Title of Invention	2-PROPYNYL ADENOSINE ANALOGS HAVING A2A AGONIST ACTIVITY AND COMPOSITIONS THEREOF
Abstract	The present invention comprises compounds and compositions for the treatment of inflammatory activity in mammalian tissue. The present compounds comprise a novel class of 2-alkynyladenosine derivatives, substituted at the ethyn-2-yl position by substituted cycloalkyl and heterocycle (heterocyclic) moicties. The present compounds having the following general formula (I):

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2-PROPYNYL ADENOSINE ANALOGS HAVING A2A AGONIST ACTIVITY AND COMPOSITIONS THEREOF Cross-Reference to Related Applications This application claims priority of U.S. provisional patent application Serial No. 60/326,517, filed October 1, 2001, and U.S. provisional patent application Serial No. 60/383,200, filed May 24, 2001, both of which are incorporated by reference herein. Government Funding The invention described herein was made with government support under Grant Number (R01-HL37942), awarded by the National Science Foundation. The United States Government has certain rights in the invention. Background of the Invention The inflammatory response serves the purpose of eliminating harmful agents from the body. There is a wide range of pathogenic insults that can initiate an inflammatory response including infection, allergens, autoimmune stimuli, immune response to transplanted tissue, noxious chemicals, and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal trauma. Inflammation normally is a very localized action which serves in expulsion, attenuation by dilution, and isolation of the damaging agent and injured tissue. The body's response becomes an agent of disease when it results in inappropriate injury to host tissues in the process of eliminating the targeted agent, or responding to a traumatic insult. As examples, inflammation is a component of pathogenesis in several vascular diseases or injuries. Examples include: ischemia/reperfusion injury (N. G. Frangogiannis et al., in Myocardial Ischemia: Mechanisms, Reperfusion, Protection, M. Karmazyn, ed., Birkhuser Verlag (1996) at 236-284; H. S. Sharma et al., Med, of Inflamm., 6,175 (1987)), atherosclerosis (R. Ross, Nature, 362. 801 (1993)), inflammatory aortic aneurysms (N. Girardi et al, Ann. Thor. Surg.. 64, 251 (1997); D. I. Walker et al., Brit. J. Surg., 59, 609 (1972); R. L. Pennell et al., J. Vase. Surg., 2, 859 (1985)), and restenosis following balloon angioplasty (see, R. Ross cited above). The cells involved with inflammation include leukocytes (i.e., the immune system cells - neutrophils, eosinophils, lymphocytes, monocytes, basophils, macrophages, dendritic cells, and mast cells), the vascular endothelium, vascular smooth muscle cells, fibroblasts, and myocytes. The release of inflammatory cytokines such as tumor necrosis factor- alpha (TNFα) by leukocytes is a means by which the immune system combats pathogenic invasions, including infections. TNFα stimulates the expression and activation of adherence factors on leukocytes and endothelial cells, primes neutrophils for an enhanced inflammatory response to secondary stimuli and enhances adherent neutrophil oxidative activity. See, Sharma et al., cited above. In addition, macrophages/dendritic cells act as accessory cells processing antigen for presentation to lymphocytes. The lymphocytes, in turn, become stimulated to act as pro-inflammatory cytotoxic cells. Generally, cytokines stimulate neutrophils to enhance oxidative (e.g., superoxide and secondary products) and nonoxidative (e.g., myeloperoxidase and other enzymes) inflammatory activity. Inappropriate and over-release of cytokines can produce counterproductive exaggerated pathogenic effects through the release of tissue-damaging oxidative and nonoxidative products (K. G. Tracey et al., J. Exp. Med.. 167. 1211 (1988); and D. N. Mannel et al., Rev. Infect. Pis.. 9 (suppl. 5), S602-S606 (1987)). For example, TNFα can induce neutrophils to adhere to the blood vessel wall and then to migrate through the vessel to the site of injury and release their oxidative and non-oxidative inflammatory products. Although monocytes collect slowly at inflammatory foci, given favorable conditions, the monocytes develop into long-term resident accessory cells and macrophages. Upon stimulation with an inflammation trigger, monocytes/macrophages also produce and secrete an array of cytokines (including TNFa), complement, lipids, reactive oxygen species, proteases and growth factors that remodel tissue and regulate surrounding tissue functions. For example, inflammatory cytokines have been shown to be pathogenic in: arthritis (C. A. Dinarello, Semin. Immunol.. 4,133 (1992)); It has been suggested that there is more than one subtype of adenosine receptor on neutrophils that can have opposite effects on superoxide release (B. N. Cronstein et al., J. Clin. Invest., 85, 1150 (1990)). The existence of A2A receptor on neutrophils was originally demonstrated by Van Calker et al. (D. Van Calker et al, Eur. J. Pharmacology, 206, 285 (1991)). There has been progressive development of compounds that are more and more potent and/or selective as agonists of A2A adenosine receptors (AR) based on radioligand binding assays and physiological responses. Initially, compounds with little or no selectivity for A2A receptors were developed, such as adenosine itself or 5'-carboxamides of adenosine, such as 5'-N- ethylcarboxamidoadenosine (NECA) (B. N. Cronstein et al., J. Immunol, 135, 1366 (1985)). Later, it was shown that addition of 2-alkylamino substituents increased potency and selectivity, e.g., CV1808 and CGS21680 (M. F. Jarvis et al., J. Pharmacol. Exp. Ther.. 251, 888 (1989)). 2-Alkoxy-substituted adenosine derivatives such as WRC-0090 are even more potent and selective as agonists at the coronary artery A2A receptor (M. Ueeda et al., J. Med. Chem., 34,1334 (1991)). The 2-alklylhydrazino adenosine derivatives, e.g., SHA 211 (also called WRC-0474) have also been evaluated as agonists at the coronary artery A2A receptor (K. Niiya et al., J. Med. Chem., 35,4557 (1992)). There is one report of the combination of relatively nonspecific adenosine analogs, R-phenylisopropyladenosine (R-PIA) and 2-chloroadenosine (CI-Ado) with a phosphodiesterase (PDE) inhibitor resulting in a lowering of neutrophil oxidative activity (M. A. Iannone et al., Topics and Perspectives in Adenosine Research. E. Garlach et al., eds., Springer-Verlag, Berlin, pp. 286- 298 (1987)). However, R-PIA and Cl-Ado analogs are actually more potent activators of A1 adenosine receptors than of A2A adenosine receptors and, thus, are likely to cause side effects due to activation of A1 receptors on cardiac muscle and other tissues causing effects such as "heart block." R. A. Olsson et al. (U.S. Pat. No. 5,278,150) disclose selective adenosine A2 receptor agonists of the formula: ischemia (A. Seekamp et al., Agents-Actions-Supp., 41, 137 (1993)); septic shock (D. N. Mannel et al., Rev. Infect. Pis.. 9 (suppl. 5), S602-S606 (1987)); asthma (N. M. Cembrzynska et al., Am. Rev. Respir. Pis., 147, 291 (1993)); organ transplant rejection (P. K. Imagawa et al., Transplantation, 51, 57 (1991); multiple sclerosis (H. P. Hartung, Ann. Neurol.. 33, 591 (1993)); ADDS (T. Matsuyama et al., AEDS, 5, 1405 (1991)); and in alkali-burned eyes (F. Miyamoto et al., Opthalmic Res., 30,168 (1997)). In addition, superoxide formation in leukocytes has been implicated in promoting replication of the human immunodeficiency virus (HIV) (S. Legrand-Poels et al, AIPS Res. Hum. Retroviruses. 6, 1389 (1990)). It is well known that adenosine and some analogs of adenosine that nonselectively activate adenosine receptor subtypes decrease neutrophil production of inflammatory oxidative products (B. N. Cronstein et al., Ann. N.Y. Acad. Sci„ 451. 291 (1985); P. A. Roberts et al., Biochem. J.. 227.669 (1985); P. J. Schrier et al., J. Immunol.. 137. 3284 (1986); B. N. Cronstein et al., Clinical Immunol, and Immunopath., 42, 76 (1987); M. A. Iannone et al., in Topics and Perspective in Adenosine Research, E. Gerlach et al., eds., Springer- Verlag, Berlin, p. 286 (1987); S. T. McGarrity et al., J. Leukocyte Biol.. 44, 411421 (1988); J. Pe La Harpe et al, J. Immunol.. 143, 596 (1989); S. T. McGarrity et al., J. Immunol.. 142,1986 (1989); and C. P. Nielson et al., Br. J. Pharmacol.. 97, 882 (1989)). For example, adenosine has been shown to inhibit superoxide release from neutrophils stimulated by chemoattractants such as the synthetic mimic of bacterial peptides, f-met-leu-phe (fMLP), and the complement component Csa (B. N. Cronstein et al., J. Immunol., 135,1366 (1985)). Adenosine can decrease the greatly enhanced oxidative burst of PMN (neutrophil) first primed with TNF-a and then stimulated by a second stimulus such as f-met-leu-phe (G. W. Sullivan et al., Clin. Res.. 41,172A (1993)). Additionally, it has been reported that adenosine can decrease the rate of HIV replication in a T-cell line (S. Sipka et al., Acta. Biochim. Biopys. Hung.. 23, 75 (1988)). However, there is no evidence that in vivo adenosine has anti- inflammatory activity (G. S. Firestein et al., Clin. Res.. 41, 170A (1993); and B. N. Cronstein et al., Clin. Res.. 41, 244A (1993)). wherein Rib is ribosyl, R1 can be H and R2 can be cycloalkyl. The compounds are disclosed to be useful for treating hypertension, atherosclerosis and as vasodilators. Olsson et al. (U.S. Pat. No. 5,140,015) disclose certain adenosine A2 receptor agonists of formula: wherein C(X)BR2 can be CH2OH and Rj can be alkyl- or alkoxyalkyl. The compounds are disclosed to be useful as vasodilators or an antihypertensives. Linden et al. (U.S. Pat. No. 5,877,180) is based on the discovery that certain inflammatory diseases, such as arthritis and asthma, may be effectively treated by the administration of compounds which are selective agonists of A2A adenosine receptors, preferably in combination with a Type IV phosphodiesterase inhibitor. An embodiment of the Linden et al. invention provides a method for treating inflammatory diseases by administering an effective amount of an A2A adenosine receptor of the following formula: wherein R and X are as described in the patent. In one embodiment, the Linden et al. invention involves the administration of a Type IV phosphodiesterase (PDE) inhibitor in combination with the A2A adenosine receptor agonist. The Type IV phosphodiesterase (PDE) inhibitor includes racemic and optically active 4-(polyalkoxyphenyI)-2- pyrrolidones of the following formula: wherein R', R18, R19 and X are as disclosed and described in U.S. Pat. No. 4,193,926. Rolipram is an example of a suitable Type IV PDE inhibitor included within the above formula. G. Cristalli (U.S. Pat. No. 5,593,975) discloses 2-arylethynyl, 2-cycloalkylethynyl or 2-hydroxyalkylethynyl derivatives, wherein the riboside residue is substituted by carboxy amino, or substituted carboxy amino (R3HNC(0)-). 2-Alkynylpurine derivatives have been disclosed in Miyasaka et al. (U.S. Pat. No. 4,956,345), wherein the 2-alkynyl group is substituted with (C3-C16)alkyl. The '975 compounds are disclosed to be vasodilators and to inhibit platelet aggregation, and thus to be useful as anti-ischemic, anti- atherosclerosis and anti-hypertensive agents. Recently, U.S. Patent 6,232,297 to Linden, et al. disclosed compounds having the general formula: wherein each R is H, X is ethylaminocarbonyl and Rl is 4- carboxycyclohexylmethyl (DWH-146a), R1 is 4- methoxycarbonylcyclohexylmethyl (DWH-146e) or R1 is 4-acetoxymethyl- cyclohexylmethyl (JMR-193). These compounds are reported to be A2A agonists. However, a continuing need exists for selective A2 adenosine receptor agonists useful for therapeutic applications, that have reduced side effects. Summary of the Invention The present invention comprises compounds and methods of their use for the treatment of inflammatory activity in mammalian tissue. The inflammatory tissue activity can be due to pathological agents or can be due to physical, chemical or thermal trauma, or the trauma of medical procedures, such as organ, tissue or cell transplantation, angioplasty (PCTA), inflammation following ischemia/reperfusion, or grafting. The present compounds comprise a novel class of 2-alkynyladenosine derivatives, substituted at the ethyn-2-yl position by substituted cycloalkyl and heterocycle (heterocyclic) moieties. Preferably, the riboside residue is substituted at the 5'-position by an N-alkyl-(or cycloalkyl)carboxyamino ("aminocarbonyl") moiety ("X"). Thus, the present invention provides a method for inhibiting the inflammatory response in a mammal, such as a human subject, and protecting the tissue subject to the response, by administering an effective amount of one or more compounds of the invention. The compounds of the invention have general formula (I): wherein Z is CR3R4R5 or NR4R5; each R1 is independently hydrogen, halo, -ORa, -SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C3-8cycloalkyl, heterocycle, hetrocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene-, -CO2Ra, RaC(0)0-, RaC(=O)-, -OCO2Ra, RaRbNC(=O)O-, RbOC(=O)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(K))N(Rb)-, RaRbNC(=O)N(Rb)-) RaRbNC(=S)N(Rb)-, -OPO3Ra, RaOC(=S)-, RaC(=S), -SSRa, RaS(=O)-, RaS(=O)2-, -N=NRa, or -OPO2Ra; each R2 is independently hydrogen, halo, (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, orheteroaryl(C1-C8)alkylene-; or Rl and R2 and the atom to which they are attached is C=O, C=S or C=NRC. R4 and R5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5,6, 7, 8, 9 or 10 ring atoms optionally comprising 1,2, 3, or 4 heteroatoms selected from non-peroxide oxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S(O)2-) or amine (-NRa-) in the ring; wherein any ring comprising R4 and R5 is substituted with from 1 to 14 R6 groups; wherein each R6 is independently halo, -OR\ -SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle or hetrocycle (CrCs)alkylene-, aryl, aryl (C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene-, -CO2Ra, RaC(=O)O-, RaC(=O)-, -OCO2Ra, RaRbNC(=O)O-5 RbOC(=O)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-, -OPO3Ra, RaOC(=S)-, RaC(=S)-, -SSRa, RaS(=O)-, -NNRa,-OP02Ra, or two R6 groups and the atom to which they are attached is C=O, C=S or; two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring. R3 is hydrogen, halo, -ORa, -SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, hetrocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene-J -C02Ra, RaC(=O)O-, RaC(=O)-, -0C02Ra, RaRbNC(=O)O-, RbOC(=O)N(Ra)-, RaRbN-, RaRbNC(=OK RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-, -OPO3Ra, RaOC(=S)-, RaC(=S)-, -SSRa, RaS(=O)-, RaS(=O)2-, -NNRa, -OPO2Ra; or if the ring formed from CR4R5 is aryl or hetreroaryl or partially unsaturated then R3 can be absent; each R7 is independently hydrogen, (C1-Cs)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene, heteroaryl, heteroaryl(C1-C8)alkylene-; X is -CH2ORa, -C02Ra, -OC(O)Ra, -CH2OC(O)Ra, -C(O)NRaRb, -CH2SRa, -C(S)ORa, -OC(S)Ra, -CH2OC(S)Ra or C(S)NRaRb or -CH2N(Ra)(Rb); wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, groups of R1, R2, R3, R6 and R7is optionally substituted on carbon with one or more (e.g. 1,2, 3, or 4) substituents selected from the group consisting of halo, -ORa, -SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle or hetrocycle(C1-C8)alkylene-, aryl, aryloxy, aryl (C1-C8)aikylene-, heteroaryl, heteroaryl(C1-C8)alkylene-, -C02Ra, RaC(=O)O-, RaC(=O)-, -0C02Ra, RaRbNC(=O)O-, RbOC(=O)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-, -0PO3Ra, RaOC(=S)-, R8C(=S)-, -SSRa, RaS(=O)p-, RaRbNC(=O)p-, N=NRa, and -OPO2Ra; wherein any (C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, (C1-C8)alkoxy, (C1-C8)alkanoyl, (C1-C8)alkylene, or heterocycle, is optionally partially unsaturated; Ra and Rb are each independently hydrogen, (C1-C8)alkyl, or (C1-C8)alkyl substituted with 1-3 (C1-C8)alkoxy, (C3-C8)cycloalkyl, (C1-C8)alkylthio, amino acid, aryl, aryl(C1-C8)alkylene, heteroaryl, or heteroaryl(C1-C8)alkylene; or Ra and Rb, together with the nitrogen to which they are attached, form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; and Rc is hydrogen or (C1-C6)alkyl; m is 0 to about 8 and p is 0 to 2; provided that when CR4R5 is a carbocyclic ring then at least one of R1, R2, or R3 is a group other than hydrogen or at least one R6 group is a group other than -CH2OH, -CO2Ra, RaC(=O)O-, RaC(=O)OCH2- or RaRbNC(=O), provided that m is at least 1 when Z is NR4R5; or a pharmaceutically acceptable salt thereof. The invention provides a compound of formula I for use in medical therapy, preferably for use in treating inflammation or protecting mammalian tissue from inflammation such as an inflammatory response, e.g., resulting from allergy, trauma or ischemia/reperfusion injury, as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of an inflammatory response due to a pathological condition or symptom in a mammal, such as a human, which is associated with inflammation. Although certain A2A adenosine receptor agonists have been reported to be vasodilators, and thus to be useful to directly treat hypertension, thrombus, atherosclerosis and the like, the tissue-protective anti-inflammatory activity of the compounds of formula (I) is not suggested by the prior art. The invention also includes the use of a combination of these compounds with type IV phosphodiesterase inhibitors to preferably cause synergistic decreases in the inflammatory response mediated by leukocytes. The invention also provides a pharmaceutical composition comprising an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, and optionally, in combination with a Type IV phosphodiesterase (PDE) inhibitor. Preferably, the composition is presented as a unit dosage form. Additionally, the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the activity of A2A adenosine receptors is implicated and agonism of said receptors is desired, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. It is believed that activation of A2A adenosine receptors inhibits inflammation by affecting neutrophils, mast cells, monocytes/macrophages, platelets T-cells and/or eosinophils. Inhibition of these inflammatory cells results in tissue protection following tissue insults. Among the inflammatory responses that can be treated (including treated prophylactically) with a compound of formula I, optionally with a Type IV PDE inhibitor, are inflammation due to: (a) autoimmune stimulation (autoimmune diseases), such as lupus erythematosus, multiple sclerosis, infertility from endometriosis, type I diabetes mellitus including the destruction of pancreatic islets leading to diabetes and the inflammatory consequences of diabetes, including leg ulcers, Crohn's disease, ulcerative colitis, inflammatory bowel disease, osteoporosis and rheumatoid arthritis; (b) allergic diseases such as asthma, hay fever, rhinitis, poison ivy, vernal conjunctivitis and other eosinophil-mediated conditions; (c) skin diseases such as psoriasis, contact dermatitis, eczema, infectious skin ulcers, open wounds, cellulitis; (d) infectious diseases including sepsis, septic shock, encephalitis, infectious arthritis, endotoxic shock, gram negative shock, Jarisch-Herxheimer reaction, anthrax, plague, tularemia, ebola, shingles, toxic shock, cerebral malaria, bacterial meningitis, acute respiratory distress syndrome (ARDS), lyme disease, HIV infection, (TNFα-enhanced HIV replication, TNFα inhibition of reverse transcriptase inhibitor activity); (e) wasting diseases: cachexia secondary to cancer and HIV; (f) organ, tissue or cell transplantation (e.g., bone marrow, cornea, kidney, lung, liver, heart, skin, pancreatic islets) including transplant rejection, and graft versus host disease; (g) adverse effects from drug therapy, including adverse effects from amphotericin B treatment, adverse effects from immunosuppressive therapy, e.g., interleukin-2 treatment, adverse effects from OKT3 treatment, contrast dyes, antibiotics, adverse effects from GM-CSF treatment, adverse effects of cyclosporine treatment, and adverse effects of aminoglycoside treatment, stomatitis and mucositis due to immunosuppression; (h) cardiovascular conditions including circulatory diseases induced or exasperated by an inflammatory response, such as ischemia, atherosclerosis, peripheral vascular disease, restenosis following angioplasty, inflammatory aortic aneurysm, vasculitis, stroke, spinal cord injury, congestive heart failure, hemorrhagic shock, ischemia/reperfusion injury, vasospasm following subarachnoid hemorrhage, vasospasm following cerebrovascular accident, pleuritis, pericarditis, and the cardiovascular complications of diabetes; (i) dialysis, including pericarditis, due to peritoneal dialysis; (j) gout; and (k) chemical or thermal trauma due to burns, acid, alkali and the like. Of particular interest and efficacy is the use of the present compounds to limit inflammatory responses where the ischemia/reperfusion injury caused by angioplasty or throbolysis. Also of particular interest and efficacy is the use of the present compounds to limit inflammatory responses due to organ, tissue or cell transplantation, i.e., the transplantation of allogeneic or xenogeneic tissue into a mammalian recipient, autoimmune diseases and inflammatory conditions due to circulatory pathologies and the treatment thereof, including angioplasty, stent placement, shunt placement or grafting. Unexpectedly, it was found that administration of one or more compounds of formula (I) was effective after the onset of the inflammatory response, e.g., after the subject was afflicted with the pathology or trauma that initiates the inflammatory response. Tissue or cells comprising ligand bound receptor sites can be used to measure the selectively of test compounds for specific receptor subtypes, the amount of bioactive compound in blood or other physiological fluids, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with receptor site activation, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent, or the cellular response to said agent {e.g., cAMP accumulation). Accompanying Brief Description of thelFigures Figure 1 illustrates the results of a comparison of the depression of blood pressure in rats using the compound ATL-146e and JR4007 at 100µg/kg. Figure 2 illustrates the results of a dose-response experiment for the depression of blood pressure in rats using the compound JR4007 at concentrations of 1,10, and 100 ug/kg. Figure 3 illustrates the results of a comparison of the depression of blood pressure in rats using test compounds at 1 ug/kg. Figure 4 illustrates the results of a comparison of the depression of blood pressure in rats using test compound JR 3223 in two animals. Figure 5 illustrates the results of a of a dose-response experiment for the depression of blood pressure in rats using for JR4051 at concentrations of 1, and 10, ug/kg. Figure 6 illustrates the results of a comparison of the depression of blood pressure in rats using the compounds of the invention. Figures 7-16 illustrate the results of the coronary blood flow for test compounds in dogs. Figure 17 illustrates the results of the liver ischemia/reperfusion injury test Detailed Description of the Invention The following definitions are used, unless otherwise described. Halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, aralkyl, alkylaryl, etc. denote both straight and branched alkyl groups; but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. Aryl includes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C1-C4)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. It will be appreciated by those skilled in the art that the compounds of formula (I) have more than one chiral center and may be isolated in optically active and racemic forms. Preferably, the riboside moiety of formula (I) is derived from D-ribose, i.e., the 3',4'-hydroxyl groups are alpha to the sugar ring and the 2' and 5' groups is beta (3R, 4S, 2R, 5S). When the two groups on the cyclohexyl group are in the 1- and 4-position, they are preferably trans. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, or enzymatic techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine adenosine agonist activity using the tests described herein, or using other similar tests which are well known in the art. Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. Specifically, (C1-C8)aIkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl or octyl. As used herein, the term "cycloalkyl" encompasses bicycloalkyl (norbornyl, 2.2.2-bicyclooctyl, etc.) and tricycloalkyl (adamantyl, etc.), optionally comprising 1-2 N, O or S. Cycloalkyl also encompasses (cycloalkyl)alkyl. Thus, (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. (C1-C8)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2-C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyI, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C1-C6)alkanoyl can be acetyl, propanoyl or butanoyl; halo(C1-C6)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifiuoroethyl, or pentafluoroethyl; hydroxy(C1-C6)a!kyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl; (C1-C6)alkoxycarbonyl (CO2R2) can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C1-C6)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio, (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyraxolyl, pyrrolyl, pyrazinyl, tetrazolyl, puridyl (or its N-oxide), thientyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide). Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl denotes a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (C1-C8)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. The term "heterocycle" generally represents a non aromatic heterocyclic group, having from 3 to about 10 ring atoms, which can be saturated or partially unsaturated, containing at least one heteroatom {e.g., 1, 2, or 3) selected from the group consisting of oxygen, nitrogen, and sulfur. Specific, "heterocycle" groups include monocyclic, bicyclic, or tricyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. A "heterocycle" group also can include one or more oxo groups (=O) attached to a ring atom. Nonlimiting examples of heterocycle groups include 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuelidine, thiomorpholine, and the like. The term "alkylene" refers to a divalent straight or branched hydrocarbon chain (e.g. ethylene -CH2CH2-). The term "aryl(C1-C8)alkylene" for example includes benzyl, phenethyl, naphthylmethyl and the like. The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj-Cj indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, (C1-C8)alkyl refers to alkyl of one to eight carbon atoms, inclusive. The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours and "rt" for room temperature). Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not. exclude other defined values or other values within defined ranges for the radicals and substituents. Specifically, (C1-C8)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, or heptyl; (C1-C8)aIkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, 1-methylhexyloxy, or heptyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide). A specific value for R1 is hydrogen, -OH, -CH2OH, -OMe, -OAc, -NH2, -NHMe, -NMe2 or -NHAc. Another specific value for R1 is hydrogen, -OH, -OMe, -OAc, -NH2, -NHMe, -NMe2 or -NHAc. Another specific value for R1 is hydrogen, -OH, -OMe, or -NH2. Another specific value for R1 is hydrogen, -OH, or -NH2. A more specific value for R1 is hydrogen or -OH. A specific value for R1, R2 and the carbon atom to which they are attached is carbonyl (C=O). A specific value for R2 is hydrogen or (C1-C8)alkyl, cyclopropyl, cyclohexyl or benzyl. Another specific value for R2 is hydrogen, methyl, ethyl or propyl. Another specific value for R2 is hydrogen or methyl. A more specific value for R2 is hydrogen A specific value for R3 is hydrogen, OH, OMe, OAc, NH2, NHMe, NMe2 or NHAc. Another specific value for R3 is hydrogen, OH, OMe, or NH2. Another specific value for R3 is hydrogen, OH, or NH2. A more specific value for R3 is hydrogen or OH. A specific value for the ring comprising R4, R5 and the atom to which they are connected is cyclopentane, cyclohexane, piperidine, dihydro-pyridine, tetrahydro-pyridine, pyridine, piperazine, decaline, tetrahydro-pyrazine, dihydro-pyrazine, pyrazine,.diliydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, imidazole, dihydro-imidazole, imidazolidine, pyrazole, dihydro-pyrazole, and. pyrazolidine. A more specific value for the ring comprising R and R5 and the atom to which they are connected is, cyclohexane, piperidine or piperazine. A specific value for R6 is (C1-C8)alkyl, or substituted (C1-C8)alkyl, -ORa, -CO2Ra, RaC(=O)-, RaC(=O)O-, RaRbN-, RaRbNC(=O)-, or aryl. Another specific value for R6 is (C1-C8)alkyl, -ORa, -C02Ra, RaC(=O)-, RaC(=O)O-, RaRbN-, RaRbC(=O)-, or aryl. Another specific value for R6 is methyl, ethyl, butyl, OH, 0Ra, -C02Ra, RaC(=O)-, OC(=O)CH2CH3, -CONRaRb, -NRaRb or phenyl. Another specific value for R6 is OH, OMe, methyl, ethyl, t-butyl, -CO2Ra, -C(=O)NRaRb, -OAc, -NH2, -NHMe, -NMe2, -NHEt or -N(Et)2. Another specific value for R6 is-(CH2)1-2ORa, -(CH2)l.2C(=O)ORa, -(CH2)1-2OC(=O)Ra, -CCH2),.2C(=O)Ra, -(CH2),-2OC02Ra, -(CH2),.2NHRa, -(CH2),.2NRaRb, -(CH2)1-2OC(=O)NHR3, or-(CH2)1-2OC(=O)NRaRb. Another specific value for R6 is -CH2OH, -CH2OAc, -CH2OCH3, -CH2C(==O)OCH3, -CH2OC(=O)CH3, -CH2C(=O)CH3, -CH2OC02CH3, -CH2NH(CH3), or-(CH2)I.2N(CH3)2. Another specific value for R6 is methyl, ethyl, t-butyl, phenyl, -C02Ra, -CONRaRb,or RaC(=O)-. Another specific value for R6 is -CH2OH, -CH2OAc, -C(=O)OCH3, -C(=O)CH3, OCO2CH3 -OC02CH3, -CH2NH(CH3), or-(CH2)1-2N(CH3)2. A more specific value for R6 is methyl, ethyl, -C02Ra -CONRaRb, or RaC(=O)-. A specific number of R6 groups substituted on the R4R5 ring is froml to about 4. A specific value for Ra and Rb is independently hydrogen, (C1-C4)alkyl, aryl or aryl(C1-C8)alkylene. A specific value for Ra and Rb is independently hydrogen, methyl, ethyl, phenyl or benzyl. A more specific value for Ra is (C1-C8)alkyl. Another specific value for Ra is methyl, ethyl, propyl or butyl. A more specific value for Ra is methyl, ethyl, i-propyl, i-butyl or tert-butyl. Another specific value for Ra and Rb is a ring A specific value for R7 is hydrogen, alkyl, aryl or aryl(C1-C8)alkylene. Another specific value for R7 is hydrogen, methyl or ethyl, phenyl or benzyl. A more specific value for R7 is H, or methyl. A specific value for -N(R7)2 is amino, methylamino, dimethylamino, ethyiamino, pentylamino, diphenylethylamino, pyridylmethylamino, diethylamino or benzylamino. A specific value for -N(R7)2 is amino, methylamino, dimethylamino, ethylamino, diethylaraino diphenylethylamino, pentylamino or benzylamino. A specific value for N(R7)2 is amino, or methylamino. A specific value for X is -CH2ORa, -CO2Ra, -OC(O)Ra, -CH2OC(O)Ra, -C(O)NRaRb. Another specific value for X is -CH2ORa or -C(O)NRaRb. A more specific value for X is -CH2OH or -C(O)NHCH2CH3. A specific value for m is 0, 1, or 2. A more specific value for m is 0, or 1. Specific examples of rings comprising R4, R5 and the atom to which A specific value for the ring comprising -C(R3)R4R5 is 2-methyl cyclohexane, 2,2-dimethylcyclohexane, 2-phenylcyclohexane, 2-ethylcyclohexane, 2,2-diethylcyclohexane, 2-tert-butyl cyclohexane, 3-methyl cyclohexane, 3,3-dimethylcyclohexane, 4-methyl cyclohexane, 4-ethylcyclohexane, 4-phenyl cyclohexane, 4-tert-butyl cyclohexane, 4-carboxymethyl cyclohexane, 4-carboxyethyl cyclohexane, 3,3,5,5-tetramethyl cyclohexane, 2,4-dimethyl cyclopentane. 4-cyclohexanecarboxyic acid, 4-cyclohexanecarboxyic acid esters, or 4-methyloxyalkanoyl-cyclohexane. A specific value for the ring comprising -C(R3)R4R5 is 4-piperidine, 4-piperidene-l-carboxylic acid, 4-piperidine-1-carboxylic acid methyl ester, 4-piperidine-1-carboxylic acid ethyl ester, 4-piperidine-1-carboxylic acid propyl ester, 4-piperidine-1-carboxylic acid tert-butyl ester, 1-piperidine, l-piperidine-4-carboxylic acid methyl ester, l-piperidine-4-carboxylic acid ethyl ester, l-piperidine-4-carboxylic acid propyl ester, l-piperidine-4-caboxylic acid tert-butyl ester, l-piperidine-4-carboxylic acid methyl ester, 3-piperidine, 3-piperidene-1-carboxylic acid, 3-piperidine-1-carboxylic acid methyl ester, 3-piperidine-1-carboxylic acid tert-butyl ester, 1,4-piperazine, 4-piperazine-1-carboxylic acid, 4-piperazine-1-carboxylic acid methyl ester, 4-piperazine-1-carboxylic acid ethyl ester, 4-piperazine-1-carboxylic acid propyl ester, 4-piperazine-1-carboxylic acid tert-butylester, 1,3-piperazine, 3-piperazine-l-carboxylic acid, 3-piperazine-1-carboxylic acid methyl ester, 3-piperazine- 1-carboxylic acid ethyl ester, 3-piperazine-l-carboxylic acid propyl ester, 3-piperidine- 1-carboxylic acid tert-butylester, l-piperidine-3-carboxylic acid methyl ester, l-piperidine-3-carboxylic acid ethyl ester, l-piperidine-3-carboxylic acid propyl ester or l-piperidine-3-caboxylic acid tert- butyl ester. A specific value for the ring comprising R4 and R5 is 2-methyl cyclohexane, 2,2-dimethylcyclohexane, 2-phenyl cyclohexane, 2-ethylcyclohexane, 2,2-diethylcyclohexane, 2-tert-butyl cyclohexane, 3-methyl cyclohexane, 3,3-dimethylcyclohexane, 4-methyl cyclohexane, 4-ethylcyclohexane, 4-phenyl cyclohexane, 4-tert-butyl cyclohexane, 4-carboxymethyl cyclohexane, 4-carboxyethyl cyclohexane, 3,3,5,5-tetramethyl cyclohexane, 2,4-dimethyl cyclopentane, 4-piperidine-1-carboxylic acid methyl ester, 4-piperidine-l-carboxylic acid tert-butyl ester 4-piperidine, 4-piperazine-l-carboxylic acid methyl ester, 4-piperidine-l-carboxylic acid tert- butylester, l-piperidine-4-carboxylic acid methyl ester, l-piperidine-4-caboxylic acid tert-butyl ester, tert-butylester, l-piperidine-4-carboxylic acid methyl ester, or l-piperidine-4-caboxylic acid tert-butyl ester, 3-piperidine-l-carboxylic acid methyl ester, 3-piperidine-l-carboxylic acid tert-butyl ester, 3-piperidine, 3-piperazine-l-carboxylic acid methyl ester, 3-piperidine-l-carboxylic acid tert- butylester, l-piperidine-3-carboxylic acid methyl ester, l-piperidine-3-caboxylic acid tert-butyl ester In another embodiment the invention includes a compound having the general formula (I): (I) wherein Z is CR3R4R5 or NR4R5; each R1 is independently hydrogen, halo, -ORa, -SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, hetrocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene-, -CO2Ra, RaC(=O)O-, RaC(=O)-, -OCO2Ra, RaRbNC(=O)O-, RbOCeO)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-, -OPO3Ra RaOC(=S)-, RaC(=S)-, -SSRa, RaS(=O)-, -N=NRa, or -OPO2Ra; each R2 independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, or heteroaryl(C1-C8)alkylene-; or. R1 and R2 and the atom to which they are attached can be C=O or C=NRC. R4 and R5 together with the atoms to which they are attached can form a saturated or unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6,7 or 8 ring atoms optionally comprising 1, 2, 3, or 4 heteroatoms selected from oxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S(O)2-) or amine (-NRa-) in the ring; wherein any ring comprising R4 and R5 is substituted with from 1 to 14 R6 groups; wherein each R6 is independently halo, -ORa, -SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle or hetrocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alylene-, heteroaryl, heteroaiyl(Ct-C8)alkylene-, -CO2Ra, RaC(=O)O-, RaC(=O)-, -OC02Ra, RaRbNC(=O)O-, RbOC(=O)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-5 -OP03Ra, RaOC(=S-, RaC(=S)-, -SSRa, RaS(=O)-, -NNRa or -OP02Ra; R3 is hydrogen, halo, -ORa, -SRa, C1-8alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle or hetrocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene-, -CO2Ra, RaC(=O)O, RaC(=O)-, -OC02Ra, RaRbNC(O)O-, RbOC(=O)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-, -OP03Ra, RaOC(=S)-, RaC(=S)-, -SSRa, RaS(=O)-, -N=NRa, -OPO2Ra; or if the ring formed from CR4R5 is aryl or hereroaryl or partially unsaturated then R3 can be absent; each R7 is independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene; X is -CH2ORa, -CO2Ra, -OC(O)R\ -CH2OC(O)Ra, -C(O)NRaRb, -CH2SRa, -C(S)ORa, -OC(S)Ra, -CH2OC(S)Ra or C(S)NRaRb or -CH2N(Ra)(Rb); wherein any of R1, R2, R3 and R6 is optionally substituted with (C1-C8)alkyl, aryl, heteroaryl, heterocycle, aryloxy, (C3-C8)cycloalkyL hydroxy, nitro, halo, cyano, (C1-C8)alkoxy, (C1-C8)alkanoyl, (C1-C8)alkoxycarbonyl, (C1-C8)alkanoyloxy, RaS(O)p-, RaRbNS(O)-, RaRbNS(O)2-, RaRbN-, or RaRbNC(=O)-; wherein any (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)bicycloalkyl, (C1-C8)alkoxy, (C1-C8)alkanoyl, (C1-C8)alkylene, or heterocycle, is optionally partially unsaturated; RaandRb are each independently hydrogen, (C1-C8)alkyl, or (C1-C8)alkyl substituted with 1-3 (C1-C8)alkoxy, (C3-C8)cycloalkyl, they are attached, form a pyrrolidine, piperidino, morpholino, or thiomorpholino ring; and Rc is hydrogen or C1-6 alkyl; m is 0 to about 8 and p is 0 to 2; provided that when m is 0 or all Rl and R groups present are hydrogen then R is not hydrogen; provided that m is at least 1 when Z is NR4R5; or a pharmaceutically acceptable salt thereof. Specific compounds of formula (I) are those wherein each R7 is H, X is ethylaminocarbonyl and R1 is hydroxy, R2 is hydrogen, and Z is 4-carboxycyclohexyl, wherein Ra is hydrogen, 4; Z is 4-methoxycarbonylcyclohexylmethyl, Ra is methyl, 5; R1 and R2 together are oxo, Z is a 4-carbonylcyclohexyl group, wherein Ra is methyl, methoxy, ethyl, ethoxy, propyl, isopropoxy, - isobutyl, tert-butyl, amine, methylamine or dimethylamine, 6. Another group of specific compounds of formula (I) are those wherein each R7 is H, X is ethylaminocarbonyl, R1 is hydroxy, R2 is hydrogen, and Z is a substituted 4-(methyleneoxy- carbonyl)cyclohexyI group, wherein Ra is methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, methylamine or dimethylamine, 7; or R and R2 together are oxo, and Z is a substituted -(methyleneoxycarbonyl)- Another group of specific compounds of formula (I) are those wherein each R7 is H, X is ethylaminocarbonyl, and R1 and R2 are each hydrogen, and Z is a l-piperidyl-4-carboxylic acid or ester group, wherein Ra is hydrogen, methyl, ethyl, propyl, isopropyl, or t-butyl, 9; R1 and R2 together are oxo, and Z is a l-piperidyl-4-carboxylic acid or ester group, wherein Ra is hydrogen, methyl, ethyl, propyl, isopropyl, or t-butyl, 10; R1 and R2 are each hydrogen and Z is a 4-(methyleneoxycarbonyl)piperidin-4-yl group wherein Ra is methyl, ethyl, propyl or t-butyl, amine, methylamine, dimethylamine, 11; or R1 and R2 together are oxo, and Z is a 4-(methyleneoxycarbonyl)piperidin- 4-yl wherein Ra is methyl, ethyl, propyl or t-butyl, amine, methylamine, dimethylamine, 12; R1 and R2 are each hydrogen and Z is a 4-(methyleneoxycarbonyl)piperidin-4-yl-oxy wherein Ra is hydrogen, methyl, ethyl, propyl isopropyl, isobutyl, or t-butyl, 13or R1 and R2 together are oxo, Z is a 4-(methyleneoxycarbonyl)piperidin-4-yl-oxy Another group of specific compounds of formula (I) are those wherein each R is H, X is ethylaminocarbonyl, R and R2 are each hydrogen, and Z is a 4-piperidyl-l-carboxylic acid or ester group, wherein Ra is methyl, ethyl, propyl, isopropyl, isobutyl, or t-butyl, 15, R1 is hydroxy, R2 is hydrogen, and Z is a 4-piperidyl- l-carboxylic acid or ester group, wherein Ra is methyl, ethyl, propyl, isopropyl, isobutyl, or t-butyl, 16; or R1 and R2 together are oxo, and Z is a 4-piperidyl-l-carboxylic acid or ester group, wherein Ra is methyl, ethyl, propyl, isopropyl, isobutyl, or t-butyl, 17. Another group of specific compounds of formula (I) are those wherein each R7 is H, X is ethylaminocarbonyl, R1 and R2 are each hydrogen, Z is a 4-piperazine-l-carboxylic acid or ester group wherein Ra is methyl, ethyl, isopropyl, isobutyl, or t-butyl, 18; or R1 and R2 together are oxo, Z is a 4-piperazine-l-carboxylic acid or ester group wherein Ra is methyl, ethyl, isopropyl, isobutyl, or t-butyl, 19. The following abbreviations have been used herein: 2-Aas 2-alkynyladenosines; l25I-ABA N6-(4-amino-3-125iodo-benzyl)adenosine APCI Atmospheric pressure chemical ionization ATL146e 4- {3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy- tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}cyclo- hexanecarboxylic acid methyl ester; CCPA 2-chloro-N6-cyclopentyladenosine; CGS21680 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethyl- carboxamidoadenosine; Cl-IB-MECA N6-3-iodo-2-chlorobenzyladenosine-5 '-N-methyluronamide; CPA N6-cyclopentyladenosine DMF dimethylformamide DMSO dimethylsulfoxide DMSO-d6 deuterated dimethylsulfoxide EtOAc ethyl acetate eq equivalent GPCR G protein coupled receptor; hA2AAR, Recombinant human A2A adenosine receptor; IADO 2-Iodoadenosine 125I-APE, 2-[2-(4-amino-3-[125I]iodophenyl)ethylamino]adenosine; NECA, 5' -N-ethylcarboxamidoadenosine; IB-MEC A N6-3-iodobenzyladenosine-5 '-N-methyluronamide; 2-Iodoadenosine 5-(6-amino-2-iodo-purin-9-yI)-3,4-dihydroxytetra- hydro-furan-2carboxylic acid ethylamide HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry 125I-ZM241385, l25I-4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]- triazin-5-yl-amino]ethyl)phenol; INECA 2-iodo-N-ethylcarboxamidoadenosine LC/MS liquid chromatography/mass spectrometry m.p. melting point MHz megahertz MRS 1220, N-(9-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]- quinazolin-5-yl)-2-phenylacetamide; MS mass spectrometry NECA N-ethylcarboxamidoadenosine NMR nuclear magnetic resonance RP-HPLC reversephase high-performance liquid chromatography TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TBDMSC1 tert-butyldimethylsilylchloride TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuan TLC thin layer chromatography p-TSOH para-toluenesulfonic acid XAC 8-(4-((2-a-minoethyl)aminocarbonyl-methyloxy)- phenyl)-1 -3-dipropylxanthine; Compounds of the invention can generally be prepared as illustrated in Schemes 1A and 1B below. Starting materials can be prepared by procedures described in these schemes, procedures described in the General methods below or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in Schemes 1A and Scheme 1B are as defined herein or as in the claims. The preparation of alkynyl cycloalkanols is illustrated in Scheme 1A. A solution of an appropriate cycloalkanone (where j is from 0-5) is prepared in a solvent such as THF. A solution of a suitable ethynylmagnesium halide compound in a solvent is added to the cycloalkanone. After additioin, the solution is allowed to stir at about 20°C for about 20 hours. The reaction is monitored via TLC until the starting material is consumed. The reaction is quenched with water, filtered over a plug of sand and silica, washed with a solvent, such as EtOAc, and evaporated to provide the product. Typically, two products are formed, the isomers formed by the axial/equatorial addition of the alkyne (where m is as defined above, and the sum of ml and m2 is from 0 to about 7) to the ketone. The compounds are purified via flash chromatography using EtOAc/Hexanes to provide the product. The preparation of 2-alkynyladenosines is illustrated in Scheme 1B. A flame-dried round bottom under nitrogen is charged with 5-(6-Amino-2-iodo- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid ethylamide (NECA 2-Iodoadenosine) and a solvent such as DMF. The appropriate alkyne, wherein R is a -(CR1-iR2)mZ group, is dissolved in acetonitrile followed by TEA, 5 mole % Pd(PPh3)4, and Cul. All solvents are thoroughly degassed. The solution is allowed to stir for about 24 hours at room temperature, and monitored until complete by HPLC. If the reaction is not complete after this time, additional catalyst, Cul, and TEA are added. After the reaction is complete, the solvents are removed under high-vacuum and the residue taken up in a small amount of DMF. This product is isolated using preparative silica TLC. The product is purified by RP-HPLC. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, malate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, -ketoglutarate, and -glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid, a liquid or in a dermatological patch. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions, which can be used to deliver the compounds of formula I to the skin are disclosed in Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508). Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949. Useful dosages of Type IV PDE inhibitors are known to the art. For example, see, U.S. Pat. No. 5,877,180, Col. 12. Generally, the concentration of the compound(s) of formula (I) in a liquid composition, such as a lotion, will be from about 0.1-25% wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%. The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 0.5 to about 100 µg/kg, e.g., from about 10 to about 75 fig/kg of body weight per day, such as 3 to about 50 µg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 µg/kg/day, most preferably in the range of 15 to 60 µg/kg/day. The compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 µg, conveniently 10 to 750 µg, most conveniently, 50 to 500 µg of active ingredient per unit dosage form. Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.1 to about 10 nM, preferably, about 0.2 to 10 nM, most preferably, about 0.5 to about 5 nM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 µg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 µg/kg/hr or by intermittent infusions containing about 0.4-15 µg/kg of the active ingredient(s). The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. For example, it is desirable to administer the present compositions intravenously over an extended period of time following the insult that gives rise to inflammation. The ability of a given compound of the invention to act as an A2A adenosine receptor agonist (or antagonist) may be determined using pharmacological models which are well known to the art, or using tests described below. The invention will be further described by reference to the following detailed examples, which are given for illustration of the invention, and are not intended to be limiting thereof. DESCRIPTION OF PREFERRED EMBODIMENTS All melting points were determined with a Thomas Hoover capillary melting point apparatus and are uncorrected. Nuclear magnetic resonance spectra for proton (1H NMR) were recorded on a 300 MHz GE spectrophotometer. The chemical shift values are expressed in ppm (parts per million) relative to tetramethylsilane. For data reporting, s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Mass spectra were measured on a Finnigan LcQ Classic. High resolution mass spectrometry (HRMS) data was provided by the Nebraska Center for Mass Spectrometry. Analytical HPLC was done on a Waters 2690 Separation Module with a Waters Symmetry C8 (2.1 x 150 mm) column operated at room temperature. Compounds were eluted at 200 µL/min with 70:30 acetonitrile:water, containing 0.5% acetic acid, with UV detection at 214 nm using a Waters 486 Tunable Detector. Preparative HPLC was performed on a Shimadzu Discovery HPLC with a Shim-pack VP-ODS C18 (20 x 100 mm) column operated at room temperature. Compounds were eluted at 30mL/min with a gradient 20-80% of water (containing 0.1% TFA) to methanol over 15 minutes with UV detection at 214 nm using a SPD10A VP Tunable detector. All final compounds presented here were determined to be greater than 98% pure by HPLC. Flash chromatography was performed on Silicyle 60A gel (230-400 mesh) or using reusable chromatography columns and system from RT Scientific, Manchester NH. Analytical thin-layer chromatography was done on Merck Kieselgel 60 F254 aluminum sheets. Preparative thin-layer chromatography was done using 1000 micron Analtech Uniplate with silica gel. All reactions were done under a nitrogen atmosphere in flame-dried glassware unless otherwise stated. To a solution of about 10 mmol of the appropriate cyclohexanone in about 50 mL of THF is added to about 60 mL (30 mmol) of 0.5 M ethynylmagnesium bromide in THF. The solution is allowed to stir at about 20°C for about 20 hours. After the starting material had been consumed, monitored by TLC, the reaction is quenched with about 5 mL of water, filtered over a plug of sand and silica, washed with EtOAc, and evaporated to yield a yellow oil. Usually the oil contained two spots on TLC with 20% EtOAc/Hexanes, which are visualized with Vanillin. Usually these two products are the different isomers formed by the axial/equatorial addition of the alkyne to the ketone. The compounds are purified via flash chromatography using 10% EtOAc/Hexanes to provide clear oils or white solids in a yield of about 50-80 %. To a solution of of the appropriate piperazine/piperadine(about 10.0 mmol), in about 20 mL acetonitrile, is added about 12.0 mmol of propargyl bromide (80% stabilized in toluene) and about 50.0 mmol of anhydrous potassium carbonate. The reaction mixture is filtered, and evaporated to dryness. The resiude is taken up in about 50 mL of dichloromethane/water and the organic layers removed. The aqueous layer is washed with an additional 3 x 25 mL dichloromethane. The organic layer is dried using anhydrous sodium sulfate, filtered, and concentrated to provide the crude product, which is purified using column chromatography. To about 100 mg of the appropriate Boc-protected piperazine/piperadine is added 2-4 mL of neat TFA. The solution is allowed to stir for 6 hours. The TFA is removed under reduced pressure to yield a yellow oil. This oil is taken up in about 10 mL of dichloromethane to which is added 10-fold excess of TEA and 3 equivalents of the appropriate acyl chloride. The yellow solution is allowed to stir at room temperature for about 12 hours, after which time the solvents are removed and the product purified using a 1.1x30 cm 14 g column from Robert Thompson Scientific with a 5%-30% gradient of ethyl acetate/hexanes. A flame-dried 25 mL round bottom under nitrogen is charged with 5-(6-aniino-2-iodo-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid ethylamide (2-Iodoadenosine) (about 40 mg) (X = CH3CH2NHC(O)-) and dissolved in about 2 mL of DMF. The appropriate alkyne (approx. 0. 1mL) is then added followed by about 4mL of acetonitrile and about 0. 1mL of TEA. All three solvents had been degassed with nitrogen for at least 24 hours. To this solution is added 5 mole percent Pd(PPh3)4 and 6 mole % copper iodide. The yellowish solution is allowed to stir for 24 hours at room temperature, or until complete by HPLC. If the reaction is not complete at this time, additional catalyst, CuI, and TEA are added. After the reaction is complete, the solvents are removed under high-vacuum and the red/black residue taken back up in a small amount of DMF. This solution is added to a preparative silica TLC plate (Analtech 1000 microns, 20cm x 20cm) and eluted first with 120 mL of 40% Hexanes/CH2Cl2, and then again after addition of 40 mL of MeOH. The UV active band (usually yellow in color) in the middle of the plate is collected, slowly washed with 4 x 25 mL 20% MeOH/CH2Cl2, and concentrated. This product is then purified by RP-HPLC. A suspension of 113 g (0.4 mol) of dry guanosine (6.1), acetic anhydride (240 mL, 2.5 mol), dry pyridine (120 mL) and dry DMF (320 mL) was heated for 3.75 hours at 75 °C without allowing the temperature to exceed 80 °C. The clear solution was then transferred to a 3L Erlenmyer flask and filled with 2-propanol. Upon cooling the solution to room temperature crystallization was initiated and allowed to proceed at 4 °C overnight. The white solid filtrate was filtered, washed with 2-propanol and recrystallized from 2-propanol to provide 6.2 (96%). 1H NMR (300 Mhz, CDCl3) 8.20 (s, 1H, H-8), 6.17 (d, J= 5.41 Hz, 1 H, H-l ) 5.75 (t, J= 5.39 Hz, 1H, H-2 ), 5.56 (t, J= 5.0, H-3 ), 4.41 (m, 3H, H-4,5 ), 2.14 (s, 3H, Ac), 2.11 (s, 3H, Ac), 2.10 (s, 3H, Ac). 13C NMR (300 MHz, CD3OD) 171.0, 170.3, 1702, 157.7, 154.8,152.4, 136.7, 117.7, 85.5, 80.4, 73.0, 71.3, 64.0, 31.3, 21.2, 21.0. To a 1 L flask was added 80 g (0.195 mol) [(2R,3R,4R,5R)-3-4-diacetyloxy-5-(2-amino-6-oxohyropurin-9-yl)oxolan-2-yl] methyl acetate (6.2), tetramethylammonium chloride (44 g, 0.4 mol), anhydrous acetonitrile (400 mL) and N.N-dimethlaniline (25 mL). The flask was placed in an ice salt bath and cooled to 2°C. To this solution was added dropwise POCl3 (107 mL 1.15 mol) at a rate that maintained the temperature below 5°C (45 minutes). The flask was then removed from the ice bath, outfitted with a condenser, placed in an oil bath and allowed to reflux for 10 minutes. The solution changed to a red/brown color. The solvent was removed under reduced pressure to yield an oily residue which was transferred to a beaker containing 1000 g of ice and 400 mL of CHCl3 and allowed to stir for 1.5 hours to decompose any remaining POCl3. The organic phase was removed and the aqueous phase extracted with 3x50 mL of CHCl3 and pooled with the organic phase. The pooled organic layeres were back extracted with 50 mL of water followed by stirring with 200 mL of saturated NaHCO3. The organic layer was further extracted with NaHCO3 until the aqueous extract was neutral (2X). The organic layer was finally extracted with brine and dried over MgSO4 for 16 hours. To the solution was added 800 mL of 2-propanol after which the solution was concentrated under reduced pressure. To the oily solid was added 200 mL of 2-propanol and the solution was refrigerated overnight. The crystalline product was filtered, washed, and allowed to dry overnight to give 6.3 (77%). 1H NMR (300 MHz, CD3OD) 8.31 (s, 1H, H-8), 7.00 (s, 2H, NH2) 6.06 (d, J= 5.8 Hz, 1H, H-l), 5.83 (t, J= 6.16 Hz, 1H, H-2 ), 5.67 (m, 1H, H-3 ), 4.29 (m, 3H, H-4,5 ), 2.07 (s, 3H, Ac), 1.99 (s, 3H, Ac), 1.98 (s, 3H, Ac). 13C NMR (300 MHz, CD3OD) 171.0, 170.4,170.2, 160.8, 154.6, 150.8, 142.2, 124.5, 85.8, 80.6, 72.8, 71.2, 63.9, 21.4, 21.3, 21.1. Isoamyl nitrite (5 mL, 37 mmol) was added to a mixture of 5.12g (12 mmol) [(2R,3R,4R,5R)-3-,4-diacetyloxy-5-(2-amino-6-chloropurin-9-yl)oxolan- 2-yl]methyl acetate (6.3), I2 (3.04 g, 12 mmol), CH2I2 (10 mL, 124 mmol), and CuI (2.4 g, 12.6 mmol) in THF (60 mL). The mixture was heated under reflux for 45 minutes and then allowed to cool to room temperature. To this solution was added 100 ml of saturated Na2S2O3. This step removed the reddish color. The aqueous layer was extracted 3X with chloroform, which was pooled, dried over MgSO4, and concentrated under reduced pressure. The product was then purified over a silica gel column using CHCl3-MeOH (98:2) to collect [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]meth yl acetate (6.4) (80% crystallized from EtOH). 1H NMR (300 MHz, CDCl3) 8.20 (s, 1H H-8), 6.17 (d, J = 5.41 Hz, 1H, H-1), 5.75 (t, J= 5.39 Hz, 1H, H-2 ), 5.56 (t, J= 5.40 Hz, 1H, H-3 ), 4.38 (m, 3H, H-4,5 ), 2.14 (s, 1H, Ac), 2.11 (s, lH,Ac), 2.10 (s, lH,Ac). To a flask containing 6.0 g (11.1 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]meth yl acetate (6.4) was added 100 ml of liquid NH3 at -78°C and the solution was allowed to stir for 6 hours. After which time it was allowed to come to room temperature overnight with concurrent evaporation of the NH3 to yield a brown oil. The product was crystallized from hot isopropanol to provide 6.5 (80%), m.p. 143-145°C, r.f. = 0.6 in 20% MeOH/CHCl3. 1H NMR (300 MHz, DMSO-d6) 8.24 (s, 1H), 7.68 (s, 2H), 5.75 (d, J = 6.16,1H), 5.42 (d, /- 5.40 Hz, 1H), 5.16 (d, J= 4.62 Hz, 1H), 4.99 (t, /= 5.39 Hz, 1H), 4.67 (d, J= 4.81 Hz, 1H), 4.06 (d, J= 3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 2H). To a solution of 2.0 g (5.08 mmol) (4S,2R,3R,5R)-2-(6-amino-2-iodopurin-9-yl)-5(hydroxyniethyl)oxolane-3,4-diol (6.6) in 100 mL acetone was added 9.6 g of p-toluenesulfonic acid and 5 ml of dimethoxypropane. The reaction was stirred at room temperature for 1 hour. Solid NaHCCO3, 15 g, was added to the solution. The slurry was stirred for an additional 3 hours. The residue was filtered and washed 2X with EtOAc. The filtrate was then concentrated under reduced pressure. The residue was chromatographed on a silica gel column with MeOH-CHCl3 (1:99) to give 6.6 (72%) as a solid, m.p. 185-187°C. 1H NMR (300 MHz, DMSO-d6) 8.22 (s, 1H, H-8), 7.69 (s, 2H), NH2), 6.00 (d, J= 2 JO Hz, 1H, H-l ), 5.21 (m, 1H, H-2 ), 5.07 (bs, 1H, OH), 4.88 (m, 1H, H-3 ), 4.13 (m, 1H, H-4), 3.47 (m, 2H, H-5 ), 1.49 and 1.28 (s, 3H, C(CH3)2). To a stirred solution of 1.6 g (3.7 mmol) of [(lR,2R,4R,5R)-4-(6-ainmo-24odopiirin-9-yl)-7-7-dimethyl-3,6,8-trioxabicyclo[ 3.3.0]oct-2-yl]methan-l-ol (6.6) in 200 mL of H2O was added 0.60 g of KOH and, dropwise, a solution of 1.70 g (10.8 mml) of KMnO4 in 50 mL of H2O. The mixture was placed in the dark at room temperature for 2-4 days. The reaction mixture was then cooled to 5-10 °C and decolorized by a solution of 4 mL of 30% H2O2 in 16 mL of water, while the temperature was maintained below 10 °C using an ice-salt bath. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to about 10 mL and then acidified to pH 4 with 2N HC1. The resulting precipitate was filtered off and washed with ether to yield 6.7 (70%) after drying as a white solid, m.p. 187-190 C. 1H NMR (300 MHz, DMSO-d6) 8.11 (s, 1H, H-8), 7.62 (s, 2H, NH2), 7.46 (s, 1H, COOH), 6.22 (s, 1H, H-l), 5.42 (d, J= 5.71 Hz, 1H, H-2 ), 5.34 (d, J= 6.16 Hz, 1H, H-3 ), 4.63 (s, 1H, H-4 ), 1.46 and 1.30 (s, 3H, C(CH3)2). A solution of 1.72 g (3.85 mrnol) of (2S,1R,4R,5R)-4-(6-amino-2-iodopurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3 .3.0]octane-2-carboxylic acid (6.7) in 80 mL of 50% HCOOH was stirred at 80 °C for 1.5 hours. The reaction mixture was evaporated under reduced pressure, dissolved in H2O, and the solvent was evaporated again. This process was repeated until there was no odor of formic acid in the residue. Recrystallization from water provided 1.33 g (85%) 6.8 as a white solid, m.p. 221-223 °C, dec. 1H NMR (300 MHz, DMSO-d6) 8.31 (s, 1H, H-8), 7.68 (s, 2H, NH2), 5.90 (d, J= 6.55 Hz, 1H, H-l ), 4.42 (m, 1H, H-2 ), 4.35 ( d, J= 2.31 Hz, 1H, H-4 ), 4.22 (m, 1H, H-3 ). To a cooled (5 °C) and stirred solution of 1.29 g (3.17 mrnol) of (2S,3S,4R,5R)-5-(6-aniino-2-iodopurin-9-yl)-3,4-dihydroxyoxolane-2-carboxyli c acid (6.8) in 150 mL of absolute ethanol was added dropwise 1.15 mL of ice-cooled SOCI2. The mixture was stirred at room temperature overnight and then brought to pH 8 with saturated aqueous NaHC03. The mixture was filtered, and then the filtrate was concentrated under reduced pressure to yield a white solid which was dried and then redissolved in 20 mL of dry ethylamine at - 20 °C for 3 hours and then at room temperature overnight. The reaction mixture was diluted with absolute ethanol, and the precipitated product was filtered off and washed with dry ether to provide 530 mg (72%) of 6.9 as a pure solid, m.p. 232-234°C. 1H NMR (300 MHz, DMSO-d6) 8.34 (s, 1H, H-8), 8.12 (t, 1H, NH), 7.73 (s, 2H, NH2), 5.85, (d, J= 6.93 Hz, 1H, H-1 ), 4.54 (m, 1H, H-2 ), 4.25 (d, J= 1.92 Hz, 1H, H-4 ), 4.13 (m, 1H, H-3 ), 3.28 (m, 2H, CH2CH3), 1.00 (t, J =1.2 Hz, 3H,CH2CH3). To a 100 mL-flask containing 79 (4.0 g, 27.8 mmol) in DMF (40 mL) was added TBDMSC1 (3.56 g, 23.6 mmol) and imidazole (3.79 g, 55.6 mmol). The reaction was allowed to stir at 25 °C for 16hoursafter which time saturated aqueous LiBr (50 mL) was added and the reaction extracted with ether (2 x 50 mL). The ether layers were pooled and extracted again with LiBr (2 x 35 mL). The ether layer became clear. The ether layer was then concentrated in vacuo and the product purified by flash chromatography, on a silica gel column, eluting with 1:2 ether/petroleum ether to yield 83 (3.80 g, 62%) as a homogenous oil. 1H NMR (CDCl3) 8 3.46 (d, J = 6.2 Hz, 2 H), 3.39 (d, J = 6.2 Hz, 2 H), 1.95-1.72 (m, 4 H), 1.65 (m, 1 H), 1.40 (m, 1 H), 1.03 - 0.89 (m, 4 H), 0.88 (s, 9 H), 0.04 (s, 6 H); l3C NMR (CDCl3) 8 69.2, 69.1, 41.2, 41.1, 29.5, 26.5, 18.9, -4.8;. APCI m/z (rel intensity) 259 (MH+, 100). To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in CHC13 (30 mL) was added tosyl chloride (3.26 g, 17.1 mmol) and pyidine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at 25 °C for 14hoursafter which time the reaction was concentrated in vacuo to yield a wet white solid. To this solid was added ether (50 mL) and the solid was filtered and subsequently washed with additional ether (2 x 50 mL). The ether layers were pooled, concentrated in vacuo to yield a clear oil which was purified by flash chromatography, on a silica gel column, eluting with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83 %) as a white solid. 1H NMR (CDCl3) 8 7.78 (d, J = 7.7, 2 H), 7.33 (d, J = 7.7 Hz, 2 H), 3,81 (d, J = 6.2 Hz, 2H), 3.37 (d, J = 6.2, 2 H), 2.44 (s, 3 H), 1.95-1.72 (m, 4 H), 1.65 (m, 1 H), 1.40 (m, 1 H), 1.03 - 0.89 (m, 4 H), 0.88 (s, 9 H), 0.04 (s, 6 H); 13C NMR (CDCI3) 5 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7, 38.0, 29.1, 26.5,22.1, 18.9, -4.9; APCI m/z (rel intensity) 413 (MH+, 100). A 3-neck 250 mL-flask equipped with a gas inlet tube and dry-ice condenser was cooled to -78 °C and charged with liquid ammonia (40 mL). To the reaction mixture was added lithium wire (600 mg, 86.4 mmol) generating a deep blue solution. The mixture was allowed to stir for 1hour. Acetylene, passed through a charcoal drying tube, was added to the ammonia until all the lithium had reacted and the solution turned colorless, at which time the flow of acetylene was stopped, the acetylene-inlet tube and condenser removed and the flask outfitted with a thermometer. DMSO (20 mL) was added and the ammonia evaporated with a warm water bath until the mixture reached a temperature of 30 °C. The solution was stirred at this temperature for 2 hours until the solution stopped bubbling. The mixture was cooled to 5 °C and compound 84 (11.25 g, 27.3 mmol), in DMSO (10 mL), was added. The temperature was maintained at 5 °C. The mixture was allowed to stir at 5 °C for 0.5 hours. Then the solution was gradually warmed to room temperature and stirred for an additional 18 hours. The brown/black reaction mixture was poured slowly over ice (300 g) and extracted with ether (4 x 100 mL), dried with anhydrous sodium sulfate, and concentrated in vacuo to yield a yellow oil. The oil was subsequently dissolved in THF (200 mL) and changed to a brownish color upon addition of TBAF hydrate (11.20 g, 35.5mmol). The solution was allowed to stir for 24hoursunder N2 atmosphere. After stirring, the reaction was quenched with water (200 mL) and extracted with ether (3 x 100 mL). The ether extracts were combined and concentrated in vacuo. The crude product was purified by chromatography, on a silica gel column, eluting with 1:1 ether/petroleum ether to yield 86 (3.91 g, 93%) as a yellow oil. lE NMR (CDCI3) 8 3.45 (d, J = 6.2, 2 H), 2.10 (d, J = 6.2, 2H), 1.9 (s, 1 H), 1.94- 1.69 (m, 4H), 1.52-1.34 (m, 2 H), 1.16-0.83 (m, 4 H); 13C NMR (CDCl3) 5 83.8, 69.5, 69.0, 40.8, 37.7, 32.3, 29.7, 26.5. To a solution of 960 mg (6.31 mmol) of 86 in 6 mL DMF was added 0.62 mL (7.57 mmol) pyridine and 0.78 mL (8.27mmol) acetic anhydride. The reaction was allowed to stir overnight at room temperature. After 16 hours, starting material still remained. The reaction mixture was heated at 75 °C for 3 hours. The solvent was removed under reduced pressure to yield a yellow oil which was purified by flash chromatography, on silica gel, eluting with 1:3 ether/petroleum ether to yield 1.12 g (91%) of 87 as an oil. 1H NMR (CDCl3) 53.87 (d, J = 6.2 Hz, 2 H), 2.06 (d, J = 4.3 Hz, 2 H), 2.03 (s, 3 H), 1.98 - 1.93 (m, 1 H), 1.92 - 1.83 (m, 2 H), 1.83 - 1.74 (m, 2 H), 1.63 - 1.36 (m, 2 H), 1.12 - 0.90 (m, 4 H); 13C NMR (CDCI3) 5 171.7, 83.7, 69.9, 69.6, 31 A, 37.3, 32.1, 29.7, 26.5, 21.4; APCI m/z (rel intensity) 195 (M+, 30), 153 (M+, 70), 135 (M+, 100). A solution of chromium trioxide (600 mg, 6.0 mmol) in 1.5 M H2SO4 (2.6 mL, 150 mmol) was cooled to 5 °C and added to a solution of 86 (280 mg, 1.84 mmol) in acetone (15 mL). The mixture was allowed to warm to room temperature and allowed to stir overnight. Isopropanol (4 mL) was added to the green/black solution, which turned light blue after 1hr. After adding water (15 mL), the solution was extracted with CHCl3 (6 x 25 mL). The organic layers were pooled and concentrated in vacuo to yield a white solid. The solid was dissolved in ether (50 mL) and extracted with 1 M NaOH (2 x 30 mL). The basic extracts were pooled, acidified w/10% HCl, and re-extracted with ether (3 x 30mL). The ether layers were combined, dried with sodium sulfate and concentrated in vacuo to yield a white solid. The product was recrystallized from acetone/water to yield 88 (222 mg, 73%) as white needles: mp 84-85 °C; 1H NMR (CDCl3) 8 2.30 -2.23 (m, 1 H), 2.17 - 2.11 (m, 2 H), 2.07-2.03 (m, 2 H), 1.97 - 1.91 (m, 3H), 1.51-1.39 (m, 3 H), 1.13- 1.01 (m, 2 H); l3C NMR (CDCl3) 6 182.5, 83.8, 69.6, 40.7, 37.7, 32.3, 29.6, 26.5; APCI m/z (rel intensity) 165 (M, 100). To a solution of 88 (240 mg, 1.45mmol) in 7:3 CH2Cl2:MeOH (10 mL) was added TMS Diazomethane (2.0 M in hexanes) (0.9 mL, 1.8 mmol) in 0.2 ml aliquots until the color remained yellow. The reaction was allowed to stir for an additional 0.25 hours at room temperature. After stirring, glacial acetic acid was added dropwise until the solution became colorless. The reaction was concentrated in vacuo to an oil which was purified by flash chromatography on silica gel using etherrpetroleum ether (1:9) to yield 89 (210 mg, 80%) as a clear oil. 1H NMR (CDCl3) 5 3.60 (s, 3H), 2.25 - 2.13 (m, 1 H), 2.08 - 1.94 (m, 3 H), 1.95 - 1.90 (m, 2 H), 1.49 - 1.31 (m, 3 H), 1.10 - 0.93 (m, 2 H); 13C NMR (CDCl3) 5 176.7, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3; APCI/H/Z (rel intensity) 181 (MH+, 100). Yield: 345 mg, 81%. 1H NMR (CDCl3) 5 0.98-1.07, 1.40-1.52, 1.57-1.70, 1.78-1.93 (4 x m, 10H, cyclohexyl), 1.96 (t, 1H, acetylene), 2.10 (dd, 2H, -C6H10CH2CCH), 3.78 (s, 3H, -OH3), 3.96 (d, -C6Hl0CH2O-). Yield: 433 mg, 83%. 1H NMR (CDCl3) 5 0.95 (d, 4H, -OCH2CH(CH3)2), 0.98-1.09, 1.40-1.51, 1.57-1.70, 1.78-1.93 (4 x m, 10H, cyclohexyl), 1.94-2.04 (m, 1H, -OCH2CH(CH3)2), 1.96 (t, 1H, acetylene), 2.10 (dd, 2H, -C6H10CH2CCH), 3.91, 3.95 (2 x d, 4H, -OCH2CH(CH3)2, -C6H10CH2O-). Yield: 340 mg, 69%. 1H NMR (CDCl3) 5 0.97-1.08, 1.40-1.49, 1.55-1.69,1.77-1.93 (4 x m, 10H, cyclohexyl), 1.96 (t, 1H, acetylene), 2.10 (dd, 2H, -C6HioCH2CCH), 3.98 (d, -C6H10CH2O-), 5.15 (s, 2H, -OCH2Ph), 7.33-7.40 (m, 5H, Ar). A solution of N-Boc-4-piperidinemethanol, 5.0 g (23.2 mmol) in chloroform, 50 mL, was prepared. Toluene sulfonyl chloride, 5.75 g (30.2 mmol), in 5.6 mL of pyridine (69.6 mmol) was added. The solution was stirred under nitrogen allowed to stir for 24 hours. Standard workup and chromatographic purification provided the title compound. Yield 6.0g To a solution of 1.0 g (8.9 mmol) (R)-(+)-3-methyl-cyclohexanone in 50 mL of THF was added 54 mL (26.7 mmol) of 0.5 M ethynylmagnesium bromide in THF. The solution was allowed to stir at 20 °C for 20 hours. Analysis by TLC indicated that the starting material had been consumed. The reaction was quenched with 5 mL of water, filtered over a plug of sand and silica, washed with EtOAc, and evaporated to yield 1.15 g of a yellow oil containing two spots (r.f.'s 0.33 (minor, JR3217A) and 0.25 (major, JR3217B), 20% EtOAc/Hexanes) which were visualized with Vanillin. The compound was purified via flash chromatography using 10% EtOAc/Hexanes (225 mL silica) to provide JR3217A and JR3217B. To a solution of methyl isonipecotate 3.5g (24.4 mmol, 3.30 mL) in 100 mL dichloromethane was added TEA (1.5 eq, 36.6 mmol, 5.1 mL), propargyl bromide (3.0eq, 73.2 mmol, 6.5 ml), at room temperature for 36 hrs. The reaction was quenched with 35 mL water to yield to provide a clear solution. The solution was extracted with dichloromethane 2x25 mL, dried with Na2S04, and the solvent evaporated to provide a yellow oil. r.f. (40% EtOAc/Hexanes) 0.26 stains faint white with Vanillin, starting material r.f. 0.05 stains yellow with Vanillin. The product appeared pure after extraction. To a solution of 10.0 g (54.8 mmol) of tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added 5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol) anhydrous potassium carbonate. Additional propargy bromide, 1.5mL, was added after stirring for 36 hours at room temperature. The residue was evaporated to dryness. Dichloromethane, 50 mL, and water, 50 mL, were added. The reaction mixture was extracted with CH2Cl2, 4 x 40 mL, dried over magnesium sulfate, and evaporate to provide a brown oil. The oil was dissolved in dichloromethane and purify with a RT Scientific system using hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil, which ultimately crystallized upon standing. To a solution of 3g (19.0 mmol) of ethyl N-piperazinecarboxylate in 25 mL of CH3CN was added 1.57g (1.32 mL 20.1mmol) of 2-chloroacetonitrile and 15.6g (95mmol) K2CO3●11/2H2O. The suspension was stirred at room temperature for 16 hours. The reaction was analyzed using TLC (35% Ethyl acetate/Hexanes, product r.f. 0.38 vs. sm r.f. of 0.02). The analysis indicated the reaction was complete. The golden yellow solution was evaporated to dryness. The residue was extracted with CH2Cl2/H2O, dried with MgSO4, and concentrated. The title compound was prepared starting with 500 mg (2.52mmol) of 2,5-Diaza--bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester according to general method 2. To a flame-dried 25 mL round bottom flask under nitrogen was added 2.1 g of 4-Prop-2-ynyl-piperazine-l-carboxylic acid tert-butyl ester. To this solid was added 5 mL of 98% TFA in 1 mL portions. The solution turned wine red, bubbled and smoked. The additional portions of TFA were added when this activity subsided. After the third portion of TFA had been added only minimal bubbling occurred. The solution was allowed to stir under nitrogen at room temperature for an additional hour and evaporated under reduced pressure to yield the product as a thick red syrup. Assumed quantitative yield of 1.16 g. The residue was suspended in 20 mL dichloromethane and used immediately without further purification for the preparation of compounds JR4031, JR4033, and JR4035. To a solution of piperidine-4-carboxylic acid (10 g, 77.5 mmol) and potassium carbonate (21.4 g, 155 mmol) in 150 mL of water was prepared. A solution of di-tert-butyl dicarbonate (16.9g, 77.5 mmol) in 40 mL of THF was added dropwise via addition funnel at 0 °C. The reaction was allowed to warm to room temperature gradually over 30 minutes and stirred for an additional 4 hours. The THF was removed under reduced pressure and the aqueous phase extracted with 50 mL of ether. The aqueous phase was then adjusted to pH 2 with 10 % HC1 and extracted with EtOAc, 4 x 50 mL. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 17.2 g (97%) of JR3183 as a white solid. Rf = 0.2 (35% EtOAc/Hexanes stained w/ vanillin). 1H NMR (CDC13) 5 11.83 (s, 1 H), 3.98 (d, J = 11.8 Hz, 2 H), 2.83 (t, J = 11.8, 2 H), 2.46 (m, 1 H), 1.88 (d, J = 12.9hz, 2 H), 1.2 (m, 2 H), 1.42 (s, 9 H). l3C NMR (CDC13)  180.0, 154.8, 79.8, 42.9,40.8, 28.3, 27.7. APCI m/z (rel intensity) M- 228.2 (100). Preparation 33: The following intermediate compounds are prepared using the general method 1 described herein and the appropriate starting materials. The reaction of 110 with five equivalents of LiOH in THF/water for 6 hours gave 109 (7 mg, 72%) as a white solid which was crystallized from MeOH/H2O(0.1% TFA) after purification by reverse phase HPLC. 'H NMR (DMSO-d6) 5 8.70 (s, 1 H), 8.41 (s, 1 H), 7.62 (s, 2 H), 5.89 (d, J - 7.25 Hz, 1 H), 4.53 (m, 1 H), 4.27 (s, 1 H), 4.08 (d, J = 3.6 Hz, 1 H), 2.29 (d, J = 6.4 Hz, 2 H), 2.15-1.99 (m, 1 H), 1.92- 1.76 (m, 4 H), 1.52 -1.38 (m, 1 H), 1.38-1.19 (m, 2 H), 1.02 (t, J = 6.3 Hz 3 H); 13C NMR (DMSO-d6) 176.7, 169.2, 155.6, 148.9, 145.2, 1.41.6, 119.0, 87.7, 85.0, 84.6, 81.6, 73.1, 71.9, 43.2, 35.9, 33.3, 31.2, 28.3, 25.6, 15.0. HRMS (FAB) m/z 474.2196 [(M + H)+ cacld for C22H29N6O6 474.2182]. The reaction of 89 with 2-IodoNECA under the general conditions described above provided 110 (74 mg, 60%) as a white solid. 1H NMR (CD3OD)  8.23 (s, 1 H), 5.92 (d, J = 7.7 Hz, 1 H), 4.69 - 4.65 (dd, J = 7.7 Hz, 4.6 Hz, 1 H), 4.40 (s, 1 H), 4.24 (d, J = 4.6 Hz, 1 H), 3.59 (s, 3 H), 3.49 -3.31 (m, 2 H), 2.31 (d, J = 6.6 Hz, 2 H), 2.10 - 2.09 (m, 1 H), 2.01 -1.89 (m, 4 H), 1.61 -1.32 (m, 5 H), 1.13 (t, J = 7.3 Hz, 3 H); I3C NMR (CD3OD) 8 177.1, 171.1, 156.3, 149.3, 146.7, 142.4, 119.7 89.6, 86.0, 85.5, 81.6, 74.0, 72.2, 51.2, 43.2, 36.8,34.2, 31.8,28.9, 26.2, 14.4; HRMS (FAB) m/z 487.2325 [(M + H)+ cacld for C23H31N6O6 487.2305]. The reaction of 87 with 2-IodoNECA under the general conditions described above gave 111 (78 mg, 62%) as a white solid. 1H NMR (CD3OD)  8.22 (s, 1 H), 5.92 (d, J = 8.1 Hz, 1 H), 4.70 - 4.66 (dd, J = 8.1 Hz, 4.6 Hz, 1 H), 4.40 (d, J = 1.2 Hz, 1 H), 4.25 - 4.23 (dd, J = 4.6 Hz, 1.2 Hz, 1 H), 3.83 (d, J = 6.5, 2 H), 3.53 - 3.31 (m, 2 H), 2.29 (d, J = 6.5 Hz, 2 H), 1.97 (s, 3 H), 1.93 - 1.89 (m, 2 H), 1.79 - 1.75 (m, 2 H), 1.64- 1.42 (m, 2 H), 1.12 (t, J = 7.3 Hz, 3 H), 1.09-0.91 (m,4H); 13C NMR (CD3OD) 5 172.0, 171.2, 156.2, 149.3, 146.7, 142.5, 119.7, 89.6, 86.3, 85.5, 81.5, 74.0, 72.2, 69.6, 37.4, 37.2, 34.2, 32.1,29.4,26.4, 19.9,14.5; HRMS (FAB) m/z 501.2469 [(M + H)+ cacld for C24H33N6O6 501.2462]. The reaction of 86 (30 mg, 0.2 mmol) with 2-IodoNECA (28 mg, 0.07 mmol) under the general conditions described above gave 112 (7 mg, 24%) as a white solid. 1H NMR (CD3OD) δ 8.22 (s, 1 H), 5.92 (d, J = 7.7 Hz, 1 H), 4.70 - 4.66 (dd, J = 7.7 Hz, 4.8 Hz, 1 H), 4.40 (d, J = 1.2 Hz, 1 H), 4.25 - 4.23 (dd, J = 4.8 Hz, 1.2 Hz, 1 H), 3.51 - 3.37 (m, 2 H), 3.31 (d, J = 6 Hz, 2 H), 2.30 (d, J = 6.8 Hz, 2 H), 1.94 - 1.89 (m, 2 H), 1.83 - 1.78 (m, 2 H), 1.64 - 1.42 (m, 2 H), 1.12 (t, J = 7.3 Hz, 3 H), 1.09 - 0.91 (m, 4 H); 13C NMR (CD3OD) δ 170.3, 155.4, 148.5, 146.0, 141.6, 118.8, 88.7, 85.5, 84.6, 80.6, 73.1, 71.3, 66.S, 39.6, 36.9,33.3,31.5,28.6,25.6,13.5; HRMS (FAB) m/z 459.2373 [(M + H)+cacld for C22H31N6O5 459.2356]. To a sealed tube containing 5 mL of freshly distilled ethylamine was added 10 mg (0.02 mmol) of ATL146e. The flask was sealed and allowed to stir at 60°C for 80hours. After this time the reaction was only about 50% complete by HPLC. The vessel was cooled to 0°C, opened, and the ethylamine was removed in vacuo to yield 4.5 mg (73%) of JR3037 as a white solid and the recovery of 4.0 mg of starting material after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) δ. 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 500.8 (MET+, 100), 327.4(3). To a sealed tube containing 10 mL of saturated MeOH/NH3 solution was added 5 mg (0.01 mmol) of ATL146e. The flask was sealed and allowed to stir at 25°C for 48hburs. The vessel was cooled to 0°C, opened, and the ammonia removed by bubbling N2 for 1 hour. The remaining solvent was then removed in vacuo to yield 4.0 mg (83%) of JR3055 as a white solid after the residue was purified by RP-HPLC. lH NMR (CD3OD-dO δ 8.41 (s, 1 H), 5.98 (d, J = 7.2 Hz, 1H), 4.65 (dd, J = 7.3 Hz, 4.8 Hz, 1 H), 4.41 (d, J = 2.0 Hz, 1 H), 4.28 (dd, J = 4.6 Hz, 2.0 Hz, 1 H), 3.35 (m, 2 H), 2,37 (d, J= 6,4 Hz, 2 H) 2.10 (m, 1 H), 1.90 (m, _ H), 1.53 (m, _ HJ, 1.23 (m, _ H), 1,12 (t, J = 7.3 Hz, 3 H). 13C NMR (CD3OD-d4) 5. APCI m/z (rel intensity) 472.3 (MH+, 100), 299.4(10). To a sealed tube containing 10 mL 2.0 M methylamine in methanol was added 16.5 mg (0.03 mmol) of ATL146e. The flask was sealed and allowed to stir at 70°C for 120hours. The vessel was cooled to 0°C, opened, and the solvent was removed in vacuo to yield 8.0 mg (48%) of JR3065 as a white solid after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) δ. l3CNMR (CD3OD-d4) δ. APCI m/z (rel intensity) 486.3 (MH+, 100), 313.4(35). The title compound was prepared using the appropriate starting materials and procedures described herein. The results are as follows: 1H NMR (CD3OD-d4) δ 8.48 (s, 1 H), 6.04 (d, J = 6.9 Hz, 1 H), 4.72 (dd, J = 6.9 Hz, J = 4.4 Hz, 1 H), 4.46 (d, J = 2.3 Hz, 1 H), 4.33 (dd, J = 4.6 Hz, J = 1.9 Hz, 1 H), 3.42 (m, 2 H), 2.04 (m, 4 H), 1.83, (m, 4 H), 1.16 (t, J = 7.3 Hz, 3 H). 13C NMR (CD3OD-Q4) 5 171.9, 155.3, 150.0, 144.3, 120.6, 95.4, 90.6, 89.5, 86.2, 79.9, 74.9, 74.0, 70.5, 42.9, 35.3, 24.4, 15.3. APCI m/z (rel intensity) 417.2 (MH+, 100), 399.4(85), 244.3(15), 26.5(25). HRMS M* actual 417.18864, observed 417.18880. The title compound was prepared using the appropriate starting materials and procedures described herein. The results are as follows: 1H NMR (CD3OD-d4) 5 8.57 (s, 1 H), 6.09 (d, J = 6.6 Hz, 1 H), 4.77 (dd, J = 6.7, Hz, J = 4.8 Hz, 1 H), 4.46 (d, J = 2.3 Hz, 1 H), 4.37 (dd, J = 4.6 Hz, J = 2.3 Hz, 1 H), 3.42 (m, 2 H) 1.80 (m, 13 H), 1.28 (m, 9 H), 1.13 (t, J = 7.3 Hz, 3 H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 527.3 (MH+, 60), 509.5(100), 354.4(5), 336.5(5), 279.5(8). HRMS M+ actual 527.29819, observed 527.29830 The title compound was prepared using the appropriate starting materials and procedures described herein. The results are as follows: 1H NMR (CD3OD-d4) δ 8.51 (s, 1 H), 6.06 (d, J = 7.0 Hz, 1 H), 4.75 (dd, J = 6.4 Hz, J = 4.9 Hz, 1 H), 4.46 (d, J = 1.9 Hz, 1 H), 4.34 (dd, J = 4.9 Hz, J = 2.1 Hz, 1 H), 3.42 (m, 2 H), 2.12 (d, J = 11.9 Hz, 2 H), 1.80 (d, J = 11.9 Hz, 2 H), 1.5S(t,J=12.1 Hz, 2H), 1.28 (m,4H), 1.15 (t, J = 7.1 Hz, 3 H), 0.91 (t, J = 7.1 Hz, 3 H). I3C NMR (CD3OD-d4) δ 171.9, 155.4,150.0, 144.2, 143.8,120.6, 94.5, 90.5, 86.1, 81.8, 74.9, 74.1, 70.3, 40.5, 39.8, 35.3, 31.0, 30.2, 15.2, 12.0. APCI m/z (rel intensity) 459.4 (MH+, 100), 441.4(60), 268.4(10). HRMS M4 actual 459.23559, observed 459.23550. The title compound was prepared using the appropriate starting materials and procedures described herein. The results are as follows: 1H NMR (CD3OD-d4) 8 8.45 (s, 1 H), 7.26 (m, 4 H), 7.14 (m, 1 H), 6.05 (d, J = 7.3 Hz, 1 H), 4.80 (dd, J = 7.3 Hz, J = 4.8 Hz, 1 H), 4.46 (d, J = 1.6 Hz, 1 H), 4.34 (dd, J = 4.7 Hz, J = 1.8 Hz, 1 H), 3.44 (m, 2 H), 2.58 (m, 1 H), 2.23 (d, J = 11.7 H, 2 H), 1.92 (m, 4 H), 1.78, (m, 2 H), 1.15 (t, J = 7.2 Hz, 3 H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 507.3 (MH+, 100) 489.4(70), 334.3(5), 316.5(8). HRMS M+ actual 507.23559, observed 507.23580. The title compound was prepared using the appropriate starting materials and procedures described herein. The results are as follows: 1H NMR (CD3OD-d4) 5 8.54 (s, 1 H), 6.04 (d, J = 6.9 Hz, 1 H), 4.74 (dd, J = 6.9 Hz, J = 5.0 Hz, 1 H), 4.46 (d, J = 1.9 Hz, 1 H), 4.34 (dd, J = 4.7 Hz, J = 1.9 Hz, 1 H), 3.44 (m, 2 H), 1.74 (s, 4 H), 1.13 (m, 17 H). APCI m/z (rel intensity) 487.3 (MH+, 75), 469.4(100), 296.4 (10). The reaction of l-Ethynyl-2-methyl-cyclohexanol (JR3169B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 mmol) under the general coupling conditions gave JR3177A (8.0 mg) and JR3177B (8.2 mg) (overall yield 65%) as white solids after purification by a silica plug and RP-HPLC. JR3177A: 1H NMR (CD3OD-d4) δ 8.47 (s, 1 H), 6.05 (d, J = 6.9 Hz, 1 H), 4.77 (dd, J = 6.9 Hz, J = 4.9 Hz, 1 H), 4.45 (d, J = 1.9 Hz, 1 H), 4.34 (dd, J = 4.6 Hz, J = 2.1 Hz, 1 H), 3.41 (m, 2 H), 2.13 (d, J = 12.7 Hz, 2 H), 1.65 (m, 5 H), 1.32 (m, 2 H), 1.14 (t, J = 7.0 Hz, 3 H), 1.13 (d, J = 6.6 Hz, 3 H).. 13C NMR (CD3OD-d4 δ. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4(80), 254.4(14). lH NMR (CD3OD-d4) 8 8.49 (s, 1 H), 6.05 (d, J = 6.9 Hz, 1 H), 4.78 (dd, J = 6.4 Hz, J = 4.9 Hz, 1 H), 4.45 (d, J = 1.9 Hz, 1 H), 4.34 (dd, J = 4.6 Hz, J = 1.6 Hz, 1 H), 3.42 (m, 2 H), 2.12 (d, J = 12.3 Hz, 2 H), 1.65 (m, 4 H), 1.35 (m, 4 H), 1.14 (t, J = 7.3 Hz, 3 H), 1.12 (d, J = 6.6 Hz, 3 H). I3C NMR (CD3OD-CI4) 8. APCI m/z (rel intensity) 445.7 (MH+, 100), 427.3(35), 254.4(3.5). The reaction of l-Ethynyl-3-methyl-cyclohexanol (JR3149B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 nirnol) under the general coupling conditions gave JR3179 (15.0 mg, 59%) as a white solid after purification by a silica plug and RP-HPLC. 1H NMR (CD3OD-d4) δ 8.49 (s, 1 H), 6.06 (d, J = 6.9 Hz, 1 H), 4.75 (dd, J = 6.4 Hz, J = 4.9 Hz, 1 H), 4.46 (d, J = 1.9 Hz, 1 H), 4.34 (dd, J = 4.9 Hz, J = 2.1 Hz, 1 H), 3.42 (m, 2 H), 2.09 (d, J = 12.3 Hz, 2 H), 1.73 (m, 4 H), 1.46 (m, 1 H), 1.23 (m, 1 H), 1.16 9 (t, J = 7.1 Hz, 3 H), 0.95 (d, J = 6.2 Hz, 3 H), 0.89 (m, 1 H). 13C NMR (CD3OD-d4) 5. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4(40), 254.4(4). The title compound was prepared using the appropriate starting materials and procedures described herein. The results are as follows: lH NMR (CD3OD-d4) δ 8.48 (s, 1 H), 6.00 (d, J = 6.9 Hz, 1 H), 4.67 (dd, J = 6.5 Hz, J = 5.0 Hz, 1 H), 4.42 (d, J = 1.9 Hz, 1 H)), 4.39 (s, 2 H), 4.35 (dd, J = 4.7 Hz, J = 1.9 Hz, 1 H), 4,13 (q,) 3.42 (m, 2 H),. 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 503.4 (MH+. 100), 330.3 (6). 35 mg (0.081 mmol) IodoNECA (62mg alkyne, 0.41mmol), 2ml DMF, 4ml Acetonitrile, 0.2ml TEA, d(PPH3)4, CuI. Stirred overnight at room temperature (11/29/01). Rxn is tan w/ brown precipitate. TLC (20%MeOH/CH2C12) indicates rxn complete (r.f. INECA = 0.67, r.f. product = 0.45). Filtered mixture through celite, washed with 3x2mL DMF, and evaporated under vacuum to brown oil. (solid precipitates out upon the addition of MeOH, thus used DMF to load on prep plate). The following compounds can be prepared by following the general method 4 described herein and the appropriate intermediate compounds described herein. Yield 3.4 mg, 10%. lH NMR (CD3OD) δ 1.18 (t, 3H, -NHCH2CH3), 1.03-1.20, 1.51-1.70, 1.79-1.85,1.94-2.01 (4 x m, 10H, cyclohexyl), 2.35 (d, 2H, -C6Hi0CH2CC-), 3.46 (m, 2H, -NHCH2CH3), 3.73 (s, 3H, -OCH3), 3.94 (d, 2H, -C6H10CH2O-), 4.29 (dd, 1H, 3'-H), 4.45 (d, 1H, 4'-H), 4.72 (dd, 1H, 2'-H), 5.97 (d, 1H, l'-H), 8.27 (s, 1H, 8-H). APCIm/z 517.4 (M+H+). Yield 8.5 mg, 30%. 1H NMR (CD3OD) δ 0.94 (d, 4H, -OCH2CH(CH3)2), 1-18 (t, 3H, -NHCH2CH3), 1.04-1.24, 1.54-1.72, 1.79-2.03 (3 x m, 11H, cyclohexyl, -OCH2CH(CH3)2), 2.38 (d, 2H, -C6H10CH2CC-), 3.43 (m, 2H, -NHCH2CH3), 3.89, 3.94 (2 x d, 4H, -C6HioCH20-, -OCH2CH(CH3)2), 4.30 (dd, 1H, 3'-H), 4.46 (d, 1H, 4'-H), 4.71 (dd, 1H, 2'-H), 6.00 (d, 1H, l'-H), 8.37 (br s, 1H, 8-H). APCI m/z 559.5 (M+H+). Yield 1.0 mg, 3%. 1H NMR (CD3OD) 5 1.17 (t, 3H, -NHCH2CH3), 1.03-1.23, 1.52-1.71, 1.78-1.86,1.93-2.02 (4 x m, 10H, cyclohexyl), 2.35 (d, 2H, -C6H10CH2CC-), 3.45 (m, 2H, -NHCH2CH3), 3.97 (d, 2H, -C6H10CH2O-), 4.29 (dd, 1H, 3'-H), 4.45 (d, 1H, 4'-H), 4.72 (dd, 1H, 2'-H), 5.13 (s, 2H, -OCH2Ph), 5.97 (d, 1H, l'-H), 7.33-7.37(m, 5H, Ar), 8.30 (br s, 1H, 8-H). APCI m/z 593.3 (M+H+). Example 52: Cell culture and membrane preparation. Sf9 cells were cultured in Grace's medium supplemented with 10% fetal bovine serum, 2.5 µg/ml amphotericin B and 50 µg/m.1 gentamycin in an atmosphere of 50% N2/50% O2. Viral infection was performed at a density of 2.5xl06 cells/mL with a multiplicity of infection of two for each virus used. Infected cells were harvested 3 days post-infection and washed twice in insect PBS (PBS pH 6.3). Cells were then resuspended in lysis buffer (20 mM HEPES pH 7.5, 150 mM NaCl, 3mM MgCl2, ImM p-mercaptoethanol (BME), 5µg/mL leupeptin, 5µg/mL pepstatin A, 1 ug/mL aprotinin, and O.lmM PMSF) and snap frozen for storage at - 80°C. Cells were thawed on ice, brought to 30 mL total volume in lysis buffer, and burst by N2 cavitation (600 psi for 20 minutes). A low-speed centrifugation was performed to remove any unlysed cells (1000 x g for 10 minutes), followed by a high-speed centrifugation (17,000 x g for 30 minutes). The pellet from the final centrifugation was homogenized in buffer containing 20 mM HEPES pH 8, 100mM NaCl, 1% glycerol, 2 µg/mL leupeptin, 2 µg/mL pepstatin A, 2 ug/mL Aprotinin, 0.1 mM PMSF, and 10 pM GDP using a small glass homogenizer followed by passage through a 26 gauge needle. Membranes were aliquoted, snap frozen in liquid N2, and stored at -80°C. Membranes from cells stably expressing the human Ai AR (CHO Kl cells) or A3 AR (HEK 293 cells) were prepared as described (Robeva et al., 1996). Example 53:Radioligand Binding Assays. Radioligand binding to recombinant human A2A receptors in Sf9 cell membranes was performed using either the radiolabeled agonist, I-APE (Luthin et al, 1995) or the radiolabeled antagonist, 125I-ZM241385 (125I-ZM). To detect the high affinity, GTPyS-sensitive state of A1 and A3 AR, we used the agonist, I25I-ABA (Linden et al, 1985;Lindenef al., 1993). Binding experiments were performed in triplicate with 5 pg (A2A) or 25 pg (A1 and A3) membrane protein in a total volume of 0. lmL HE buffer (20 mM HEPES and 1 mM EDTA) with1 U/mL adenosine deaminase and 5 mM MgCl2 with or without 50 µM GTPS. Membranes were incubated with radioligands at room temperature for three hours (for agonists) or two hours (for antagonists) in Millipore Multiscreen® 96-well GF/C filter plates and assays were terminated by rapid filtration on a cell harvester (Brandel, Gaithersburg, MD) followed by 4 x 150 µl washes over 30 seconds with ice cold 10 mM Tris-HCl, pH 7.4, 10 mM MgCl2. Nonspecific binding was measured in the presence of 50 µM NEC A. Competition binding assays were performed as described (Robeva et ai, 1996) using 0.5-1 nM 125I-APE, 125I-ZM241385, or l25I-ABA. We found that it was sometimes important to change pipette tips following each serial dilution to prevent transfer on tips of potent hydrophobic compounds. The Ki-values for competing compound binding to a single site were derived from IC50 values with correction for radioligand and competing compound depletion as described previously (Linden, 1982). Linden J (1982) Calculating the Dissociation Constant of an Unlabeled Compound From the Concentration Required to Displace Radiolabel Binding by 50%. J Cycl Nucl Res 8: 163-172. Linden J, Patel A and Sadek S (1985) [125I]Aminobenzyladenosine, a New Radioligand With Improved Specific Binding to Adenosine Receptors in Heart. Circ Res 56: 279-284. Linden J, Taylor HE, Robeva AS, Tucker AL, Stehle JH, Rivkees SA, Fink JS and Reppert SM (1993) Molecular Cloning and Functional Expression of a Sheep A3 Adenosine Receptor With Widespread Tissue Distribution. Mol Pharmacol 44: 524-532. Luthin DR, Olsson RA, Thompson RD, Sawmiller DR and Linden J (1995) Characterization of Two Affinity States of Adenosine A2A Receptors With a New Radioligand, 2-[2-(4-Amino-3- [125I]Iodophenyl)EthyIamino]Adenosine. Mol Pharmacol 47: 307-313. Robeva AS, Woodard R, Luthin DR, Taylor HE and Linden J (1996) Double Tagging Recombinant A1- and A2A-Adenosine Receptors With Hexahistidine and the FLAG Epitope. Development of an Efficient Generic Protein Purification Procedure. Biochem Pharmacol 51: 545-555. Chemiluminescence Methods: Luminol enhanced chemiluminescence, a measure of neutrophil oxidative activity, is dependent upon both superoxide production and mobilization of the granule enzyme myeloperoxidase. The light is emitted from unstable high-energy oxygen species such as hypochlorous acid and singlet oxygen generated by activated neutrophils. Purified human neutrophils (2 X 106/ml) suspended in Hanks balanced salt solution containing 0.1% human serum albumin (HA), adenosine deaminase (1U/mL) and rolipram (100 nM) were incubated (37C) in a water bath for 15 min with or without rhTNF(10U/ml). Following incubation 100 L aliquots of the PMN were transferred to wells (White walled clear bottom 96 well tissue culture plates Costar #3670; 2 wells /condition) containing 501 HA and luminol (final concentration 100M) with or without adenosine agonist (final agonist concentrations 0.01-1000nM). The plate was incubated 5 min (37C) and then fMLP (50 1 in HA; final concentration 1M) was added to all wells. Peak chemiluminescence was determined with a Victor 1420 Multilabel Counter in the chemiluminescence mode using the Wallac Workstation software. Data are presented as peak chemiluminescence as percent of activity in the absence of an adenosine agonist. The EC50 was determined using PRISM software. All compounds were tested with PMNs from three separate donors. The results are summarized in Table 8. Example 54: Effect of A2A Agonists on Neutrophil Oxidative Activity A. Materials. f-met-leu-phe (fMLP), luminol, superoxide dismutase, cytochrome C, fibrinogen, adenosine deaminase, and trypan blue were obtained from Sigma Chemical. Ficoll-hypaque was purchased from ICN (Aurora, OH), and Cardinal Scientific (Santa Fe, NM) and Accurate Chemicals and Scientific (Westerbury, NY), endotoxin (lipopolysaccharide; E. coli K235) was from List Biologicals (Campbell, CA). Hanks balanced salt solution (HBSS), and limulus amebocyte lysate assay kit were from BioWittaker (Walkersville, MD). Human serum albumin (HS A) was from Cutter Biological (Elkhart, IN). Recombinant human tumor necrosis factor-alpha was supplied by Dianippon Pharmaceutical Co. Ltd. (Osaka, Japan). ZM241385 (4-(2-[7-ammo-2-(2-furyl)[ 1,2,4]- triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol) was a gift from Simon Poucher, Zeneca Pharmaceuticals, Cheshire, UK. Stock solutions (1 mM and 10 mM in DMSO) were made and stored at -20°C. B. Human neutrophil preparation Purified neutrophils (-98% neutrophils and >95% viable by trypan blue exclusion) containing endotoxin (limulus amebocyte lysate assay) were obtained from normal heparinized (10 U/ml) venous blood by a one step Ficoll-hypaque separation procedure (A. Ferrante et al., J. Immunol. Meth., 36, 109 (1980)). C. Release of inflammatory reactive oxygen species from primed and stimulated human neutrophils Chemiluminescence Luminol-enhanced chemiluminescence, a measure of neutrophil oxidative activity, is dependent upon both superoxide production and mobilization of the lysosomal granule enzyme myeloperoxidase. The light is emitted from unstable high-energy oxygen species generated by activated neutrophils. Purified neutrophils (5-10 x 105/ml) were incubated in Hanks balanced salt solution containing 0.1% human serum albumin (1 ml) with the tested A2A agonist with or without rolipram and with or without tumor necrosis factor-alpha (1 U/ml) for 30 minutes at 37°C in a shaking water bath. Then luminol (1 x 10-4 M) enhanced f-met-leu-phe (1 mcM) stimulated chemiluminescence was read with a Chronolog® Photometer (C1-ono-log Corp., Havertown, PA) at 37°C for 2-4 minutes. Chemilurninescence is reported as relative peak light emitted (= height of the curve) compared to samples with tumor necrosis factor-alpha and without agonist or rolipram. Example 55. In vivo rat blood pressure experiments. Sprague-Dawley rats (mean weights, 250-300 grams) were anthesthetized and jugular and carotid catheters are implanted ipsilaterally and the animals are allowed to recover 24-48 hours. Prior to each experiment a baseline blood pressure reading is established for 30 minutes with each drug injection being preceeded by a vehicle control. Drags are injected bolus I.V. through a jugular catheter in a 200 microliter volume of saline and the catheter is flushed with an additional 300 microliters of saline. To measure blood pressure, a central line from the carotid catheter is attached to the pressure transducer of a Digi-Med Blood Pressure Analyzer. Systolic pressure, diastolic pressure, mean pressure, and heart rate are all recorded in real time at 30-60 second intervals. Data is recorded until mean blood pressure has returned to baseline and remained constant for 20 minutes. The data is presented as a fraction of the mean blood pressure averaged over the 10 minutes immediately prior to drug injection. The blood pressures are recorded and plotted over time as a means of determining potency of the compounds as well as biological half-life. The results are illustrated in Figures 1-6. EXAMPLE 56. In vivo Coronary Dog Flow Experiments Fasted, adult mongrel dogs (mean weight, 24.8+0.6 kg; range, 20.9 to 28.2 kg) were anaesthetized with sodium pentobarbital (30 mg-kg"1), tracheally intubated, and mechanically ventilated with room air on a respirator (model 613, Harvard Apparatus) with positive end-expiratory pressure of 5 cm H2O. The surgical preparation and instrumentation of the animals has been thoroughly described previously (Glover D.K. et al., Circulation 1996,94, pages 1726-1732). Throughout each experiment, heart rate, mean arterial and left atrial pressures, ulrrasonically measured LCx flow, and dP/dt were continuously monitored and recorded on a 16-channel thermal array chart recorder (K2-G, Astro-med, Iac) and digitised and stored on an IBM-compatible personal computer. All experiments were performed with the approval of the University of Virginia Animal Care and Use Committee and were in compliance with the position of the American Heart Association on the use of research animals. The compounds tested were intravenously administered by bolus injection and the parameters above were measured and recorded. The results are illustrated in Figures 7-16. Example 57: Liver I/R injury protocol. Mice were anesthetized by intraperitoneal injection of ketamine 100 mg/kg and xylazine 10 mg/kg. Glycopyrrolate (Robinul-V) 0.05 mg/kg was delivered subcutaneously before the operation. The ambient temperature was controlled in the range of 24°C to 26°C. Mice were placed on a 37°C heat pad with their core temperature monitored by a TH-S Thermalert Monitoring Thermometer (Physitemp) and maintained at 36-37°C by a TCAT-1A Temperature Control and Alarm Unit (Physitemp) during the entire procedure. After midline laparotomy, a microaneurysm clip was applied to the hepatic triad above the bifurcation to clamp the flow of the hepatic artery, portal vein, and bile duct. The peritoneum was closed after superfusion of 200 u.1 of warm saline. After 60 minutes of ischemia, the peritoneum was reopened and the microaneurysm clip was removed. Immediately after reperfusion was initiated, each mouse received a loading dose of ATL-146e (1 ug/kg) or vehicle in 200 uL warm saline, and a primed Alzet osmotic minipump was placed intraperitoneally. The surgical wound was closed with metal staples. Mice were maintained on the heat pad to monitor and maintain body temperature until the anesthetic wore off. Drug Administration. Alzet osmotic minipumps (model 1003D; Alza Corp., Palo Alto, CA, USA) were primed according to the manufacture's instruction in order to release compounds shortly after implantation. A solution containing ATL146e was prepared in normal saline and placed in osmotic minipumps to deliver 10 ng/kg/min. Minipumps containing vehicle or ATL146e were implanted during operation. Example 58: Serum enzyme determination Serum GPT (ALT) levels were measured using a Transaminase kit (505, Sigma). Briefly, 20 uL serum sample was mixed with 100 (L pre-heated Alanine-a-KG substrate and incubated in a 37 °C water bath for 30 minutes. Then we added 100 (L Sigma Color Reagent to the reaction and left it at room temperature for 20 minutes. We stopped the reaction with 1.0 ml 0.4N sodium hydroxide solution. Absorbance of each sample at 505 nm was measured and converted into SF unit/ml. Example 59: Tissue myeloperoxidase measurement Mouse livers were removed after 24 hours reperfusion. The tissue was immediately submerged in 10 volumes of ice-cold 50 mM KP04 buffer, pH 7.4 and homogenized with a Tekmar tissue grinder. The homogenate was centrifuged at 15,000 x g for 15 minutes at 4oC, and the supernatant was discarded. The pellet was washed twice, resuspended in 10 volumes of ice-cold 50 mM KP04 buffer pH 7.4 with 0.5% hexadecyltrimethylammonium bromide and then sonicated. The suspension was subjected to three freeze/thaw cycles. Samples were sonicated for 10 seconds, and centrifuged at 15,000 x g for 15 minutes at 4oC. The supernatant was added to an equal volume of a solution consisting of o-dianisidine (10mg/ml), 0.3% H202, and 50 mM KP04, pH 6.0. Absorbance was measured at 460 nm over a period of five minutes. Figure 17 illustrates the longer duration of action of JR3223 vs. a control compound and ATL146e for liver tissue protection after an ischemia/reperfusion injury. The test compounds were administered 6 hours prior to I/R injury. Tissue protection is measured by amount of Serum GPT present in the in a serum sample 24 hours later, with smaller GPT concentrations indicating better liver function. All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. WE CLAIM: I. A compound having formula (I): wherein Z is CR3R4R5; each R1 is independently hydrogen, halo, -OR2, -SRS, (C1-C8)alkyl, cyano, nitro, tiifluoromethyl, trifluoromethoxy, C3-8cycloalkyl, heterocyclyl, heterocycIyl(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene', -CO2Ra, R4C(=0)0-, RaC(-O)-, -OCO2Ra, RaRbNC(=O)O-, RbOC(=0)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-, RaOC(=S)-, RaC(=S)-, -SSRa, RaS(=O)-, RaSO-O)2-, or -N=NRa; each R2 is independently hydrogen, halo, (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocyclyl, heterocyclyl(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, or heteroaryl(C1-C8)alkylene-; or R1 and R2 and the atom to which they are attached is C=0, C=S, or C=NRC. R4.and R5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (-0-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S(O)2-), or amine (-NR'-) in the ring; wherein any ring comprising CR3R4R5 is substituted with from 1 to 14 R6 groups at any position other than at the 1-position; wherein each R6 is independently halo, -OR", -SRa, (C1-C8)alkyl, cyano, nitro, tiifluoromethyl, trifluoromethoxy, (C1-C8)cycloalkyl, (C6-C12)bicycloaIkyl, heterocyclyl, heterocyclyI(C1-C8)alkylene-, aryl, aryl (C,-Cg)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene-, -CO2R4, RaC(=O)O-, RaC(=O)-, -OCO2Ra, RaRbNC(=O)O-, RbOC(=O)N(Ra)-, RaRbN, RaRbNC(=O)-, RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-, RaOC(=S)-, RaC(=S)-, -SSRa, RaS(=O)-, or -NNRa; or two R6 groups and the atom to which they are attached is C=O or C=S; or two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring; R3 is hydrogen, halo, -ORa, -SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocyclyl, heterocyclyl(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylcnc-, -CO2Ra, RaC(=O)O-, RuC(=O)-, -OCO2R2 RaRbNCC-O)O-, RbOC(=O)N(Ra)-, RaRbN-, RaRbNC(=O)-, RaC(=O)N(Rb)-, R"RbNC(=O)N(Rb)-, RaRbNC(=S)N(Rb)-,RaOC(=S)-, RaC(=S)-, -SSRa, RaS(=O)-, RaS(=O)2-, or -NNRa; or if the ring formed from CR4R5 is partially unsaturated then R3 can be absent; each R7 is independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, aryl(C1-C8)alkylene, heteroaryl, or hetcroaryl(C1-C8)alkylcne-; X is -CH2ORa, -CO2Ra, -OC(O)R3 -CH2OC(O)Ra, -C(O)NRaRb, -CH2SRa, -C(S)ORa, -OC(S)R3, -CH2OC(S)Ra, C(S)NRaRb, or -CH2N(Ra)(Rb); wherein any of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, groups of R1, R2, R3, R6, and R7is optionally substituted on carbon with one or more substituents selected from the group consisting of halo, -ORa, -SRa (C1-C8)alkyl, cyano, nitro, trifjuoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocyclyl, heterocydyl(C1-C8)alkylene-, aryl, aryloxy, aryl (C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)a]kylene-, -CO2Ra, RaC(=O)O-, RaC(=O)-, -OCO2Ra, RaRbNC(=O)O-. RbOC(=O)N(Ra), RaRbN-, RaRbNC(=O)-, RaC(=O)N(Rb)-, RaRbNC(=O)N(Rb)-, RuRbNC(=S)N(Rb)-, RaOC(=S)-, R8C(=S), -SSRa, RaS(=O)p--, RaRbNS(O)p-, and N=NRa; wherein any (C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, (C1-C8)alkoxy, (C1-C8)alkanoyl, (C1-C8)alkylene, or heterocyclyl, is optionally partially unsaturated; Ra and Rb are each independently hydrogen, (C1-C8)alkyl, or (C1-C8)alkyl substituted with 1-3 (C1-C8)alkoxy, (C3-C8)cycloalkyl, (C1-C8)alkylthio, amino acid, aryl, aryl(C1-C8)alkylene, heteroaryl, or heteroaryl(C1-C8)alkylene; or Ra and Rb together with the nitrogen to which they are attached, form a pyrrolidine, piperidino, morpholino, or thiomorpholino ring; and Rc is hydrogen or (C1-C6)alkyl; m is 0 to about 8 and p is 0 to 2; or a pharmaceutically acceptable salt thereof. 2. The compound as claimed in claim 1, wherein R1 is hydrogen, -OH,-CHzOH. -OMe, -OAc,-NH2, -NHMe, -NMe2, or -NHAc. 3. The compound as claimed in claims 1 or 2. wherein R1 is hydrogen, -OH, -OMe,-; -OAc, -NH2, -NHMe, -NMe2, or -NHAc. 4. The compound as claimed in claims 1, 2, or 3, wherein R1 is hydrogen, OH, OMe, or NH2. 5. The compound as claimed in claims 1,2, or 3, wherein R1 is hydrogen, OH, or NH2 6. The compound as claimed in any of claims 1-5, wherein R1 is hydrogen or OH. 7. The compound as claimed in any of claims 1-6, wherein R2 is hydrogen, (C1-C8)alkyl, cyclopropyl, cyclohexyl, or benzyL 8. The compound as claimed in any of claims 1-7, wherein R2 is hydrogen, methyl, ethyl, or propyl. 9. The compound as claimed in any of claims 1-8, wherein R2 is hydrogen or methyl. 10. The compound as claimed in any of claims 1-9, wherein R2 is hydrogen. 11. The compound as claimed in claim 1, wherein R', R2 and the carbon atom to which they are attached is carbonyl (C=O). 12. The compound as claimed in any of claims 1-11, wherein R3 is hydrogen, OH, OMe, OAc, NH2, NHMe, NMe2, or NHAc. 13. The compound as claimed in any of claims 1-12, wherein R3 is hydrogen, OH, OMe, or NH2 14. The compound as claimed in any of claims 1-13, wherein R3 is hydrogen, OH, or NH2 15. The compound as claimed in any of claims 1-14, wherein R3 is hydrogen or OH. 16. The compound as claimed in any of claims 1-15, wherein the ring comprising R4, R5, and the atom to which they are connected is piperidine, dihydro-pyridine, tetrahydro-pyridine, piperazine, tetrahydro-pyrazine, dihydro-pyrazine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrirnidine, dihydro-imidazole, imidazolidine, dihydro-pyrazole, and pyrazolidine. 17. The compound as claimed in any of claims 1-16, wherein R6 is (C1-C8)alkyl, substituted (C1-C8) alkyl, -ORa, -CO2Ra, RaC(=O)-, RaC(=O)-, Ra Rb N-, Ra Rb NC(=O)-, or aryl. 18. The compound as claimed in any of claims 1-17, wherein R6 is (C1-C8)alkyl, -ORa, -CO2R, RaC(=O)-, RaC(=O)-, Ra Rb N-, Ra Rb NC(=O)-, or aryl. 19. The compound as claimed in any of claims 1-18, wherein R6 is methyl, ethyl, butyl. OH, ORa, -CO2Ra, RaC(=O)-, OC(=O)CH2CH3, -CONRa Rb, NRa Rb, or phenyl. 20. The compound as claimed in any of claims 1-19, wherein R6 is OH, OMe, methyl, ethyl, t-butyl, -C02Ra, -CONRa Rb, OAc, NH2, NHMe, NMe2, NHEt, or N(Et)2. 21. The compound as claimed in any of claims 1-20, wherein R6 is methyl, ethyl, t-butyl, -CO2Ra, -CONRa Rb, or -(=O)CRa. 22. The compound as claimed in any of claims 1-21, wherein R6 is methyl, ethyl, -CO2Ra, -CONRa Rb, or -OAc. 23. The compound as claimed in any of claims 1-16, wherein R6 is-(CH2)1-2ORa -(CH2),.2C(=O)ORa, -(CH2)1-2OC(=O)Ra, -(CH2)1-2C(=Q)Ra, -(CH2),.2OCO2Ra, -(CH2)-1-2NHRa, -(CH2)1-2NRa Rb, -(CH2)1-2OC(=O)NHRa, or(CH2),.2OC(=O)NRa Rb 24. The compound as claimed in claim 23, wherein R6 is -CH20H, -CH20Ac, -CH20CH), -CH2C(=O)OCH), -CH20C(=O)CHJ, -CH2C(=O)CH3, -CH20CO2CHJ, -CH1 NH(CH3),or- {CH2) 1 -2N(CH. 1 )2. 25. The compound as claimed in claim 24, wherein R6 is -CHzOH, -CH20Ac, -CHIC (=O)OCH3, CH2C(=O)CH3, _CH20CChCH3, -CH2NH(CH3), or -(CH2)l-2N(CH3h. 26. The compound as claimed in any of claims 1-25, wherein number of R6 groups substituted on the R4R5 ring is from 1,2,3, or 4. 27. The compound as claimed in any of claims 1-26, wherein Ra and Rb are hydrogen, (C1-C4)alkyl, aryl, or aryl(C1-C8)alkylene. 28. The compound as claimed in any of claims 1-27, wherein Ra and Rb are hydrogen, methyl,ethyl, phenyl, or benzyl. 29. The compound as claimed in any of claims 1-28, wherein Ra is (C1-C8)alkyl. 30. The compound as claimed in any of claims 1-29, wherein Rb is methyl, ethyl, propyl, or butyl. 31. The compound as claimed in any of claims 1-30, wherein Ra is methyl, ethyl, i- propyl, i-butyl, or tert-butyl. 32. The compound as claimed in any of claims 1-31, wherein Ra and Rb is a ring. 33. The compound as claimed in any of claims 1-32, wherein R7 is hydrogen, alkyl, aryl, or aryl(Ci-C8)alkylene. 34. The compound as claimed in any of claims 1-33, wherein R7 is hydrogen, methyl, ethyl, phenyl, or benzyl. 35. The compound as claimed in any of claims 1-34, wherein R7 is H or methyl. 36. The compound as claimed in any of claims 1-35, wherein N(R7 )2 is amino, methylamino, dimethylamino, ethylarnino, pentylamino, diphenylethylamino, diethylamino, or benzylamino. 37. The compound as claimed in claim 36, wherein-N(R7)2 is amino, methylamino, dimethyl amino, ethyl amino, diethylamino, or benzylamino. 38. The compound as claimed in any of claims 1-37, wherein N(R7 )2 is amino or methylamino. 39. The compound as claimed in any of claims 1-38, wherein X is -CH2ORa, .C02Ra, -OC (0)Ra, -CH2OC(0)Ra, or -C(0)N RaRb. 40. The compound as claimed in any of claims 1-39, wherein X is ~CH2ORa or -C(0)N Ra Rb. 41. The compound as claimed in any of claims 1-40, wnerein X is --CH2OH or -C(O) NHCH2CH3. 42. The compound as claimed in any of claims 1-41, wherein m is 0,1, or 2. 43. The compound as claimed in any of claims 1-42, wherein m is 0 or 1. 44. The compound as claimed in any of claims 1-43, wherein the rings-comprising R4, R5, and the atom to which they are connected are selected from the group consisting of: 46. The compound as claimed in any of claims 1-45, wherein the ring comprises -C(R3) R4 R5, is 4-piperidene-I-carboxylic acid, 4-piperidine-l-carboxylic acid methyl ester, -' 4- piperidine-1-carboxylic acid ethyl ester, 4-piperidine-l-carboxylic acid propyl ester, 4-piperidine-l-carboxylic acid tert-butyl ester, 3-piperidine-l-carboxylic acid methyl ester, 3-piperidinc-l-earboxylic acid tert-butyl ester, 3-piperazine-l-carboxylic acid, 3- piperazine-I-carboxylic acid methyl ester, 3-piperazine-l-carboxylic acid ethyl ester, 3- piperazine-1-carboxylic acid propyl ester, or 3-piperidine-l-carboxylic acid tert-butylester. 52. A composition as claimed in any of claims 1-51, to inhibit an inflammatory response in a mammal in need of therapy. 53. The composition as claimed in any of claims 1-52, in combination with a pharmaceutically acceptable carrier. 54. The composition as claimed in claim 53, comprising a Type N phosphodiesterase inhibitor. 55. The composition as claimed in claim 54, wherein the inhibitor is rolipram. 56. The composition as claimed in any of claims 53 - 55, wherein the carrier is a liquid carrier. 57. The composition as claimed in any of claims 53- 56t which is adapted for parenteral aerosol, or transdermal administration. 58. A composition as claimed in any of claims 1-51, to prevent or treat a pathological condition or symptom in a mammal, wherein the activity of A2A adenosine receptors is implicated and agonism of such activity is desired. 59. The composition as claimed in claim 58, wherein the mammal is a human. 60. The composition as claimed in claim 58 or 59, comprising a Type IV phosphodiesterase inhibitor. 61. A compound as claimed in claim 1-61, for use in medical therapy. 62. A compound as claimed in any of claims 1-51, wherein the medical therapy IS inhibition of an inflammatory response. 63. The compound as claimed in claim 62, wherein the inflammatory response is due to a pathological condition or symptom in a mammal, wherein the activity of A2A adenosine receptors is implicated and agonism of such activity is desired. 64. A composition as claimed in any of claims 1-51, to prepare a medicament for treating an inflammatory response. 65. The composition as claimed in claim 64, wherein the medicament comprises a Type IV phosphodiesterase inhibitor. 66. The composition as claimed in claim 65, wherein the phosphodiesterase inhibitor is rolipram. 67. The composition as claimed in anyone of claims 64-66, wherein the medicament comprises a liquid carrier. 68. The composition as claimed in any of claims 64-67, wherein the medicament is adapted for parenteral, aerosol, or transdermal administration. The present invention comprises compounds and compositions for the treatment of inflammatory activity in mammalian tissue. The present compounds comprise a novel class of 2-alkynyladenosine derivatives, substituted at the ethyn-2-yl position by substituted cycloalkyl and heterocycle (heterocyclic) moicties. The present compounds having the following general formula (I):

Documents:

383-KOLNP-2004-CORRESPONDENCE_.pdf

383-KOLNP-2004-FORM 27_.pdf

383-KOLNP-2004-FORM-27.pdf

383-kolnp-2004-granted-abstract.pdf

383-kolnp-2004-granted-assignment.pdf

383-kolnp-2004-granted-claims.pdf

383-kolnp-2004-granted-correspondence.pdf

383-kolnp-2004-granted-description (complete).pdf

383-kolnp-2004-granted-drawings.pdf

383-kolnp-2004-granted-examination report.pdf

383-kolnp-2004-granted-form 1.pdf

383-kolnp-2004-granted-form 18.pdf

383-kolnp-2004-granted-form 3.pdf

383-kolnp-2004-granted-form 5.pdf

383-kolnp-2004-granted-gpa.pdf

383-kolnp-2004-granted-reply to examination report.pdf

383-kolnp-2004-granted-specification.pdf