodiment R4 is selected from H, alkyl (including arylalkyl (including heteroarylalkyl)), halogen, COR5, CO2R5, CONR6R7 and CONR5NR6R7, preferably from H, alkyl (including arylalkyl (including heteroarylalkyl)) and halogen, and preferably from H.

[0091] In the compounds of formula (I), R5, R6 and R7 are independently selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl), or where R6 and R7 are in any NR6R7 group R6 and R7 may be linked to form a heterocyclic group, or where R5, R6 and R7 are in a CONR5NR6R7 group, R5 and R6 may be linked to form a heterocyclic group.

[0092] In the compounds of formula (I), R12 and R13 are independently selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl), or where R12 and R13 are in any NR12R13 group R12 and R13 may be linked to form a heterocyclic group, or where R5, R12 and R13 are in a CONR5NR12R13 group, R5 and R12 may be linked to form a heterocyclic group.

[0093] In the compounds of formula (I), R8 is selected from alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl).

[0094] Where R5 to R10, R12 and R13, are independently selected from alkyl, preferably R5 to R10, R12 and R13 are independently selected from C1-6 alkyl, preferably C1-6 saturated alkyl and more preferably from lower alkyl.

[0095] Where R6 and R7, or R12 and R13, are linked to form a heterocyclic ring, said heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated. Said heterocyclic ring is preferably a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatom(s) preferably selected from N, O and S.

[0096] Where R5 and R6, or R5 and R12, are linked to form a heterocyclic ring, said heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated. Said heterocyclic ring is preferably a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatom(s) preferably selected from N, O and S.

[0097] In a particularly preferred embodiment of the invention, the compounds of the present invention are selected from:

[0098] 7-bromo-4(2-furyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine;

[0099] N-allyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine;

[0100] 2-ethyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine;

[0101] 2-methyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine;

[0102] 2-n-propyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine;

[0103] N-(2-hydroxyethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine;

[0104] 2-isopropyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine;

[0105] N-(2-methoxyethyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine;

[0106] N,N-dimethyl-4-(4-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine;

[0107] 4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine;

[0108] 2-ethyl-4-(4-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine;

[0109] 2-ethyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine;

[0110] N,N-dimethyl-4-(5-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine;

[0111] N,N-dimethyl-4-(4,5-dimethyl-2-thiazolyl)thieno[3,2-d]pyridine-2-amine;

[0112] 4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine;

[0113] (2R)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine;

[0114] N-allyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine;

[0115] 2-isopropyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine;

[0116] N,N-dimethyl-4-(5-methyl-2-pyridyl)thieno[3,2-d]pyrimidine-2-amine;

[0117] 2-tert-butyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine;

[0118] 2-cyclopropyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine;

[0119] 2-ethyl 4-(6-methyl-2-pyridyl)thieno[3,2-d]pyrimidine;

[0120] (2S)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-thiazolyl)thieno[3,2-d]pyridine; and

[0121] 2-(2-chloroethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine.

[0122] Where chiral the compounds of the present invention may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.

[0123] According to a further aspect of the invention, there is provided for use in therapy a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.

[0124] The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.

[0125] 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).

[0126] 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.

[0127] 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.

[0128] 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, a typical 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.

[0129] According to a further aspect of the present invention, there is provided the use of a compound of the present invention or a pharmaceutically acceptably salt 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.

[0130] 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 the present invention or a pharmaceutically acceptable salt or prodrug thereof.

[0131] The disorder may be caused by the hyperfunctioning of the purine receptors.

[0132] According to a further aspect of the present invention there is provided use of a compound of the present invention 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.

[0133] 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 the present invention or a pharmaceutically acceptable salt or prodrug thereof.

[0134] According to a further aspect of the invention there is provided use of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.

[0135] 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 the present invention or a pharmaceutically acceptable salt or prodrug thereof.

[0136] 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.

[0137] 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.

[0138] Compounds of formula (1) are prepared from halides of formula (2) by standard methods such as aryl coupling reactions which may be advantageously carried out in the presence of a catalyst such as a palladium catalyst. The aryl coupling reaction may be carried out by reaction of a halide of formula (2) with, for example, an aryl or heteroaryl trialkyltin reagent, an aryl or heteroaryl boronic acid or boronic ester reagent or an aryl or heteroaryl zinc halide reagent according to methods described in the literature. Suitable aryl or heteroaryl trialkyl tin, boronic acid, boronic ester or zinc halide reagents are either commercially available or may be prepared by standard literature methods.

[0139] Halides of formula (2) are either known in the literature or may be prepared from compounds of formula (3) by standard methods, for example by treatment with a chlorinating reagent such as POCl3. Compounds of formula (3) are either known in the literature or may be prepared from compounds of formula (4) by standard methods such as treatment with an appropriate ester (RICO2Et) in the presence of a suitable base such as NaOEt, or by treatment with an appropriate anhydride (RICO)2O in the presence of a base such as Et3N followed by heating in the presence of a stronger base such as NaOH. Alternatively compounds of formula (3) may be prepared from compounds of formula (5) by standard methods such as treatment with an appropriate nitrile (RICN) in the presence of dry HCl gas. Compounds of formula (4) and formula (5) are either known in the literature or may be prepared by standard methods.

[0140] Compounds of formula (1) where R1 is NR6R7 may be prepared from compounds of formula (1) where R1 is halogen by standard methods such as reaction with an appropriate amine (R6R7NH). Compounds of formula (1) where R1 is halogen may be prepared from compounds of formula (2) where R1 is halogen as described above. Compounds of formula (2) where R1 is halogen are either known in the literature or may be prepared by methods analogous to those described in the literature.

[0141] Compounds of formula (1) where R1 is NR5CONR6R7, NR5COR6, NR5CO2R8 or NR5SO2R8 wherein R5 is H may be prepared from compounds of formula (1) where R1 is NH2 by standard methods for example by treatment with an appropriate isocyanate (R6NCO or R7NCO), carbamoyl chloride (R6R7NCOCl), acid chloride (R6COCl), chloroformate (ClCO2R8) or sulphonyl chloride (ClSO2R8). Analogous compounds wherein R5 is alkyl may be prepared by initial alkylation or reductive alkylation followed by reaction with the appropriate reagent as described above.

[0142] Compounds of formula (1) where R1 is NH2 may be prepared from compounds of formula (1) where R1 is halogen either by direct displacement with ammonia or by reaction with an appropriate protected amine, for example 3,4-dimethoxybenzylamine, followed by removal of the protecting group, if desired, by treatment with TFA.

[0143] Compounds of formula (1) where R1 is hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, or CN may be prepared from compounds of formula (1) where R1 is halogen by direct displacement with an appropriate nucleophile such as water, an alcohol, thiol or cyanide in the presence of a suitable base.

[0144] Compounds of formula (1) where R1 is CONR6R7 or CONR5NR6R7 may be prepared from compounds of formula (1) where R1 is CO2R5 by standard methods such as reaction with an appropriate amine (R6R7NH) or substituted hydrazine (HNR5N6R7), either directly or in the presence of a suitable reagent such as trimethylaluminium.

[0145] Compounds of formula (1) where R1 is COR5, wherein R5 is H, may be prepared from compounds of formula (1) where R1 is CO2R5 by standard methods such as reduction with an appropriate reducing agent such as DIBAL at low temperature. Compounds of formula (1) where R1 is COR5, wherein R5 is alkyl or aryl, may be prepared from compounds of formula (1) where R1 is COR5, wherein R5 is H, by standard methods such as initial treatment with an appropriate alkyl or aryllithium or Grignard reagent, followed by oxidation.

[0146] Compounds of formula (1) where R1 is CO2R5 may be prepared according to Reaction Scheme 1 by the methods described above.

[0147] In a compound of formula (1) where R1 is alkyl or aryl or where the group R1 contains an alkyl or aryl substituent, the alkyl or aryl group may be substituted as defined above. Where the alkyl or aryl group is substituted by a reactive functional group it will be appreciated that derivatisation of the reactive functional group may lead to a wide variety of additional substituent groups. By way of example where the alkyl or aryl group is substituted by an amino group then the amino group may be derivatised to form a mono- or dialkylamine, urea, thiourea, amide, carbamate or sulphonamide by the use of standard reactions such as those described above. Where the alkyl or aryl group is substituted by an amino group it may be advantageous to protect the amino group during the synthesis by the use of a standard protecting group such as a BOC group. The protecting group may then be removed at the appropriate step in the synthesis, by standard methods such as treatment with TFA.

[0148] Compounds of formula (1) where R3 is halogen or NO2 may be prepared from compounds of formula (2) where R3 is halogen or NO2 as described above. Compounds of formula (2) where R3 is halogen or NO2 are either known in the literature or may be prepared from compounds of formula (2) where R3 is H by standard literature methods such as halogenation or nitration.

[0149] Compounds of formula (1) where R3 is hydroxy, alkoxy or cyano may be prepared from compounds of formula (2) where R3 is hydroxy, alkoxy or cyano as described above. Compounds of formula (2) where R3 is hydroxy, alkoxy or cyano may be prepared from compounds of formula (2) where R3 is halogen by standard literature methods such as nucleophilic displacement.

[0150] Compounds of formula (1) where R4 is aryl or heteroaryl may be prepared from compounds of formula (1) where R4 is halogen by standard methods such as palladium catalysed aryl coupling reactions as described above. Compounds of formula (1) where R4 is halogen are prepared from compounds of formula (2) where R4 is halogen as described above. Compounds of formula (2) where R4 is halogen are either known in the literature or prepared by methods analogous to those described in the literature.

[0151] Compounds of formula (1) where R4 is NH2 are prepared from compounds of formula (1) where R4 is NO2 by standard methods such as reduction. Compounds of formula (1) where R4 is NO2 are prepared from compounds of formula (2) where R4 is NO2 as described above. Compounds of formula (2) where R4 is NO2 are either known in the literature or prepared by methods analogous to those described in the literature.

[0152] Compounds of formula (1) where R4 is NR6R7, NR5CONR6R7, NR5COR6, NR5CO2R8 or NR5SO2R8 wherein R5 is H may be prepared from compounds of formula (1) where R4 is NH2 by standard methods for example by mono- or dialkylation, reductive alkylation or by treatment with an appropriate isocyanate (R6NCO or R7NCO), carbamoyl chloride (R6R7NCOCl), acid chloride (R6COCl), chloroformate (ClCO2R8) or sulphonyl chloride (ClSO2R8). Analogous compounds wherein R5 is alkyl may be prepared by initial alkylation or reductive alkylation followed by reaction with the appropriate reagent as described above.

[0153] Compounds of formula (1) where R4 is COR5 may be prepared from compounds of formula (2) where R4 is COR5 as described above. Compounds of formula (2) where R1 is COR5 may be prepared from compounds of formula (2) where R4 is H by standard methods such as Friedel-Crafts acylation.

[0154] Compounds of formula (1) where R4 is CO2R5, CONR6R7 or CONR5NR6R7 may be prepared from compounds of formula (2) where R4 is CO2R5, CONR6R7 or CONR5NR6R7 as described above. Compounds of formula (2) where R4 is CO2R5 or CONR6R7 may be prepared from compounds of formula (2) where R4 is halogen by standard methods such as palladium catalysed carbonylation reactions in the presence of an appropriate alcohol (R5OH) or amine (HNR6R7). Compounds of formula (2) where R4 is CONR6R7 or CONR5NR6R7 may be prepared from compounds of formula (2) where R4 is CO2R5 by standard methods such as reaction with a suitable amine (HNR6R7) or hydrazine (HNR5NR6R7) derivative.

[0155] Compounds of formula (1) where R4 is cyano may be prepared from compounds of formula (1) where R4 is CONR6R7, wherein R6 and R7 are both H, by standard literature methods such as dehydration.

[0156] Compounds of formula (1) where R4 is hydroxy, alkoxy, aryloxy, thioalkyl or thioaryl may be prepared by standard literature methods known to those skilled in the art. Such standard methods may include treatment of a compound of formula (1) where R4 is halogen with an appropriate nucleophile. Alternatively compounds of formula (1) where R4 is hydroxy or alkoxy may be prepare from a compound of formula (1) where R4 is COR5 by use of the Bayer Villiger reaction, followed by a hydrolysis step and followed, if desired, by an alkylation step.

[0157] According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the present invention 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.

[0158] The pharmaceutical compositions employed in the present invention comprise a compound of the present invention, 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.

[0159] Where the compounds of the present invention 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.

[0160] Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of the present invention. 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 of the present invention 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.

[0161] In practical use, the compounds of the present invention 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.

[0162] 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.

[0163] In addition to the common dosage forms set out above, the compounds of the present invention 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.

[0164] Pharmaceutical compositions employed in the present invention 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.

[0165] 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.

[0166] 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

[0167] The invention is illustrated with reference to the following Examples, as set out in Table 1. The syntheses of the Examples are performed using the general Synthetic Methods described hereinafter. The Method used for each Example is given in parentheses in column 1 of Table 1. Analytical data are given in Table 2.

1TABLE 1ExampleStructureCompound Name1 (A)

2-chloro-4-(2-thienyl)thieno[3,2-d]pyrimidine2 (E)

N,N-dimethyl-4-(2-thienyl)thieno[3,2-d]pyrimidine- 2-amine3 (A)

2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine4 (E)

(2R)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2- thienyl)thieno[3,2-d]pyrimidine5 (E)

N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2- amine6 (E)

N-(3-(1H-imidazol-1-yl)propyl)-4-(2- thienyl)thieno[3,2-d]pyrimidine-2-amine7 (E)

N-(2-hydroxyethyl)-4-(2-thienyl)thieno[3,2- d]pyrimidine-2-amine8 (E)

2-methoxy-4-(2-thienyl)thieno[3,2-d]pyrimidine9 (B)

2-ethyl-4-(2-thienyl)thieno[3,2-d]pyrimidine10 (E)

N-(3-(1H-imidazol-1-yl)propyl)-4-(2- furyl)thieno[3,2-d]pyrimidine-2-amine11 (A)

4-(2-furyl)-2-trifluoromethylthieno[3,2-d]pyrimidine12 (A)

2-chloro-4-(2-furyl)-7-methylthieno[3,2- d]pyrimidine13 (A)

7-bromo-2-chloro-4-(2-furyl)thieno[3,2- d]pyrimidine14 (E)

4-(2-furyl)-N-(2-hydroxyethyl)thieno[3,2- d]pyrimidine-2-amine15 (E)

7-bromo-4-(2-furyl)-N-(2-hydroxyethyl)thieno[3,2- d]pyrimidine-2-amine16 (E)

4-(2-furyl)-N-(2-hydroxyethyl)-7-methylthieno[3,2- d]pyrimidine-2-amine17 (A)

4-(2-benzothiophenyl)-2-chlorothieno[3,2- d]pyrimidine18 (A)

2-ethyl-4-(2-furyl)thieno[3,2-d]pyrimidine19 (E)

4-(2-benzothiophenyl)-N,N-dimethylthieno[3,2- d]pyrimidine-2-amine20 (E)

4-(2-benzothiophenyl)-N-(2- hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine21 (E)

N-ethyl-4-(2-thienyl)thieno[3,2-d]pyrimidine-2- amine22 (E)

7-bromo-N,N-dimethyl-4-(2-furyl)thieno[3,2- d]pyrimidine-2-amine23 (E)

4-(2-furyl)-7,N,N-trimethylthieno[3,2-d]pyrimidine- 2-amine24 (A)

2-chloro-4-(2-pyridyl)thieno[3,2-d]pyrimidine25 (E)

4-(2-furyl)-2-morpholinothieno[3,2-d]pyrimidine26 (E)

N-benzyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2- amine27 (E)

N,N-dimethyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine- 2-amine28 (B)

2-chloro-4-(1H-pyrrol-1-yl)thieno[3,2-d]pyrimidine29 (A)

Ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-acetate30 (A)

2-chloro-4-(2-pyrazinyl)thieno[3,2-d]pyrimidine31 (P)

4,7-bis(2-furyl)-N,N-dimethylthieno[3,2- d]pyrimidine-2-amine32 (E)

N,N-dimethyl-4-(1H-pyrrol-1-yl)thieno[3,2- d]pyrimidine-2-amine33 (E)

N,N-dimethyl-4-(2-pyrazinyl)thieno[3,2- d]pyrimidine-2-amine34 (E)

N-(2-hydroxyethyl)-4-(2-pyrazinyl)thieno[3,2- d]pyrimidine-2-amine35 (E)

4-(2-furyl)-2-(4-methylpiperazinyl)thieno[3,2- d]pyrimidine36 (E)

4-(2-furyl)-2-isopropylthiothieno[3,2-d]pyrimidine37 (E)

2-ethylthio-4-(2-furyl)thieno[3,2-d]pyrimidine38 (E)

(2R)-4-(2-furyl)-2-(2-hydroxymethylpyrrolidin-1- yl)thieno[3,2-d]pyrimidine39 (E)

4-(2-furyl)-2-methylthiothieno[3,2-d]pyrimidine40 (E)

N-allyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine41 (A)

2-chloro-4-(2-furyl)-7-nitrothieno[3,2-d]pyrimidine42 (E)

N-ethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine43 (E)

4-(2-furyl)-2-(pyrrolidin-1-yl)thieno[3,2- d]pyrimidine44 (E)

N,N-dimethyl-4-(2-furyl)-7-nitrothieno[3,2- d]pyrimidine-2-amine45 (E)

4-(2-furyl)-N-(2-pyridylmethyl)thieno[3,2- d]pyrimidine-2-amine46 (A)

Ethyl 3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- yl)propionate47 (E)

N-(2-dimethylaminoethyl)4-(2-furyl)thieno[3,2- d]pyrimidine-2-amine48 (K)

3-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)propanol49 (M)

3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)propionic acid50 (N)

4-(2-furyl)-2-(3-oxo-3-(1- pyrrolidinyl)propyl)thieno[3,2-d]pyrimidine51 (J)

7-amino-N,N-dimethyl-4-(2-furyl)thieno[3,2- d]pyrimidine-2-amine52 (C)

2-ethyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine53 (E)

4-(5-chloro-2-thienyl)-N,N-dimethylthieno[3,2- d]pyrimidine-2-amine54 (K)

2-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)ethanol55 (I)

N-(2-dimethylamino-4-(2-furyl)thieno[3,2- d]pyrimidine-7-yl)-N′-phenylurea56 (G)

N-(2-dimethylamino-4-(2-furyl)thieno[3,2- d]pyrimidine-7-yl)acetamide57 (G)

N-(2-dimethylamino-4-(2-furyl)thieno[3,2- d]pyrimidine-7-yl)benzamide58 (E)

4-(2-furyl)-N-methylthieno[3,2-d]pyrimidine-2- amine59 (G)

N-(2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine-7- yl)methanesulphonamide60 (G)

N-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)-N- methyl-3-oxobutanamide61 (E)

4-(5-chloro-2-thienyl)-N-(2- hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine62 (C)

2-methyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine63 (C)

2-n-propyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine64 (C)

2-chloro-4-(2-thiazolyl)thieno[3,2-d]pyrimidine65 (E)

N,N-dimethyl-4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-amine66 (C)

4-(2-pyridyl)thieno[3,2-d]pyrimidine67 (E)

N-(2-hydroxyethyl)-4-(2-pyridyl)thieno[3,2- d]pyrimidine-2-amine68 (E)

N-(2-hydroxyethyl)-4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-amine69 (L)

4-(2-furyl)-2-vinylthieno[3,2-d]pyrimidine70 (C)

2-isopropyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine71 (E)

N-(2-methoxyethyl)-4-(2-furyl)thieno[3,2- d]pyrimidine-2-amine72 (E)

(2R)-7-bromo-4-(2-furyl)-2-(2- hydroxymethylpyrrolidin-1-yl)thieno[3,2- d]pyrimidine73 (A)

Ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2- carboxylate74 (E)

tert-butyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)carbamate75 (F)

N-(2-aminoethyl)-4-(2-furyl)thieno[3,2- d]pyrimidine-2-amine76 (E)

N,N-dimethyl-4-(4-methyl-2-thiazolyl)thieno[3,2- d]pyrimidine-2-amine77 (H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)trifluoroacetamide78 (E)

N-(3,4-dimethoxybenzyl)-4-(2-furyl)thieno[3,2- d]pyrimidine-2-amine79 (F)

4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine80 (C)

2-ethyl-4-(4-methyl-2-thiazolyl)thieno[3,2- d]pyrimidine81 (K)

4-(2-furyl)thienol[3,2-d]pyrimidine-2-methanol82 (C)

2-ethyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine83 (H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)acetamide84 (H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)-3-methylbutanamide85 (H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)benzamide86 (H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)thiophene-2-carboxamide87 (H)

methyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)carbamate88 (H)

isobutyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)carbamate89 (H)

benzyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)carbamate90 (H)

9-fluorenylmethyl (2-(4-(2-furyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)carbamate91 (I)

N-allyl-N′-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)urea92 (I)

N-benzyl-N′-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine- 2-ylamino)ethyl)urea93 (I)

N-cyclohexyl-N′-(2-(4-(2-furyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea94 (I)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)-N′-phenylurea95 (I)

N-(4-chlorophenyl)-N′-(2-(4-(2-furyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea96 (I)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)-N′-phenylthiourea97 (I)

100

N-(4-chlorophenyl)-N′-(2-(4-(2-furyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)thiourea98 (H)

101

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)methanesulphonamide99 (H)

102

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)4-tert-butylphenylsulphonamide100 (A)

103

4-(2-furyl)-2-(2-pyridyl)thieno[3,2-d]pyrimidine101 (G)

104

N-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)acetamide102 (C)

105

2-chloro-4-(5-methyl-2-thiazolyl)thieno[3,2- d]pyrimidine103 (C)

106

2-chloro-4-(4,5-dimethyl-2-thiazolyl)thieno[3,2- d]pyrimidine104 (E)

107

N,N-dimethyl-4-(5-methyl-2-thiazolyl)thieno[3,2- d]pyrimidine-2-amine105 (E)

108

N,N-dimethyl-4-(4,5-dimethyl-2- thiazolyl)thieno[3,2-d]pyrimidine-2-amine106 (C)

109

2-ethyl-4-(5-phenyl-2-oxazolyl)thieno[3,2- d]pyrimidine107 (D)

110

N,N-dimethyl-4-(1H-imidazol-2-yl)thieno[3,2- d]pyrimidine-2-amine108 (E)

111

N-(3,4-dimethoxybenzyl)-4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-amine109 (C)

112

2-chloro-4-(5-methyl-2-pyridyl)thieno[3,2- d]pyrimidine110 (F)

113

4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine111 (E)

114

(2R)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2- thiazolyl)thieno[3,2-d]pyrimidine112 (E)

115

N-allyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- amine113 (C)

116

2-isopropyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine114 (C)

117

2-ethyl-4-(5-(4-methoxyphenyl)-2- oxazolyl)thieno[3,2-d]pyrimidine115 (E)

118

N,N-dimethyl-4-(5-methyl-2-pyridyl)thieno[3,2- d]pyrimidine-2-amine116 (G)

119

N-(4-(2-thiazolyl)thieno[3,2-d]pyrimidin-2- yl)acetamide117 (A)

120

4-(2-furyl)-2-(2-thienylmethyl)thieno[3,2- d]pyrimidine118 (A)

121

2-ethyl-4-(5-thiazolyl)thieno[3,2-d]pyrimidine119 (A)

122

2-ethyl-4-(2-ethylthieno[3,2-d]pyrimidin-4- yl)thieno[3,2-d]pyrimidine120 (D)

123

2-ethyl-4-(1H-triazol-3-yl)thieno[3,2-d]pyrimidine121 (D)

124

2-ethyl-4-(1H-imidazol-2-yl)thieno[3,2-d]pyrimidine122 (C)

125

4-(2-benzothiazolyl)-2-ethylthieno[3,2-d]pyrimidine123 (E)

126

tert-butyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine- 2-ylamino)ethyl)carbamate124 (F)

127

N-(2-aminoethyl)4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-amine125 (H)

128

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)acetamide126 (I)

129

N-ethyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea127 (I)

130

N-allyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea128 (I)

131

N-cyclohexyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea129 (H)

132

N-(2-(4-(2-thiazolyl)thieno[3,2-d)pyrimidine-2- ylamino)ethyl)-3-methylbutanamide130 (H)

133

methyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)carbamate131 (H)

134

isobutyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine- 2-ylamino)ethyl)carbamate132 (I)

135

N-tert-butyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea133 (I)

136

N-benzyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea134 (I)

137

N-phenyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea135 (I)

138

N-(4-chlorophenyl)-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)urea136 (I)

139

N-cyclohexyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)thiourea137 (I)

140

N-phenyl-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)thiourea138 (I)

141

N-(4-chlorophenyl)-N′-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)thiourea139 (C)

142

2-tert-butyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine140 (C)

143

2-cyclopropyl-4-(2-thiazolyl)thieno[3,2- d]pyrimidine141 (C)

144

2-ethyl-4-(6-methyl-2-pyridyl)thieno[3,2- d]pyrimidine142 (H)

145

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)cyclohexylcarboxamide143 (H)

146

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)benzamide144 (H)

147

4-chloro-N-(2-(4-(2-thiazolyl)thieno[3,2- d]pyrimidine-2-ylamino)ethyl)benzamide145 (H)

148

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)thiophene-2-carboxamide146 (H)

149

phenyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)carbamate147 (H)

150

benzyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)carbamate148 (H)

151

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)methanesulphonamide149 (H)

152

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2- ylamino)ethyl)butanesulphonamide150 (E)

153

(1RS)-N-(2-hydroxy-1-methylethyl)-4-(2- thiazolyl)thieno[3,2-d]pyrimidine-2-amine151 (E)

154

N-(3-(1H-imidazol-1-yl)propyl)-4-(2- thiazolyl)thieno[3,2-d]pyrimidine-2-amine152 (E)

155

(2S)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2- thiazolyl)thieno[3,2-d]pyrimidine153 (C)

156

4-(2-thiazolyl)-2-(2-thienyl)thieno[3,2-d]pyrimidine154 (C)

157

2-(2-chloroethyl)4-(2-thiazolyl)thieno[3,2- d]pyrimidine155 (O)

158

4-(2-furyl)thieno[3,2-d]pyrimidine-2-carboxamide156 (B)

159

2-chloro-4-(3-thienyl)thieno[3,2-d]pyrimidine157 (E)

160

N,N-dimethyl-4-(3-thienyl)thieno[3,2-d]pyrimidine- 2-amine158 (B)

161

2-chloro-4-phenylthieno[3,2-d]pyrimidine159 (E)

162

N,N-dimethyl-4-phenylthieno[3,2-d]pyrimidine-2- amine160 (B)

163

2-chloro-4-(3-furyl)thieno[3,2-d]pyrimidine161 (E)

164

N,N-dimethyl-4-(3-furyl)thieno[3,2-d]pyrimidine-2- amine162 (A)

165

2-chloro-4-(2-furyl)-6-nitrothieno[3,2-d]pyrimidine163 (B)

166

2-ethyl-4-(3-furyl)thieno[3,2-d]pyrimidine164 (B)

167

4-(3,5-dimethyl-4-isoxazolyl)-2-ethylthieno[3,2- d]pyrimidine165 (B)

168

2-chloro-4-(3-pyridyl)thieno[3,2-d]pyrimidine166 (E)

169

N,N-dimethyl-4-(3-pyridyl)thieno[3,2-d]pyrimidine- 2-amine167 (C)

170

2-chloro-4-(1-methyl-1H-imidazol-2-yl)thieno[3,2- d]pyrimidine168 (E)

171

N,N-dimethyl-4-(1-methyl-1H-imidazol-2- yl)thieno[3,2-d]pyrimidine-2-amine169 (E)

172

N,N-dimethyl-4-(3-hydroxymethyl-2- furyl)thieno[3,2-d]pyrimidine-2-amine170 (E)

173

2-hydroxyethyl)-4-(1-methyl-1H-imidazol-2- yl)thieno[3,2-d]pyrimidine-2-amine171 (E)

174

N-(2-hydroxyethyl)-4-(3-hydroxymethyl-2- furyl)thieno[3,2-d]pyrimidine-2-amine172 (C)

175

2-chloro-4-(1-ethyl-1H-imidazol-2-yl)thieno[3,2- d]pyrimidine173 (E)

176

N,N-dimethyl-4-(1-ethyl-1H-imidazol-2- yl)thieno[3,2-d]pyrimidine-2-amine174 (H)

177

4-(1-ethyl-1H-imidazol-2-yl)-N-(2- hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine175 (C)

178

2-chloro-4-(1-(2-trimethylsilylethoxymethyl)-1H- imidazol-2-yl)thieno[3,2-d]pyrimidine176 (E)

179

N,N-dimethyl-4-(1-(2-trimethylsilylethoxymethyl)- 1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine177 (C)

180

N,N-dimethyl-4-((1-ethoxycarbonylmethyl)-1H- imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine178 (K)

181

N,N-dimethyl-4-(1-(2-hydroxyethyl)-1H-imidazol-2- yl)thieno[3,2-d]pyrimidine-2-amine179 (C)

182

2-ethyl-4-(1-methoxymethyl-1H-imidazol-2- yl)thieno[3,2-d]pyrimidine180 (C)

183

2-ethyl-4-(4-(2-trimethylsilylethoxymethyl)-4H- 1,2,4-triazol-3-yl)thieno[3,2-d]pyrimidine181 (C)

184

2-chloro-4-(1-(2-trimethylsilylethoxymethyl)-1H- pyrazol-4-yl)thieno[3,2-d]pyrimidine182 (C)

185

2-chloro-4-(1-methyl-1H-pyrazol-5-yl)thieno[3,2- d]pyrimidine183 (E)

186

N,N-dimethyl-4-(1-(2-trimethylsilylethoxymethyl)- 1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-2-amine184 (E)

187

N,N-dimethyl-4-(1-methyl-1H-pyrazol-5- yl)thieno[3,2-d]pyrimidine-2-amine185 (D)

188

dimethyl-4-(1H-pyrazol-4-yl)thieno[3,2- d]pyrimidine-2-amine186 (C)

189

N,N-dimethyl-4-(1-methyl-1H-pyrazol-4- yl)thieno[3,2-d]pyrimidine-2-amine187 (C)

190

2-ethyl-4-(4-methyl-4H-1,2,4-triazol-3- yl)thieno[3,2-d]pyrimidine188 (A)

191

2-ethyl-4-(2-furyl)-6-methylthieno[3,2-d]pyrimidine

[0168] The general synthetic methods used for the preparation of these examples are set out below as Methods A to T.

[0169] Method A

[0170] 2-Chloro-4-(2-furyl)thieno[3,2-d]pyrimidine (Example 3)

[0171] A solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in DMF (4 mL) was treated with PdCl2(PPh3)2 (35 mg, 0.05 mmol) and 2-(tributylstannyl)-furan (315 μL, 1 mmol), stirred at room temperature for 16 h, the reaction mixture purified directly by chromatography (SiO2:EtOAc:Heptane, 1:9) and the resulting cream solid recrystallised (EtOAc/Heptane) to give the title compound (122 mg, 52%) as a cream solid.

[0172] Method B

[0173] 2-Chloro-4-(5-chloro-2-thienyl)thieno[3,2-d]pyrimidine

[0174] A solution of Pd(OAc)2 (12 mg, 5 mol %) and PPh3 (52 mg, 20 mol %) in THF (2 mL) was stirred for 5 min, treated dropwise with a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in THF (1 mL), stirred for 5 min, treated with 5-chlorothiophene-2-boronic acid (244 mg, 1.5 mmol) then saturated aqueous NaHCO3 (1 mL) refluxed for 4 h, cooled, diluted with H2O and filtered to give the title compound (268 mg, 94%) as a grey solid; NMR δH (400 MHz, CDCl3) 7.10 (1H, d, J 4.0 Hz), 7.55 (1H, d, J 5.5 Hz), 7.85 (1H, d, J 4.5 Hz) and 8.08 (1H, d, J 5.5 Hz)

[0175] Method C

[0176] 2-Chloro-4-(2-thiazolyl)thieno[3,2-d]pyrimidine (Example 64)

[0177] A stirred solution of thiazole (0.14 mL, 2 mmol) in dry THF (10 mL) at −78° C., under argon was treated with n-BuLi (1.6-M in hexanes, 1.3 mL, 2 mmol), stirred for 30 min, treated with a solution of ZnCl2 (1.0-M in Et2O, 2.0 mL, 2 mmol) and allowed to warm gradually to room temperature. The mixture was treated with a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in THF (5 mL) then Pd(PPh3)4 (100 mg, 10 mol %) refluxed for 17 h, cooled, diluted with saturated NH4Cl solution and extracted with EtOAc. The organic extracts were dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:CH2Cl2 (2:1)] to give the title compound (75 mg, 26%) as a white solid.

[0178] Method D

[0179] 2-Ethyl-4-(1H-imidazol-2-yl)thieno[3,2-d]pyrimidine (Example 121)

[0180] A stirred solution of 1-(2-trimethylsilyl)ethoxymethyl-1H-imidazole (295 mg, 1.5 mmol) in dry THF (10 mL) at −78° C., under argon was treated with n-BuLi (1.6-M in hexanes, 0.93 mL, 1.5 mmol), stirred for 30 min, treated with a solution of ZnCl2 (1.0-M in Et2O, 1.5 mL, 1.5 mmol) and the mixture allowed to warm gradually to room temperature. The mixture was treated with 4-chloro-2-ethylthieno[3,2-d]pyrnidine (148 mg, 0.75 mmol) and Pd(PPh3)4 (100 mg), refluxed for 3 h, cooled, diluted with saturated NH4Cl solution, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane: EtOAc (7:1) then (4:1)] to give the intermediate coupled product as a viscous oil (140 mg). A portion of this material (130 mg, 0.36 mmol) was dissolved in THF (5 mL), treated with a solution of tetra-n-butylammonium fluoride (1-M in THF, 0.72 mL, 0.72 mmol), refluxed for 4 hr, cooled, extracted with EtOAc, dried (MgSO4) concentrated in vacuo and purified by chromatography [SiO2; heptane:EtOAc (4:1) then (2:1)] to give the title compound (62 mg, 39%) as a white solid.

[0181] Method E

[0182] 7-Bromo-4-(2-furyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine (Example 15)

[0183] A solution of 7-bromo-2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine (110 mg, 0.35 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was treated with ethanolamine (32 μL, 0.52 mmol), heated at 90° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2: EtOAc:Heptane, 1:1) to give the title compound (45 mg, 38%) as a yellow solid.

[0184] Method F

[0185] 4-(2-Furyl)thieno[3,2-d]pyrimidine-2-amine (Example 79)

[0186] A solution of N-(3,4-dimethoxybenzyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (199 mg, 0.54 mmol) in TFA (1 mL) was heated at 60° C. for 1 h, cooled, poured into sat. NaHCO3, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:1 and MeOH:DCM, 1:19) to give the title compound (108 mg, 92%) as a cream solid.

[0187] Method G

[0188] N-(4-(2-Furyl)thieno[3,2-d]pyrimidin-2-yl)acetamide (Example 101)

[0189] An ice-cold solution of 4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (130 mg, 0.6 mmol) in pyridine (1 mL) was treated with acetyl chloride (47 μL, 0.66 mmol), stirred at room temperature for 16 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:1) to give the title compound (125 mg, 80%) as a cream solid.

[0190] Method H

[0191] N-(2-(4-(2-Thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)acetamide (Example 125)

[0192] A solution of N-(2-aminoethyl)-4-(2-thiazolyl))thieno[3,2-d]pyrimidine-2-amine (0.040 g, 0.14 mmol) in DMF (2 mL) was treated with triethylammonium methylpolystyrene carbonate (0.066 g, 0.22 mmol) followed by acetyl chloride (0.023 g, 0.29 mmol), shaken at room temperature for 7 h, treated with tris-(2-aminoethyl)amine polystyrene (0.19 g, 0.87 mmol), shaken at room temperature for 16 h, treated with polystyrene 4-benzyloxybenzaldehyde (0.19 g, 0.28 mmol), shaken for a further 3 h, filtered and concentrated in vacuo to give the title compound as a yellow solid.

[0193] Method I

[0194] N-Ethyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea (Example 126)

[0195] A solution of N-(2-aminoethyl)4-(2-thiazolyl))thieno[3,2-d]pyrimidine-2-amine (0.040 g, 0.14 mmol) in anhydrous DMF (2 mL) was treated with ethyl isocyanate (0.015 g, 0.22 mmol), shaken at 35° C. for 1 h, treated with tris-(2-aminoethyl)amine polystyrene (0.19 g, 0.88 mmol), shaken at 35° C. for 4 h, filtered and concentrated in vacuo to give the title compound as a yellow solid.

[0196] Method J

[0197] 7-Amino-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (Example 51)

[0198] A solution of N,N-dimethyl-4-(2-furyl)-7-nitrothieno[3,2-d]pyrimidine (85 mg, 0.29 mmol) in MeOH (4 mL), under argon, was treated with a catalytic amount of Pd on carbon (10%), hydrogenated at room temperature for 1 h, filtered through celite, concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:4) to give the title compound (62 mg, 82%) as a brown solid.

[0199] Method K

[0200] 2-(4-(2-Furyl)thieno[3,2-d]pyrimidin-2-yl)ethanol (Example 54)

[0201] A solution of ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-acetate (0.10 g, 0.35 mmol) in dichloromethane (13 mL) at −75° C. was treated dropwise with di-iso-butylaluminium hydride (0.87 mL, 1.0-M), stirred for 17 h, warmed to ambient temperature and partitioned between Rochelle's salt and dichloromethane. The combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc) to give the title compound (21 mg, 25%) as a white solid.

[0202] Method L

[0203] 4-(2-Furyl)-2-vinylthieno[3,2-d]pyrimidine (Example 69)

[0204] A solution of 2-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)ethanol (0.15 g, 0.61 mmol) in THF (5 mL) at 0° C. was treated with diisopropylethylamine (0.095 g, 0.73 mmol) then methanesulfonyl chloride (0.72 g, 0.67 mmol), warmed to room temperature over 16 h, partitioned between ethyl acetate and water, the organic phase dried (MgSO4) and concentrated in vacuo to give the intermediate mesylate (0.10 g, 50%) as a white solid. A sample of this compound (59 mg, 0.18 mmol) was dissolved in CH2Cl2, treated with DBU (0.042 g, 0.27 mmol), stirred at room temperature for 18 h, partitioned between ethyl acetate and water and the organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (22 mg, 50%) as a white solid.

[0205] Method M

[0206] 3-(4-(2-Furyl)thieno[3,2-d]pyrimidine-2-yl)propionic Acid (Example 49)

[0207] A solution of ethyl 3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)propionate (0.07 g, 0.23 mmol) in THF (1.0 mL) and water (1.0 mL) was treated with lithium hydroxide (0.10 g, 2.32 mmol), stirred at room temperature for 16 h, concentrated in vacuo, dissolved in water, acidified to pH 2 by the addition of HCl (0.1 mL, 6.0-M), cooled in ice and filtered to give the title compound (0.052 g, 81%) as a white solid.

[0208] Method N

[0209] 4-(2-Furyl)-2-(3-oxo-3-(1-pyrrolidinyl)propyl)thieno[3,2-d]pyrimidine (Example 50)

[0210] A mixture of trimethylaluminium in toluene (1.3 mL, 2.0-M) and pyrrolidine (0.22 mL, 2.65 mmol) in toluene was heated at 80° C. for 0.5 h, treated with a solution of ethyl 3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl) (0.1 g, 0.33 mmol) in toluene (2.0 mL), stirred at 80° C. for 17 h, cooled to room temperature and partitioned between sat. aq. NH4Cl and ethyl acetate. The combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2: EtOAc-methanol, 9:1) to give the title compound (27 mg, 25%).

[0211] Method O

[0212] 4-(2-Furyl)thieno[3,2-d]pyrimidine-2-carboxamide (Example 155)

[0213] Ammonia gas was bubbled through a hot solution of ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-carboxylate (0.156 g, 0.57 mmol) in ethanol (20 mL) for 3 h then the mixture cooled and the resulting white solid filtered to give the title compound (94 mg, 67%) as a white solid.

[0214] Method P

[0215] 4,7-Bis(2-furyl)-N,N-dimethylthieno[3,2-d]pyrimidine-2-amine (Example 31)

[0216] A mixture of AsPh3 (73 mg, 0.24 mmol) in DMF (2 mL) was treated with Pd(OAc)4 (13 mg, 0.06 mmol), stirred at room temperature for 10 min, treated with 7-bromo-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (194 mg, 0.6 mmol) and 2-(tributylstannyl)-furan (340 μL, 1.1 mmol), heated to 100° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:9) to give the title compound (27 mg, 15%) as a orange solid.

[0217] Method Q

[0218] 2-Isopropylthieno[3,2-d]pyrimidine-4-ol

[0219] A mixture of 3-aminothiophene-2-carboxamide (2.0 g, 14.1 mmol) and triethylamine (1.71 g, 16.9 mmol) in toluene (20 mL) at room temperature was treated with 2-methylpropionic anhydride (2.45 g, 15.5 mmol), refluxed for 4 h, cooled, poured into saturated NaHCO3 (100 mL) and extracted with ethyl acetate (4×50 mL). The combined organic phase was washed with brine(2×50 mL), dried (Na2SO4) and concentrated in vacuo to the intermediate N-acylated compound (2.90 g, 99%) as a pale yellow solid. A sample of this compound (2.85 g, 13.44 mmol) was dissolved in NaOH (34 mL, 1.0-M), refluxed for 1 h, cooled, acidified to pH 2 by addition of HCl (7.0 mL, 6.0-M), filtered and dried to give the title compound (2.30 g, 88%) as a white solid: IR νmax (Nujol)/cm−1 2956, 2925, 1676, 1599, 1464, 780; NMR δH (400 MHz, DMSO) 1.20 (6H, d J 6.5 Hz), 2.90 (1H, heptet, J 6.5 Hz), 7.40 (1H, d J 5.0 Hz), 8.15 (1H, d, J 5.0 Hz) and 12.30 (1H, br).

[0220] Method R

[0221] 2-Cyclopropylthieno[3,2-d]pyrimidine-4-ol

[0222] Dry HCl gas was bubbled through a solution of methyl 3-aminothiophene-2-carboxylate (1.64 g, 10.4 mmol) and cyclopropanecarbonitrile (27 mL) in dioxane (40 mL) for 1 h then the reaction mixture was diluted with cold water (2 volumes), basified with NH4OH (50 mL) and the resulting solid filtered and air dried to give the title compound (1.44 g, 72%) as a white solid: IR νmax (Nujol)/cm−1 2925, 1664, 1597, 788; NMR δH (400 MHz, DMSO) 1.04 (4H, m), 2.00 (1H, m), 7.20 (1H, d J 5.0 Hz), 8.10 (1H, d, J 5.0 Hz) and 12.60 (1H, br).

[0223] Method S

[0224] 4-Chloro-2-isopropylthieno[3,2-d]pyrimidine

[0225] A suspension of 2-isopropylthieno[3,2-d]pyrimidine-4-ol (1.66 g, 8.56 mmol) in POCl3 (30 mL) was refluxed for 1 h, cooled, diluted with chloroform (100 mL) and poured into a mixture of ice and NH4OH (150 mL). The organic phase was separated, washed with saturated NaHCO3 (20 mL), water and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (2.01 g, 99%) as a pale yellow solid: IR νmax (Nujol)/cm−1 3065, 2960, 2926, 2855, 1561, 1513, 1457, 803; NMR δH (400 MHz, CDCl3) 1.40 (6H, d J 6.5 Hz), 3.38 (1H, heptet, J 6.5 Hz), 7.60 (1H, d J 5.0 Hz), 8.05 (1H, d, J 5.0 Hz).

[0226] Method T

[0227] Ethyl 4-hydroxythieno[3,2-d]pyrimidine-2-carboxylate

[0228] A mixture of 3-aminothiophene-2-carboxamide (1.23 g, 8.65 mmol) and EtOH (25 mL) was treated with NaOEt (1.2 g, 17.3 mmol) and diethyloxalate (2.3 mL, 17.3 mmol), refluxed for 18 h, cooled, concentrated in vacuo, treated with water, acidified with HOAc and filtered to give the title compound (1.43 g, 74%) as a cream solid: IR νmax Nujol)/cm−1 3180, 3119, 3078, 3006, 2955, 2924, 2854, 1737, 1667, 1651, 1300 and 1176; NMR δH (400 MHz, DMSO) 1.37 (3H, t, J 7.0 Hz), 4.40 (2H, q, J 7.0 Hz), 7.58 (1H, d, J 5.0 Hz), 8.30 (1H, d, J 5.1 Hz), and 12.92 (1H, s).

2TABLE 2Analytical dataHPLC is carried out using the following conditions: Column.Supelcosil ABZ+ (170 × 4.6 mm),particle size 5 μM, mobile phase MeOH: 10 mM aqNH4OAc (80:20), (70:30) or (60:40) (specifiedin Table 2), flow rate 1.0 mL/min.,detection wavelength λ = 230 nM(unless otherwise stated), retentiontimes are provided in Table 2.ExampleYield(%)Physical Data161Mp 135.6-135.8° C.; IR νmax(Nujol)/cm−1 3111, 3082, 3072, 1529,1467, 1425, 1254, 1238 and 1205; NMR δH(400MHz, CDCl3) 7.28(1H,dd, J 5.0, 4.0Hz), 7.54(1H, d, J 5.5Hz), 7.69(1H, dd, J 5.0, 1.0Hz),8.07(1H, d, J 5.5Hz), 8.08(1H, dd, J 4.0, 1.0Hz); Anal. Calcd forC10H5ClN2S2: C, 47.52; H, 1.99, N, 11.08. Found: C, 47.54; H, 2.00; N,10.93; M/Z 253(M+H)+.298mp 139.2-140.0° C.; IR νmax(Nujol)/cm−1 1551, 1517, 1466, 1393,1361, 793 and 707; NMR δH(400MHz, CDCl3) 3.30(6H, s), 7.22(1H,dd, J 5.0, 4.0Hz), 7.27(1H, d, J 5.5Hz), 7.54(1H, dd, J 5.5, 1.0Hz),7.79(1H, d, J 5.5Hz), 7.95(1H, dd, J 3.5, 1.0Hz); Anal. Calcd forC12H11N3S2: C, 55.15; H, 4.24, N, 16.07. Found: C, 55.05; H, 4.12; N,15.88.352mp 146.9-147.6° C.; IR νmax(Nujol)/cm−1 3132, 3105, 3064, 1594,1522, 1463 and 1264; NMR δH(400MHz, CDCl3) 6.69-6.72(1H, m),5.50(1H, d, J 5.5Hz), 7.60(1H, dd, J 3.5, 1.0Hz), 7.80(1H, d, J 1.0Hz),8.10(1H, d, J 5.5Hz); Anal. Calcd for C10H5ClN2OS+0.4 H2O: C,49.25; H, 2.40, N, 11.49. Found: C, 48.87; H, 2.04; N, 11.65.478mp 128.5-128.9° C.; IR νmax(Nujol)/cm−1 3314, 3065, 1542, 1498, 1466and 1363; NMR δH(400MHz, CDCl3) 1.71-1.81(1H, m), 1.88-2.08(2H, m), 2.13-2.23(1H, m), 3.68-3.79(3H, m), 3.82-3.98(2H, m),4.40(1H, s), 7.21-7.27(2H, m), 7.56(1H, dd, J 5.0, 1.0Hz), 7.83(1H,d, J 5.5Hz), 7.98(1H, dd, J 4.0, 1.0Hz); Anal. Calcd for C15H15N3OS2:C, 56.76; H, 4.76, N, 13.23. Found: C, 56.72; H, 4.80; N, 13.14.577mp 129.3-130.4° C.; IR νmax(Nujol)/cm−1 3125, 3095, 3066, 1601,1554, 1462, 1403 and 792; NMR δH(400MHz, CDCl3) 3.29(6H, s),6.60-6.64(1H, m), 7.23(1H, d, J 5.5Hz), 7.38(1H, d, J 3.5Hz), 7.70-7.72(1H, m), 7.80-7.84(1H, d, J 5.5Hz); Anal. Calcd for C12H11N3OS:C, 58.76; H, 4.52, N, 17.12. Found: C, 58.89; H, 4.52; N, 16.89.675mp dec. >230° C.; IR νmax(Nujol)/cm−1 3426, 3160, 3075, 1616, 1573,1523 and 1447; NMR δH(400MHz, DMSO) 2.13-2.22(2H, m), 3.45(2H, t, J 6.5Hz), 4.33(2H, t, J 7.0Hz), 4.49-4.87(1H, s), 7.36-7.39(1H, m), 7.43-7.46(1H, m), 7.69-7.72(1H, m), 7.84-7.87(1H, m),8.00(1H, d, J 4.5Hz), 8.04(1H, d, J 4.0Hz), 8.42(1H, d, J 5.5Hz), 9.23(1H, s); Anal. Calcd for C16H15N5S2+2HCl+0.25 H2O: C, 44.44, H,4.43, N, 16.20. Found: C, 44.09; H, 4.34; N, 16.14.761mp 110.6-111.8° C.; IR νmax(Nujol)/cm−1 3266, 1590, 1553, 1516, 1461and 791; NMR δH(400MHz, CDCl3) 3.67-3.73(2H, m), 3.89-3.93(2H, m), 3.93-4.08(1H, s), 5.56(1H, t, J 5.0Hz), 7.21-7.25(2H, m),7.56(1H, dd, J 5.0, 1.0Hz), 7.83(1H, d, J 5.5Hz), 7.97(1H, dd, J 3.5,1.0Hz); Anal. Calcd for C12H11N3OS2: C, 51.97, H, 4.00, N, 15.14.Found: C, 51.75; H, 3.96; N, 15.11.895mp 114.6-115.1° C.; IR νmax(Nujol)/cm−1 3412, 3059, 1549, 1481,1464, 1341, 1327 and 725; NMR δH(400MHz, CDCl3) 4.13(3H, s),7.24-7.27(1H, m), 7.42(1H, d, J 5.5Hz), 7.62(1H, dd, J 5.0, 1.0Hz),7.96(1H, d, J 5.5Hz), 8.04(1H, dd, J 3.5, 1.0Hz); Anal. Calcd forC11H8N2OS2: C, 53.21, H, 3.25, N, 11.28. Found: C, 53.21; H, 3.27; N,11.24.936IR νmax(Nujol)/cm−1 3065, 2925, 2855, 1539, 1464, 1352, 716; NMR δH(400MHz, CDCl3) 1.50(3H, t J 7.5Hz), 3.10(2H, q, J 7.5Hz), 7.26(1H, m), 7.54(1H, d, J 5.5Hz), 7.61(1H, dd, J 1.0, 5.0Hz), 7.96(1H, d,J 5.5Hz), 8.04(1H, dd, J 1.0, 3.8Hz).1057mp dec. >235° C.; IR νmax(Nujol)/cm−1 3417, 3105, 2623, 1654, 1633,1508 and 1466; NMR δH(400MHz, DMSO) 2.13-2.22(2H, m), 3.49(2H, t, J 6.5Hz), 4.33(2H, t, J 7.0Hz), 4.02-4.66(2H, s), 6.88-6.90(1H, m), 7.45(1H, s), 7.51(1H, s), 7.70(1H, t, J 1.7Hz), 7.85(1H, t, J1.7Hz), 8.23(1H, s), 8.45(1H, d, J 5.0Hz), 9.22(1H, s), 14.59-14.87(1H, s); Anal. Calcd for C16H15N5OS+2HCl+1.5 H2O: C, 45.18, H,4.74, N, 16.47, Cl, 16.67. Found: C, 45.40; H, 4.39; N, 16.59, Cl, 16.42.1182mp 147.6-148.8° C.; IR νmax(Nujol)/cm−1 3141, 3112, 3074, 1594,1536, 1524, 1487, 1471, 1239, 1192, 1167, 1131 and 810; NMR δH(400MHz,CDCl3) 6.71-6.73(1H, m), 7.66(1H, dd, J 3.5, 1.0Hz), 7.69(1H,d, J 5.5Hz), 7.81-7.83(1H, m), 8.19(1H, d, J 5.5Hz); Anal. Calcd forC11H5F3N2OS: C, 48.89, H, 1.86, N, 10.36. Found: C, 48.67; H, 1.92; N,10.25.1278mp 164.4-164.9° C.; IR νmax(Nujol)/cm−1 3153, 3121, 1596, 1498,1466, 1272 and 804; NMR δH(400MHz, CDCl3) 2.51(3H, s), 6.68-6.70(1H, m), 7.57(1H, dd, J 3.5, 1.0Hz), 7.72(1H, dd, J 2.5, 1.0Hz),7.78-7.79(1H, m); Anal. Calcd for C11H7ClN2OS: C, 52.70, H, 2.82, N,11.17. Found: C, 52.91; H, 2.82; N, 11.05.1334mp dec. 213.9° C.; IR νmax(Nujol)/cm−1 3142, 3113, 3898, 3070, 1594,1515, 1460, 1271 and 765; NMR δH(400MHz, DMSO) 6.90-6.93(1H,m), 7.68(1H, d, J 3.5Hz), 8.27(1H, s), 8.83(1H, s); Anal. Calcd forC10H4BrClN2OS: C, 38.06, H, 1.28, N, 8.87. Found: C, 38.22; H, 1.38;N, 8.74.1475mp 107.9-108.9° C.; IR νmax(Nujol)/cm−1 3279, 1607, 1572, 1460,1377, 1067 and 791; NMR δH(400MHz, CDCl3) 3.66-3.72(2H, m),3.88-3.93(2H, m), 4.33-4.60(1H, s), 5.56(1H, t, J 5.0Hz), 6.62-6.65(1H, m), 7.21(1H, d, J 5.5Hz), 7.38(1H, d, J 3.5Hz), 7.73(1H, s),7.88(1H, d, J 5.5Hz); Anal. Calcd for C12H11N3O2S: C, 55.16, H, 4.24,N, 16.07. Found: C, 55.16; H, 4.23; N, 15.97.1538mp 173.4-174.4° C.; IR νmax(Nujol)/cm−1 3394, 3260, 3110, 3083,1600, 1555, 1463 and 1439; NMR δH(400MHz, CDCl3) 3.70-3.72(2H, m), 3.89-3.95(2H, m), 4.47-4.67(1H, s), 5.67-5.74(1H, m),6.64-6.67(1H, m), 7.40(1H, d, J 3.5Hz), 7.74(1H, s), 7.87(1H, s);Anal. Calcd for C12H10BrN3O2S+0.25 H2O: C, 41.27; H, 3.18, N, 12.03.Found: C, 41.28; H, 3.04; N, 12.04.1675mp 149.9-150.6° C.; IR νmax(Nujol)/cm−1 3404, 3219, 1602, 1550,1507, 1464 and 1440; NMR δH(400MHz, CDCl3) 2.38(3H, s), 3.67-3.73(2H, m), 3.88-3.94(2H, m), 5.13(1H, s), 5.57(1H, t, J 5.0Hz),6.62-6.64(1H, m), 7.37(1H, dd, J 3.5, 1.0Hz), 7.51(1H, d, J 1.0Hz),7.72-7.73(1H, m); Anal. Calcd for C13H13N3O2S: C, 56.71; H, 4.76, N,15.25. Found: C, 56.67; H, 4.79; N, 15.19.1764mp 231.0-231.6° C.; IR νmax(Nujol)/cm−1 3109, 3094, 1531, 1469, 1232and 790; NMR δH(400MHz, DMSO) 7.48-7.58(2H, m), 7.72(1H, d, J5.5Hz), 8.10-8.17(2H, m), 8.52(1H, s), 8.75(1H, d, J 5.5Hz); Anal.Calcd for C14H7ClN2S2: C, 55.33; H, 2.33, N, 9.25. Found: C, 55.22; H,2.32; N, 9.41.1856IR νmax(Nujol)/cm−1 3096, 2924, 1595, 1528, 1488, 1463, 1303, 1016,808 and 768; NMR δH(400MHz, DMSO) 1.36(3H, t, J 7.7Hz), 3.00(2H, q, J 7.7Hz), 6.85(1H, dd, J 1.8, 3.5Hz), 7.54(1H, dd, J 0.8, 3.5Hz),7.58(1H, d, J 5.5Hz), 8.17(1H, dd, J 0.8, 1.8Hz), 8.49(1H, d, J5.5Hz).1989mp 166.5-167.3° C.; IR νmax(Nujol)/cm−1 3094, 3053, 1556, 1463,1407, 1354 and 793; NMR δH(400MHz, CDCl3) 3.33(6H, s), 7.29(1H,d, J 5.5Hz), 7.37-7.43(2H, m), 7.82(1H, d, J 5.5Hz), 7.87-7.92(2H,m), 8.16(1H, s); Anal. Calcd for C16H13N3S2: C, 61.71; H, 4.21, N,13.49. Found: C, 61.82; H, 4.26; N, 13.52.2064mp 173.4-174.4° C.; IR νmax(Nujol)/cm−1 3409, 3260, 3126, 3094,1587, 1545 and 1339; NMR δH(400MHz, CDCl3) 3.70-3.77(2H, m),3.90-3.97(2H, m), 5.60(1H, t, J 5.0Hz), 7.27(1H, d, J 5.5Hz), 7.39-7.46(2H, m), 7.86-7.93(3H, m), 8.19(1H, s); Anal. Calcd forC16H13N3OS2+0.25 H2O: C, 57.93; H, 4.10, N, 12.66. Found: C, 57.78;H, 3.96; N, 12.76.2142mp 112.3-122.7° C.; NMR δH(400MHz, CDCl3) 1.30(3H, t, J 7.3Hz),3.54-3.62(2H, m), 5.06(1H, s), 7.26(1H, d, J 5.5Hz), 7.45-7.48(1H,m), 7.81(1H, d, J 5.5Hz), 7.90(1H, dd, J 5.0Hz), 8.20-8.23(1H, m);Anal. Calcd for C12H11N3S2: C, 55.15; H, 4.24, N, 16.07. Found: C,55.13; H, 4.29; N, 15.90.2263mp 118.7-119.5° C.; IR νmax(Nujol)/cm−1 3094, 1602, 1552, 1464 and1377; NMR δH(400MHz, CDCl3) 3.33(6H, s), 6.61-6.64(1H, m),7.40(1H, d, J 3.5Hz), 7.71-7.72(1H, m), 7.81(1H, s); Anal. Calcd forC12H10BrN3OS: C, 44.46; H, 3.11, N, 12.96. Found: C, 44.24; H, 3.06; N,13.01.2390mp 113.1-113.7° C.; IR νmax(Nujol)/cm−1 3115, 1602, 1560, 1548,1508, 1466 and 1409; NMR δH(400MHz, CDCl3) 2.38(3H, s), 3.31(6H, s), 6.58-6.62(1H, m), 7.36(1H, d, J 3.5Hz), 7.44-7.45(1H, m),7.69-7.70(1H, m); Anal. Calcd for C16H13N3OS+0.15 H2O: C, 59.59;H, 5.12, N, 16.04. Found: C, 59.83; H, 2.89; N, 15.70.2431mp 209.2-209.5° C.; IR νmax(Nujol)/cm−1 1531, 1523, 1463, 1377, 1247and 781; NMR δH(400MHz, CDCl3) 7.47(1H, m), 7.54(1H, d, J 6.0Hz),7.95(1H, dt, J 8.0, 2.0Hz), 8.19(1H, d, J 5.5Hz), 8.73-8.77(1H,m), 8.84-8.87(1H, m); Anal. Calcd for C11H6ClN3S+0.1 H2O: C,52.56; H, 2.45, N, 16.72. Found: C, 52.69; H, 2.41; N, 16.64.25IR νmax(Nujol)/cm−1 2955, 2924, 2854, 1600, 1555, 1526, 1490, 1456,1378 and 1270; NMR δH(400MHz, DMSO) 8.18(1H, m) 7.97(1H, s),7.35(1H, m), 7.14(1H, m), 6.67(1H, m), 3.68-3.58(4H, m), 3.58-3.48(4H, m).26IR νmax(Nujol)/cm−1 3261, 2924, 2854, 1604, 1573, 1547, 1513, 1455,1443 and 1330; NMR δH(400MHz, CDCl3) 7.86(1H, d, J 5.5Hz), 7.72(1H, s), 7.48-7.23(7H, m), 6.62(1H, dd, J 4.0, 1.5Hz), 5.53(1H, br s),4.76(2H, d, J 5.9Hz).2713mp 186.6-188.0° C.; IR νmax(Nujol)/cm−1 3053, 1556, 1466, 1359 and786; NMR δH(400MHz, CDCl3) 3.37(6H, s), 7.27-7.33(1H, m), 7.39-7.45(1H, m), 7.86-7.95(2H, m), 8.66(1H, d, J 8.0Hz), 8.81-8.84(1H, m).2840mp 197.1-197.7° C.; IR νmax(Nujol)/cm−1 3406, 3103, 3084, 1569, 1520and 1464; NMR δH(400MHz, CDCl3) 6.49-6.50(1H, m), 7.14(1H, dt,J 3.0, 1.0Hz), 7.20-7.23(1H, m), 7.48(1H, d, J 5.5Hz), 8.01(1H, d, J5.5Hz), 9.88-10.01(1H, s); Anal. Calcd for C10H6ClN3S: C, 50.96; H,2.57, N, 17.82. Found: C, 50.87; H, 2.54; N, 17.64.2931IR νmax(Nujol)/cm−1 2924, 2854, 1739, 1727, 1598, 1532, 1467, 1369,1348 and 1191; NMR δH(400MHz, CDCl3) 8.05(1H, m), 7.78(1H, m),7.60(1H, m), 7.49(1H, m), 6.42(1H, m), 4.20(2H, q, J 7.0Hz), 4.18(2H, s) and 1.22(3H, t, J 7.0Hz); M/Z 289(M+H)+.3067mp 183.2-183.8° C.; IR νmax(Nujol)/cm−1 3071, 1536, 1522, 1465 and1252; NMR δH(400MHz, CDCl3) 7.58(1H, d, J 5.5Hz), 8.23(1H, d, J5.5Hz), 8.79-8.83(2H, m), 9.95(1H, d, J 1.5Hz); Anal. Calcd forC10H5ClN4S: C, 48.30; H, 2.03, N, 22.52. Found: C, 48.28; H, 2.10; N,22.40.3115IR νmax(Nujol)/cm−1 2726, 1561, 1509, 1461 and 1377; NMR δH(400MHz,CDCl3) 3.35(6H, s), 6.54-6.55(1H, m), 6.62-6.64(1H, m),7.41(1H, dd, J 3.5, 1.0Hz), 7.45(1H, d, J 3.5Hz), 7.48-7.49(1H, m),7.72-7.73(1H, m), 8.05(1H, s); Anal. Calcd for C16H13N3O2S+0.3H2O: C, 60.67; H, 4.33, N, 13.27. Found: C, 60.49; H, 4.09; N, 13.33.3294mp 247.4-248.6° C.; IR νmax(Nujol)/cm−1 3080, 3072, 1568, 1544, 1462and 1402; NMR δH(400MHz, CDCl3) 3.29(6H, s), 6.41-6.44(1H, m),7.04-7.06(1H, m), 7.09-7.12(1H, m), 7.23(1H, d, J 5.5Hz), 7.76(1H, d, J 5.0Hz), 9.74-9.83(1H, s); Anal. Calcd for C12H12N4S+0.2H2O: C, 58.14; H, 5.04, N, 22.60. Found: C, 58.16; H, 4.84; N, 22.64.33100mp 173.9-174.3° C.; IR νmax(Nujol)/cm−1 1586, 1558, 1531, 1462, 1352and 793; NMR δH(400MHz, CDCl3) 3.36(6H, s), 7.29(1H, d, J 5.5Hz),7.92(1H, d, J 5.5Hz), 8.70(1H, d, J 2.5Hz), 8.76-8.78(1H, m),8.76-8.78(1H, m), 9.87(1H, d, J 1.5Hz); Anal. Calcd for C12H11N5S+0.1H2O: C, 55.62; H, 4.36, N, 27.03. Found: C, 55.46; H, 4.25; N, 26.83.3455mp 191.5-192.4° C.; IR νmax(Nujol)/cm−1 3298, 3082, 3060, 1589,1567, 1533, 1465, 1344, 1062 and 797; NMR δH(400MHz, DMSO)3.47-3.56(2H, m), 3.57-3.65(2H, m), 4.73(1H, s), 7.19(1H, s), 7.28(1H, d, J 5.0Hz), 8.31(1H, d, J 5.5Hz), 8.86(1H, d, J 2.5Hz), 8.91(1H, dd, J 2.5, 1.5Hz), 9.72(1H, s).35IR νmax(Nujol)/cm−1 3140, 3089, 2925, 2854, 1601, 1552, 1527, 1519,1493, 1455 and 1265; NMR δH(400MHz, CDCl3) 7.85(1H, d, J 5.5Hz),7.72(1H, s), 7.38(1H, m), 7.22(1H, d, J 5.5Hz), 6.65(1H, m),4.05-3.91(4H, m), 2.68-2.53(4H, m), 2.41(3H, s).36IR νmax(Nujol)/cm−1 3107, 3080, 2963, 2927, 2865, 1596, 1525, 1484,1463, 1272 and 1236; NMR δH(400MHz, CDCl3) 7.97(1H, d, J 5.5Hz),7.77(1H, s), 7.48(1H, m), 7.39(1H, d, J 5.5Hz), 6.67(1H, m),4.13(1H, sept, J 7.0Hz), 1.52(3H, J 7.0Hz).3795mp 207-208° C.; IR νmax(Nujol)/cm−1 3073, 2956, 1592, 1513, 14621263, 1012, 794 and 768; NMR δH(400MHz, CDCl3) 1.47(3H, t, J 7.5Hz),3.28(2H, q, J 7.5Hz), 6.66(1H, dd, J 3.5, 1.5Hz), 7.49(1H, d, J5.5Hz), 7.74-7.79(1H, m) and 7.97(1H, d, J 5.5Hz)3875mp 109-110° C.; IR νmax(Nujol)/cm−1 3314, 2927, 1598, 1551, 1379,1346, 1078, 795 and 744; NMR δH(400MHz, CDCl3) 1.60-1.80(2H,m), 1.86-2.07(2H, m), 2.14-2.26(1H, m), 3.64-3.99(4H, m), 4.38(1H, m), 6.61-6.66(2H, m), 7.22-7.28(1H, m), 7.41(1H, d, J 3.5Hz),7.74(1H, d, J 2.5Hz) and 7.88(1H, d, J 5.5Hz)3966IR νmax(Nujol)/cm−1 3058, 22925, 1595, 1524, 1462, 1268 and 794;NMR δH(400MHz, CDCl3) 2.69(3H, s), 6.66(1H, dd, J 4.0, 2.0Hz),7.42(1H, d, J 5.5Hz), 7.51(1H, d, J 3.5Hz), 7.76(1H, d, J 2.5Hz) and7.98(1H, d, J 5.5Hz)4073mp 101-102° C.; IR νmax(Nujol)/cm−1 3255, 2925, 1610, 1550, 1515,1446, 1331, 907 and 793; NMR δH(400MHz, CDCl3) 4.16-4.23(2H,m), 5.16(1H, dq, J 10.0, 1.5Hz), 5.21-5.29(1H, m); 5.32(1H, dq, J17.0, 1.5Hz), 5.97-6.09(1H, m), 6.63(1H, dd, J 3.5, 2.0Hz), 7.25(1H,d, J 5.5Hz), 7.39(1H, d, J 3.5Hz), 7.73(1H, dd, J 2.5, 1.0Hz) and 7.86(1H, d, J 5.5Hz)4156mp 220.5-221.0° C; IR νmax(Nujol)/cm−1 3135, 3082, 3080, 1594,1544, 1519, 1505, 1463, 1341, 1265, 867, 782 and 750; NMR δH(400MHz,DMSO) 6.94-6.96(1H, m), 7.75(1H, dd, J 3.5, 1.0Hz), 8.33(1H, d, J 1.0Hz), 9.79(1H, s); Anal. Calcd for C10H4ClN5O3S2O: C,42.64; H, 1.43, N, 14.91. Found: C, 42.94; H, 1.81; N, 15.05.42IR νmax(Nujol)/cm−1 3261, 2925, 2854, 1608, 1599, 1549, 1516, 1458,1377 and 1329. NMR δH(400MHz, CDCl3) 7.86(1H, d, J 5.5Hz), 7.72(1H, s), 7.38(1H, m), 7.25(1H, d, J 5.5Hz), 7.65(1H, m), 5.16(1H, brs), 5.59(2H, q, J 8.5Hz), 1.32(3H, t, J 8.5Hz).43IR νmax(Nujol)/cm−1 2956, 2925, 2855, 1598, 1547, 1521, 1508, 1478,1458 and 1349; NMR δH(400MHz, CDCl3) 7.80(1H, m), 7.72(1H, m),7.39(1H, m), 7.22(1H, m), 6.62(1H, m), 3.68(4H, m) and 2.02(4H, m).4421mp 182.8-183.8° C.; IR νmax(Nujol)/cm−1 3152, 3128, 3107, 1601,1558, 1543, 1498, 1477, 1406, 1321, 765 and 756; NMR δH(400MHz,CDCl3) 3.35(6H, s), 6.65-6.67(1H, m), 7.45(1H, d, J 3.5Hz), 7.74 -7.75(1H, m), 8.88(1H, s); Anal. Calcd for C12H10N4O3S: C, 49.65; H,3.47, N, 19.29. Found: C, 49.27; H, 3.49; N, 19.04.45IR νmax(Nujol)/cm−1 3250, 3084, 2924, 2854, 1608, 1580, 1548, 1515,1485, 1443 and 1330; NMR δH(400MHz, CDCl3) 8.59(1H, m), 7.88(1H, m), 7.72(1H, m), 7.66(1H, m), 7.41-7.38(1H, m), 7.25(1H, m),7.18(1H, m), 6.63(1H, m), 6.21(1H, br s) and 4.89(2H, d, J 5.6Hz).4644IR νmax(Nujol)/cm−1 3094, 2926, 2855, 1716, 1593, 1523, 1489, 1468,1421, 1332 and 1190; NMR δH(400MHz, CDCl3) 8.00(1H, m), 7.78(1H, m), 7.50(2H, m), 6.62(1H, m), 4.15(2H, m), 3.40(2H, m), 2.95(2H, m) and 1.20(3H, t, J 7.0Hz); M/Z 303(M+H)+.47IR νmax(Nujol)/cm−1 3417, 3103, 2974, 2944, 2859, 2820, 2776, 1599,1556, 1538, 1488, 1462, 1337 and 1256. NMR δH(400MHz, CDCl3)7.84(1H, d, J 5.5Hz), 7.73(1H, s), 7.38(1H, m), 7.22(1H, d, J 5.5Hz),6.63(1H, m), 5.64(1H, br s), 3.60(2H, q, J 6.0Hz), 2.59(2H, t, J 6.0Hz),2.28(6H, s).4844NMR δH(400MHz, CDCl3) 8.01(1H, m), 7.79(1H, m), 7.50(2H, m),6.80(1H, m), 4.10(1H, br m), 3.80(2H, m), 3.30(2H, m) and 2.18(2H,m); Retention time 2.42(80:20).4981IR νmax(Nujol)/cm−1 3079, 2923, 1745, 1729, 1698, 1594, 1531, 1466,1336, 809; NMR δH(400MHz, DMSO) 2.84(2H, t, J 7.0Hz), 3.24(2H,t, J 7.0Hz), 6.86(1H, dd, J 1.8, 3.5Hz), 7.54(1H, dd, J 0.8, 3.5Hz),7.58(1H, d, J 5.5Hz), 8.17(1H, dd, J 0.8, 1.8Hz), 8.51(1H, d, J 5.5Hz),12.05(1H, br).5025NMR δH(400MHz, CDCl3) 1.85(2H, m), 1.95(2H, m), 2.95(2H, t, J7.8Hz), 3.50(6H, m), 6.65(1H, dd, J 1.7, 3.5Hz), 7.48(2H, m), 7.76(1H, m), 7.99(1H, d, J 5.5Hz).5182mp 145.8-146.5° C.; IR νmax(Nujol)/cm−1 3403, 3310, 3135, 1600,1551, 1517, 1463 and 750; NMR δH(400MHz, CDCl3) 3.30(6H, s),4.13(2H, s), 6.59-6.61(2H, m), 7.35(1H, dd, J 3.5, 1.0Hz), 7.68-7.71(1H, m); Anal. Calcd for C12H12N4OS+0.3 H2O: C, 54.24; H, 4.78,N, 21.08. Found: C, 54.37; H, 4.51; N, 20.93.5252IR νmax(Nujol)/cm−1 3070, 2924, 2854, 1541, 1464, 1352, 779, 650;NMR δH(400MHz, CDCl3) 1.50(3H, t, J 7.50Hz), 3.20(2H, q, J 7.50Hz),7.45(1H, m), 7.53(1H, d, J 5.6Hz), 7.92(1H, m), 8.07(1H, d, J5.6Hz), 8.79(1H, m), 8.85(1H, m).53IR νmax(Nujol)/cm−1 2924, 2854, 1567, 1548, 1522, 1461, 1440, 1377and 1353; NMR δH(400MHz, CDCl3) 7.80(1H, d, J 5.5Hz), 7.67(1H,d, J 4.0Hz), 7.26(1H, d, J 5.5Hz), 7.02(1H, d, J 4.0Hz), 3.28(6H, s).5425NMR δH(400MHz, CDCl3) 3.35(2H, m), 4.12(2H, m), 4.41(1H, m),6.65(1H, d, J 1.8, 3.5Hz), 7.46(2H, m), 7.78(1H, d, J 0.8, 1.8Hz), 8.05(1H, d, J 5.5Hz).5552mp 244.4-244.9° C.; IR νmax(Nujol)/cm−1 3309, 3139, 1663, 1652,1602, 1557, 1510, 1490, 1470, 1465, 1446, 1377 and 743; NMR δH(400MHz,CDCl3) 3.23(6H, s), 6.61-6.63(1H, m), 6.75(1H, s), 7.17-7.22(1H, m), 7.34-7.46(5H, m), 7.72(1H, s), 7.93(1H, s), 8.04(1H, s).5651mp 210.9-211.3° C.; IR νmax(Nujol)/cm−1 3346, 3140, 1666, 1558,1541, 1462 and 1377; NMR δH(400MHz, CDCl3) 2.29(3H, s), 3.31(6H, s), 6.61-6.64(1H, m), 7.39(1H, d, J 3.5Hz), 7.73(1H, d, J 1.0Hz),8.25(1H, s), 8.30(1H, s); Anal. Calcd for C14H14N4O2S: C, 55.62;H, 4.67, N, 18.52. Found: C, 55.46; H, 4.57; N, 18.27.5747mp 192.2-192.8° C.; IR νmax(Nujol)/cm−1 3409, 3133, 3110, 1665, 1603,1550, 1526, 1463, 1376 and 1261; NMR δH(400MHz, CDCl3) 3.33(6H,s), 6.62-6.64(1H, m), 7.40(1H, dd, J 3.5, 1.0Hz), 7.51-7.62(3H, m),7.73-7.74(1H, m), 7.96-8.01(2H, m), 8.45(1H, s), 9.10(1H, s);Anal. Calcd for C19H16N4O2S+0.75 H2O: C, 60.38; H, 4.67, N, 14.82.Found: C, 60.47; H, 4.63; N, 14.72.5865mp 183.8-184.3° C.; IR νmax(Nujol)/cm−1 3269, 3134, 3069, 1613, 1583,1551, 1520, 1449 and 794; NMR δH(400MHz, CDCl3) 3.10(3H, d, J5.0Hz), 5.09-5.10(1H, s), 6.62-6.64(1H, m), 7.26(1H, d, J 4.5Hz),7.38(1H, dd, J 3.5, 1.0Hz), 7.71-7.73(1H, m), 7.85(1H, d, J 5.5Hz);Anal. Calcd for C11H9N3OS+0.3 H2O: C, 55.82; H, 4.09, N, 17.75.Found: C, 55.85; H, 3.94; N, 17.68.596mp 211.9° C.; NMR δH(400MHz, CDCl3) 3.09(3H, s), 6.72-6.74(1H,m), 7.40(1H, s), 7.63(1H, d, J 3.5Hz), 7.83(1H, d, J 1.0Hz), 7.90(1H,s); M/Z 330(M+H)+.6032mp 108.3-108.6° C.; IR νmax(Nujol)/cm−1 3104, 3073, 1702, 1667,1598, 1545, 1467, 1373, 804 and 744; NMR δH(400MHz, CDCl3) 2.31(3H, s), 3.66(3H, s), 3.96(2H, s), 6.68-6.70(1H, m), 7.42(1H, d, J 5.5Hz),7.47(1H, d, J 3.5Hz), 7.87(1H, d, J 1.0Hz), 8.07(1H, d, J 5.5Hz);Anal. Calcd for C15H13N3O3S+0.2 H2O: C, 56.49; H, 4.23, N, 13.17.Found: C, 56.63; H, 4.14; N, 13.09; M/Z 316(M+H)+.6123NMR δH(400MHz, CDCl3) 3.69(2H, q, J 5.5Hz), 3.90(2H, t, J 4.5Hz),5.47-5.58(1H, m), 7.03(1H, d, J 4.0Hz), 7.24(1H, d, J 5.5Hz),7.71(1H, d, J 4.0Hz) and 7.84(1H, d, J 5.5Hz); Retention time(80/20):5.12 min6282IR νmax(Nujol)/cm−1 2925, 2855, 1541, 1406, 1362, 783; NMR δH(400MHz,CDCl3) 2.93(3H, s), 7.45(1H, m), 7.51(1H, d, J 5.6Hz), 7.92(1H, m), 8.07(1H, d, J 5.6Hz), 8.76(1H, m), 8.85(1H, m).6383IR νmax(Nujol)/cm−1 3048, 2926, 2855, 1541, 1468, 1335, 790; NMR δH(400MHz, CDCl3) 1.05(3H, t, J 7.5Hz), 2.00(2H, sextet, J 7.5Hz),3.10(2H, m), 7.45(1H, m), 7.51(1H, d, J 5.6Hz), 7.92(1H, m), 8.07(1H, d, J 5.6Hz), 8.76(1H, m), 8.85(1H, m).6426IR νmax(Nujol)/cm−1 3418, 3096, 2924, 1516, 1460, 1377, 1228, 827 and795; NMR δH(400MHz, CDCl3) 7.55(1H, d, J 6.0Hz), 7.69(1H, d, J3.0Hz), 8.18(1H, d, J 3.0Hz) and 8.20(1H, d, J 5.5Hz)6562mp 152-153° C.; IR νmax(Nujol)/cm−1 3056, 2925, 1566, 1532, 1464,1354, 1132 and 792; NMR δH(400MHz, CDCl3) 3.32(6H, s), 7.26(1H,d, J 5.5Hz), 7.54(1H, d, J, 3.0Hz), 7.91(1H, d, J 5.5Hz) and 8.10(1H,d, J 3.0Hz)6610IR νmax(Nujol)/cm−1 3057, 2956, 2855, 1530, 1467, 1450; NMR δH(400MHz,CDCl3) 7.45(1H, m), 7.51(1H, d, J 5.6Hz), 7.92(1H, m), 8.07(1H, d, J 5.6Hz), 8.76(1H, m), 8.85(1H, m), 9.28(1H, s).67IR νmax(Nujol)/cm−1 3288, 2956, 2925, 2554, 1597, 1584, 1557, 1523,1459, 1427 and 1333. NMR δH(400MHz, CDCl3) 8.82(1H, d, J 5.0Hz),8.57(1H, d, J 8.0Hz), 7.95(1H, d, J 5.0Hz), 7.92-7.82(1H, m), 7.44(7.40(1H, m), 7.29-7.22(1H, m), 5.60(1H, br s), 4.10(1H, br s), 3.95 -3.92(2H, m), 3.77-3.75(2H, m).6887mp 140-142° C.; IR νmax(Nujol)/cm−1 3435, 2924, 1572, 1528, 1462,1320, 1086, 793, 702 and 600; NMR δH(400MHz, CDCl3) 3.73(2H, m),3.93(2H, t, J 5.0Hz), 5.53-5.66(1H, m), 7.24(1H, d, J 5.5Hz), 7.96(1H, d, J 5.5Hz) and 8.12(1H, d, J 3.0Hz)6950NMR δH(400MHz, CDCl3) 5.78(1H, dd, J 1.8, 10.5Hz), 6.68(1H, dd,J 1.7, 3.5Hz), 6.75(1H, dd, J 1.8, 17.3Hz), 7.05(1H, dd, J 10.5, 17.3 HZ),7.53(1H, d, J 5.5Hz), 7.55(1H, dd, J 3.5, 5.5Hz), 7.78(1H, dd, J0.8, 1.7Hz), 8.01(1H, d, J 5.5Hz).7016IR νmax(Nujol)/cm−1 3072, 2923, 1696, 1540, 1464, 788; NMR δH(400 MHZ,CDCl3) 1.50(6H, d, J 6.9Hz), 3.44(1H, heptet, J 6.9Hz), 7.44(1H, ddd, J 1.3, 4.9, 7.5Hz), 7.54(1H, d, J 5.5Hz), 7.93(1H, dt, J 1.3,7.5Hz), 8.06(1H, d, J 5.5Hz), 8.81(1H, m), 8.85(1H, m).7113mp 65.0-65.4° C.; IR νmax(Nujol)/cm−1 3326, 3090, 1598, 1558, 1488,1466, 1330 and 1088; NMR δH(400MHz, CDCl3) 3.41(3H, s), 3.63(2H, t, J 5.5Hz), 3.79(2H, q, J 5.5Hz), 5.61(1H, t, J 5.0Hz), 6.63-6.65(1H, m), 7.38(1H, d, J 3.0Hz), 7.72-7.73(1H, m), 7.84(1H, s);Anal. Calcd for C13H12N3BrO2S: C, 44.08; H, 3.41, N, 11.86. Found: C,43.89; H, 3.48; N, 11.77.7242mp 75.4-76.3° C.; IR νmax(Nujol)/cm−1 3288, 3098, 1597, 1548, 1516,1462, 1376, 1341 and 767; NMR δH(400MHz, CDCl3) 1.68-1.80(1H,m), 1.83-2.08(2H, m), 2.17-2.28(1H, m), 3.65-3.81(2H, m), 3.82-3.90(1H, m), 3.97-4.07(1H, m), 4.34-4.43(1H, m), 6.63-6.65(1H,m), 7.42(1H, d, J 1.0Hz), 7.73-7.74(1H, m), 7.85(1H, s).7368IR νmax(Nujol)/cm−1 3061, 2925, 2854, 1727, 1595, 1523, 1484, 1467,1377 and 1230; NMR δH(400MHz, CDCl3) 8.15(1H, m), 7.82(1H, m),7.74(1H, m), 7.70(1H, m), 6.70(1H, m), 4.60(2H, q, J 7.0Hz), and1.50(3H, t, J 7.0Hz).7447NMR δH(400MHz, CDCl3) 1.43(9H, s), 3.42(2H, q, J 5.5Hz), 3.65(2H, q, J 5.5Hz), 5.34(1H, t, J 5.5Hz), 6.63(1H, dd, J 2.0, 3.5Hz), 7.20(1H, d, J 5.5Hz), 7.39(1H, d, J 3.5Hz), 7.72(1H, dd, J 1.0, 1.5Hz) and7.85(1H, d, J 5.5Hz); Retention time 3.26 min(8:2)7567NMR δH(400MHz, CDCl3) 1.40(2H, br s), 2.99(2H, t, J 6.0Hz), 3.60(2H, q, J 6.0Hz), 5.40(1H, t, J 5.5Hz), 6.63(1H, dd, J 2.0, 3.5Hz), 7.22(1H, d, J 5.5Hz), 7.37(1H, d, J 3.5Hz), 7.72(1H, dd, J 1.0, 2.0Hz) and7.84(1H, d, J 5.5Hz); Retention time 2.65 min (7:3)7649mp 112-113° C.; IR νmax(Nujol)/cm−1 3089, 2925, 1561, 1352, 1136 and794; NMR δH(400MHz, CDCl3) 2.60(3H, s), 3.31(6H, s), 7.09(1H, s),7.24(1H, d, J 5.5Hz) and 7.90(1H, d, J 5.5Hz)775NMR δH(400MHz, CDCl3) 3.61(2H, q, J 6.0Hz), 3.75(2H, q, J 6.0Hz),5.56(1H, t, J 6.0Hz), 6.65(1H, dd, J 1.5, 3.5Hz), 7.21(1H, d, J 5.5Hz,)7.39(1H, d, J 3.5Hz) 7.75(1H, dd, J 1.0, 2.0Hz), 7.92(1H, d, J 5.5Hz)and 9.31(1H, br s); Retention time 2.89 min(80:20)7851mp 155-156° C.; NMR δH(400MHz, CDCl3) 3.86(3H, s), 3.87(3H, s),4.68(2H, d, J 5.5Hz), 5.40(1H, t, J 5.5Hz), 6.62-6.64(1H, m), 6.82(1H, d, J 8.0Hz), 6.94-6.99(2H, m), 7.24(1H, d, J 5.5Hz), 7.37(1H,dd, J 3.5, 1.0Hz), 7.72-7.73(1H, m), 7.86(1H, d, J 5.5Hz); Anal.Calcd for C19H17N3O3S: C, 62.11; H, 4.66, N, 11.43. Found: C, 62.19; H,4.67; N, 11.44.7992mp 169.6-169.9° C.; NMR δH(400MHz, CDCl3) 5.02(2H, s), 6.63-6.66(1H, m), 7.22(1H, d, J 5.5Hz), 7.39(1H, dd, J 3.5, 1.0Hz), 7.22-7.74(1H, m), 7.89(1H, d, J 5.5Hz); Anal. Calcd for C10H7N3OS+0.2H2O: C, 54.38; H, 3.38, N, 19.03. Found: C, 54.69; H, 3.35; N, 18.74.8045IR νmax(Nujol)/cm−1 2925, 2855, 1545, 1464, 1356; NMR δH(400MHz,CDCl3) 1.45(3H, t, J 7.5Hz), 2.61(3H, s), 3.15(2H, q, J 7.5Hz), 7.15(1H, s), 7.50(1H, d, J 5.5Hz), 8.02(1H, d, J 5.5Hz).8120NMR δH(400MHz, CDCl3) 8.08(1H, m), 7.80(1H, m), 7.55(2H, m),6.70(1H, m), 4.90(2H, s) and 3.80(1H, br m); Retention time 3.06(80:20).8237IR νmax(Nujol)/cm−1 3050, 2925, 2855, 1543, 1526, 1460, 1356; NMR δH(400MHz, CDCl3) 1.45(3H, t, J 7.5Hz), 3.18(2H, q, J 7.5Hz), 7.54(1H, d, J 7.5Hz), 7.61(1H, d, J 3.1Hz), 8.09(1H, d, J 7.5Hz), 8.15(1H, d, J 3.1Hz).83IR νmax(Nujol)/cm−1 3287, 3089, 2924, 2854, 1633, 1603, 1548, 1516,1486, 1462, 1377 and 1331; NMR δH(400MHz, CDCl3) 1.93(3H, s),3.54(2H, q, J 5.5Hz), 3.69(2H, q, J 5.5Hz), 5.43(1H, t, J 6.0Hz), 6.65(1H, dd, J 1.5, 3.5Hz), 6.76(1H, br s), 7.22(1H, d, J 5.5Hz), 7.39(1H,dd, J 1.0, 3.5Hz), 7.73(1H, dd, J 1.0, 1.5Hz) and 7.89(1H, d, J 5.5Hz);Retention time 3.08 min (70:30).84IR νmax(Nujol)/cm−1 3317, 3265, 2924, 2854, 1635, 1613, 1580, 1558,1514, 1463, 1377 and 1335; NMR δH(400MHz, CDCl3), 0.90(6H, d, J5.5Hz), 2.01(2H, m), 2.07(1H, m), 3.56(2H, q, J 5.5Hz), 3.68(2H, q,J 5.5Hz), 5.49(1H, t, J 6.0Hz), 6.65(1H, dd, J 1.5, 3.5Hz), 7.21(1H, d,J 5.5Hz), 7.39(1H, dd, J 1.0, 3.5Hz), 7.73(1H, dd, J 1.0, 1.5Hz) and7.89(1H, d, J 5.5Hz); Retention time 4.43 min (70:30).85IR νmax(Nujol)/cm−1 3318, 3083, 2974, 2871, 1644, 1600 1549, 1488,1461 and 1337; NMR δH(400MHz, CDCl3) 3.75(2H, q, J 5.5Hz), 3.83(2H, q, J 5.5Hz), 5.68(1H, t, J 5.0Hz), 6.62(1H, dd, J 1.5, 3.5Hz), 7.21(1H, d, J 5.5Hz), 7.29(2H, m), 7.38(2H, m), 7.71(3H, m), 7.87(1H, m)and 7.90(1H, d, J 5.5Hz); Retention time 5.05 min (70:30).86IR νmax(Nujol)/cm−1 3267, 3108, 2925, 2854, 1641, 1611, 1548, 1517,1485, 1464, 1422 and 1334; NMR δH(400MHz, CDCl3) 3.71(2H, q, J5.5Hz), 3.81(2H, q, J 5.5Hz), 5.65(1H, t, J 6.0Hz), 6.63(1H, dd, J 1.5,3.5Hz), 6.92(1H, m), 7.24(1H, d, J 5.5Hz), 7.37(3H, m), 7.56(1H, brs), 7.72(1H, dd, J 1.0, 1.5Hz) and 7.89(1H, d, J 5.5Hz); Retention time4.79 min. (70:30).87NMR δH(400MHz, CDCl3) 3.52(2H, m), 3.64(3H, s), 3.79(2H, m),5.53(1H, br s), 6.73(1H, dd, J 1.5, 3.5Hz), 7.34(1H, d, J 5.5Hz), 7.65(1H, m), 7.83(1H, m) and 8.02(1H, d, J 5.5Hz); Retention time 3.46 min.(70:30).88NMR δH(400MHz, CDCl3) 0.87(6H, d, J 6.4Hz), 1.83(2H, m), 3.52(2M, q, J 5.5Hz), 3.73(2H, m), 3.85(2H, m), 5.50(1H, br s) 6.71(1H,dd, J 1.5, 3.5Hz), 7.32(1H, d, J 5.5Hz), 7.61(1H, m), 7.81(1H, m) and7.96(1H, d, J 5.5Hz); Retention time 5.69 min. (70:30).8999NMR δH(400MHz, CDCl3) 3.55(2H, q, J 5.8Hz), 3.78(2H, q, J 5.8Hz,)5.07(2H, s), 5.55(1H, m), 6.73(1H, dd, J 1.5, 3.5Hz), 7.29(5H,m), 7.40(1H, d, J 5.5Hz), 7.76(1H, m), 7.85(1H, m), 8.11(1H, d, J 5.5Hz)and 10.05(1H, br s); Retention time 6.16 min (70:30)90NMR δH(400MHz, CDCl3) 3.01(1H, t, J 5.8Hz), 3.60(2H, q, J 5.5Hz),4.04(2H, d, J 5.8Hz), 4.11(2H, q, J 5.5Hz), 5.46(1H, m), 6.61(1H, dd, J 1.5, 3.5Hz), 7.31(1H, d, J 5.5Hz), 7.33-7.45(4H, m), 7.71-7.79(4H, m) and 7.82(1H, d, J 5.5Hz); Retention time 17.2 min(70:30).91NMR δH(400MHz, DMSO) 3.27(2H, m), 3.42(2H, m), 3.63(2H, m),5.01(1H, m), 5.08(1H, m), 5.77(1H, m), 6.10(1H, br s), 6.85(1H, dd, J1.5, 3.5Hz), 7.29(1H, d, J 5.5Hz), 7.48(2H, m), 8.17(1H, m) and 8.35(1H, d, J 5.5Hz); Retention time 3.39 min. (70:30).9299NMR δH(400MHz, DMSO) 3.30(2H, t, J 6.0Hz), 3.45(2H, t, J 6.0Hz),4.23(2H, s), 6.46(1H, br s), 6.85(1H, dd, J 2.0, 3.5Hz), 7.18-7.33(7H, m), 7.49(2H, m), 8.17(1H, m) and 8.36(1H, d, J 5.5Hz);Retention time 4.61 min (7:3)93NMR δH(400MHz, DMSO) 1.02-1.25(5H, m), 1.51-1.78(5H, m),3.26(2H, m), 3.34(1H, m), 3.43(2H, m), 5.75(1H, br s), 6.78(1H, br s),6.87(1H, dd, J 1.5, 3.5Hz), 7.34(1H, d, J 5.5Hz), 7.49(1H, m), 7.96(1H, br s), 8.15(1H, m) and 8.36(1H, d, J 5.5Hz); Retention time 5.30 min,(70:30).94NMR δH(400MHz, DMSO) 3.35(2H, m), 3.44(2H, m), 6.30(1H, t, J6.0Hz), 6.79(1H, dd, J 1.5, 3.5Hz), 7.17-7.31(5H, m), 7.36-7.47(3H, m), 8.10(1H, m), 5.27(1H, d, J 5.5Hz) and 8.52(1H, m);Retention time 5.46 min, (70:30).95NMR δH(400MHz, DMSO) 3.35(2H, q, J 5.8Hz), 3.46(2H, q, J 5.8Hz),6.35(1H, t, J 6.0Hz), 6.80(1H, dd, J 1.5, 3.5Hz), 7.19(1H, m),7.25(3H, m), 7.41(3H, m), 8.10(1H, dd, J 1.0, 1.5Hz), 8.28(1H, d, J5.5Hz) and 8.70(1H, m); Retention time 9.61 min. (70:30).96NMR δH(400MHz, CDCl3) 3.56(2H, q, J 5.8Hz), 3.78(2H, m), 5.07(2H, s), 5.55(1H, br s), 6.73(1H, dd, J 1.5, 3.5Hz), 7.29-7.36(5H, m),7.39(1H, d, J 5.5Hz), 7.76(1H, m), 7.85(1H, m) 8.11(1H, d, J 5.5Hz)and 10.07(1H, br s); Retention time 6.16 min (70:30).97NMR δH(400MHz, DMSO) 3.58(2H, m), 3.76(2H, m), 6.80(1H, dd, J1.5, 3.5Hz), 7.22(1H, d, J 5.5Hz), 7.35(4H, m), 7.42(3H, m), 7.96(1H, m) 8.11(1H, m), 8.27(1H, d, J 5.5Hz) and 9.68(1H, br s);Retention time 8.41 min, (70:30).98NMR δH(400MHz, DMSO) 2.93(3H, s), 3.21(2H, m), 3.64(2H, m),6.86(1H, dd, J 1.5, 3.5Hz), 7.18(1H, m), 7.32(1H, m), 7.52(1H, m),7.86(1H, m), 8.17(1H, m) and 8.37(1H, m); Retention time 2.93 min(70:30).99NMR δH(400MHz, CDCl3) 1.21(9H, s), 3.28(2H, q, J 5.8Hz), 3.61(2H, q, J 5.9Hz), 5.41(1H, t, J 6.0Hz), 6.58(1H, t, J 6.0Hz) 6.65(1H,dd, J 1.5, 3.5Hz), 7.23(1H, d, J 5.5Hz), 7.40(3H, m), 7.69(2H, d, J 6.4Hz),7.74(1H, m) and 7.87(1H, d, J 5.5Hz); Retention time 10.30 min10035NMR δH(400MHz, CDCl3) 8.88(1H, m), 8.70(1H, m), 8.08(1H, m),7.88(1H, m), 7.82(1H, m), 7.78(1H, m), 7.64(2H, m) and 6.30(1H,m); Retention time 3.52 (80:20).10180mp 193.9-195.0° C.; IR νmax(Nujol)/cm−1 3246, 3149, 3080, 3064,1683, 1664, 1599, 1547, 1497, 1315 and 1298; NMR δH(400MHz,DMSO) 2.26(3H, s), 6.86-6.88(1H, m), 7.51(1H, d, J 3.0Hz), 7.48(1H, d, J 5.5Hz), 8.20(1H, s), 8.51(1H, d, J 5.5Hz), 10.58(1H, s);Anal. Calcd for C12H9N3O2S+0.5 H2O: C, 53.72; H, 3.76, N, 15.66.Found: C, 53.81; H, 3.44; N, 15.41.102Mp 243-244° C., IR νmax(Nujol)/cm−1 2955, 2924, 2854, 1543, 1526,1574, 1468, 1435, 1358 and 1236. NMR δH(400MHz, CDCl3) 8.18(1H,d, J 5.5Hz), 7.82(1H, s), 7.53(1H, d, J 5.5Hz), 2.63(3H, s).103Mp 240-241° C., IR νmax(Nujol)/cm−1 2955, 2925, 2854, 1537, 1516,1481, 1460, 1359 and 1230. NMR δH(400MHz, CDCl3) 8.15(1H, d, J5.5Hz), 7.51(1H, d, J 5.5Hz), 2.50(6H, s).10471mp 208-211° C.; IR νmax(Nujol)/cm−1 2855, 1567, 1520, 1358, 1101, 817and 794; NMR δH(400MHz, CDCl3) 2.57(3H, d, J 1.0Hz), 3.30(6H,s), 7.24(1H, d, J 5.5Hz), 7.74(1H, d, J 1.5Hz) and 7.89(1H, d, J 5.5Hz)10599Mp 148-149° C.; IR νmax(Nujol)/cm−1 2854, 1564, 1356, 1236 and 7932;NMR δH(400MHz, CDCl3) 2.45(3H, s), 2.47(3H, s), 3.30(6H, s), 7.23(1H, d, J 5.5Hz) and 7.87(1H, d, J 5.5Hz)106Mp 170-170.5° C.; IR νmax(Nujol)/cm−1 3061, 2955, 2925, 2854, 1545,1519, 1480, 1465, and 1377. NMR δH(400MHz, CDCl3) 8.09(1H, d, J5.5Hz), 7.88(2H, d, J 7.0Hz), 7.71(1H, s), 7.57(1H, d, J 5.5Hz), 7.50(2H, t, J 7.5Hz), 7.42(1H, t, J 7.5Hz), 3.25(2H, q, J 7.5Hz), 1.53(3H,t, J 7.5Hz).107Mp 258-258.5° C.; IR νmax(Nujol)/cm−1 3136, 3073, 2955, 2924, 2854,1573, 1559, 1514, 1475, 1408, 1335 and 1251. NMR δH(400MHz,CDCl3) 10.43(1H, br s), 7.91(1H, d, J 5.5Hz), 7.43(1H, s), 7.25-7.21(2H, m), 3.30(6H, s)10880Mp 178.7-179.5° C.; IR νmax(Nujol)/cm−1 3245, 2924, 2845, 1600,1554, 1530, 1515, 1467, 1344, 1321, 1251 and 1232, NMR δH(400MHz,CDCl3) 8.11(1H, d, J 3.2Hz), 7.97(1H, m), 7.55(1H, d, J 3.2Hz),7.25(1H, s), 7.00(1H, s), 6.98(1H, m), 6.84(1H, m), 5.46(1H, t, J5.6Hz), 4.70(2H, d, J 6.0Hz), 3.87(3H, s) and 3.87(3H, s); AnalCalcd. for C18H16N4O2S2: C, 56.23; H, 4.19; N, 14.57. Found: C, 56.23;H, 4.11; N 14.41.109Mp 221-222° C.; IR νmax(Nujol)/cm−1 3083, 2925, 2854, 1528, 1519,1461, 1377, 1303, 1241 and 1161. NMR δH(400MHz, CDCl3) 8.68(1H, s), 8.63(1H, d, J 8.0Hz), 8.17(1H, d, J 5.5Hz), 7.74(1H, d, J 8.0Hz),7.52(1H, d, J 5.5Hz), 2.48(3H, s).11063mp 190.1-190.7° C.; IR νmax(Nujol)/cm−1 3464, 3296, 3165, 3122,3038, 1635, 1555, 1541, 1481 and 1360; NMR δH(400MHz, CDCl3)5.10(2H, s), 7.24(1H, d, J 5.5Hz), 7.58(1H, d, J 3.0Hz), 7.98(1H, d, J5.5Hz), 8.12(1H, d, J 3.0Hz); Anal. Calcd for C9H6N4S2: C, 46.14; H,2.58, N, 23.90. Found: C, 46.14; H, 2.67; N, 23.02.11185mp 139.3-139.7° C.; IR νmax(Nujol)/cm−1 3326, 3118, 3078, 3062,1557, 1537, 1506, 1356 and 795; NMR δH(400MHz, CDCl3) 1.75-7.84(1H, m), 1.91-2.10(2H, m), 2.15-2.26(1H, m), 3.70-3.82(2H,m), 3.84-3.98(2H, m), 4.38-4.56(1H, s), 7.24(1H, d, J 5.5Hz), 7.56(1H, d, J 3.5Hz), 7.95(1H, d, J 5.5Hz), 8.12(1H, d, J 3.5Hz); Anal.Calcd for C14H14N4OS2: C, 52.81; H, 4.43, N, 17.59. Found: C, 53.08; H,4.53; N, 17.22.11262mp 128-129° C.; IR νmax(Nujol)/cm−1 3251, 3102, 3076, 3019, 1596,1552, 1528, 1448, 1336 and 794; NMR δH(400MHz, CDCl3) 4.19-4.24(2H, m), 5.14-5.37(3H, m), 5.99-6.10(1H, m), 7.24(1H, d, J 5.5Hz),7.56(1H, d, J 3.0Hz), 7.95(1H, d, J 5.5Hz), 8.11(1H, d, J 3.0Hz).11384mp 90.6-90.7° C.; IR νmax(Nujol)/cm−1 3056, 2961, 2855, 1546, 1529,1480, 806; NMR δH(400MHz, CDCl3) 1.48(6H, d, J 6.9Hz), 3.40(1H,heptet, J 6.9Hz), 7.55(1H, d, J 5.5Hz), 7.59(1H, d, J 3.1Hz), 8.08(1H,d, J 5.5Hz), 8.14(1H, d, J 3.1Hz).1147IR νmax(Nujol)/cm−1 2925, 2854, 1615, 1545, 1498, 1459, 1377, 1265and 1174; NMR δH(400MHz, CDCl3) 8.05(1H, m), 7.80(1H, m), 7.60(2H, m), 7.00(1H, m), 3.83(3H, s), 3.25(2H, q, J 7.0Hz) and 1.50(3H,t, J 7.0Hz).11593mp 133-133.5° C.; IR νmax(Nujol)/cm−1 2925, 1553, 1467, 1404, 1356,1241 and 796; NMR δH(400MHz, CDCl3) 2.44(3H, s), 3.35(6H, s),7.25(1H, d, J 5.5Hz), 7.67(1H, dd, J 7.5, 2.5Hz), 7.89(1H, d, J 5.5Hz),8.54(1H, d, J 8.5Hz) and 8.64(1H, d J 2.0Hz)11637mp 242.6-243.9° C.; IR νmax(Nujol)/cm−1 3251, 3079, 3060, 1687,1672, 1560, 1496 and 1320; NMR δH(400MHz, DMSO) 2.29(3H, s),7.54(1H, d, J 5.5Hz), 8.15(1H, d, J 3.5Hz), 8.27(1H, d, J 3.0Hz), 8.56(1H, d, J 5.5Hz), 10.68(1H, s).11767Mp 149° C.; IR νmax(Nujol)/cm−1 2955, 2925, 2854, 1595, 1523, 1485,1468 and 1333; NMR δH(400MHz, CDCl3) 8.00(1H, m), 7.76(1H, m),7.60(1H, m), 7.56(1H, m), 7.36(1H, m), 7.05(1H, m), 6.92(1H, m),6.63(1H, m) and 4.59(2H, s).118IR νmax(Nujol)/cm−1 3036, 2925, 2854, 1535, 1481, 1468, 1351, 1129 and1098; NMR δH(400MHz, CDCl3) 9.01(1H, m), 8.78(1H, s), 8.01(1H,d, J 5.6Hz), 7.57(1H, d, J 5.2Hz), 3.13(2H, q, J 7.6Hz) and 1.47(3H,t, J 7.6Hz).1193Mp 179° C.; IR νmax(Nujol)/cm−1 3057, 2924, 2854, 1525, 1465, 1438,1378 and 1296; NMR δH(400MHz, CDCl3) 8.12(2H, m), 7.58(2H, m),3.30(4H, q, J 7.0Hz) and 1.60(6H, t, J 7.0Hz); M/Z 327(M+H)+.120IR νmax(Nujol)/cm−1 3388, 3060, 2924, 2855, 1662, 1561, 1541, 1461,1376, 1356, 1309, 1266 and 1096. NMR δH(400MHz, CDCl3) 8.32(1H,br s), 8.13(1H, d, J 5.5Hz), 7.58(1H, J 5.5Hz), 7.26(1H, s), 3.19(2H,q, J 7.5Hz), 1.48(3H, t, 7.5Hz).12139mp 178.6-179.6° C.; IR νmax(Nujol)/cm−1 3080, 2925, 1569, 1525, 1468,1092, 854, 815 and 750; NMR δH(400MHz, CDCl3) 1.47(3H, t, J 7.5Hz),3.11(2H, q, J 7.5Hz), 7.29(1H, s), 7.47(1H, s), 7.51(1H, d, J, 5.5Hz),8.07(1H, d, J 5.5Hz) and 10.65(1H, br s)12213Mp 131° C.; IR νmax(Nujol)/cm−1 2960, 1547, 1529, 1377, 1314, 1301and 1096; NMR δH(400MHz, CDCl3) 8.24(1H, m), 8.12(1H, m), 8.02(1H, m), 7.48-7.60(3H, m), 3.20(2H, q, J 7.0Hz) and 1.50(3H, t, J 7.0Hz).12373IR νmax(Nujol)/cm−1 3392, 3254, 1681, 1586, 1552, 1515, 1342, 1318,1274, 1252, 1165 and 1150; NMR δH(400MHz, CDCl3) 1.43(9H, s),3.46(2H, q, J 5.5Hz), 3.70(2H, q, J 5.5Hz), 5.12(1H, br s), 5.42(1H, t,J 5.5Hz), 7.23(1H, d, J 5.5Hz), 7.55(1H, d, J 3.5Hz), 7.95(1H, d, J5.5Hz) and 8.11(1H, d, J 3.0Hz); Retention time 5.17 min (70:30)12460IR νmax(Nujol)/cm−1 3352, 3241, 3045, 1558, 1349, 1315, 1280 and1116; NMR δH(400MHz, CDCl3) 1.27(2H, br s), 3.02(2H, t, J 6.0Hz),3.63(2H, q, J 6.0Hz), 5.46(1H, m), 7.23(1H, d, J 5.5Hz), 7.55(1H, d,J 3.5Hz), 7.94(1H, d, J 5.5Hz) and 8.11(1H, d, J 3.5Hz); Retentiontime 2.35 min (60:40)12561NMR δH(400MHz, DMSO) 1.81(3H, s), 3.30(2H, q, J 6.0Hz), 3.44(2H, q, J 6.0Hz), 7.28(2H, m), 7.97(1H, m), 8.07(1H, d, J 3.0Hz),8.21(1H, d, J 3.0Hz) and 8.32(1H, d, J 5.5Hz); Retention time 2.83 min(70:30)126NMR δH(400MHz, DMSO) 0.97(3H, t, J 7.2Hz), 3.00(2H, m), 3.26(2H, q, J 6.0Hz), 3.40(2H, q, J 6.0Hz), 5.86(1H, t, J 5.5Hz), 5.96(1H,t, J 5.5Hz), 7.29(2H, m), 8.08(1H, d, J 3.2Hz), 8.22(1H, d, J 3.3Hz)and 8.32(1H, d, J 5.5Hz); Retention time 2.42 (80:20).127NMR δH(400MHz, DMSO) 3.30(2H, q, J 5.8Hz), 3.42(2H, q, J 5.8Hz),3.63(2H, m), 5.00(1H, dd, J 1.6, 10.2Hz), 5.09(1H, dd, J 1.8, 17.2Hz),5.79(1H, m), 6.05(2H, m), 7.29(2H, m) 8.08(1H, d, J 3.1Hz),8.22(1H, d, J 3.1Hz) and 8.32(1H, d, J 5.5Hz); Retention time 2.50 min(80:20).12881NMR δH(400MHz, DMSO) 0.99-1.28(5H, m), 1.48-1.74(5H, m),3.25(2H, q, J 6.0Hz), 3.33(1H, m), 3.39(2H, q, J 6.0Hz), 5.77(1H, d,J 8.0Hz), 5.86(1H, t, J 5.5Hz), 7.28(1H, m), 8.07(1H, d, J 3.0Hz),8.21(1H, d, J 3.0Hz) and 8.31(1H, d, J 5.5Hz); Retention time 3.11 min(80:20)12942NMR δH(400MHz, DMSO) 0.84(6H, d, J 6.5Hz), 1.95(3H, m), 3.37(2H, m), 3.43(2H, q, J 6.0Hz), 7.26(2H, m), 7.89(1H, m), 8.08(1H, d,J 3.0Hz), 8.21(1H, d, J 3.0Hz) and 8.32(1H, d, J 5.5Hz); Retentiontime 2.77 min (80:20)13058NMR δH(400MHz, DMSO) 3.25(2H, q, J 6.0Hz), 3.44(2H, q, J 6.0Hz),3.52(3H, s), 7.21(1H, t, J 5.5Hz), 7.26(1H, d, J 5.5Hz), 7.30(1H,m), 8.07(1H, d, J 3.0Hz), 8.21(1H, d, J 3.0Hz) and 8.32(1H, d, J 5.5Hz); Retention time 2.53 min (80:20)13162NMR δH(400MHz, DMSO) 0.84(6H, d, J 6.5Hz), 1.79(1H, m), 3.25(2H, q, J 6.0Hz), 3.45(2H, q, J 6.0Hz), 3.71(2H, d, J 6.5Hz), 7.16(1H, t, J 5.5Hz), 7.26(1H, d, J 5.5Hz), 7.30(1H, m), 8.07(1H, d, J 3.0Hz),8.21(1H, d, J 3.0Hz) and 8.32(1H, d, J 5.5Hz); Retention time3.23 min (80:20)132NMR δH(400MHz, DMSO) 1.21(9H, s), 3.24(2H, q, J 5.8Hz), 3.39(2H, q, J 5.8Hz), 5.68(1H, s), 5.80(1H, t, J 6.0Hz), 7.28(2H, m), 8.07(1H, d, J 3.1Hz), 8.22(1H, d, J 3.1Hz), and 8.32(1H, d, J 5.5Hz);Retention time 2.83 min, (80:20).13395NMR δH(400MHz, DMSO) 3.30(2H, q, J 6.0Hz), 3.42(2H, q, J 6.0Hz),4.20(2H, d, J 5.6Hz), 6.10(1H, t, J 5.9Hz), 6.41(1H, t, J 6.0Hz),7.16-7.33(7H, m), 8.07(1H, d, J 3.5Hz), 8.21(1H, d, J 3.0Hz) and8.31(1H, d, J 5.5Hz); Retention time 2.87 min (80:20)134NMR δH(400MHz, DMSO) 3.38(2H, q, J 5.8Hz), 3.47(2H, q, J 5.8Hz),6.29(1H, t, J 6.0Hz), 6.88(1H, t, J 6.0Hz), 7.21(1H, t, J 6.0Hz),7.27(3H, m), 7.37(3H, m), 8.07(1H, d, J 3.1Hz), 8.22(1H, d, J 3.2Hz)and 8.32(1H, d, J 5.5Hz); Retention time 3.22 min (80:20).135NMR δH(400MHz, DMSO) 3.38(2H, q, J 5.8Hz), 3.48(2H, q, J 5.8Hz),6.33(1H, t, J 6.0Hz), 7.27(3H, m), 7.40(3H, m), 8.06(1H, d, J3.1Hz), 8.21(1H, d, J 3.1Hz), 8.32(1H, d, J 5.5Hz) and 8.67(1H, s);Retention time 4.32 min (80:20).136NMR δH(400MHz, DMSO) 1.08-1.32(6H, m), 1.51-1.85(4H, m),3.53(2H, m), 3.62(3H, m), 7.29(2H, m), 7.36(1H, m), 8.08(1H, d, J3.1Hz), 8.22(1H, d, J 3.1Hz) and 8.31(1H, d, J 5.5Hz); Retention time3.58 min. (80:20).137NMR δH(400MHz, DMSO) 3.60(2H, m), 3.79(2H, m), 7.07(1H, t, J6.0Hz), 7.26(3H, m), 7.36(2H, m), 7.42(1H, m), 7.83(1H, br s), 8.07(1H, d, J 3.2Hz), 8.22(1H, d, J 3.2Hz), 8.32(1H, d, J 5.5Hz) and 9.58(1H, br s); Retention time 2.98 min (80:20).13899NMR δH(400MHz, DMSO) 3.59(2H, q, J 6.0Hz), 3.78(2H, m), 7.25(1H, d, J 5.5Hz), 7.29(2H, d, J 9.1Hz), 7.41(1H, m), 7.42(2H, d, J 9.0Hz),7.95(1H, m), 8.07(1H, d, J 3.5Hz), 8.21(1H, d, J 3.0Hz), 8.32(1H, d, J 5.5Hz) and 9.63(1H, br s); Retention time 3.98 min (80:20)13993IR νmax(Nujol)/cm−1 3063, 2926, 2855, 1547, 1530, 1466; NMR δH(400MHz,CDCl3) 1.55(9H, s), 7.56(1H, d, J 7.5Hz), 7.58(1H, d, J 3.1Hz),8.60(1H, d, J 7.5Hz), 8.18(1H, d, J 3.1Hz).14013IR νmax(Nujol)/cm−1 3061, 2924, 1550, 1531, 1480; NMR δH(400MHz,CDCl3) 1.10(2H, m), 1.24(2H, m), 2.39(1H, m), 7.42(1H, d, J 7.5Hz),7.58(1H, d, J 3.1Hz), 8.00(1H, d, J 7.5Hz), 8.10(1H, d, J 3.1Hz).14165mp 74.7-74.9° C.; IR νmax(Nujol)/cm−1 2925, 1531, 1455, 1350, 1078,and 799; NMR δH(400MHz, CDCl3) 1.52(3H, t, J 7.5Hz), 2.74(3H, s),3.19(2H, q, J 7.5Hz), 7.29(1H, d, J 7.5Hz), 7.52(1H, d, J 6.0Hz), 7.80(1H, t, J 8.0Hz), 8.06(1H, d, J 5.5Hz) and 8.58(1H, d, J 8.0Hz)142NMR δH(400MHz, DMSO) 8.32(1H, m), 8.22(1H, m), 8.08(1H, m),7.79(1H, m), 7.34-7.26(2H, m), 3.45-3.29(4H, m), 2.19(1H, m) and1.81-1.15(10H, m); Retention time 3.26 min, (80:20).143NMR δH(400MHz, DMSO) 8.59(1H, br s), 8.33(1H, m), 8.22(1H, m),8.08(1H, m), 7.94(1H, m), 7.85(2H, m), 7.63(1H, m), 7.52-7.43(1H,m), 7.28(1H, m) and 3.60-3.37(4H, br m); Retention time 3.03 min,(80:20).144NMR δH(400MHz, DMSO) 8.66(1H, br s), 8.33(1H, m), 8.22(1H, m),8.08(1H, m), 7.88(2H, m), 7.52(2H, m), 7.45(1H, br s), 7.27(1H, m),3.59-3.54(2H, br m) and 3.30-3.20(2H, m); Retention time 3.95 min,(80:20).14570NMR δH(400MHz, DMSO) 3.36(2H, q, J 6.0Hz), 3.46(2H, q, J 6.0Hz),7.12(1H, dd, J 4.0, 5.0Hz), 7.26(1H, d, J 5.5Hz), 7.72(1H, m),7.88(1H, d, J 5.0Hz), 8.07(1H, d, J 3.0Hz), 8.21(1H, d, J 3.5Hz), 8.32(1H, d, J 5.5Hz) and 8.60(1H, m); Retention time 2.98 min (80:20)14645NMR δH(400MHz, DMSO) 3.34(2H, q, J 6.0Hz), 3.53(2H, q, J 6.0Hz),7.22-7.40(8H, m), 8.08(1H, d, J 3.0Hz), 8.22(1H, d, J 3.0Hz)and 8.33(1H, d, J 5.5Hz); Retention time 3.08 min (80:20)14762NMR δH(400MHz, DMSO) 3.28(2H, q, J 6.0Hz), 3.46(2H, q, J 6.0Hz),5.01(2H, s), 7.22-7.38(8H, m), 8.07(1H, d, J 3.0Hz), 8.21(1H,d, J 3.5Hz) and 8.32(1H, d, J 5.5Hz); Retention time 3.39 min (80:20)14829NMR δH(400MHz, DMSO) 2.92(3H, s), 3.22(2H, q, J 6.0Hz), 3.51(2H, q, J 6.0Hz), 7.14(1H, t, J 5.9Hz), 7.31(1H, d, J 5.5Hz), 7.35(1H,m), 8.08(1H, d, J 3.5Hz), 8.22(1H, d, J 3.5Hz) and 8.34(1H, d, J 5.5Hz);Retention time 2.36 min (80:20)14970NMR δH(400MHz, DMSO) 0.83(3H, t, J 7.5Hz), 1.32(2H, m), 1.60(2H, m), 2.99(2H, m), 3.20(2H, q, J 6.0Hz), 3.49(2H, q, J 6.0Hz),7.15(1H, t, J 5.9Hz), 7.26(1H, d, J 5.6Hz), 7.32(1H, m), 8.08(1H, d, J3.0Hz), 8.22(1H, d, J 3.0Hz) and 8.33(1H, d, J 5.5Hz); Retention time2.82 min (80:20)15022NMR δH(400MHz, CDCl3) 1.34(3H, d, J 6.5Hz), 3.71(1H, dd, J 6.7,10.7Hz), 3.85(1H, dd, J 3.0, 11.0Hz), 4.29(1H, m), 5.20(1H, d, J 6.5Hz),7.22(1H, d, J 5.5Hz), 7.56(1H, d, J 3.5Hz), 7.95(1H, d, J 5.5Hz)and 8.11(1H, d, J 3.0Hz); Retention time 2.67 min (80:20)15133NMR δH(400MHz, CDCl3) 2.21(2H, quintet, J 6.7Hz), 3.59(2H, q, J6.5Hz), 4.12(2H, t, J 7.0Hz), 5.20(1H, t, J 6.0Hz), 6.98(1H, m), 7.09(1H, m), 7.24(1H, d, J 5.5Hz), 7.55(1H, m), 7.56(1H, d, J 3.0Hz),7.97(1H, d, J 5.5Hz) and 8.12(1H, d, J 3.0Hz); Retention time 2.65 min(80:20)15264NMR δH(400MHz, CDCl3) 1.80(1H, m), 1.97(1H, m), 2.03(1H, m),2.20(1H, m), 3.71-3.80(2H, m), 3.85-3.97(2H, m), 4.41(1H, m),7.23(1H, d, J 5.5Hz), 7.57(1H, d, J 3.0Hz), 7.94(1H, d, J 5.5Hz) and8.12(1H, d, J 3.0Hz); Retention time 3.63 min (80:20)15323Mp 221.9° C.; IR νmax(Nujol)/cm−1 3069, 2923, 2854, 1539, 1523, 1465,1377, 1366 and 1319; NMR δH(400MHz, CDCl3) 8.16(2H, m), 8.10(1H, m), 7.64(1H, m), 7.58(1H, m), 7.50(1H, m) and 7.20(1H, m).15450IR νmax(Nujol)/cm−1 3074, 2924, 1546, 1529, 1473 and 1350; NMR δH(400MHz, CDCl3) 3.60(2H, m), 4.15(2H, m), 7.42(1H, d, J 7.5Hz),7.58(1H, d, J 3.1Hz), 8.1(1H, d, J 7.5Hz), 8.15(1H, d, J 3.1Hz).15567mp 300° C. dec; IR νmax(Nujol)/cm−1 3472, 3051, 2925, 2853, 1707,1598, 1525, 1466, 791, 742, 506; NMR δH(400MHz, DMSO) 6.91(1H,dd J 1.7, 3.6Hz), 7.75(1H, d, J 5.5Hz), 7.82(1H, br), 7.89(1H, dd, J0.8, 3.6Hz), 8.23(1H, dd, J 0.8, 1.7Hz), 8.40(1H, br), 8.64(1H, d, J 5.5Hz).156Mp 117.7-118.2° C.; IR νmax(Nujol)/cm−1 3062, 2924, 2854, 1545, 1528,1517, 1465, 1378, 1239 and 1134; NMR δH(400MHz, CDCl3) 8.39(1H,m), 8.08(1H, d, J 5.5Hz), 7.98(1H, dd, J 5.1, 1.1Hz), 7.55(1H, d, J 5.5Hz)and 7.52(1H, dd, J 5.1, 2.8Hz); Anal Calcd for C10H5ClN2S20.5H2O: C45.89; H, 2.31; N, 10.70. Found C, 45.48; H, 2.18; N, 10.53.15784Mp 119.0-119.4° C.; IR νmax(Nujol)/cm−1 2924, 2854, 1557, 1524,1468, 1388, 1334, 1279, 1234 and 1092; NMR δH(400MHz, CDCl3)8.23(1H, dd, J 2.9, 1.3Hz), 7.95(1H, dd, J 5.0, 1.0Hz), 7.45(1H, dd, J5.1, 3.0Hz), 7.27(1H, m) and 3.31(6H, s). Anal Calcd for C12H11N3S2: C,55.15; H, 4.24; N, 16.07. Found: C55.36; H, 4.22; N, 16.0515828Mp 146.5-147.2° C.; IR νmax(Nujol)/cm−1 3054, 2925, 2854, 1537,1516, 1495, 1467, 1365, 1244 and 1138; NMR δH(400MHz, CDCl3)8.20(2H, m), 8.11(1H, d, J 5.6Hz), and 7.62-7.57(4H, m); AnalCalcd for C12H7ClN2S 0.25 H2O; C, 57.37; H, 3.01; N, 11.15. Found: C,57.25; H, 2.84; N, 11.40.15997Mp 112.9-114.1° C.; IR νmax(Nujol)/cm−1 2924, 2854, 1585, 1556,1523, 1468, 1409, 1355 and 1241, NMR δH(400MHz, CDCl3) 8.18(2H,m), 7.80(1H, d, J 5.5Hz), 7.56-7.51(3H, m), 7.29(1H, d, J 5.5Hz) and3.33(6H, s). Anal. Calcd for C14H13N3S 0.1 H2O: C, 65.39; H, 5.13; N,16.45; Found: C, 65.18; H, 5.14; N, 16.16.16033Mp 129.3-129.9° C.; IR νmax(Nujol)/cm−1 3117, 2955, 2924, 2854,1576, 1542, 1527, 1512, 1472, 1382, 1264, 1243, 1226, 1184 and 1155,NMR δH(400MHz, CDCl3) 8.40(1H, s), 8.05(1H, d, J 5.5Hz), 7.62(1H, m), 7.54(1H, d, J 5.5Hz), and 7.22(1H, m); Anal. Calcd forC10H5ClN2OS: C, 50.75; H, 2.13; N, 11.83. Found: C, 50.71; H, 2.13; N,11.72.16150Mp 98.4-99.0° C.; IR νmax(Nujol)/cm−1 2924, 2854, 1562, 1540, 1527,1463, 1404, 1381, 1348 and 1229, NMR δH(400MHz, CDCl3) 8.27(1H,d, J 1.2Hz), 7.76(1H, d, J 5.4Hz), 7.55(1H, m), 7.26(1H, m), 7.17(1H, d, J 1.2Hz), and 3.28(6H, s); Anal Calcd. for C12H11N3OS 0.1 H2O:C, 58.33; H, 4.57; N, 17.01. Found: C, 58.59; H, 4.56; N, 16.69.16231Mp 204.0-204.9° C.; IR νmax(Nujol)/cm−1 2926, 2854, 1590, 1526,1494, 1465, 1377, 1335 and 1268, NMR δH(400MHz, DMSO) 8.71(1H, s), 8.33(1H, d, J 1.2Hz), 7.76(1H, d, J 4.1Hz), and 6.95(1H, dd, J3.8, 1.8Hz): Anal Calcd for C10H4ClN3O3S 0.1 H2O: C, 42.37; H, 1.49; N,14.82. Found: C, 42.01; H, 1.42; N, 14.75.16369IR νmax(Nujol)/cm−1 2924, 2854, 1585, 1547, 1529, 1463, 1377 and1154; NMR δH(400MHz, CDCl3) 8.39(1H, m), 7.95(1H, m), 7.62(1H,m), 7.53(1H, m), 7.24(1H, m), 3.10(2H, d, J 7.0Hz) and 1.42(3H, t, J7.0Hz); M/Z 231(M+H)+.16441IR νmax(Nujol)/cm−1 2925, 2854, 1615, 1546, 1526, 1482, 1463, 1420and 1376; NMR δH(400MHz, CDCl3) 8.00(1H, m), 7.58(1H, m), 3.18(2H, m), 2.50(3H, s), 2.39(3H, s) and 1.43(3H, m); M/Z 260(M+H)+.165IR νmax(Nujol)/cm−1 3093, 2955, 2924, 2854, 1589, 1572, 1538, 1522,1467 and 1253. NMR δH(400MHz, CDCl3) 9.45(1H, d, J 2.0Hz), 8.85(1H, m), 8.54-8.51(1H, m), 8.18(1H, d, J 5.5Hz), 7.62(1H, d, J 5.5Hz),7.56-7.53(1H, m).166IR νmax(Nujol)/cm−1 3056, 2925, 2854, 1580, 1557, 1524, 1467, 1361and 1249. NMR δH(400MHz, CDCl3) 9.43(1H, d, J 1.8Hz), 8.76(1H,dd, J 4.7, 1.5Hz), 8.48-8.45(1H, m), 7.83(1H, d, J 5.5Hz), 7.53-7.46(1H, m), 7.32(1H, d, J 5.5Hz), 3.32(6H, s).167NMR δH(400MHz, CDCl3) 8.12(1H, d, J 5.5Hz), 7.49(1H, d, J 5.5Hz),7.38(1H, s), 7.16(1H, s), 7.30(3H, s).168NMR δH(400MHz, CDCl3) 7.86(1H, d, J 5.5Hz), 7.31(1H, s), 7.24(1H, d, J 5.5Hz), 7.06(1H, s), 4.28(3H, s), 3.29(6H, s).169IR νmax(Nujol)/cm−1 3332, 3072, 2924, 2854, 1606, 1547, 1516, 1489,1464, 1409, 1387 and 1261; NMR δH(400MHz, CDCl3) 7.87 1H, d, J5.5Hz), 7.64 (1H, d, J 1.5Hz), 7.23(1H, d, J 5.5Hz), 6.57(1H, d, J 1.5Hz),5.79(1H, t, J 7.0Hz), 4.83(2H, d, J 7.0Hz), 3.28(6H, s).170IR νmax(Nujol)/cm−1 3443, 3218, 3122, 2954, 2925, 2854, 1560, 1532,1513, 1484, 1457, 1389 and 1318; NMR δH(400MHz, CDCl3) 7.90(1H,dd, J 5.5, 1.8Hz), 7.30(1H, s), 7.20(1H, dd, J 5.5, 1.8Hz), 7.06(1H, s),5.46(1H, br s), 4.22(3H, s), 3.91-3.90(2H, m), 3.72-3.68(3H, m).171IR νmax(Nujol)/cm−1 3267, 3124, 2924, 2854, 1609, 1547, 1514, 1487,1459, 1378; NMR δH(400MHz, CDCl3) 7.91(1H, d, J 5.5Hz), 7.65(1H, s), 7.21(1H, d, J 5.5Hz), 6.56(1H, s), 6.20(1H, br s), 5.50(1H, brs), 4.79(2H, s), 3.90-3.88(2H, m), 3.70-3.66(2H, m), 1.61(1H, br s).172IR νmax(Nujol)/cm−1 2925, 2854, 1546, 1528, 1517, 1465, 1377 and1222; NMR δH(400MHz, CDCl3) 8.12(1H, d, J 5.5Hz), 7.50(1H, d, J5.5Hz), 7.38(1H, s), 7.20(1H, s), 4.80(2H, q, J 7.0Hz), 1.55(3H, t, J7.0Hz).173IR νmax(Nujol)/cm−1 3041, 2926, 2855, 1563, 1528, 1511, 1478, 1460,1392 and 1377; NMR δH(400MHz, CDCl3) 7.86(1H, d, J 5.5Hz), 7.32(1H, s), 7.23(1H, d, J 5.5Hz), 7.11(1H, s), 4.83(1H, q, J 7.0Hz), 3.28(6H, s), 1.52(3H, t, J 7.0Hz),174IR νmax(Nujol)/cm−1 3458, 3334, 2925, 2855, 1560, 1516, 1480, 1466,1427 and 1334; NMR δH(400MHz, CDCl3) 7.90(1H, d, J 5.5Hz), 7.32(1H, s), 7.19(1H, d, J 5.5Hz), 7.11(1H, s), 5.45(1H, br t, J 5.5Hz),4.74(2H, q, J 7.0Hz), 3.91-3.89(2H, m), 3.71-3.67(2H, m), 1.52(3H, t, J 7.0Hz).175IR νmax(Nujol)/cm−1 3069, 2954, 2925, 2854, 1548, 1531, 1517, 1467,1408, 1249 and 1225; NMR δH(400MHz, CDCl3) 8.19(1H, d, J 5.5Hz),7.54(1H, d, J 5.5Hz), 7.47-7.41(2H, m), 6.22(2H, s), 3.76(2H, t,J 8.5Hz), 1.02(2H, t, J 8.5Hz).176Mp 131-132° C.; IR νmax(Nujol)/cm−1 2924, 2854, 1560, 1533, 1512,1480, 1465, 1419, 1389, 1250 and 1089; NMR δH(400MHz, CDCl3)7.95(1H, d, J 5.5Hz), 7.43(1H, d, J 1.5Hz), 7.38(1H, d, J 1.5Hz), 7.30(1H, d, J 5.5Hz), 6.28(2H, s), 3.66(2H, t, 8.0Hz), 3.36(6H, s), 0.97(3H, t, J 8.0Hz).177Mp 209-210° C.; IR νmax(Nujol)/cm−1 2925, 2854, 1749, 1559, 1530,1508, 1476, 1388, 1376, 1241 and 1214; NMR δH(400MHz, CDCl3)7.88(1H, d, J 5.5Hz), 7.37(1H, d, J 1.0Hz), 7.21(1H, d, J 5.5Hz), 7.08(1H, d, J 1.5Hz), 5.61(2H, s), 4.18(2H, q, J 7.5Hz), 3.24(6H, s), 1.18(3H, t, J 7.0Hz).178Mp 162.2-164.9° C.; IR νmax(Nujol)/cm−1 3365, 2924, 2854, 1559,1528, 1512, 1465, 1389, 1378, 1336, and 1236; NMR δH(400MHz,CDCl3) 7.89(1H, d, J 5.5Hz), 7.34(1H, d, J 1.0Hz), 7.22(1H, d, J 5.5Hz),7.19(1H, d, J 1.0Hz), 4.94(2H, t, J 5.0Hz), 4.09(2H, br q, J 5.0Hz),3.26(6H, s), 2.50(1H, br t, J 5.0Hz).179Mp 69-70° C.; IR νmax(Nujol)/cm−1 3090, 2925, 2854, 1542, 1514, 1477,1376, 1336, 1221 and 1109; NMR δH(400MHz, CDCl3) 8.04(1H, d, J5.5Hz), 7.50(1H, d, J 5.5Hz), 7.40(1H, d, J 1.0Hz), 7.34(1H, d, J 1.0Hz),6.29(2H, s), 3.40(3H, s), 3.15(2H, q, 7.5Hz), 1.49(3H, t, 7.5Hz).180Mp <100° C.; IR νmax(Nujol)/cm−1 2953, 2925, 2854, 1547, 1514, 1495,1458, 1378, 1316, 1248 and 1095; NMR δH(400MHz, CDCl3) 8.17(1H,s), 8.10(1H, d, J 5.5Hz), 7.56(1H, d, J 5.5Hz), 6.41(2H, s), 3.73(2H,t, J 8.0Hz), 3.20(2H, q, J 7.5Hz), 1.50(3H, t, J 8.0Hz), 0.90(2H, t, J8.0Hz), 0.09(9H, s).181Mp 108-109° C.; IR νmax(Nujol)/cm−1 3076, 2954, 2923, 2854, 1571,1537, 1519, 1443, 1400, 1249, 1129 and 1116; NMR δH(400MHz,CDCl3) 8.49(1H, s), 8.38(1H, s), 8.05(1H, d, J 5.5Hz), 7.54(1H, d, J5.5Hz), 5.55(2H, s), 3.66(2H, t, J 8.0Hz), 0.96(2H, t, J 8.5Hz), 0.00(9H, s).182Mp 141-142° C.; IR νmax(Nujol)/cm−1 2925, 2854, 1545, 1522, 1462,1378 and 1225; NMR δH(400MHz, CDCl3) 8.10(1H, d, J 5.5Hz), 7.65(1H, d, J 2.0Hz) 7.57(1H, d, J 5.5Hz), 7.11(1H, d, J 2.0Hz), 4.37(3H,s).183Mp 60-61° C.; IR νmax(Nujol)/cm−1 2924, 2854, 1579, 1556, 1458, 1404,1377, 1278, 1247 and 1100; NMR δH(400MHz, CDCl3) 8.36(1H, s),8.32(1H, s), 7.77(1H, d, J 5.5Hz), 7.27(1H, d, J 5.5Hz), 5.53(2H, s),3.66 2H, t, J 8.5Hz) 3.30(6H, s), 0.96(3H, t, J 8.0Hz), 0.00(9H, s).184Mp 126.5-127° C.; IR νmax(Nujol)/cm−1 3052, 2954, 2924, 2854, 1553,1515, 1465, 1412, 1386, 1353 and 1232; NMR δH(400MHz, CDCl3)7.80(1H, d, J 5.5Hz), 7.60(1H, d, J 2.0Hz), 7.27(1H, d, J 5.5Hz), 7.01(1H, d, J 2.0Hz), 4.34(3H, s), 3.29(6H, s).185Mp 210-211° C.; IR νmax(Nujol)/cm−1 3146, 3090, 3058, 2924, 2854,1582, 1556, 1465, 1404, 1377, 1277 and 1236; NMR δH(400MHz,CDCl3) 10.47(1H, br s), 8.39(2H, s), 7.77(1H, d, J 5.5Hz), 7.33-7.23(1H, d, J 5.5Hz), 3.30(6H, s).186Mp 175.4-175.9° C.; IR νmax(Nujol)/cm−1 2925, 2854, 1548, 1458,1407, 1383, 1279 and 1228; NMR δH(400MHz, CDCl3) 8.25(1H, s),8.15(1H, s), 7.75(1H, d, J 5.5Hz), 7.25(1H, d, J 5.5Hz), 4.02(3H, s),3.29(6H, s),187Mp 110.2-111.4° C.; NMR δH(400MHz, CDCl3) 8.10(1H, d, J 5.5Hz),7.56(1H, d, J 5.5Hz), 7.26(1H, s), 4.58(3H, s), 3.20(2H, q, J 7.5Hz),1.50(3H, t, J 7.5Hz).188Mp 104.7-104.8° C.; IR νmax(Nujol)/cm−1 3095; 2926, 2854, 1595,1552, 1532, 1505, 1483, 1458, 1434, 1377, 1349 and 1302; p NMR δH(400MHz, CDCl3) 7.45(1H, d, J 3.5Hz), 7.26(1H, s), 7.15(1H, d, J 1.5Hz),6.64(1H, dd, J 3.5Hz, 2.0Hz), 3.08(2H, q, J 7.5Hz), 2.69(3H, s),1.45(3H, t, J 7.5Hz).

[0229] Adenosine Receptor Binding

[0230] Binding Affinities at hA2A Receptors

[0231] 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

3TABLE 3ExampleKi (nM)Example 1511Example 4019Example 652Example 704Example 718Example 761Example 7914Example 801Example 822Example 8920Example 1045Example 1056Example 11035Example 1112Example 1131Example 1393Example 1402Example 1419Example 1523Example 1546

[0232] Evaluation of Potential Anti-Parkinsonian Activity In Vivo

[0233] Haloperidol-Induced Hypolocomotion Model

[0234] 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.

[0235] Method

[0236] 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.

[0237] Drugs

[0238] 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.

[0239] Procedure

[0240] 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.

[0241] 6-OHDA Model

[0242] 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.

[0243] 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.

[0244] Animals

[0245] 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.

[0246] Drugs

[0247] 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 warrn 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.

[0248] Surgery

[0249] 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.

[0250] Apparatus

[0251] 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.

[0252] Procedure

[0253] 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.

Thieno(3,2-d)pyrimidines and furano(3,2-d)pyimidines and their use as purinergic receptor antagonists

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