Abstract:
This invention relates to a novel thieno[2,3-d]pyrimidine, Z, and its therapeutic and prophylactic uses, wherein R 1  and R 2  are defined in the specification. Disorders treated and/or prevented include Parkinson&#39;s Disease.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    The present application claims the benefits of the filing of U.S. Provisional Application No. 61/104,789 filed Oct. 13, 2008. The complete disclosures of the aforementioned related patent applications are hereby incorporated herein by reference for all purposes. 
     
    
     FIELD OF THE INVENTION 
       [0002]    This invention relates to a novel arylindenopyrimidine and its therapeutic and prophylactic uses. Disorders treated and/or prevented include neurodegenerative and movement disorders ameliorated by antagonizing Adenosine A2a receptors. 
       BACKGROUND OF THE INVENTION 
       [0003]    Adenosine A2a Receptors Adenosine is a purine nucleotide produced by all metabolically active cells within the body. Adenosine exerts its effects via four subtypes of cell surface receptors (A1, A2a, A2b and A3), which belong to the G protein coupled receptor superfamily (Stiles, G. L. Journal of Biological Chemistry, 1992, 267, 6451). A1 and A3 couple to inhibitory G protein, while A2a and A2b couple to stimulatory G protein. A2a receptors are mainly found in the brain, both in neurons and glial cells (highest level in the striatum and nucleus accumbens, moderate to high level in olfactory tubercle, hypothalamus, and hippocampus etc. regions) (Rosin, D. L.; Robeva, A.; Woodard, R. L.; Guyenet, P. G.; Linden, J. Journal of Comparative Neurology, 1998, 401, 163). 
         [0004]    In peripheral tissues, A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S.; Varani, K.; Merighi, S.; Ongini, E.; Bores, P. A. British Journal of Pharmacology, 2000, 129, 2). The striatum is the main brain region for the regulation of motor activity, particularly through its innervation from dopaminergic neurons originating in the substantial nigra. The striatum is the major target of the dopaminergic neuron degeneration in patients with Parkinson&#39;s Disease (PD). Within the striatum, A2a receptors are co-localized with dopamine D2 receptors, suggesting an important site for the integration of adenosine and dopamine signaling in the brain (Fink, J. S.; Weaver, D. Ri; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Brain Research Molecular Brain Research, 1992, 14, 186). 
         [0005]    Neurochemical studies have shown that activation of A2a receptors reduces the binding affinity of D2 agonist to their receptors. This D2R and A2aR receptor-receptorinteraction has been demonstrated instriatal membrane preparations of rats (Ferre, S.; con Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proceedings of the National Academy of Sciences I of the United States of America, 1991, 88, 7238) as well as in fibroblast cell lines after transfected with A2aR and D2R cDNAs (Salim, H. ; Ferre, S.; Dalal, A.; Peterfreund, R. A.; Fuxe, K.; Vincent, J. D.; Lledo, P. M. Journal of Neurochemistry, 2000, 74, 432). In vivo, pharmacological blockade of A2a receptors using A2a antagonist leads to beneficial effects in dopaminergic neurotoxin MPTP(1-methyl-4-pheny-1,2,3,6-tetrahydropyridine)-induced PC) in various species, including mice, rats, and monkeys (Ikeda, K.; Kurokawa, M.; Aoyana, S.; Kuwana, Y. Journal of Neurochemistry, 2002, 80, 262). 
         [0006]    Furthermore, A2a knockout mice with genetic blockade of A2a function have been found to be less sensitive to motor impairment and neurochemical changes when they were exposed to neurotoxin MPTP (Chen, J. F.; Xu, K.; I Petzer, J. P.; Steal, R.; Xu, Y. H.; Beilstein, M.; Sonsalla, P. K.; Castagnoli, K.; Castagnoli, N., Jr.; Schwarsschild, M. A. Journal of Neuroscience, 2001, 1 21, RC1 43). 
         [0007]    In humans, the adenosine receptor antagonist theophylline has been found to produce beneficial effects in PD patients (Mally, J.; Stone, T. W. Journal of the Neurological Sciences, 1995, 132, 129). Consistently, recent epidemiological study has shown that high caffeine consumption makes people less likely to develop PD (Ascherio, A.; Zhang, S. M.; Heman, M. A.; Kawachi, I.; Colditz, G. A.; Speizer, F. E.; Willett, W. C. Annals of Neurology, 2001, 50, 56). In summary, adenosine A2a receptor blockers may provide a new class of antiparkinsonian agents (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635). 
         [0008]    Antagonists of the A 2A  receptor are potentially useful therapies for the treatment of addiction. Major drugs of abuse (opiates, cocaine, ethanol, and the like) either directly or indirectly modulate dopamine signaling in neurons particularly those found in the nucleus accumbens, which contain high levels of A 2A  adenosine receptors. Dependence has been shown to be augmented by the adenosine signaling pathway, and it has been shown that administration of an A 2A  receptor antagonist redues the craving for addictive substances (“The Critical Role of Adenosine A 2A  Receptors and Gi βγ Subunits in Alcoholism and Addiction: From Cell Biology to Behavior”, by Ivan Diamond and Lina Yao, (The Cell Biology of Addiction, 2006, pp 291-316) and “Adaptations in Adenosine Signaling in Drug Dependence: Therapeutic Implications”, by Stephen P. Hack and Macdonald J. Christie, Critical Review in Neurobiology, Vol. 15, 235-274 (2003)). See also Alcoholism: Clinical and Experimental Research (2007), 31(8), 1302-1307. 
         [0009]    An A 2A  receptor antagonist could be used to treat attention deficit hyperactivity disorder (ADHD) since caffeine (a non selective adenosine antagonist) can be useful for treating ADHD, and there are many interactions between dopamine and adenosine neurons. Clinical Genetics (2000), 58(1), 31-40 and references therein. 
         [0010]    Antagonists of the A 2A  receptor are potentially useful therapies for the treatment of depression. A 2A  antagonists are known to induce activity in various models of depression including the forced swim and tail suspension tests. The positive response is mediated by dopaminergic transmission and is caused by a prolongation of escape-directed behavior rather than by a motor stimulant effect. Neurology (2003), 61(suppl 6) S82-S87. 
         [0011]    Antagonists of the A 2A  receptor are potentially useful therapies for the treatment of anxiety. A2A antagonist have been shown to prevent emotional/anxious responses in vivo. Neurobiology of Disease (2007), 28(2) 197-205. 
       SUMMARY OF THE INVENTION 
       [0012]    The present invention includes compounds of Formula Z 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein: 
         [0013]    X is selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0014]    R 1  is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH 3 , or a single substituent selected from the group consisting of: OH, OCH 2 CF 3 , OC (1-4) alkyl, C (1-4) alkyl, CHF 2 , OCF 3 , CF 3 , CN, and cyclopropyl; 
         [0015]    R 2  is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH 3 , or a single substituent selected from the group consisting of: OH, OCH 2 CF 3 , OC (1-4) alkyl, C (1-4) alkyl, CHF 2 , OCF 3 , CF 3 , and CN; wherein said C (1-4) alkyl is optionally substituted with a ring selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             wherein R a , R b , and R c  are independently H or C (1-4) alkyl; 
             R d  is H, —C (1-4) alkyl, —CH 2 CH 2 OCH 2 CH 2 OCH 3 , —CH 2 CO 2 H, —C(O)C (1-4) alkyl, or —CH 2 C(O)C (1-4) alkyl;
 
and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 
           
         
       
     
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0018]    The present invention includes compounds of Formula Z 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein: 
         [0019]    X is selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0020]    R 1  is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH 3 , or a single substituent selected from the group consisting of: OH, OCH 2 CF 3 , OC (1-4) alkyl, C (1-4) alkyl, CHF 2 , OCF 3 , CF 3 , CN, and cyclopropyl; 
         [0021]    R 2  is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH 3 , or a single substituent selected from the group consisting of: OH, OCH 2 CF 3 , OC (1-4) alkyl, C (1-4) alkyl, CHF 2 , OCF 3 , CF 3 , and CN; wherein said C (1-4) alkyl is optionally substituted with a ring selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             wherein R a , R b , and R c  are independently H or C (1-4) alkyl; 
             R d  is H, —C (1-4) alkyl, —CH 2 CH 2 OCH 2 CH 2 OCH 3 , —CH 2 CO 2 H, —C(O)C (1-4) alkyl, or —CH 2 C(O)C (1-4) alkyl;
 
and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 
           
         
       
     
         [0024]    In another embodiment of the invention 
         [0025]    X is selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0026]    R 1  is phenyl optionally substituted with one substituent selected from the group consisting of: —OH, OC (1-4) alkyl, OCF 3 , Cl, Br, —CN, F, CHF 2 , C (1-4) alkyl, and cyclopropyl; 
         [0027]    R 2  is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH 3 , or a single substituent selected from the group consisting of: OH, OCH 2 CF 3 , OC (1-4) alkyl, C (1-4) alkyl, CHF 2 , OCF 3 , CF 3 , and CN; 
         [0000]    and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. 
         [0028]    In another embodiment of the invention 
         [0029]    X is selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0030]    R 1  is phenyl optionally substituted with one substituent selected from the group consisting of: —OH, OCH 3 , OCH 2 CH 3 , OCF 3 , Cl, Br, —CN, F, CHF 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , and C(CH 3 ) 3 ; 
         [0031]    R 2  is phenyl, wherein said phenyl is optionally substituted with one or two fluorine atoms, or a single substituent selected from the group consisting of: —OH, OCH 3 , OCH 2 CH 3 , OCF 3 , Cl, Br, —CN, CHF 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , and C(CH 3 ) 3 ; 
         [0000]    and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. 
         [0032]    In another embodiment of the invention 
         [0033]    X is selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0034]    R 1  is phenyl optionally substituted with one substituent selected from the group consisting of F, Cl, CN, OCF 3 , CF 3 , or OCH 3 ; 
         [0035]    R 2  is phenyl, wherein said phenyl is optionally substituted with one or two fluorine atoms, or a single substituent selected from the group consisting of: CN, Cl, OCF 3 , CF 3 , and OCH 3 ; and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. 
         [0000]    and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. 
         [0036]    In another embodiment of the invention 
         [0037]    X is selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0038]    R 1  is phenyl optionally substituted with one substituent selected from the group consisting of F, CN, OCF 3 , CF 3 , or OCH 3 ; 
         [0039]    R 2  is phenyl, wherein said phenyl is optionally substituted with one or two fluorine atoms, or a single substituent selected from the group consisting of: Cl, OCF 3 , and OCH 3 ; 
         [0000]    and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. 
         [0040]    Another embodiment of the invention comprises a compound selected from the group consisting of: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0000]    and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. 
         [0041]    This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of a compound of Formula Z. 
         [0042]    This invention further provides a method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in a subject, comprising of administering to the subject a prophylactically effective dose of the compound of claim  1  either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in the subject. 
         [0043]    Compounds of Formula Z can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts. 
         [0044]    Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, adipic, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2 naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharinc. 
         [0045]    This invention also provides a pharmaceutical composition comprising a compound of Formula Z and a pharmaceutically acceptable carrier. 
         [0046]    Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buyer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer&#39;s dextrose, dextrose and sodium chloride, lactated Ringer&#39;s and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer&#39;s dextrose and the like. 
         [0047]    Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. 
         [0048]    This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of a compound of Formula Z. 
         [0049]    In one embodiment, the disorder is a neurodegenerative or movement disorder. Examples of disorders treatable by the instant pharmaceutical composition include, without limitation, Parkinson&#39;s Disease, Huntington&#39;s Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer&#39;s Disease, and Senile Dementia. 
         [0050]    In one preferred embodiment, the disorder is Parkinson&#39;s disease. 
         [0051]    As used herein, the term “subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by antagonizing adenosine A2a receptors. In a preferred embodiment, the subject is a human. 
         [0052]    Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. Compounds of Formula Z can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods. 
         [0053]    As used herein, a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder&#39;s onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies. 
         [0054]    In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of a compound of Formula Z. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0, ug/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1. 
         [0055]    The invention also provides a method of treating addiction in a mammal, comprising administering a therapeutically effective dose of a compound of Formula Z. 
         [0056]    The invention also provides a method of treating ADHD in a mammal, comprising administering a therapeutically effective dose of a compound of Formula Z. 
         [0057]    The invention also provides a method of treating depression in a mammal, comprising administering a therapeutically effective dose of a compound of Formula Z. 
         [0058]    The invention also provides a method of treating anxiety in a mammal, comprising administering a therapeutically effective dose of a compound of Formula Z. 
         [0059]    Definitions: 
         [0060]    The term “C a-b ” (where a and b are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive. For example, C 1-4  denotes a radical containing 1, 2, 3 or 4 carbon atoms. 
         [0061]    The term “alkyl,” whether used alone or as part of a substituent group, refers to a saturated branched or straight chain monovalent hydrocarbon radical, wherein the radical is derived by the removal of one hydrogen atom from a single carbon atom. Unless specifically indicated (e.g. by the use of a limiting term such as “terminal carbon atom”), substituent variables may be placed on any carbon chain atom. Typical alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl and the like. Examples include C 1-8 alkyl, C 1-6 alkyl and C 1-4 alkyl groups. 
         [0062]    Abbreviations: 
         [0063]    Herein and throughout this application, the following abbreviations may be used. 
         [0064]    DMF dimethylformamide 
         [0065]    DMSO dimethylsulfoxide 
         [0066]    Et ethyl 
         [0067]    EtOAc ethyl acetate 
         [0068]    EtOH ethyl alcohol 
         [0069]    t-BuOK potassium tert-butoxide 
         [0070]    Me methyl 
         [0071]    Me 3 SOI trimethylsufoxonium iodide 
         [0072]    MeOD CD 3 OD 
         [0073]    n-BuLi n-butyllithium 
         [0074]    NBS N-bromo succinimide 
         [0075]    OAc acetate 
         [0076]    Pd(dppf)Cl 2  [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) 
         [0077]    TEMPO 2,2,6,6-Tetramethyl-piperidin-1-oxyl 
         [0078]    TFA trifluoroacetic acid 
         [0079]    THF tetrahydrofuran 
         [0080]    The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, Ed. H. Bundgaard, Elsevier, 1985. 
         [0081]    Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. 
         [0082]    Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. 
         [0083]    During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in  Protective Groups in Organic Chemistry,  ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene &amp; P. G. M. Wuts,  Protective Groups in Organic Synthesis,  John Wiley &amp; Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. 
         [0084]    General Schemes: 
         [0085]    Compounds of Formula Z can be prepared by methods known to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention. 
         [0086]    Procedure 
         [0000]    
       
                 
         
             
             
         
       
     
         [0087]    Scheme 1 illustrates the synthetic routes (Paths 1, 2 and 3) leading to compounds of Formula Z (A, B, C, D, E, and F). Starting with 2-amino-3cyanothiophene I and following the path indicated by the arrows, condensation under basic conditions with R 1 —CN, where R 1  is as defined in Formula Z, affords the aminopyrimidine II. The aminopyrimidine II is reacted with N-bromosuccinimide (NBS), to give the bromothiophene III. Following path 1 bromothiophene III is reacted with R 2 CH 2 ZnHal, where R 2  is as defined in Formula Z and Hal is Cl or Br, in the presence of a palladium catalyst to afford compounds of Formula Z, where X is CH 2  (A). Alternatively bromothiophene III is reacted with excess n-BuLi to generate an intermediate dianion that is then reacted with R 2 CH 2 Hal, where R 2  is as defined in Formula Z and Hal is Cl or Br, to give compounds of Formula A. Compounds of Formula A can be oxidized under basic conditions with air to afford compounds of the Formula Z, where X is C(O) (B). Following path 2 bromothiophene III is reacted with R 2 CHCHB(OH) 2 , where R 2  is as defined in Formula Z, in the presence of palladium to give compounds of Formula Z, where X is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    Compounds of Formula C are reduced by hydrogenation to give compounds of Formula Z, where X is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    Following path 3 bromothiophene III is reacted with R 2 C(CH 2 )B(OH) 2 , where R 2  is as defined in Formula Z, in the presence of palladium to give compounds of Formula Z, where X is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    Compounds of Formula E are reacted with trimethylsufoxonium iodide under basic conditions to afford compounds of Formula Z, where X is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0088]    Scheme 2 illustrates the synthetic routes (Paths 1 and 2) leading to compounds of Formulae A and B. Starting with 2-amino-3cyanothiophene I and following the path indicated by the arrows, condensation under basic conditions with R 1 —CN, where R 1  is as defined in Formula Z, affords the aminopyrimidine II. The aminopyrimidine II is reacted with di-tert-butyldicarbonate [(Boc) 2 O] in the presence of 4-dimethylamino pyridine (DMAP) to give the corresponding protected amine IV. The thiophene IV is deprotonated with lithium diisopropylamide (LDA) and reacted with R 2 CHO, where R 2  is as defined in Formula Z, to give an intermediate alcohol V that is then oxidized to the corresponding ketone with Dess-Martin periodinane and finally deprotected with TFA to give compounds of Formula B. Following path 2 thiophene IV is deprotonated with lithium diisopropylamide (LDA) and reacted with trimethoxy borane to give the corresponding boronic acid ester VI that is then reacted with R 2 CH 2 X, where R 2  is as defined in Formula Z, in the presence of palladium to give compounds of Formula A. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0089]    Scheme 3 illustrates the synthetic routes (Paths 1 and 2) leading to compounds of Formula A. Starting with R 2 CH 2 CH 2 CHO (VII), where R 2  is as defined in Formula Z and Ra is H or CH 3 , reaction with malononitrile and elemental sulfur under basic conditions gives the thiophene VIII. The thiophene VIII is then condensed under basic conditions with R 1 —CN, where R 1  is as defined in Formula Z, to afford compounds of Formula A. Alternatively aldehydes that are not commercially available can be synthesized following path 2 using R 2 —I, where R 2  is as defined in Formula Z and R a  is H; reaction with allyl alcohol in the presence of palladium (II) acetate gives aldehydes VII, which then follow the arrows as described above in path 1. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0090]    Scheme 4 illustrates the synthetic route leading to compounds of Formula B. Starting with 2-amino-5-methyl-thiophene-3-carbonitrile X and following the path indicated by the arrows, condensation under basic conditions with R 1 —CN, where R 1  is as defined in Formula Z, affords the aminopyrimidine XI. Oxidation of XI with SeO 2  affords the corresponding aldheyde XII. The aldehyde XII is reacted with R 2 MgX, where R 2  is as defined in Formula Z, to give the intermediate alcohol XIII that oxidized to the corresponding ketone to give compounds of Formula B. 
       EXAMPLES  
       [0091]    The following examples are for illustrative purposes only, and are in no way meant ot be a limit of the invention. 
       Example 1  
     3-(4-Amino-6-benzyl-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile 
     Example 1: Step a 
     3-(4-Amino-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile 
       [0092]    
       
                 
         
             
             
         
       
     
         [0093]    Solid potassium-tert-butoxide (1.1 g, 10.1 mmol) was added to a dioxane solution (20 mL) of 2-amino-thiophene-3-carbonitrile (5.0 g, 40.3 mmol) and 1,3-dicyanobenzene (7.2 g, 56.5 mmol). The resulting slurry was stirred vigorously at 130° C. for 15 minutes. The dark slurry was cooled to room temperature, diluted with THF, and dry packed onto silica gel. The material was the purified via column chromatography to give 10.2 g of the title compound. 
       Example 1: Step b 
     3-(4-Amino-6-bromo-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile 
       [0094]    
       
                 
         
             
             
         
       
     
         [0095]    Solid NBS (1.6 g, 8.7 mmol) was added to a DMF solution (20 mL) of 3-(4-Amino-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile (2.0 g, 7.9 mmol, as prepared in the previous step). After 45 minutes water was added and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 2.4 g of the title compound. 
       Example 1: Step c 
     3-(4-Amino-6-benzyl-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile 
       [0096]    
       
                 
         
             
             
         
       
     
         [0097]    A 0.5 M THF solution of benzylzinc bromide (1.4 mL, 0.68 mmol) was added to a THF solution of 3-(4-amino-6-bromo-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile (75 mg, 0.23 mmol) and Pd(dppf)Cl 2  (19 mg, 0.02 mmol) and the mixture was heated to reflux. After 3 h the mixture was cooled, diluted with EtOAc, washed with water, brine, dried (Na 2 SO 4 ), and dry packed onto silica gel. Chromatography gave 47 mg of the title compound.  1 H NMR (DMSO-d 6 , 300 MHz): δ=8.57-8.66 (m, 2H), 7.93 (d, J=7.9 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.60 (br. s., 2H), 7.22-7.41 (m, 6H), 4.23 ppm (s, 2H) 
       Example 2  
     3-(4-Amino-6-phenethyl-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile 
       [0098]    
       
                 
         
             
             
         
       
     
         [0099]    The title compound was prepared using phenethylzinc bromide in place of benzylzinc bromide as described in Example 1.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=8.76 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.27-7.34 (m, 2H), 7.17-7.25 (m, 3H), 6.78 (s, 1H), 5.19 (br. s., 2H), 3.18-3.27 (m, 2H), 3.02-3.11 ppm (m, 2H) 
       Example 3  
     6-Benzyl-2-phenyl-thieno[2,3-d]pyrimidin-4-ylamine 
       [0100]    
       
                 
         
             
             
         
       
     
         [0101]    The title compound was prepared using benzonitrile in place of 1,3-dicyanobenzene as described in Example 1.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=8.01-8.10 (m, 3H), 7.85-7.91 (m, 1H), 7.71 (dd, J=4.1, 2.6 Hz, 2H), 7.45-7.60 (m, 5H), 5.79 (br. s., 2H), 4.56 ppm (s, 2H) 
       Example 4  
     2-Phenyl-6-styryl-thieno[2,3-d]pyrimidin-4-ylamine 
       [0102]    
       
                 
         
             
             
         
       
     
         [0103]    A dioxane (1.6 mL)/water (0.4 mL) solution of 6-bromo-2-phenyl-thieno[2,3-d]pyrimidin-4-ylamine (50 mg, 0.16 mmol, an intermediate prepared in Example 3), trans-2-phenylvinylboronic acid (48 mg, 0.33 mmol), Pd(dppf)Cl 2  (13 mg, 0.02 mmol), and K 2 CO 3  (46 mg, 0.33 mmol) was heated to 80° C. After 18 h the mixture was diluted with EtOAc and the solution was washed with water, brine, dried (Na 2 SO 4 ), concentrated and purified via column chromatography to give 43 mg of the title compound.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=8.38-8.47 (m, 2H), 7.43-7.55 (m, 5H), 7.34-7.42 (m, 2H), 7.27-7.34 (m, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 6.95-7.03 (m, 1H), 5.27 ppm (br. s., 2H) 
       Example 5  
     3-[4-Amino-6-(1-phenyl-vinyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
       [0104]    
       
                 
         
             
             
         
       
     
         [0105]    The title compound was prepared using 1-phenylvinylboronic acid and 3-(4-amino-6-bromo-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile in place of trans-2-phenylvinylboronic acid and 6-bromo-2-phenyl-thieno[2,3-d]pyrimidin-4-ylamine, respectively, as described in Example 4.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=8.77 (s, 1H), 8.68 (d, J=7.9 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.36-7.51 (m, 5H), 6.86 (s, 1H), 5.73 (s, 1H), 5.42 (s, 1H), 5.24 ppm (br. s., 2H) 
       Example 6  
     3-[4-Amino-6-(1-phenyl-cyclopropyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
       [0106]    
       
                 
         
             
             
         
       
     
         [0107]    Solid t-BuOK (121 mg, 1.1 mmol) was added to a DMSO solution (1.4 mL) of Me 3 SOI (206 mg, 0.9 mmol). After 30 min a THF solution (4 mL) of 3-[4-Amino-6-(1-phenyl-vinyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile (166 mg, 0.5 mmol, prepared as described in Example 5) was added. After 16 h the mixture was diluted with EtOAc and the organic layer was washed with water, brine, dried (Na 2 SO 4 ), and dry packed onto silica gel. Column chromatography gave 48 mg of the title compound.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=8.73 (s, 1H), 8.63 (d, J=7.9 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.28-7.45 (m, 5H), 6.64 (s, 1H), 5.19 (br. s., 2H), 1.49 ppm (d, J=5.3 Hz, 4H) 
       Example 7  
     6-(4-Fluoro-benzyl)-2-phenyl-thieno[2,3-d]pyrimidin-4-ylamine 
       [0108]    
       
                 
         
             
             
         
       
     
         [0109]    A 1.5 M hexanes solution of n-BuLi was added to a −78° C. THF solution (1.6 mL) of 3-(4-amino-6-bromo-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile (50 mg, 0.16 mmol, prepared as described in Example 1: step b). After 25 minutes at −78° C., neat 4-fluorobenzyl bromide (22 μL, 0.18 mmol) was added. After 2 h at −78° C., water was added and the aqueous phase was extracted with EtOAc. The combined organics were washed with water, brine, dried (Na 2 SO 4 ), and dry packed onto silica gel. Chromatography gave 11 mg of the title compound.  1 H NMR (CHLOROFORM-d, 400 MHz): δ=8.39 (dd, J=7.6, 2.0 Hz, 2H), 7.37-7.51 (m, 3H), 7.22-7.29 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.74 (s, 1H), 5.17 (br. s., 2H), 4.18 ppm (s, 2H) 
       Example 8  
     6-Phenethyl-2-phenyl-thieno[2,3-d]pyrimidin-4-ylamine 
       [0110]    
       
                 
         
             
             
         
       
     
         [0111]    An EtOH solution (2 mL) of 2-phenyl-6-styryl-thieno[2,3-d]pyrimidin-4-ylamine (30 mg, 0.09 mmol, prepared as described in Example 4) and 5% Pd/C (20 mg) was hydrogenated at 55 psi. After 20 h the solution was filtered through Celite and purified via column chromatography to give 12 mg of the title compound.  1 H NMR (Acetone, 300 MHz): δ=8.33-8.53 (m, 2H), 7.36-7.50 (m, 3H), 7.29 (d, J=4.3 Hz, 4H), 7.16-7.25 (m, 2H), 6.74 (br. s., 2H), 3.14-3.29 (m, 2H), 2.99-3.12 ppm (m, 2H) 
       Example 9  
     3-[4-Amino-6-(2-methoxy-benzyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
       [0112]    
       
                 
         
             
             
         
       
     
         [0113]    The title compound was prepared using 2-methoxybenzylzinc chloride in place of benzylzinc bromide as described in Example 1.  1 H NMR (CHLOROFORM-d, 400 MHz): δ=8.74 (s, 1H), 8.64 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48-7.58 (m, 1H), 7.27-7.32 (m, 1H), 7.17-7.25 (m, 1H), 6.88-6.99 (m, 2H), 6.73-6.81 (m, 1H), 5.17 (br. s., 1H) 4.21 (s, 2H), 3.87 ppm (s, 3H) 
       Example 10  
     (±)-3-[4-Amino-6-(1-phenyl-ethyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
     Example 10: Step a 
     (±)-2-Amino-5-(1-phenyl-ethyl)-thiophene-3-carbonitrile 
       [0114]    
       
                 
         
             
             
         
       
     
         [0115]    Triethylamine (7.07 mL, 50.8 mmol, 0.6 equiv) was added dropwise by addition funnel to an ice-cold mixture of sulfur (2.71 g, 84.5 mmol, 1 equiv) and racemic 3-phenylbutyraldehyde (15.1 mL, 101.5 mmol, 1.2 equiv) in DMF (17 mL). The resulting suspension was stirred at room temperature for 50 min. After cooling to 0° C., a solution of malononitrile (5.59 g, 84.5 mmol, 1 equiv) in DMF (11 mL) was added. The resulting suspension was stirred at room temperature for 40 min, then was poured into 200 mL stirred ice water, resulting in a tarry suspension. Methanol (100 mL) was added and the suspension was heated to boiling, hot-filtered, and allowed to cool. The resulting brown precipitate was collected by vacuum filtration and was washed with water. Column chromatography gave 579 mg of the title compound. 
       Example 10: Step b 
     (±)-3-[4-Amino-6-(1-phenyl-ethyl)-thieno [2,3-d]pyrimidin-2-yl]-benzonitrile 
       [0116]    
       
                 
         
             
             
         
       
     
         [0117]    A mixture of (±)-2-amino-5-(1-phenyl-ethyl)-thiophene-3-carbonitrile (103 mg, 0.451 mmol, 1 equiv), 1,3-dicyanobenzene (63.5 mg, 0.496 mmol, 1.1 equiv), and potassium tert-butoxide (10.1 mg, 0.090 mmol, 0.2 equiv) in 1,4-dioxane (0.20 mL) was heated by microwave irradiation (150° C., 10 min, 300 W). The reaction mixture was diluted with dichloromethane and methanol and the resulting solution was dried onto silica gel. Column chromatography gave 131 mg of the title compound.  1 H NMR (300 MHz, CHLOROFORM-D) δ ppm 8.74 (t, J=1.5 Hz, 1H), 8.65 (dt, J=7.9, 1.5 Hz, 1H), 7.69 (dt, J=7.8, 1.4 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.25-7.39 (m, 5H), 6.79 (d, J=1.1 Hz, 1H), 5.20 (s, 2H), 4.39 (q, J=7.0 Hz, 1H), 1.78 (d, J=7.2 Hz, 3H). MS m/z (MH + ) 357.1 
       Example 11  
     6-Benzyl-2-(2-methoxy-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine 
     Example 11: Step a 
     2-Amino-5-benzyl-thiophene-3-carbonitrile 
       [0118]    
       
                 
         
             
             
         
       
     
         [0119]    The title compound was prepared using 3-phenyl-propionaldehyde in place of 3-phenylbutyraldehyde as described in Example 10. 
       Example 11: Step b 
     6-Benzyl-2-(2-methoxy-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine 
       [0120]    
       
                 
         
             
             
         
       
     
         [0121]    The title compound was prepared using 2-methoxy-benzonitrile and 2-amino-5-benzyl-thiophene-3-carbonitrile in place of 1,3-dicyanobenzene and (±)-2-amino-5-(1-phenyl-ethyl)-thiophene-3-carbonitrile, respectively, as described in Example 10.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=7.59 (dd, J=7.5, 1.9 Hz, 1H), 7.27-7.41 (m, 6H), 6.96-7.07 (m, 2H), 6.77 (s, 1H), 5.28 (d, J=10.9 Hz, 2H), 4.20 (s, 2H), 3.83 ppm (s, 3H); MS m/e 348 (M+H) 
       Example 12  
     6-Benzyl-2-(3-trifluoromethyl-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine 
       [0122]    
       
                 
         
             
             
         
       
     
         [0123]    The title compound was prepared using 3-trifluoromethyl-benzonitrile and 2-amino-5-benzyl-thiophene-3-carbonitrile in place of 1,3-dicyanobenzene and (±)-2-amino-5-(1-phenyl-ethyl)-thiophene-3-carbonitrile, respectively, as described in Example 10.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=8.71 (s, 1H), 8.60 (d, J=7.9 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.28-7.41 (m, 5H), 6.76 (s, 1H), 5.20 (br. s., 2H), 4.22 ppm (s, 2H); MS m/e 386 (M+H). 
       Example 13  
     6-Benzyl-2-(3-methoxy-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine hydrochloride 
       [0124]    
       
                 
         
             
             
         
       
     
         [0125]    The title compound was prepared using 3-methoxy-benzonitrile and 2-amino-5-benzyl-thiophene-3-carbonitrile in place of 1,3-dicyanobenzene and (±)-2-amino-5-(1-phenyl-ethyl)-thiophene-3-carbonitrile, respectively, as described in Example 10.  1 H NMR (CHLOROFORM-d, 300 MHz): δ=7.91-8.02 (m, 2H), 7.27-7.43 (m, 8H), 7.01 (dd, J=7.9, 2.6 Hz, 1H), 6.88 (s, 1H), 4.21 (s, 2H), 3.91 ppm (s, 3H); MS m/e 348 (M+H) 
       Example 14  
     6-Benzyl-2-(3-fluoro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine 
       [0126]    
       
                 
         
             
             
         
       
     
         [0127]    The title compound was prepared using 3-fluoro-benzonitrile and 2-amino-5-benzyl-thiophene-3-carbonitrile in place of 1,3-dicyanobenzene and (±)-2-amino-5-(1-phenyl-ethyl)-thiophene-3-carbonitrile, respectively, as described in Example 10.  1 H NMR (DMSO-d 6 , 300 MHz): δ=7.64-7.77 (m, 3H), 7.47-7.59 (m, 1H), 7.16-7.26 (m, 5H), 6.49 (s, 1H), 4.24 (s, 2H), 3.86 ppm (s, 2H); MS m/e 336 (M+H) 
       Example 15  
     3-[4-Amino-6-(2-trifluoromethoxy-benzyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
     Example 15: Step a 
     [2-(3-Cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester 
       [0128]    
       
                 
         
             
             
         
       
     
         [0129]    Solid DMAP (42 mg, 0.3 mmol) was added to a THF solution (17 mL) of 3-(4-Amino-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile (850 mg, 3.4 mmol, as prepared in Example 1, step a) and (Boc) 2 O (1.8 g, 8.4 mmol). After 4 h the mixture was diluted with EtOAc and then washed consecutively with water, brine, dried (Na 2 SO 4 ), concentrated and purified via column chromatography to give 1.2 g of the title compound. 
       Example 15: Step b 
     [2-(3-Cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester-6-boronicacid  dimethylester 
       [0130]    
       
                 
         
             
             
         
       
     
         [0131]    A 1.8 M LDA solution in THF (0.15 mL, 0.27 mmol) was added to a −78° C. THF solution (5 mL) of [2-(3-cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester (100 mg, 0.22 mmol, as prepared in the previous step). After 3 minutes, excess trimethylborate (0.05 mL) was added and the reaction was warmed to room temperature. Water was added and the product was extracted with ethyl acetate to give 90 mg of the title compound that was used without further purification. 
       Example 15: Step c 
     3-[4-Amino-6-(2-trifluoromethoxy-benzyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
       [0132]    
       
                 
         
             
             
         
       
     
         [0133]    Solid Pd(dppf)Cl 2  (22 mg, 0.03 mmol) was added to an 1:2 EtOH/toluene solution (3 mL) of, [2-(3-Cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester-6-boronicacid dimethylester (90 mg, 0.18 mmol, as prepared in the previous step), and Na 2 CO 3  [2 M] (0.73 mL) and the reaction was heated to 80° C. After 24 hours the mixture was cooled to rt, Water was added and the aqueous layer was extracted with EtOAc, dried (Na 2 SO 4 ), concentrated and purified via column chromatography to give 3.0 mg of the title compound. MS m/e 427 (M+H). 
       Example 16  
     3-[4-Amino-6-(2-chloro-benzyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
     Example 16: Step a 
     3-(2-Chloro-phenyl)-propionaldehyde 
       [0134]    
       
                 
         
             
             
         
       
     
         [0135]    Solid tetrabutylammonium chloride (1.2 g, 4.2 mmol) was added to a DMF solution (5.5 mL) of Pd(OAc) 2  (57 mg, 0.1 mmol), NaHCO 3  (880 mg, 10.5 mmol), 1-chloro-2-iodo-benzene (1.0 g, 4.2 mmol), and allyl alcohol (370 mg, 6.29 mmol) in a sealed tube and the mixture was heated to 45° C. After 22 h at 45° C., the solution was cooled to room temperature; water was added, and the aqueous phase was extracted with ether, dried (Na 2 SO 4 ) and concentrated to give 0.66 g of the title compound that was used in the next step without further purification. 
       Example 16: Step b 
     2-Amino-5-(2-chloro-benzyl)-thiophene-3-carbonitrile 
       [0136]    
       
                 
         
             
             
         
       
     
         [0137]    The title compound was prepared using 3-(2-Chloro-phenyl)-propionaldehyde in place of 3-phenylbutyraldehyde as described in Example 10. 
       Example 16: Step c 
     3-[4-Amino-6-(2-chloro-benzyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
       [0138]    
       
                 
         
             
             
         
       
     
         [0139]    The title compound was prepared using 2-Amino-5-(2-chloro-benzyl)-thiophene-3-carbonitrile (as prepared in the previous step) in place of (±)-2-amino-5-(1-phenyl-ethyl)-thiophene-3-carbonitrile as described in Example 10.  1 H NMR (300 MHz, CHLOROFORM-d, MeOD) δ 8.65 (s, 1H), 8.58 (d, J=7.91 Hz, 1H), 7.74 (d, J=7.91 Hz, 1H), 7.57-7.67 (m, 1H), 7.34-7.48 (m, 2H), 7.21-7.34 (m, 2H), 7.11 (s, 1H), 4.37 (s, 2H); MS m/e 377 (M+H). 
       Example 17  
     3-[4-Amino-6-(2-methoxy-benzoyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
     Example 17: Step a 
     {2-(3-Cyano-phenyl)-6-[hydroxy-(2-methoxy-phenyl)-methyl]-thieno[2,3-d]pyrimidin-4-yl}-bis-carbamic  acid tert-butyl ester 
       [0140]    
       
                 
         
             
             
         
       
     
         [0141]    A 1.8 M LDA solution in THF (0.44 mL, 0.79 mmol) was added to a −78° C. THF solution (3 mL) of [2-(3-cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester (300 mg, 0.66 mmol, as prepared in Example 15: step a). After 3 minutes a THF solution (1 mL) of 2-methoxy-benzaldehyde (110 mg, 0.80 mmol) was added and the reaction was warmed to room temperature. Saturated aqueous NH 4 Cl was added and the crude reaction mixture was extracted with ethyl acetate. The organic extracts were washed with water, brine, dried (Na 2 SO 4 ), concentrated and purified via column chromatography to give 170 mg of the title compound. 
       Example 17: Step b 
     [2-(3-Cyano-phenyl)-6-(2-methoxy-benzoyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester 
       [0142]    
       
                 
         
             
             
         
       
     
         [0143]    Solid Dess-Martin reagent (130 mg, 0.31 mmol) was added to a CH 2 Cl 2  solution (2 mL) of {2-(3-cyano-phenyl)-6-[hydroxy-(2-methoxy-phenyl)-methyl]-thieno[2,3-d]pyrimidin-4-yl}-bis-carbamic acid tert-butyl ester (150 mg, 0.26 mmol, as prepared in the previous step). After 2 h the reaction mixture was concentrated in vacuo and purified via column chromatography to give 15 mg of the title compound. 
       Example 17: Step c 
     3-[4-Amino-6-(2-methoxy-benzoyl)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile 
       [0144]    
       
                 
         
             
             
         
       
     
         [0145]    [2-(3-Cyano-phenyl)-6-(2-methoxy-benzoyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester (0.0 12g, 0.020mmol, as prepared in the previous step) was dissolved in 1:1 CH 2 Cl 2 /TFA (0.4 mL). After 1 h the reaction mixture was concentrated in vacuo and purified via HPLC to give 2.2 mg of the title compound.  1 H NMR (300 MHz, MeOD): δ 8.67-8.79 (m, 2H), 7.96 (s, 1H), 7.81-7.91 (m, 1H), 7.64-7.75 (m, 1H), 7.52-7.64 (m, 1H), 7.41-7.50 (m, 1H), 7.18-7.27 (m, 1H), 7.06-7.18 (m, 1H), 3.83 (s, 3H); 387 (M′H). 
       Example 18  
     [4-Amino-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidin-6-yl]-(2-methoxy-phenyl)-methanone 
     Example 18: Step a 
     6-Methyl-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine 
       [0146]    
       
                 
         
             
             
         
       
     
         [0147]    The title compound was prepared using 3-trifluoromethoxy-benzonitrile and 2-amino-5-methyl-thiophene-3-carbonitrile in place of 1,3-dicyanobenzene and 2-amino-thiophene-3-carbonitrile, respectively, as described in Example 1. 
       Example 18: Step b 
     4-Amino-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidine-6-carbaldehyde 
       [0148]    
       
                 
         
             
             
         
       
     
         [0149]    Solid SeO 2  (2.0 g, 17.6 mmol) was added to a dioxane slurry (20 mL) of 6-methyl-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine (2.2 g, 6.9 mmol, as prepared in the previous step) and the resulting mixture was heated to 180° C. in the microwave for 40 min. The mixture was diluted with THF, filtered, and the filtrate was dry packed onto silica gel. Column chromatography afforded 1.5 g of the title compound. 
       Example 18: Step c 
     [4-Amino-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidin-6-yl]-(2-methoxy-phenyl)-methanol 
       [0150]    
       
                 
         
             
             
         
       
     
         [0151]    A 1.0 M 2-methoxyphenylmagnesium bromide solution in THF (0.71 mL, 0.71 mmol) was added to a 4° C. THF solution (2 mL) of 4-amino-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidine-6-carbaldehyde (120 mg, 0.354 mmol, as prepared in the previous step) and the mixture was allowed to warm to rt overnight. The mixture was quenched with saturated aqueous NH 4 Cl, and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2  and the combined organics were dried (Na 2 SO 4 ) concentrated, and purified via column chromatography to give 60 mg of the title compound. 
       Example 18: Step d 
     [4-Amino-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidin-6-yl]-(2-methoxy-phenyl)-methanone 
       [0152]    
       
                 
         
             
             
         
       
     
         [0153]    Solid TEMPO (4 mg, 0.03 mmol) was added to a 4° C. CH 2 Cl 2  solution (2 mL) of [4-amino-2-(3-trifluoromethoxy-phenyl)-thieno[2,3-d]pyrimidin-6-yl]-(2-methoxy-phenyl)-methanol (60 mg, 0.13 mmol, as prepared in the previous step), KBr (34 mg, 0.29 mmol), and Clorox bleach containing 6.15% NaClO (280 mg, 0.23 mmol). After 4 h at 4° C., the mixture was partitioned between CH 2 Cl 2  and saturated aqueous NH 4 Cl solution. The organic layer was dried (Na 2 SO 4 ), concentrated, and purified via column chromatography to give 13 mg of the title compound.  1 H NMR (300 MHz, CDCl 3 ) δ=8.42 (d, J=7.9 Hz, 1H), 8.34 (s, 1H), 7.58 (s, 1H), 7.39-7.56 (m, 3H), 7.33 (d, J=8.3 Hz, 1H), 6.99-7.13 (m, 2H), 5.52 (br. s., 2H), 3.82 (s, 3H); MS (ES) m/z: 446 (M+H + ). 
       Example 19  
     2-(3-Fluoro-phenyl)-6-(2-methoxy-benzyl)-thieno[2,3-d]pyrimidin-4-ylamine 
       [0154]    
       
                 
         
             
             
         
       
     
         [0155]    The title compound was prepared using 3-fluoro-benzonitrile and 2-methoxybenzylzinc chloride in place of 1,3-dicyanobenzene and benzylzinc bromide, respectively, as described in Example 1.  1 H NMR (300 MHz, CDCl 3 ) δ=8.19 (d, J=7.9 Hz, 1H), 8.11 (dd, J=2.6, 10.5 Hz, 1H), 7.40 (td, J=6.0, 8.1 Hz, 1H), 7.20-7.34 (m, 1H), 7.11 (td, J=2.3, 8.1 Hz, 1H), 6.87-7.00 (m, 3H), 6.77 (s, 1H), 5.15 (br. s., 2H), 4.21 (s, 2H), 3.87 (s, 3H)l MS (ES) m/z: 366 (M+H − ). 
       Example 20  
     6-(3,5-Difluoro-benzyl)-2-(3-fluoro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine 
       [0156]    
       
                 
         
             
             
         
       
     
         [0157]    The title compound was prepared using 3-fluoro-benzonitrile and 3,5-difluorobenzylzinc bromide in place of 1,3-dicyanobenzene and benzylzinc bromide, respectively, as described in Example 1.  1 H NMR (300 MHz, CDCl 3 ) δ=8.21 (d, J=7.9 Hz, 1H), 8.12 (d, J=10.5 Hz, 1H), 7.35-7.50 (m, 1H), 7.13 (td, J=2.6, 8.3 Hz, 1H), 6.66-6.97 (m, 4H), 5.26 (br. s., 2H), 4.19 (s, 2H); MS (ES) m/z: 372 (M+H + ). 
       Example 21  
     [4-Amino-2-(3-fluoro-phenyl)-thieno[2,3-d]pyrimidin-6-yl]-(2-methoxy-phenyl)-methanone 
       [0158]    
       
                 
         
             
             
         
       
     
         [0159]    Solid NaOH (58 mg, 1.4 mmol) was added to a DMF solution (0.5 mL) of 2-(3-fluoro-phenyl)-6-(2-methoxy-benzyl)-thieno[2,3-d]pyrimidin-4-ylamine (38 mg, 0.10 mmol, as prepared in Example 19) and the mixture was heated at 80° C. under air overnight. The mixture was concentrated in vacuo and the residue was partitioned between CH 2 Cl 2  and water. The extracts were dried (Na 2 SO 4 ), concentrated, and purified via column chromatography to yield 16 mg of the title compound.  1 H NMR (300 MHz, CDCl 3 ) δ=8.27 (d, J=7.9 Hz, 1H), 8.14-8.22 (m, 1H), 7.57 (s, 1H), 7.50-7.56 (m, 1H), 7.41-7.47 (m, 2H), 7.17 (td, J=2.6, 8.3 Hz, 1H), 7.04-7.11 (m, 2H), 5.45 (br. s., 2H), 3.83 (s, 3H); MS (ES) m/z: 380 (M+H + ). 
       Biological Assays and Activity 
     Ligand Binding Assay for Adenosine A2a Receptor 
       [0160]    Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (PerkinElmer, RB-HA2a) and radioligand [ 3 H]CGS21680 (PerkinElmer, NET1021). Assay was set up in 96-well polypropylene plate in total volume of 200 μL by sequentially adding 20 μL1:20 diluted membrane, 130 μL assay buffer (50 mM Tris•HCl, pH7.4 10 mM MgCl 2 , 1 mM EDTA) containing [ 3 H] CGS21680, 50 μL diluted compound (4×) or vehicle control in assay buffer. Nonspecific binding was determined by 80 mM NECA. Reaction was carried out at room temperature for 2 hours before filtering through 96-well GF/C filter plate pre-soaked in 50 mM Tris•HCl, pH7.4 containing 0.3% polyethylenimine. Plates were then washed 5 times with cold 50 mM Tris•HCl, pH7.4, dried and sealed at the bottom. Microscintillation fluid 30 μL was added to each well and the top sealed. Plates were counted on Packard Topcount for [ 3 H]. Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Varani, K.; Gessi, S.; Dalpiaz, A.; Borea, P. A. British Journal of Pharmacology, 1996, 117, 1693) 
       Adenosine A2a Receptor Functional Assay (A2AGAL2) 
       [0161]    To initiate the functional assay, cryopreserved CHO—K1 cells overexpressing the human adenosine A2a receptor and containing a cAMP inducible beta-galactosidase reporter gene were thawed, centrifuged, DMSO containing media removed, and then seeded with fresh culture media into clear 384-well tissue culture treated plates (BD #353961) at a concentration of 10K cells/well. Prior to assay, these plates were cultured for two days at 37° C., 5% CO 2 , 90% Rh. On the day of the functional assay, culture media was removed and replaced with 45 uL assay medium (Hams/F-12 Modified (Mediatech #10-080CV) supplemented w/0.1% BSA). Test compounds were diluted and 11 point curves created at a 1000× concentration in 100% DMSO. Immediately after addition of assay media to the cell plates, 50 nL of the appropriate test compound antagonist or agonist control curves were added to cell plates using a Cartesian Hummingbird. Compound curves were allowed to incubate at room temperature on cell plates for approximately 15 minutes before addition of a 15 nM NECA (Sigma E2387) agonist challenge (5 uL volume). A control curve of NECA, a DMSO/Media control, and a single dose of Forskolin (Sigma F3917) were also included on each plate. After additions, cell plates were allowed to incubate at 37° C., 5% CO 2 , 90% Rh for 5.5-6 hours. After incubation, media was removed, and cell plates were washed 1× 50 uL with DPBS w/o Ca &amp; Mg (Mediatech 21-031-CV). Into dry wells, 20 uL of 1× Reporter Lysis Buffer (Promega E3971 (diluted in dH 2 O from 5× stock)) was added to each well and plates frozen at −20° C. overnight. For β-galactosidase enzyme calorimetric assay, plates were thawed out at room temperature and 20 μL 2× assay buffer (Promega) was added to each well. Color was allowed to develop at 37° C., 5% CO 2 , 90% Rh for 1-1.5 h or until reasonable signal appeared. The calorimetric reaction was stopped with the addition of 60 μL/well 1M sodium carbonate. Plates were counted at 405 nm on a SpectraMax Microplate Reader (Molecular Devices). Data was analyzed in Microsoft Excel and IC/EC50 curves were fit using a standardized macro. 
       Adenosine A1 Receptor Functional Assay (A1GAL2) 
       [0162]    To initiate the functional assay, cryopreserved CHO—K1 cells overexpressing the human adenosine A1 receptor and containing a cAMP inducible beta-galactosidase reporter gene were thawed, centrifuged, DMSO containing media removed, and then seeded with fresh culture media into clear 384-well tissue culture treated plates (BD #353961) at a concentration of 10K cells/well. Prior to assay, these plates were cultured for two days at 37° C., 5% CO 2 , 90% Rh. On the day of the functional assay, culture media was removed and replaced with 45 uL assay medium (Hams/F-12 Modified (Mediatech #10-080CV) supplemented w/0.1% BSA). Test compounds were diluted and 11 point curves created at a 1000× concentration in 100% DMSO. Immediately after addition of assay media to the cell plates, 50 nL of the appropriate test compound antagonist or agonist control curves were added to cell plates using a Cartesian Hummingbird. Compound curves were allowed to incubate at room temperature on cell plates for approximately 15 minutes before addition of a 4 nM r-PIA (Sigma P4532)/1 uM Forskolin (Sigma F3917) agonist challenge (5 uL volume). A control curve of r-PIA in 1 uM Forskolin, a DMSO/Media control, and a single dose of Forskolin were also included on each plate. After additions, cell plates were allowed to incubate at 37° C., 5% CO 2 , 90% Rh for 5.5-6 hours. After incubation, media was removed, and cell plates were washed lx 5OuL with DPBS w/o Ca &amp; Mg (Mediatech 21-031-CV). 
         [0163]    Into dry wells, 20 uL of 1× Reporter Lysis Buffer (Promega E3971 (diluted in dH 2 O from 5× stock)) was added to each well and plates frozen at −20° C. overnight. For β-galactosidase enzyme calorimetric assay, plates were thawed out at room temperature and 20 μL 2× assay buffer (Promega) was added to each well. Color was allowed to develop at 37° C., 5% CO 2 , 90% Rh for 1-1.5 h or until reasonable signal appeared. The calorimetric reaction was stopped with the addition of 60 μL/well 1M sodium carbonate. Plates were counted at 405 nm on a SpectraMax Microplate Reader (Molecular Devices). Data was analyzed in Microsoft Excel and IC/EC50 curves were fit using a standardized macro. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 A2a ASSAY DATA 
               
             
          
           
               
                 Example 
                 A2AGAL2 Ki μM 
                 A2A-B Ki μM 
                 A1GAL2 Ki μM 
               
               
                   
               
             
          
           
               
                 1 
                 0.0105828 
                 0.0167649 
                 0.204786 
               
               
                 2 
                 0.802232 
                 ND 
                 4.63554 
               
               
                 3 
                 ND 
                 ND 
                 ND 
               
               
                 4 
                 ND 
                 ND 
                 ND 
               
               
                 5 
                 0.0633724 
                 ND 
                 &gt;1.03825 
               
               
                 6 
                 0.221769 
                 ND 
                 &gt;0.610098 
               
               
                 7 
                 ND 
                 ND 
                 ND 
               
               
                 8 
                 ND 
                 ND 
                 ND 
               
               
                 9 
                 0.00615176 
                 0.0125199 
                 0.12933 
               
               
                 10 
                 0.339625 
                 ND 
                 1.77133 
               
               
                 11 
                 0.21737 
                 ND 
                 0.374455 
               
               
                 12 
                 1.016 
                 ND 
                 &gt;1.038 
               
               
                 13 
                 0.118195 
                 ND 
                 0.266256 
               
               
                 14 
                 0.0422474 
                 ND 
                 0.123055 
               
               
                 15 
                 0.0391291 
                 ND 
                 1.01415 
               
               
                 16 
                 ND 
                 ND 
                 ND 
               
               
                 17 
                 0.0229509 
                 ND 
                 1.03657 
               
               
                 18 
                 0.175227 
                 ND 
                 0.865366 
               
               
                 19 
                 0.0623591 
                 0.0393278 
                 0.417734 
               
               
                 20 
                 0.187586 
                 ND 
                 0.563508 
               
               
                 21 
                 0.0800756 
                 ND 
                 0.161957 
               
               
                   
               
               
                 ND indicates no data was available. 
               
             
          
         
       
     
         [0164]    While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. 
         [0165]    All publications disclosed in the above specification are hereby incorporated by reference in full.