Selective antagonists of A2A adenosine receptors

Selective antagonists of A2A adenosine receptors like those of formula I are provided, wherein Y forms a ring. The novel A2A Blockers are useful for the treatment of Parkinson's disease and other diseases.

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Description
CROSS REFERENCE TO RELATED APPLICATION

The present application is a continuation of “Selective Antagonists of A2A Adenosine Receptors,” U.S. application Ser. No. 11/097,251 filed Apr. 4, 2005, which is hereby incorporated by reference thereto, and claims benefit of U.S. Provisional Application No. 60/559,159, filed Apr. 2, 2004, entitled “Selective Antagonists of A2A Adenosine Receptors,” the disclosure of which is incorporated herein.

FIELD OF THE INVENTION

The present invention relates to compounds and pharmaceutical compositions that are selective antagonists of the A2A adenosine receptor (AR). These compounds are useful as pharmaceutical agents.

Selective antagonists of A2A adenosine receptors have proven to be effective for the treatment of Parkinson's disease (PD) both in animal models and in a human trial.1 However, the initial clinical trial was stopped in phase 3 due to detection of animal toxicity of the investigational drug, KW6002. Other investigational compounds lack sufficient potency, selectivity or bioavailability to be considered clinical candidates.

BACKGROUND OF THE INVENTION

Parkinson's disease is the second most common neurodegenerative disorder and affects over 1 million people in North America.2 The pathological process, degeneration of the dopaminergic neurons in the substantial nigra, causes profound depletion of striatal dopamine and motor impairment. This insight led to the introduction of L-dopa as a dopamine-replacement treatment for PD.3 Today, L-dopa continues to be the “Gold Standard” treatment for the motor symptoms of PD.4,5 Despite the considerable symptomatic relief it affords, long-term treatment with L-dopa has major limitations.6 After five to ten years of treatment with L-dopa, up to 60% of patients experience loss of L-dopa effectiveness and some debilitating complications,7,8 notably, an “on” and “off” motor fluctuation and involuntary choreic or dystonic movements, dyskinesia. This has become the limiting factor in management of patients in the later stages of PD.9 The development of dyskinesia might reflect desensitization of dopamine receptors.10 Most importantly, there is no clear evidence that L-dopa slows or halts the degeneration of dopaminergic neurons. In fact, in vitro cell culture studies suggested that dopamine and its oxidative metabolites are toxic to dopaminergic neurons, and raised the concern that L-dopa may actually accelerate the degeneration of dopaminergic neurons. Because of this concern, many clinicians avoid prescribing L-dopa early in the course of PD.11

These major limitations of L-dopa therapy are linked to the activation of dopamine receptors. This has prompted a search for alternative treatment for PD not targeting the dopaminergic system.12 Striatal neuromodulators and transmitters other than dopamine are increasingly appreciated as critical regulators of motor function and offer new therapeutic opportunities to complement dopamine-replacement.

Over the last 10 years, the A2A adenosine receptor (A2AAR) has received increasing attention as a treatment for PD.13,14 This contention is based on our understanding of the role of the A2AAR in the basal ganglia and on the recent development of new, more selective A2AAR antagonists. Anatomical, neurochemical and behavioral evidence of adenosine-dopamine interactions underlie this new therapeutic approach.15-17 Anatomically, A2AAR density is high in the striatum, where receptor mRNA is co-expressed with D2 receptor mRNA in the striatopallidal neurons.18-20 This unique cellular distribution of A2A receptors suggests that A2A receptor antagonists can selectively modulate the “indirect” striatopallidal pathway to affect motor activity. At the neurochemical level, activation of the A2AAR reduces the binding affinity of D2 receptors in the striatum,21 and antagonizes many neurochemical and cellular changes brought about by the activation of striatal D2 receptors, including release of acetylcholine and GABA and expression of c-Fos. Furthermore, behavioral studies have demonstrated that the unselective adenosine antagonists caffeine and theophylline stimulate locomotor activity22,23 whereas the unselective agonist NECA24 inhibits spontaneous locomotor activity as well as motor activity induced by dopamine agonists. Thus, A2AAR agonists and antagonists function as dopamine antagonists and agonists, respectively, in modulating motor activity. The three possible mechanisms have been proposed to explain for motor enhancement by the A2A antagonists: (1) a direct receptor-receptor (A2A-D2) antagonistic interaction,25,26 (2) an opposing but independent of A2A and D2 receptor signaling27-29 or (3) A2AAR modulation of GABA release in the basal ganglia.30-32 These receptors also form A2AAR-D2 heterodimers,33 but how dimerization affects receptor function is unclear.

A2A Receptor Antagonists May Offer Multiple Therapeutic Benefits for PD Patients

First, A2A antagonists stimulate motor activity in normal as well as dopamine-depleted animals. In rodent models of PD, unselective adenosine antagonists (caffeine and theophylline)22,34 and the A2AAR-selective antagonists SCH58261, KW6002 and CSC can reverse motor deficits induced by MPTP, 6-hydroxydopamine, haloperidol or reserpine35-41 as well as by genetic deletion of D2 receptors.42 More recently, the A2A antagonists KW6002 reversed motor deficit in MPTP-treated non-human primates.43,44 Furthermore, A2A antagonists can stimulate motor activity when combined with sub-threshold doses of dopaminergic agents such as L-dopa or D1 and D2 agonists such as aporphormine or quinpirole.45 For example, combining KW6002 with L-dopa reduces the dose of L-dopa, thereby reducing the complications associated with L-dopa. In contrast to some non-specific adenosine antagonists or some dopamine agonists, motor stimulation was observed after acute treatment and persisted following treatment continued for 15 days.44,46,47 Thus, tolerance to the motor stimulant effect of A2A antagonists did not develop.

Second, studies of the MPTP-treated monkey model of PD revealed a novel feature of A2A antagonists, namely, stimulation of motor activity without dyskinesia.43,44,48 In contrast to L-dopa, repeated treatment with KW6002 reversed the motor deficit but did not induce dyskinesia, even in monkeys primed with L-dopa. Further, our recent findings in A2AAR knockout mice suggest that development of behavioral sensitization by chronic treatment of L-dopa requires activation of the A2AAR. Genetic inactivation of the A2A receptor attenuated L-dopa-induced rotational behavior.49 This is consistent with a recent study showing that co-administration of KW6002 with apomorphine to MPTP-treated monkeys completely abolished the development of apomorphine-induced dyskinesia.50 Further studies are warranted to explore the molecular mechanism underlying this novel aspect of A2AAR function.

Third, accumulating evidence suggests that the specific inactivation of A2AARs consistently attenuates brain damage induced by ischemia51-53 and excitoxicity,54,55 as well as in animal models of Huntington's disease56 and Alzheimer's disease.57 The neuroprotection by A2AAR antagonists has been recently extended to a rodent model of PD. Co-administration of A2AAR antagonists, such as CSC, DMPX, SCH58261 and KW6002 (but not the A1AR antagonist DPCPX) attenuated dopaminergic neurotoxicity in several neurotoxin models of PD.58 A2AAR antagonists provided not only functional protection (such as reduced dopamine content and expression of molecular markers for the dopaminergic terminals), but also reduced the loss of dopaminergic neurons in substantia nigra in both MPTP- and 6-OHDA models of PD.59,60 Likewise, knockout of A2AARs attenuated MPTP-induced dopaminergic neurotoxicity in mice.59 Together with the demonstration of neuroprotection by A2AAR antagonists against a wide range of neuronal injury models. These results raise the possibility that A2A antagonists may offer a neuroprotection, slowing or even halting degeneration of dopaminergic neurons.

Finally, in contrast to the widespread distribution of other neurotransmitter receptors, for example, glutamate receptors, the expression of the A2AAR is almost exclusively in striatum, which might allow selective modulation of dopamine-mediated motor pathways without serious side effects due to drug actions outside the basal ganglia (a serious problem for drugs such as glutamate antagonists). It is important to emphasize that ambient adenosine levels and A2AAR density are normal in PD patients,61 indicating that A2A antagonists might remain effective, even in the later stages of PD.

The prospective use of A2AR antagonists as potential neuroprotective agents against dopaminergic neuron degeneration was markedly enhanced by a May 2000 report of an epidemiological study of the relationship between caffeine and PD. Ross et al described a large prospective study with a 30-year follow-up of 8004 Japanese-American men that showed that in this population there is an inverse relationship between caffeine consumption and the risk of developing PD.62 Two other ongoing, large-cohort studies (Heath Professional Follow-up Studies and Nurse's Heath Study) involving 47,351 men and 88,565 women also showed that moderate caffeine consumption (3-5 cups/day) reduced their risk of developing PD.63 Thus, the inverse relationship of caffeine consumption and the risk of developing PD seem firmly established by these two large, prospective epidemiological studies. These results are consistent with the animal studies showing neuroprotection by A2AAR antagonists and strongly argue that A2A antagonists including caffeine may offer an opportunity to slow down or halt the degeneration of dopaminergic neurons.

Initial clinical trial results of KW6002 indicated that (20-80 mg/day) enhanced motor activity in one study and potentiated a motor stimulant effect by low (but not high) doses of L-dopa in another study.64,65 KW6002 was well tolerated and had few side effects. Unfortunately, trials with KW6002 have been stopped because this compound was found to produce a long-term toxicity in rats. Hence, there is a pressing need to develop alternative molecules that lack toxicity.

The first relatively selective A2AAR antagonists, the 8-styrylxanthines, appeared about ten years ago. This class includes KW-6002, which has low nanomolar affinity for the A2AAR and >100-fold selectivity for the A2AAR over the A1AR. KW-6002, entered clinical trials in 2002 as an agent for the treatment of PD.1,66 SCH58261, a pyrazolo[4,3-e]-1,2,4 triazolo[1,5-c]pyrimidine was a prototype for a series of second-generation derivatives that appeared over the next several years. These, too, had low nanomolar affinity and good selectivity for the A2AAR in vitro.67 The third class of antagonists to appear, the 1,2,4-triazolo[4,5-e]-1,3,5-triazines, was typified by ZM241385, which was active at the A2AAR in the sub-nanomolar range but less selective, interacting with A2BAR as well.68 These potent A2A antagonists have been important research tools, greatly facilitating pharmacological investigations of A2AAR function in vitro as well as in vivo significantly enhancing our understanding of the neurobiology of the A2AAR. However, each of these antagonists has important drawbacks. KW-6002 is light-sensitive, undergoing photoisomerization from the active E-isomer to the 800-fold less active Z-isomer.69 SCH58261 is very poorly soluble and even its second-generation derivatives have marginal bioavailability.70 As mentioned above, ZM241385 is unselective and, additionally, has poor bioavailability. Other nitrogen heterocycles such as the 1,2,4-triazolo[4,3-a]quinoxalin-1-ones71 and the oxazolo[4,5-d]pyrimidines from ICI are also unselective, and their bioavailability is unknown. Therefore a continuing need exists for compounds that are selective A2A AR antagonists.

SUMMARY OF THE INVENTION

In one aspect, there is provided a compound of the formula I:
wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OMe, —SMe, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R1 and R2 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R1 and R2 are independently absent, with the proviso that Ra is not thio or halogen in the case where R1 and R2 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OMe and —SMe; R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, hetrocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, RaS(═O)2—, —NNRa and —OPO2Ra; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated, then R3 can be absent; R4 and R5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic- or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, hetrocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —NNRa and —OPO2Ra or two R6 groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring; R7 and R8 are each independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene, heteroaryl, heteroaryl(C1-C8)alkylene-; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring; R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OMe, —SMe, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R9 and R10 are independently absent, with the proviso that Ra is not thio or halogen in the case where R9 and R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OMe and —SMe; Y is —CR3R4R5 or NR4R5; Z is selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl, (C1-C8)cycloalkyl, (C6-C12)bicycloalkyl, (C6-C20)polycyclyl, heterocyclyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heterocyclyl(C1-C8)alkyl, aryl, aryl(C5-C14), aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —NRaRb, —ORa, —SRa, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO2Ra, RaC(═O)O—, RaC(═O)—, —OCO2Ra, RaRbNC(═O)O—, RbOC(═O)NRa—, RaRbNC(═O)—, RaC(═O)NRb, RaRbNC(═O)NRb—, RaRbNC(═S)NRb—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —NNRa, —OPO2Ra, —OS(O2)Ra, —OS(═O)ORa, —OS(O2)ORa and —O(SO2)NRaRb; Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OMe, —SMe, propargyl, cyano, —NNH, —NNCH3, —OPO2H, —OPO2CH3, OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1-4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRc); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, —SRc, cyano, —NNH, —NNCH3, —OPO2H, —OPO2CH3, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that Ra is not a heteroatom when it is attached to another heteroatom; Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and m is 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is not halogen, cyano, nitro or a heteroatom, and when n is 0, Y is not —NR4R5; or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

In another aspect, there is provided a compound of the formula II:
wherein R1, R2, R7, R8, R9, R10, m, n, Y and Z are as defined above; and L is a linker selected from the group consisting of —(C1-C3)alkyl-C≡C—, —C≡C—(C1-C3)alkyl-, —(CH2)1-3—CH═CH—, —CH═CH—CH2)1-3—, —(CH2)1-2—CH═CH—CH2— and —CH2—CH═CH—(CH2)1-2—; or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

In another aspect, there is provided a compound of the formula III:
wherein R1, R2, R7, R8, R9, R10, m, n, Y and Z are as defined above; and L is a linker selected from the group consisting of —NH—, —N═N—, —NH—N═, —O—, —S—, —SO2— and pyrazolyl; a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

In one variation of each of the above compound of formulae I, II and III, the group (CR1R2)m together is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, iso-propylene, iso-butylene, sec-butylene and tert-butylene. In another variation, (CR1R2)m together is selected from the group consisting of methylene, ethylene, propylene and iso-propylene. In another variation, (CR1R2)m-Z together is selected from the group consisting of —CH2CH═CH2—, —CH2C≡CH, —CH2C≡CCH3 or —CH2CH2C≡CH. In yet another variation, (CR1R2)m-Z together is —CH2C≡CH.

In another variation of the above formulae, R1 and R2 are hydrogen or are absent, m is 2 to 8 and the group (CR1R2)m optionally comprises 1 to 4 alkenyl or alkynyl conjugated or unconjugated groups. In another variation, m is 1 to 8 and Z is selected from the group consisting of —NH2, —OH, —SH, —NRaRb, —ORa, —SRa and cyano. In another particular variation, (CR1R2)m-Z together is selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, hexanol, iso-propanol, iso-butanol, sec-butanol and tert-butanol. In yet another variation, (CR1R2)m-Z together is selected from the group consisting of methanol, ethanol, propanol and —CH2CN.

In one variation of each of the above, R1 and R2 are hydrogen, and the group (CR1R2)m is linear or branched, m is 1 to 6, and Z is selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxy and hexyloxy. In another variation, Z is selected from the group consisting of methoxy, ethoxy and propoxy. In another variation, Z is a mono-, bicyclic-, tricyclic- or aromatic or non-aromatic (C3-C20)cycloalkyl ring, wherein the ring atoms are optionally interrupted by 1 to 8 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRa—). In yet another variation, Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl ring optionally substituted with 1 to 4 substituents of Ra. In yet another variation, Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, where m is 0 or 1. In another variation, Z is cyclopentyl and where m is 0. In a particular variation, Z is cyclobutyl, m is 1 and R1 and R2 are hydrogen.

In one particular variation of each of the above; Y and Z are each independently selected from the group consisting of hydrogen, or
wherein each Y or Z group is optionally comprises 1, 2 or 3 double bonds; each carbon in the ring is optionally replaced by or interrupted by 1 to 6 heteroatoms selected from —O—, —S—, —SO—, —S(O)2—, or amino (—NRa—), and is optionally further substituted with from 1 to 10 R6 groups, provided that the Y or Z ring is not attached at a bridgehead carbon atom or at a trisubstituted carbon atom. In another variation, each Y or Z is independently hydrogen or a bicyclic ring selected from the group consisting of
wherein any two adjacent carbon ring atom is optionally interrupted with 1 to 6 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), and the ring is optionally substituted with from 1 to 7 Ra groups selected from the group consisting of —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OMe, —SMe, propargyl, cyano, —NNH, —NNCH3, —OPO2H, —OPO2CH3, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, and m and n are each independently 0 or 1. In another variation, each Y or Z is independently selected from the group consisting of hydrogen, or
wherein m and n are each independently 0 or 1, and R1, R2, R9 and R10 are each independently absent or selected from the group consisting of hydrogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2—OMe and —SMe, and each Z group is optionally substituted with from 1 to 7 Ra groups selected from the group consisting of halo, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OMe, —SMe, propargyl, cyano, —NNH, —NNCH3, —OPO2H, —OPO2CH3, —S(SO2)H, —S(SO2)OH, —S(SO2)CH3 and —S(SO2)OCH3.

In another variation of the above, R1 and R2 are hydrogen, m is 0, 1, 2 or 3 and Z is selected from the group consisting of furan, dihydro-furan, tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole, dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine, tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane, wherein each Z group is optionally substituted with from 1 to 10 Ra groups.

In yet another variation, R1 and R2 are hydrogen, m is 0 or 1, and Z is selected from the group consisting of furan, thiophene, pyrrole, 2H-pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole and 1H-tetrazole, wherein each Z group is optionally substituted with from 1 to 3 Ra groups selected from the group consisting of methyl, ethyl, propyl, iso-propyl, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 and —SCH3. In another variation, Z is selected from the group consisting of —CO2Ra, RaC(═O)O—, RaC(═O)—, —OCO2Ra, RaRbNC(═O)O—, RbOC(═O)NRa—, RaRbN—, RaRbNC(═O)—, RaC(═O)NRb—, RaRbNC(═O)NRb—, RaRbNC(═S)NRb, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, RaS(O2)—, —N═NRa, —OPO2Ra, —OS(O2)Ra, —OS(═O)ORa, —OS(O2)ORa and —OS(O2)NRaRb, wherein m is 1 to 8, and the group (CR1R2)m is optionally saturated or partially unsaturated. In yet another variation, Z is selected from the group consisting of —CO2Ra, RaC(═O)O—, RaC(═O)—, —OCO2Ra, RaRbNC(═O)O—, RbOC(═O)NRa—, RaRbN—, RaRbNC(═O)—, RaC(═O)NRb—, RaRbNC(═O)NRb—, RaRbNC(═S)NRb—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, RaS(═O)2—, —N═NRa, —OPO2Ra, —OS(O2)Ra, —OS(═O)ORa, —OS(O2)ORa and —O(SO2)NRaRb, and wherein (R1R2)m together is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2—, —CH═CHCH2—, —CH2CH═CH—, —CH═CHCH2CH2—, —CH2CH═CHCH2—, —CH2CH2CH═CH—, —C≡CCH2—, —CH2C≡C—, —C≡CCH2CH2—, —CH2C≡CCH2— and —CH2CH2C≡C—. In still another variation of the above, Z is independently —CO2Ra, RaC(═O)—, RaRbN—, —OPO3Ra, RaOC(S)—, RaC(═S)—, RaS(═O), RaS(═O)2—, —OPO2Ra, —OS(O2)Ra, —OS(═O)ORa, —OS(O2)ORa or —OS(O2)NRaRb, and wherein (CR1R2)m together is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2—, —CH═CHCH2, —CH2CH═CH—, —CH═CHCH2CH2—, —CH2CH═CHCH2—, —CH2CH2CH═CH—, —C≡CCH2—, —CH2C≡C—, —C≡CCH2CH2—, —CH2C≡CCH2— and —CH2CH2C≡C—.

In one particular variation of each of the above; each R9 is independently selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocyclyl, hetrocyclyl(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl, heteroaryl(C1-C8)alkylene-, —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)—, RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, RaS(═O)2—, —N═NRa and —OPO2Ra. In another variation, R1 and R2 together with the carbon atom to which they are attached is C═O, C═S or C═NRc. In yet another variation, R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, cyano, nitro, trifluoromethyl, trifluoromethoxy, —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), RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRA, RaS(═O)—, RaS(═O)2—, —NNRa and —OPO2Ra; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated then R3 can be absent. In another variation of the above, R3 is selected from the group consisting of hydrogen, OH, OMe, OAc, NH2, NHMe, NMe2 and NHAc. In a particular variation, R3 is hydrogen or OH.

In one particular variation of each of the above; R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic ring, or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, hetrocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —NNRa, —OPO2Ra, or two R6 groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring. In another variation, the ring comprising R4 and R5 and the atom to which they are attached is selected from the group consisting of cyclopentane, cyclohexane, piperidine, dihydro-pyridine, tetrahydro-pyridine, pyridine, piperazine, decaline, tetrahydro-pyrazine, dihydro-pyrazine, pyrazine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, imidazole, dihydro-imidazole, imidazolidine, pyrazole, dihydro-pyrazole, pyrazolidine, norbornane and adamantane, each unsubstituted or substituted.

In one particular variation of each of the above, R6 is selected from the group consisting of substituted or unsubstituted (C1-C8)alkyl, —ORa, —CO2Ra, RaC(═O)—, RaC(═O)O—, RaRbN—, RaRbNC(═O)— and aryl, provided that when the ring comprising R4 and R5 contains a heteroatom that is O or S, the heteroatom is not substituted with R6. In another variation, R6 is selected from the group consisting of OH, OMe, methyl, ethyl, t-butyl, —CO2Ra, —CONRaRb, OAc, NH2, NHMe, NMe2, NHEt and N(Et)2, provided that when the ring comprising R4 and R5 contains a heteroatom that is O or S, the heteroatom is not substituted with R6. In yet another variation, R6 is selected from the group consisting of methyl, ethyl, —CO2Ra, —CONRaRb and OAc, provided that when the ring comprising R4 and R5 contains a heteroatom, the heteroatom is not substituted with OAc. In yet another variation, R6 is selected from the group consisting of —(CH2)1-2ORa, —(CH2)1-2C(═O)ORa, —(CH2)1-2OC(═O)Ra, —(CH2)1-2C(═O)Ra, —(CH2)1-2OCO2Ra, —(CH2)1-2NHRa, —(CH2)12NRaRb, —(CH2)1-2C(═O)NHRa and —(CH2)1-2C(═O)NRaRb. In yet another variation, R6 is —CH2C(═O)ORa, —CH2C(═O)ORa, —CH2OH, —CH2OAc, —CH2NH(CH3) and —(CH2)1-2N(CH3)2. In another variation, the number of R6 groups substituted on the R4R5 ring is from 1 to 4.

In another variation, R7 and R8 is selected from the group consisting of hydrogen, (C1-C8)alkyl-, aryl, aryl(C1-C8)alkylene-, mono-, bicyclic- or aromatic or nonaromatic ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, and each is optionally substituted with from 1, 2, 3 or 4 Ra groups. In yet another variation, R7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl,3-pentyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, phenyl and benzyl, or wherein R7 is hydrogen, methyl or sec-butyl. In another variation, R7 and R8 are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, aryl(C1-C8)alkylene, heteroaryl and heteroaryl(C1-C8)alkylene-; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring.

In one particular variation of each of the above, —NR7R8 is selected from the group consisting of amino, methylamino, dimethylamino, ethylamino, pentylamino, diphenylethylamino, pyridylmethylamino, diethylamino and benzylamino. In another variation, —NR7R8 is selected from the group consisting of amino, methylamino, dimethylamino, ethylamino, diethylamino and benzylamino, or wherein —NR7R8 is amino.

In one particular variation of each of the above; Ra and Rb are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl and (C1-C8)alkyl substituted with 1 to 3 (C1-C8)alkoxy, (C3-C8)cycloalkyl, (C1-C8)alkylthio, 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; Rc is hydrogen or (C1-C6)alkyl; m is 0 to about 8 and p is 0 to 2; and Y is —CR3R4R5 or NR4R5.

In another variation, R7 is selected from the group consisting of benzyl, phenethyl, phenylpropyl and each is optionally substituted with from 1, 2 or 3 substituents of Ra. In a particular variation, R7 is selected from the group consisting of benzyl, phenethyl, phenylpropyl and each is optionally substituted with from 1, 2 or 3 substituents of Ra selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy and propoxy; or wherein R7 is benzyl and Ra is methoxy.

In another aspect of the above, R9 is selected from the group consisting of hydrogen, fluoro, —OH, —CH2OH, —OMe, —OAc, —NH2, —NHMe, —NMe2 and —NHAc; or wherein R9 is hydrogen or OH. In one variation, each R10 is independently selected from the group consisting of hydrogen, fluoro, (C1-C8)alkyl, (C3-C8)cycloalkyl, heterocyclyl, heterocycle(C1-C8)alkylene-, aryl, aryl(C1-C8)alkylene-, heteroaryl and heteroaryl(C1-C8)alkylene-. In another variation, R10 is selected from the group consisting of hydrogen, (C1-C8)alkyl, cyclopropyl, cyclohexyl and benzyl; or wherein R10 is hydrogen. In yet another variation of the above, R9 and R10 and the carbon atom to which they are attached is a C═O group.

In a variation of the above compound, Ra and Rb are each independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C8)alkylene. In a particular variation, Ra and Rb are each independently selected from the group consisting of hydrogen, methyl, ethyl, phenyl and benzyl. In another variation, Ra is (C1-C8)alkyl. In yet another variation, Ra is selected from the group consisting of methyl, ethyl, propyl and butyl. In yet another variation, Ra is selected from the group consisting of methyl, ethyl, i-propyl, i-butyl and tert-butyl. In still another variation, Ra and Rb is a ring.

In one variation of each of the above, Y is —CR3R4R5 or NR4R5, and is selected from the group consisting of:
wherein q is 0, 1, 2, 3 or 4; R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, hetrocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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), RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, RaS(═O)2—, —NNRa and —OPO2Ra; and each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, hetrocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —NNRa and —OPO2Ra, provided that R6 is not halogen or a heteroatom when R6 is attached to a heteroatom.

In another variation, Y is —CR3R4R5 or NR4R5 and is selected from the group consisting of:
wherein R3 is selected from the group consisting of hydrogen, halo, —ORa, SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, hetrocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, RaS(═O)2—, —NNRa and —OPO2Ra; and each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, hetrocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, —OPO3Ra, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —NNRa and —OPO2Ra.

In another variation, the ring comprising —C(R3)R4R5 is 2-methylcyclohexan-1-yl, 2,2-dimethylcyclohexan-1-yl, 2-ethylcyclohexan-1-yl, 2,2-diethylcyclohexan-1-yl, 2-tert-butylcyclohexan-1-yl, 2-phenylcyclohexan-1-yl, 3-methylcyclohexan-1-yl, 3-ethylcyclohexan-1-yl, 3,3-dimethylcyclohexan-1-yl, 4-methylcyclohexan-1-yl, 4-ethylcyclohexan-1-yl, 4,4-dimethylcyclohexan-1-yl, 4-tert-butylcyclohexan-1-yl, 4-phenylcyclohexan-1-yl, 3,3,5,5-tetramethylcyclohexan-1-yl, 2,4-dimethylcyclopentan-1-yl, 4-(carboxyl)cyclohexan-1-yl, 4-(carboxymethyl)cyclohexan-1-yl and 4-(carboxyethyl)cyclohexan-1-yl. In yet another variation, the ring comprises —C(R3)R4R5 is piperidin-4-yl, 1-carboxypiperiden-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1-(ethoxycarbonyl)piperidin-4-yl, 1-(n-propoxycarbonyl)piperidin-4-yl, 1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl, 4-carboxypiperiden-1-yl, 4-(methoxycarbonyl)piperidine-1-yl, 4-(ethoxycarbonyl)piperidine-1-yl, 4-(n-propoxy)piperidine-1-yl, 4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl, 1-carboxypiperidene-3-yl, 1-(methoxycarbonyl)piperidine-3-yl, 1-(ethoxycarbonyl)piperidine-3-yl, 1-(n-propoxycarbonyl)piperidine-3-yl, 1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl, 3-carboxypiperidene-1-yl, 3-(methoxycarbonyl)piperidine-1-yl, 3-(ethoxycarbonyl)piperidine-1-yl, 3-(n-propoxycarbonyl)piperidine-1-yl, 3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperazin-1-yl, 1-caboxypiperazin-4-yl, 1-(methoxycarbonyl)piperazin-4-yl, 1-(ethoxycarbonyl)piperazin-4-yl and 1-(n-propoxycarbonyl)piperazin-4-yl.

In another variation, the ring comprising —C(R3)R4R5 is selected from the group consisting of 2-methylcyclohexan-1-yl, 2,2-dimethylcyclohexan-1-yl, 2-ethylcyclohexan-1-yl, 2,2-diethylcyclohexan-1-yl, 2-tert-butylcyclohexan-1-yl, 2-phenylcyclohexan-1-yl, 3-methylcyclohexan-1-yl, 3-ethylcyclohexan-1-yl, 3,3-dimethylcyclohexan-1-yl, 4-methylcyclohexan-1-yl, 4-ethylcyclohexan-1-yl, 4,4-dimethylcyclohexan-1-yl, 4-tert-butylcyclohexan-1-yl, 4-phenylcyclohexan-1-yl, 3,3,5,5-tetramethylcyclohexan-1-yl, 2,4-dimethylcyclopentan-1-yl, 4-(carboxyl)cyclohexan-1-yl, 4-(carboxymethyl)cyclohexan-1-yl, 4-(carboxyethyl)cyclohexan-1-yl, piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl, 4-(methoxycarbonyl)piperidine-1-yl, 4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl, 1-(methoxycarbonyl)piperidine-3-yl, 1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl, 3-(methoxycarbonyl)piperidine-1-yl and 3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl.

In a particular variation, Z is a mono-, bicyclic-, tricyclic- or aromatic or non-aromatic (C3-C20)cycloalkyl ring, wherein the ring atoms are optionally interrupted by 1-8 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRa—). In one variation of the above, R1 and R2 are hydrogen, m is 0, 1, 2 or 3 and Z is selected from the group consisting of furan, dihydro-furan, tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole, dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine, tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane, wherein each Z group is optionally substituted with from 1 to 10 Ra groups. In another variation, Z is a mono-, bicyclic-, tricyclic- or aromatic or non-aromatic (C3-C20)cycloalkyl ring, wherein the ring atoms are optionally interrupted by 1-8 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRa—).

In a particular variation, R1 and R2 are hydrogen, m is 0, 1, 2 or 3 and Z is selected from the group consisting of furan, dihydro-furan, tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole, dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine, tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane, wherein each Z group is optionally substituted with from 1 to 10 Ra groups.

In another aspect, there is provided a compound of the formula:
wherein R7 and R8 are each independently selected from the group consisting of hydrogen, (C2-C4)alkyl, 3-pentyl, aryl(C2-C4)alkyl, heteroaryl(C2-C4)alkyl, each unsubstituted or substituted, R8 is selected from the group consisting of hydrogen or (C1-C4)alkyl; and R11 is selected from the group consisting of (C1-C4)alkyl, propargyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C4)alkyl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, heterocyclyl(C1-C4)alkyl, HO(C1-C4)alkyl, halo(C1-C4)alkyl, —COO(C1-C4)alkyl, (C1-C4)alkylCOO(C1-C4)alkyl, each unsubstituted or substituted; R13 is methyl, iso-propyl, iso-butyl, or tert-butyl; and R1, R2 and m are as defined herein; or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

In another aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of each of the above, and a pharmaceutically acceptable excipient. Some of the compounds of formulae I, II, and III may further form pharmaceutically acceptable salts and esters. All of these forms are included within the scope of the present invention. Pharmaceutically acceptable base addition salts of the compounds of formulae I, II, and III include salts which may be formed when acidic protons present in the parent compound are capable of reacting with inorganic or organic bases as known in the art. Acceptable inorganic bases, include for example, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium-hydroxide. Salts may also be prepared using organic bases, such as choline, dicyclohexylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, procaine, N-methylglucamine, and the like [see, for example, Berge et al., “Pharmaceutical Salts,” J Pharma. Sci. 66:1 (1977)]. Pharmaceutically acceptable acid addition salts of the compounds of formulae I, II, and III include salts which may be formed when the parent compound contains a basic group. Acid addition salts of the compounds may be prepared in a suitable solvent from the parent compound and an excess of a non-toxic inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, or a non-toxic organic acid such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, tert-butylacetic acid, laurylsulfuric acid, glucuronic acid, glutamic acid, and the like. The free base form may be regenerated by contacting the acid addition salt with a base and isolating the free base in the conventional manner. The free base forms can differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.

Also included in the above embodiments, aspects and variations are salts of amino acids such as arginate and the like, gluconate, and galacturonate. Some of the compounds of the invention may form inner salts or Zwitterions. Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms, and are intended to be within the scope of the present invention. Certain of the above compounds may also exist in one or more solid or crystalline phases or polymorphs, the variable biological activities of such polymorphs or mixtures of such polymorphs are also included in the scope of this invention. Also provided are pharmaceutical compositions comprising pharmaceutically acceptable excipients and a therapeutically effective amount of at least one compound of this invention.

Pharmaceutical compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are especially suitable for parenteral administration but may also be used for oral administration. Excipients, such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate, may also be added. Alternatively, these compounds may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols, or water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar, or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing, and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule. Suitable formulations for each of these methods of administration may be found in, for example, Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

In one variation, there is provided the above compound, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof. In one aspect, there is provided a method for stimulating motor activity without dyskinesia in a mammal, comprising administering a therapeutically effective amount of an A2A anatagonist compound of the above to the mammal in need of such treatment. In one variation of the above method, the therapeutically effective amount is effective to treat ischemia, brain damage induced by ischemia and excitoxicity, Huntington disease, catalepsy, cancer, drug addiction and withdrawal, Parkinson's disease (drug induced, post-encephalitic, poison induced or post-traumatic induced), acute or chronic pain, narcolepsy and Alzheimert's disease. In another variation of the above, the therapeutically effective amount is effective to stimulate motor activity for treating a movement disorder, where the disorder is progressive supemuclear palsy, Huntington's disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in dyskinesias. In another variation of the above, the compound is used in combination with one or more additional drugs in the treatment of movement disorders (i.e. L-DOPA or dopamine agonist), addiction, or cancer with the components being in the same formulation or in a separate formulation for administration simultaneously or sequentially. In yet another variation of the method, the therapeutically effective amount is effective to provide neuroprotection and slow or halt the degeneration of dopaminergic neurons. In yet another variation, the therapeutically effective amount is effective to enhance the immune response by increasing the activity of an immune cell in a mammal. In one variation, the activity is pro-inflammatory cytokine production. In another variation, the activity of the immune cell results in an increase in inflammation. In yet another variation of the above method, the mammal is human.

In another embodiment of the invention, there is provided a method for stimulating motor activity without dyskinesia in a mammal, comprising administering a therapeutically effective amount of an A2A antagonist compound of the above to the mammal in need of such treatment. In one variation of the above embodiment, there is provided a method as described above wherein the A2A antagonist is selected from a compound of each of the above embodiments, aspects and variations.

In another embodiment, there is provided a method to evaluate novel A2A antagonists in four mouse models of PD. These include: A) motor function in normal and dopamine-depleted mice; B) synergistic activity with L-dopa to stimulate motor activity in dopamine-depleted mice; C) attenuation MPTP-induced neurotoxicity by inhibiting MPTP metabolism; and D) delayed L-dopa-induced locomotor sensitization in unilateral 6-OHDA-lesioned mice.

In another embodiment, there is provided a method comprising contacting a compound of each of the above formula with an isotope such as those from hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, or iodine (e.g. 2H, 3H, 13C, 14C, 15N, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, 125I) optionally being a radioactive isotope (radionuclide), such as, for example, tritium, radioactive iodine (for example, 125I for binding assays or 123I for Spect Imaging) or other non-radioactive isotope (such as deuterium) and the like. Isotopically labeled compounds may be useful for drug/tissue distribution assays and/or manipulating oxidative metabolism via the primary kinetic isotope effect. They are also valuable in identifying potential therapeutic agents for the treatment of diseases or conditions associated with target-receptor mediation, by contacting said agents with said radioligands and receptors, and measuring the extent of displacement of the radioligand and/or binding of the agent. Representative references for Deuterium-for hydrogen substitution include Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al. Carcinogenesis 16(4) 683-688, 1993, the references of which are incorporated herein in their entirety. The use of radiolabelled compounds that may be detected using imaging techniques, such as, for instance, Single Photon Emission Computerized Tomography (SPECT) or Positron Emission Tomography (PET) and the like, are known in the art. See for example, U.S. Pat. Nos. 6,395,742; 6,472,667 and references cited therein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows locomotors stimulant activity of A2AAR antagonists injected into mice.

FIG. 2 sows the effect of A2A AR gene deletion on locomotor effect of ATL-2.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of organic synthesis and pharmaceutical sciences.

Where a carbonyl group or a carbonyl derivative such as a thio carbonyl or an imine and the like, is represented by a group such as —C(═O)O— or —C(═O)NRa—, for example, it is intended that the corresponding isomeric group that is —OC(═O)— or —NRaC(═O)— is also included.

An “alkyl” group is a straight, branched, saturated or unsaturated, aliphatic group having a chain of carbon atoms, optionally with oxygen, nitrogen or sulfur atoms inserted between the carbon atoms in the chain or as indicated. A (C1-C20)alkyl, for example, includes alkyl groups that have a chain of between 1 and 20 carbon atoms, and include, for example, the groups methyl, ethyl, propyl, isopropyl, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl, and the like. An alkyl group may also be represented, for example, as a —(CR1R2)m— group where R1 and R2 are independently hydrogen or are independently absent, and for example, m is 1 to 8, and such representation is also intended to cover both saturated and unsaturated alkyl groups. An alkyl as noted with another group such as an aryl group, represented as “arylalkyl” for example, is intended to be a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group (as in (C1-C20)alkyl, for example) and/or aryl group (as in (C5-C14)aryl, for example) or when no atoms are indicated means a bond between the aryl and the alkyl group. Nonexclusive examples of such group include benzyl, phenethyl and the like.

An “alkylene” group is a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group (as in —(C1-C20)alkylene- or —(C1-C20)alkylenyl-, for example), optionally with one or more oxygen, nitrogen or sulfur atoms inserted (or “interrupted”) between the carbon atoms in the chain or as indicated.

A “cyclyl” such as a monocyclyl or polycyclyl group includes monocyclic, or linearly fused, angularly fused or bridged polycycloalkyl, or combinations thereof. Such cyclyl group is intended to include the heterocyclyl analogs. A cyclyl group may be saturated, partically saturated or aromatic.

“Halogen” or “halo” means fluorine, chlorine, bromine or iodine.

A “heterocyclyl” or “heterocycle” is a cycloalkyl wherein one or more of the atoms forming the ring is a heteroatom that is a N, O, or S. Non-exclusive examples of heterocyclyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, and the like.

“Pharmaceutically acceptable salts” means salt compositions that is generally considered to have the desired pharmacological activity, is considered to be safe, non-toxic and is acceptable for veterinary and human pharmaceutical applications. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, malonic acid, succinic acid, malic acid, citric acid, gluconic acid, salicylic acid and the like.

“Substituted or unsubstituted” means that a group such as, for example, alkyl, aryl, heterocyclyl, (C1-C8)cycloalkyl, (C6-C12)bicycloalkyl, hetrocyclyl(C1-C8)alkyl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, the mono-, bi- or polycyclic rings that define the Z group, and the like, unless specifically noted otherwise, may be unsubstituted or, may substituted by 1, 2, 3, 4 or 5 substitutents selected from the group such as halo, nitro, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —SMe, propargyl, cyano, —NNH, —NNCH3, —OPO2H, —OPO2CH3, —S(SO2)H, —S(SO2)OH, —S(SO2)CH3 and —S(SO2)OCH3, and the like.

Representative A2AAR Antagonists:

TABLE 1 Binding Affinity and Selectivity of A2AAR Ligandsa Ki, nM ATL # R12 R7 (CR1R2)m-Z A1AR A2AAR A2BAR A3AR Antagonists 11 A 3-P Me 172 (1.3) 137 20% 30% 17 A 3-P Proparg 11 (2) 5 147 (29) 188 (38) 2 A NH2 Proparg 4.6 (5) 0.95 50 (11) 599 (630) 3 A NH2 cPent 368 (37) 10 357 (36) 633 (63) 51 B NH2 Proparg 25 (16) 1.6 155 (97) >650 (>400) 50 B NH2 cPent >325 (>27) 12 40% 40%
aAbbreviations: 3-P, 3-pentyl; Me, methyl; Proparg, prop-2-ynyl; cPent, cyclopentyl.

Numbers in parentheses are selectivity ratios vs. the A2AAR.

Activities expressed as percentage are displacement of radioligand by 1 μM candidate ligand.

Motor Enhancement by the Lipophilic A2A Receptor Antagonist ATL-2 in Normal Mice

The ability of compounds to stimulate motor activity in normal mice was measured using a simple, computer-assisted locomotor activity cage system. C57BL/6 mice (n=6-8 purchased from the Jackson's lab) were habituated for the testing environment for 120 minute prior to drug treatment. The test compounds were dissolved in vehicle (10% DMSO, 10% castrol oil EL-620 and 80% saline). The drug was administrated intraperitoneally at a dose of 15 mg/kg, and locomotor activity was recorded for 2 hours before and after drug administration.

FIG. 1 shows that ATL-2 produced strong motor stimulation, reaching peak within 20 minutes and lasting for about 60 minutes (arrow marks the injection). From our previous experience with other A2AR antagonists, the motor stimulant effect of ATL2 is comparable or stronger than other A2AR antagonists such as SCH58261 and KW6002.

Absence of Motor Stimulant Effect of ATL-2 in Mice Lacking the A2A Receptor

We validated that ATL-2 acts on the A2A receptor to stimulate motor activity by using A2AR KO mice (in both mixed (129sv X C57BL/6) as well as congenic (C57BL/6 genetic background) developed over the last several years. We evaluated the motor stimulant effect of ATL-2 in A2A receptor KO and their WT littermates. WT and A2A KO mice (n=4) were habituated for 60 minutes and treated with ATL-2 (15 mg/kg) and recorded for motor activity for 120 minutes.

FIG. 2 shows that ATL-2 produced motor activity in WT mice (relatively high basal locomotion is likely due to short habituation time (60 minute instead of 120 minutes) and demonstrates relatively higher basal locomotion in WT compared to KO mice as we noted previously,35 but this motor stimulation was absent in A2A receptor KO mice.

Experimental

Synthesis of A2AAR Antagonists

The following procedures may be employed for the preparation of the compounds of the present invention. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N.Y., 1991; March J: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989. In some cases, protective groups may be introduced and finally removed. Suitable protective groups for amino, hydroxy, and carboxy groups are described in Greene et al., Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991. Standard organic chemical reactions can be achieved by using a number of different reagents, for examples, as described in Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

In one variation, the compounds of this invention can be synthesized by the steps outlined in Scheme 1. Guanosine, A′, is acetylated to protect the ribose during reductive chlorination by POCl3/diethylaniline to form 6-chloroguanosine, C′. Non-aqueous diazotization in the presence of elemental iodine in diiodomethane is a standard route to the protected 6-chloro-2-iodonebularine, D′. Heating in methanolic ammonia deprotects the sugar and displaces the 6-chloro substituent to form 2-iodoadenosine, E′. Palladium-catalyzed coupling of E′ with a terminal alkyne generates 2-alkynyladenosine F′, which undergoes acid hydrolysis to form 9H-adenine G′. Alkylation with an appropriate halide (alkyl, cycloalkyl or heterocyclic) completes the synthesis of target 2,9-disubstituted adenine H′.

Preparation of the terminal alkynes (S)-1-ethynyl-1-hydroxy-(R)-3-methylcyclohexane and 2-ethynyladamantan-2-ol is achieved by treatment of the corresponding ketone with ethynylmagnesium bromide.

Preparation of the Substituted Piperidine-Carboxylate Terminal Alkynes (Scheme 2) starts with 4-carboxypiperidine (isonipecotic acid) I′ in anticipation of acylating the methyl ester, J′, with the appropriate alkyl chloroformate to form the N-carbamoyl ester K′. Borohydride reduction of the ester generates the 4-hydroxymethylpiperidine, L′, which undergoes tosylation to M′ in preparation for condensation with lithium acetylide to form terminal alkyne N′.

Scheme 3: Representative Processes for the Preparation of A2a Antagonists and Examples of A2a Antagonists:

Compound No. R7 R8 (CR1R2)m-Z Human Ki (nM) 1 H H ++++ 2 H H Propargyl ++++ 3 H H Cyclopentyl ++++ 4 H H —CH2CN ++++ 5 H H 4-Methoxybenzyl ++++ 6 H H 3,4-Dichlorobenzyl ++++ 7 H H 4- ++++ (Trifluoromethyl)benzyl 8 H H ++++ 9 H H ++++ 10 H H +++ 11 Pent-3-yl H —CH3 +++ 12 Pent-3-yl H —CH2CH2CH3 ++++ 13 Pent-3-yl H Iso-propyl +++ 14 Pent-3-yl H ++++ 15 Pent-3-yl H Cyclopentyl ++++ 16 Pent-3-yl H Allyl ++++ 17 Pent-3-yl H Propargyl ++++ 18 Pent-3-yl H —(CH2)3C≡CH ++++ 19 Pent-3-yl H —CH2CH2OH ++++ 20 Pent-3-yl H —CH2CH2CH2OH +++ 21 Pent-3-yl H —CH2CH2Cl 22 Pent-3-yl H +++ 23 Pent-3-yl H 24 Pent-3-yl H 25 Pent-3-yl H +++ 26 Pent-3-yl H 27 Pent-3-yl H Benzyl ++++ 28 Pent-3-yl H ++++ 29 Pent-3-yl H 4-Nitrobenzyl 30 Pent-3-yl H ++++ 31 Pent-3-yl H 32 H Propargyl ++++ 33 H ++++ 34 H —CH3 +++ 35 H Propargyl +++ 36 3-Methoxybenzyl H Propargyl ++++ 37 H Propargyl ++++ 38 —CH3 Propargyl
+Ki < 10,000 nM;

++Ki < 1,000 nM;

+++Ki < 500 nM;

++++Ki < 100 nM.
Compound No. R7 (CR1R2)m-Z Human Ki (nM) 39 H —CH3 ++++ 40 H —CH2CH3 ++++ 41 H —CH2CH2CH3 ++++ 42 H —(CH2)5CH3 ++ 43 H —(CH2)8CH3 44 H Iso-propyl +++ 45 H ++++ 46 H ++++ 47 H +++ 48 H 49 H Cyclobutyl ++++ 50 H Cyclopentyl ++++ 51 H Propargyl ++++ 52 H —CH2CH2OH +++ 53 H —CH2CH2CH2OH +++ 62 H But-3-ynyl ++++
+Ki < 10,000 nM;

++Ki < 1,000 nM;

+++Ki < 500 nM;

++++Ki < 100 nM.
Compound No. (CR9R10)n-Y (CR1R2)m-Z Human Ki (nM) 60 Propargyl ++++ 61 Propargyl ++++ 63 Propargyl ++++
+Ki < 10,000 nM;

++Ki < 1,000 nM;

+++Ki < 500 nM;

++++Ki < 100 nM.

Synthesis:

(S)-1,1-Ethynyl-hydroxy-(R)-3-methylcyclohexane. A solution of 0.5 M ethynylmagnesium bromide in THF (150.0 mL, 0.0750 mol) was added to an ice cold solution of (R)-(+)-3-methylcyclohexanone (2.77 g, 0.02469 mol) in anhydrous THF (100 mL). The ice bath was removed and the mixture stirred at room temperature 24 h. The mixture was cooled over ice and quenched with water (15.0 mL). The volume of THF was reduced to approximately 50 mL and the mixture filtered through a bed of celite/sand, washing with ether. The solution is then evaporated to dryness and the crude purified by column chromatography, eluting with a gradient of hexanes to hexanes/ethyl acetate (10%) to afford the pure product as a white crystalline solid: yield 1.412 g, 41%. 1H NMR (CDCl3) δ 0.73-0.95, 1.10-1.19, 1.35-1.45, 1.51-1.84, 1.93-2.03 (5×m, 9H, cyclohexyl), 0.93 (d, 3H, —CH3), 2.48 (s, 1H, alkyne).

2-Ethynyl-adamantan-2-ol. A solution of 0.5 M ethynylmagnesium bromide in THF (400.0 mL, 0.2000 mol) was added to an ice cold solution of 2-adamantone (7.706 g, 0.05130 mol) in anhydrous THF (250 mL). The mixture was stirred over ice 0.5 h and then at room temperature 21 h. The volume was reduced to half and the solution cooled over ice. The reaction was quenched with water (5.0 mL), filtered through a bed of celite/sand and evaporated to dryness. The crude was taken up in ether (400 mL) and washed with water (2×40 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated to dryness to afford the pure product as a crystalline white solid: yield 8.961 g, 99%. 1H NMR (CDCl3) δ 1.54-1.61, 1.68-1.72, 1.76-1.99, 2.11-2.21 (4×m, 14H, adamantly), 2.53 (s, 1H, alkyne).

Representative procedure for N6-amino substitution: 2-Iodoadenosine. A suspension of 6-chloro-2-iodo-9-(2′,3′,5′-O-triacetylfuranosyl)-9H-purine (14.70 g, 0.02729 mol) in MeOH (300 mL) was cooled over an ice bath. Ammonia gas was then bubbled through the mixture until it was saturated. The reaction vessel was sealed and heated at 40° C. for 18 h and at 60° C. for 5 days. The mixture was cooled over ice and nitrogen gas bubbled through the solution, the mixture being allowed to warm to room temperature. The solvent was then removed under reduced pressure and the crude recrystallized from water containing 3-4 drops of glacial acetic acid. The resulting precipitate was filtered and washed with water and ether to afford a white solid: yield 7.167 g, 67%.

Representative procedure for N6-alkylamino substitution: 2-Iodo-6-(3-pentyl)adenosine. 6-chloro-2-iodo-9-(2′,3′,5′-O-triacetylfuranosyl)-9H-purine (6.723 g, 0.01248 mol), 3-aminopentane (1.673 mL, 0.01436 mol) and diisopropylethylamine (2.725 mL, 0.01560 mol) were stirred in denatured ethanol (150 mL) at 90° C. in a pressure apparatus for 21 h. The reaction was then cooled over ice and ammonia gas bubbled through the mixture until it was saturated. The reaction vessel was closed and the mixture stirred at room temperature 21 h. The mixture was cooled over ice and nitrogen gas bubbled through the solution, the mixture being allowed to warm to room temperature. The solvent was removed under reduced pressure and the crude purified by column chromatography, eluting with a gradient of DCM/MeOH (0-4%) to afford the pure product as an off white solid: yield 4.838 g, 84%.

Representative procedure for C2 coupling: 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenosine. To a solution of 2-iodoadenosine (3.105 g, 7.898 mmol) in freshly degassed acetonitrile/DMF (100 mL, 1:1) was added degassed triethylamine (11.0 mL, 78.9 mmol), Pd(PPh3)4 (113 mg, 0.09779 mmol), CuI (catalytic), and 2,2-ethynyl-hydroxy-adamantanyl (1.516 g, 8.601 mmol). The mixture was stirred at room temperature under and inert atmosphere for 71 h. Silica bound Pd(II) scavenger Si-thiol (561 mg) and Pd(0) scavenger Si-TAAcOH (541 mg) were added and stirring continued a further 4.5 h. The suspension was filtered through celite and the resulting solution evaporated to dryness. The crude was purified by column chromatography, eluting with a gradient of DCM/MeOH (0-15%) to afford the pure product as a white solid: yield 3.476 g, 100%.

Representative procedure for ribose cleavage: 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine. A solution of 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenosine (3.486 g, 7.896 mmol) in methanol (100 mL) and 1.0 M HCl (10.0 mL) was stirred at 90° C. in a pressure apparatus for 18-50 h. The pH was adjusted to 4.2 with 5.0 M NaOH and the volume was reduced to half under reduced pressure. After cooling the resulting precipitate was filtered and washed with methanol to afford the pure product as a white solid: yield 2.153 g, 88%. 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 7.25 (br s, 2H), 5.56 (s, 1H), 2.18-2.09, 1.94-1.89, 1.82-1.64, 1.52-1.45 (4×m, 12H). LRMS ESI (M+H+) 310.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)adenine. Using the representative procedure for ribose cleavage above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)adenosine (1.03 g) gave the product as a white solid: yield 0.725 g, 98%. LRMS ESI (M+H+) 342.2.

Synthesis of C2, N9-Adenines:

Representative procedure for N9-alkylation using an appropriate alkyl halide:

An appropriate 9-unsubstituted adenine (1.649 mmol) was dissolved in DMF (80 mL). Anhydrous potassium carbonate (358 mg, 2.590 mmol) and an appropriate alkyl halide (3.295 mmol) were added and the mix stirred at between 25-100° C. for 5-100 h. The reaction mixture was adhered to silica and purified by column chromatography, eluting with a gradient of DCM/MeOH (0-10%) to afford the pure product.

9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (1). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (29 mg) gave 1 as a white solid: yield 19 mg, 55%. 1H NMR (CD 30D) δ 8.21 (s, 1H), 4.06 (d, 2H, J=7.3 Hz), 2.13-2.05, 1.94-1.66, 1.49-1.28, 0.92-0.80, 0.66-0.59, 0.49-0.44 (6×m, 14H), 1.17 (t, 1H, J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 326.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenine (2). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (112 mg) gave 2 as an off white solid: yield 88 mg, 69%. 1H NMR (CD3OD) δ 8.23 (s, 1H), 5.04 (s, 2H), 2.98 (t, 1H, J=2.6 Hz), 2.13-2.05, 1.94-1.65, 1.49-1.38, 0.91-0.80, (4×m, 7H), 1.17 (t, 1H, J=12.3 Hz), 0.95 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 310.1.

9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (3). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (34 mg) gave 3 as a white solid: yield 21 mg, 50%. 1H NMR (CD3OD) δ 8.21 (s, 1H), 4.91 (tt, 1H, J=7.0 Hz), 2.31-2.19, 2.13-1.65, 1.49-1.38, 0.92-0.79 (4×m, 17H), 1.15 (t, 1H, J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 340.2.

9-Acetonitrile-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (4). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (43 mg) gave 4 as a white solid: yield 25 mg, 51%. 1H NMR (CD3OD) δ8.20 (s, 1H), 5.35 (s, 1H), 2.33-2.05, 1.93-1.66, 1.49-1.38, 0.92-0.80 (4×m, 9H), 1.18 (t, 1H, J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 311.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-methoxybenzyl)adenine (5). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (24 mg) gave 5 as a white solid: yield 29 mg, 84%. 1H NMR (CD3OD) δ 8.10 (s, 1H), 7.26 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.32 (s, 2H), 3.75 (s, 3H), 2.33-2.05, 1.92-1.66, 1.49-1.38, 0.92-0.80 (4×m, 9H), 1.17 (t, 1H, J=12.3 Hz), 0.95 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 392.2.

9-(3,4-Dichlorobenzyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (6). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (26 mg) gave 6 as a white solid: yield 28 mg, 68%. 1H NMR (CD3OD) δ 8.20 (s, 1H), 7.52 (d, 1H, J=2.1 Hz), 7.48 (d, 1H, J=8.3 Hz), 7.19 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 5.40 (s, 2H), 2.11-2.04, 1.92-1.64, 1.48-1.37, 0.92-0.79 (4×m, 9H), 1.16 (t, 1H, J=12.3 Hz), 0.94 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 430.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-trifluoromethylbenzyl)adenine (7). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (30 mg) gave 7 as a white solid: yield 33 mg, 70%. 1H NMR (CD3OD) δ 8.20 (s, 1H), 7.64 (d, 2H, J=8.2 Hz), 7.44 (d, 2H, J=8.1 Hz), 5.52 (s, 2H), 2.10-2.03, 1.90-1.63, 1.47-1.36, 0.90-0.78 (4×m, 9H), 1.15 (t, 1H, J=12.3 Hz), 0.93 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 430.1.

9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (8). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (32 mg) gave 8 as a white solid: yield 36 mg, 80%. 1H NMR (CD3OD) δ 8.15 (s, 1H), 5.20 (s, 2H), 2.50 (s, 3H), 2.22 (s, 3H), 2.11-2.03, 1.92-1.65, 1.49-1.38, 0.92-0.81 (4×m, 9H), 1.18 (t, 1H, J=12.2 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 381.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-[2-(trifluoromethylphenyl)thiazol-4-ylmethyl]adenine (9). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (26 mg) gave 9 as a white solid: yield 30 mg, 61%. 1H NMR (CD3OD) δ 8.31 (s, 1H), 8.09 (d, 2H, J=8.8 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.55 (s, 1H), 5.58 (s, 2H), 2.12-2.04, 1.91-1.64, 1.48-1.37, 0.91-0.78 (4×m, 9H), 1.16 (t, 1H, J=12.4 Hz), 0.94 (d, 2H, J=6.6 Hz). LRMS ESI (M+H+) 513.1.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(3-(thiophen-2-yl)prop-2-ynyl)adenine (10). To a solution of 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenine (30 mg, 0.09697 mmol) in freshly degassed acetonitrile/DMF (15 mL, 2:1) was added degassed triethylamine (1.0 mL, 7.0175 mmol), Pd(PPh3)4 (30 mg, 0.02596 mmol), CuI (catalytic), and 98+% 2-bromothiophene (13.7 μL, 0.1161 mmol). The mixture was stirred at room temperature under and inert atmosphere for 28 h. Silica bound Pd(II) scavenger Si-thiol (240 mg) and Pd(0) scavenger Si-TAAcOH (155 mg) were added and stirring continued a further 72 h. The suspension was filtered through celite and the resulting solution evaporated to dryness. The crude was purified by column chromatography, eluting with a gradient of DCM/MeOH (0-6%) to afford the impure product (27 mg). The product was further purified by reverse phase column chromatography, eluting with a gradient of H2O/MeOH (50-75%) to afford the pure product 10 as a white solid: yield 8.5 mg, 22%. 1H NMR (CD3OD) δ 8.27 (s, 1H), 7.41(dd, 1H, J=1.1 Hz, J=5.3 Hz), 7.25 (dd, 2H, J=1.1 Hz, J=3.5 Hz), 6.99 (dd, 1H, J=3.7 Hz, J=5.0 Hz), 5.29 (s, 2H), 2.14-2.05, 1.94-1.65, 1.49-1.37, 0.99-0.79 (4×m, 12H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 392.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-methyl-N6-(3-pentyl)adenine (11). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (20 mg) gave 11 as a white solid: yield 9 mg, 43%. 1H NMR (CD3OD) δ 8.02 (s, 1H), 4.23 (m, 1H), 3.79 (s, 3H), 2.14-2.06, 1.96-1.38, 0.99-0.80 (3×m, 20H), 1.17 (t, 1H, J=12.3 Hz). LRMS ESI (M+H+) 356.3.

2-{2-[1 (S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-propyladenine (12). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (29 mg) gave 12 as a white solid: yield 26 mg, 80%. 1H NMR (CD3OD) δ 8.08 (s, 1H), 4.28-4.13 (m, 3H), 2.15-2.06, 1.95-1.38, 0.99-0.80 (3×m, 26H), 1.17 (t, 1H, J=12.3 Hz). LRMS ESI (M+H+) 384.3.

9-Isobutyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (13). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (27 mg) gave 13 as a white solid: yield 23 mg, 73%. 1H NMR (CD3OD) δ 8.06 (s, 1H), 4.21 (m, 1H), 4.01 (d, 2H, J=7.4 Hz), 2.21 (septet, 1H, J=6.8 Hz), 2.12-2.05, 1.96-1.38, 0.98-0.81 (3×m, 27H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 398.2.

9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (14). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (30 mg) gave 14 as a white solid: yield 17 mg, 57%. 1H NMR (CD3OD) δ 8.15 (s, 1H), 4.22 (m, 1H), 4.05 (d, 2H, J=7.3 Hz), 2.14-2.05, 1.96-1.28, 0.98-0.79 (3×m, 22H), 1.17 (t, 1H, J=12.2 Hz), 0.65-0.58 (m, 2H), 0.48-0.44 (m, 2H). LRMS ESI (M+H+) 396.3.

9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (15). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (37 mg) gave 15 as a white solid: yield 29 mg, 65%. 1H NMR (CD3OD) δ 8.15 (s, 1H), 4.91 (tt, 1H, J=7.0 Hz), 4.21 (m, 1H), 2.31-2.17, 2.14-1.35, 0.98-0.79 (3×m, 29H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 410.3.

9-Allyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (16). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (33 mg) gave 16 as a white solid: yield 26 mg, 71%. 1H NMR (CDCl3) δ 7.77 (br s, 1H), 6.09-5.95 (m, 1H), 5.34-5.20 (m, 2H), 4.79 (dt, 2H, J=5.8 Hz, J=1.5 Hz), 4.28 (m, 1H), 2.21-2.11, 1.96-1.42, 0.96-0.78 (3×m, 21H), 1.23 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 382.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(propargyl)adenine (17). Using the representative procedure for N9-alkylation above 2-{2-[(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (134 mg) gave 17 as a white solid: yield 79 mg, 53%. 1H NMR (CD3OD) δ 8.17 (s, 1H), 5.03 (d, 2H, J=2.6 Hz), 4.22 (m, 1H), 2.97 (t, 1H, J=2.6), 2.14-2.06, 1.95-1.38, 0.98-0.80 (3×m, 21H), 1.17 (t, 1H, J=12.4 Hz). LRMS ESI (M+H+) 380.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pent-4-yne)adenine (18). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (35 mg) gave 18 as a white solid: yield 31 mg, 74%. 1H NMR (CD3OD) δ 8.07 (s, 1H), 4.32 (t, 2H, J=6.9 Hz), 4.21 (m, 1H), 2.31-2.19, 2.14-2.00, 1.95-1.38, 1.00-0.79 (4×m, 21H), 1.17 (t, 1H, J=12.3 Hz). LRMS ESI (M+H+) 408.1.

9-(2-Hydroxyethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (19). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (103 mg) gave 19 as a white solid: yield 60 mg, 52%. 1H NMR (CD3OD) δ 8.06 (s, 1H), 4.30 (t, 2H, J=5.1 Hz), 4.22 (m, 1H), 3.86 (t, 2H, J=5.1 Hz), 2.14-2.05, 1.95-1.38, 0.99-0.80 (3×m, 21H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 386.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(3-hydroxypropyl)-N6-(3-pentyl)adenine (20). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (59 mg) gave 20 as a white solid: yield 35 mg, 51%. 1H NMR (CD3OD) δ 8.11 (s, 1H), 4.32 (t, 2H, J=7.0 Hz), 4.20 (m, 1H), 3.56 (t, 2H, J=5.9 Hz), 2.14-2.00, 1.93-1.38, 0.99-0.80 (3×m, 23H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 400.3.

9-(2-Chloroethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (21). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (38 mg) gave 21 as a white solid: yield 28 mg, 62%. 1H NMR (CD3OD) δ 8.11 (s, 1H), 4.55 (t, 2H, J=5.7 Hz), 4.22 (m, 1H), 3.96 (t, 2H, J=5.7 Hz), 2.14-2.05, 1.94-1.38, 0.99-0.79 (3×m, 21H), 1.17 (t, 1H, J=12.1 Hz). LRMS ESI (M+H+) 404.2.

9-([1,3]-Dioxolan-2-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (22). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (37 mg) gave 22 as a white solid: yield 32 mg, 69%. 1H NMR (CD3OD) δ 8.04 (s, 1H), 5.20 (t, 1H, J=3.3 Hz), 4.40 (d, 2H, J=3.3 Hz), 4.21 (m, 1H), 3.88-3.76 (m, 4H), 2.14-2.06, 1.92-1.38, 0.98-0.79 (3×m, 21H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 428.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(tetrahydro-pyran-2-ylmethyl)adenine (23). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (32 mg) gave 23 as a white solid: yield 27 mg, 66%. 1H NMR (CD3OD) δ 8.01 (s, 1H), 4.31-4.07 (m, 3H), 3.96-3.87 (m, 1H), 3.67-3.58 (m, 1H), 3.93-3.32 (m, 1H), 2.14-2.06, 1.95-1.38, 1.31-1.12, 0.99-0.80 (4×m, 28H). LRMS ESI (M+H+) 440.4.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(isopropylcarboxylate)adenine (24). A 1.0 M solution of isopropyl chloroformate in toluene (150 μL, 0.1500 mmol) was added to an ice cold solution of 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (34 mg) in anhydrous pyridine (2.0 mL). After stirring over ice 1.5 h the solvent was removed under reduced pressure and the crude purified by column chromatography, eluting with a gradient of DCM/MeOH (0-5%) to afford the pure product 24 as an off white solid: yield 18 mg, 42%. 1H NMR (CD3OD) δ 8.44 (s, 1H), 5.29 (septet, 1H, J=6.4, J=6.2 Hz), 4.21 (m, 1H), 2.14-2.05, 1.97-1.37, 1.00-0.79 (3×m, 27H), 1.16 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 427.9.

9-(Acetic acid ethyl ester)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (25). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (38 mg) gave 25 as a white solid: yield 9 mg, 19%. 1H NMR (CD3OD) δ 8.06 (s, 1H), 5.06 (s, 2H), 4.24 (br q, 3H, J=7.0, 7.3 Hz), 2.15-2.05, 1.95-1.37, 1.05-0.79 (3×m, 22H), 1.29 (t, 3H, J=7.0, 7.3 Hz), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 428.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-oxo-oxazolidin-5-ylmethyl)-N6-(3-pentyl)adenine (26). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (56 mg) gave 26 as a white solid: yield 43 mg, 60%. 1H NMR (CD3OD) δ 8.09 (s, 1H), 5.04 (m, 1H), 4.52 (d, 2H, J=4.8 Hz), 4.21 (m, 1H), 3.79-3.70 (m, 1H), 3.47-3.39 (m, 1H), 2.13-2.04, 1.95-1.38, 0.99-0.79 (3×m, 21H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 441.3.

9-Benzyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (27). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (37 mg) gave 27 as a white solid: yield 31 mg, 66%. 1H NMR (CD3OD) δ 8.06 (s, 1H), 7.37-7.25 (m, 5H), 5.40 (s, 2H), 4.22 (m, 1H), 2.14-2.05, 1.95-1.37, 0.99-0.79 (3×m, 21H), 1.16 (t, 1H, J=12.3 Hz). LRMS ESI (M+H+) 432.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pyridin-3-ylmethyl)adenine (28). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (34 mg) gave 28 as a white solid: yield 8 mg, 19%. 1H NMR (CD3OD) δ 8.57 (m, 1H), 8.48 (m, 1H), 8.17 (s, 1H), 7.77 (m, 1H), 7.41 (m, 1H), 5.49 (s, 2H), 4.22 (m, 1H), 2.13-2.04, 1.93-1.37, 0.99-0.79 (3×m, 21H), 1.16 (t, 1H, J=12.3 Hz). LRMS ESI (M+H+) 433.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-nitrobenzyl)-N6-(3-pentyl)adenine (29). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (33 mg) gave 29 as a white solid: yield 36 mg, 78%. 1H NMR (CD3OD) δ 8.19 (d, 2H, J=8.8 Hz), 8.16 (s, 1H), 7.46 (d, 2H, J=8.8 Hz), 5.55 (s, 2H), 4.22 (m, 1H), 2.12-2.02, 1.92-1.36, 1.00-0.78 (3×m, 211H), 1.15 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 477.3.

9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (30). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (50 mg) gave 30 as a white crystalline solid: yield 50 mg, 76%. 1H NMR (CD3OD) δ 8.08 (s, 1H), 5.18 (s, 2H), 4.19 (m, 1H), 2.50 (s, 3H), 2.23 (s, 3H), 2.13-2.04, 1.94-1.38, 0.99-0.80 (3×m, 21H), 1.18 (t, 1H, J=12.1 Hz). LRMS ESI (M+H+) 451.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-methyl-thiazol-5-ylmethyl)-N6-(3-pentyl)adenine (31). 2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (56 mg, 0.1640 mmol) and 4-chloromethyl-2-methylthiazole hydrochloride (127 mg, 0.6899 mmol) were stirred in DMF (8 mL) at 150° C. for 22 h. The reaction mixture was adhered to silica and purified by column chromatography, eluting with a gradient of DCM/MeOH (0-6%) to afford pure 31 as an off white solid: yield 2 mg, 3%. 1H NMR (CD3OD) δ 8.12 (s, 1H), 7.29 (s, 1H), 5.44 (s, 2H), 4.22 (m, 1H), 2.65 (s, 3H), 2.14-2.05, 1.94-1.37, 0.99-0.80 (3×m, 21H), 1.18 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 453.2.

N6-[(S)-(+)-sec-Butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyl-adenine (32). Using the representative procedure for N9-alkylation above N6-[(S)-(+)-sec-butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (29 mg) gave 32 as a white solid: yield 20 mg, 62%. 1H NMR (CD3OD) δ 8.17 (s, 1H), 5.03 (d, 2H, J=2.6 Hz), 4.32 (m, 1H), 2.97 (t, 1H, J=2.6 Hz), 2.14-2.06, 1.95-1.58, 1.49-1.38, 1.00-0.79 (4×m, 16H), 1.25 (d, 3H, J=6.4 Hz), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 366.1.

N6-[(s)-(+)-sec-Butyl]-9-(3,5-dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (33). Using the representative procedure for N9-alkylation above N6-[(S)-(+)-sec-butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (42 mg) gave 33 as a white solid: yield 31 mg, 55%. 1H NMR (CD3OD) δ 8.08 (s, 1H), 5.19 (s, 2H), 4.29 (m, 1H), 2.50 (s, 3H), 2.22 (s, 3H), 2.14-2.04, 1.95-1.57, 1.49-1.38, 0.99-0.82 (4×m, 16H), 1.24 (d, 3H, J=6.4 Hz), 1.18 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 437.2.

N6-(2-Diphenylethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-methyladenine (34). Using the representative procedure for N9-alkylation above N6-(2-diphenylethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (14 mg) gave 34 as a white solid: yield 5 mg, 35%. LRMS ESI (M+H+) 466.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(s)-(−)-alpha-napthalen-1-yl-ethyl]-9-(propargyl)adenine (35). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(S)-(−)-alpha-napthalen-1-yl-ethyl]adenine (29 mg) gave 35 as a white solid: yield 22 mg, 70%. 1H NMR (CD3OD) δ 8.23 (m, 1H), 8.15 (s, 1H), 7.88-7.84 (m, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.64 (d, 1H, J=7.0 Hz), 7.53-7.40 (m, 3H), 6.33 (br s, 1H), 5.00 (d, 2H, J=2.6 Hz), 2.96 (t, 1H, J=2.6 Hz), 2.08-1.99, 1.87-1.59, 1.45-1.33, 1.18-1.08, 0.95-0.70 (5×m, 12H). LRMS ESI (M+H+) 464.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-methoxybenzyl)-9-(propargyl)adenine (36). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-methoxybenzyl)adenine (48 mg) gave 36 as a white solid: yield 40 mg, 76%. 1H NMR (CD3OD) δ 8.14 (s, 1H), 7.18 (t, 1H, J=7.9 Hz), 6.96-6.90 (m, 2H), 6.77 (m, 1H), 5.01 (d, 2H, J=2.6 Hz), 4.75 (br s, 2H), 3.74 (s, 3H), 2.97 (t, 1H, J=2.6 Hz), 2.13-2.04, 1.94-1.64, 1.48-1.37, 1.21-1.11, 0.96-0.77 (5×m, 12H). LRMS ESI (M+H+) 430.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(propargyl)-N6-(pyridin-2-ylmethyl)adenine (37). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(pyridin-2-ylmethyl)adenine (29 mg) gave 37 as a white solid: yield 27 mg, 84%. 1H NMR (CD3OD) δ 8.49 (d, 1H, J=4.4 Hz), 8.20 (s, 1H), 7.76 (dt, 1H, J=1.8 Hz, J=7.7 Hz), 7.43 (d, 1H, J=7.9 Hz), 7.29 (m, 1H), 5.04 (d, 2H, J=2.6 Hz), 4.91 (br s, 2H), 2.98 (t, 1H, J=2.6 Hz), 2.10-2.03, 1.90-1.63, 1.47-1.36, 1.20-1.10, 0.96-0.73 (5×m, 12H). LRMS ESI (M+H+) 401.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(methyl)(2-phenethyl)]-9-(propargyl)adenine (38). Using the representative procedure for N9-alkylation above 2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(methyl)(2-phenethyl)]adenine (54 mg) gave 38 as a white solid: yield 47 mg, 79%. 1H NMR (CD3OD) δ 8.09 (s, 1H), 7.30-7.11 (m, 5H), 5.00 (d, 2H, J=2.6 Hz), 4.19 (br s, 2H), 3.35 (br s, 3H), 2.98-2.91 (m, 3H), 2.14-2.06, 1.96-1.66, 1.50-1.39, 1.27-1.13, 0.98-0.80 (5×m, 12H). LRMS ESI (M+H+) 428.3.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-methyladenine (39). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (58 mg) gave 39 as a white solid: yield 39 mg, 64%. 1H NMR (CD3OD) δ 8.08 (s, 1H), 3.80 (s, 3H), 2.37-2.22, 2.08-2.03, 1.89-1.74, 1.64-1.57 (4×m, 14H). LRMS ESI (M+H+) 324.2.

9-Ethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (40). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (59 mg) gave 40 as a white solid: yield 42 mg, 65%. 1H NMR (CD3OD) δ 8.15 (s, 1H), 4.25 (t, 2H, J=7.4 Hz), 2.36-2.22, 2.08-2.03, 1.89-1.74, 1.64-1.57 (4×m, 14H), 1.47 (t, 3H, J=7.3 Hz). LRMS ESI (M+H+) 338.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propyladenine (41). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (56 mg) gave 41 as a white solid: yield 46 mg, 72%. 1H NMR (CD3OD) δ 8.13 (s, 1H), 4.17 (t, 2H, J=7.2 Hz), 2.36-2.22, 2.08-2.03, 1.92-1.74, 1.64-1.57 (4×m, 16H), 0.93 (t, 3H, J=7.5 Hz). LRMS ESI (M+H+) 352.2.

9-Hexyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (42). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50 mg) gave 42 as a white solid: yield 43 mg, 68%. 1H NMR (CD3OD) δ 8.13 (s, 1H), 4.21 (t, 2H, J=7.0, 7.5 Hz), 2.37-2.22, 2.08-2.03, 1.91-1.74, 1.65-1.57, 1.37-1.27 (5×m, 22H), 0.88 (t, 3H). LRMS ESI (M+H+) 394.1.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-nonyladenine (43). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (43 mg) gave 43 as a white solid: yield 47 mg, 78%. 1H NMR (CD3OD) δ 8.13 (s, 1H), 4.20 (t, 2H, J=7.3 Hz), 2.36-2.22, 2.08-2.03, 1.90-1.74, 1.64-1.56, 1.35-1.23 (5×m, 28H), 0.87 (t, 3H, J=7.0 Hz). LRMS ESI (M+H+) 436.1.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-isobutyl-adenine (44). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (52 mg) gave 44 as a white solid: yield 46 mg, 75%. 1H NMR (CD3OD) δ 8.11 (s, 1H), 4.02 (d, 2H, J=7.5 Hz), 2.36-2.16, 2.08-2.03, 1.88-1.73, 1.64-1.56, (4×m, 15H), 0.91 (d, 6H, J=6.6 Hz). LRMS ESI (M+H+) 366.2.

9-Cyclopropylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (45). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (33 mg) gave 45 as a white solid: yield 11 mg, 28%. 1H NMR (CD3OD) δ 8.21 (s, 1H), 4.06 (d, 2H, J=7.3 Hz), 2.36-2.22, 2.08-2.03, 1.89-1.74, 1.65-1.57, (4×m, 14H), 1.42-1.27 (m, 1H), 0.65-0.58, 0.49-0.43 (2×m, 4H). LRMS ESI (M+H+) 364.2.

9-Cyclobutylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (46). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (54 mg) gave 46 as a white crystalline solid: yield 21 mg, 32%. 1H NMR (CD3OD) δ 8.12 (s, 1H), 4.22 (d, 2H, J=7.5 Hz), 2.87 (quintet, 1H, J=7.7 Hz), 2.37-2.22, 2.09-1.74, 1.65-1.57, (3×m, 20H). LRMS ESI (M+H+) 378.2.

9-Cyclopentylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (47). 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (44 mg, 0.1422 mmol) was dissolved in DMF (20 mL) with heating. Anhydrous potassium carbonate (51 mg, 0.3690 mmol) and cyclopentylmethyl 4-methylbenzenesulfonate (54 mg, 0.2123 mmol) were added and the mixture stirred at 70° C. for 72 h. Extra cyclopentylmethyl 4-methylbenzenesulfonate (82 mg, 0.3224 mmol) was added and stirring continued at 100° C. a further 4.5 h. The reaction mixture was adhered to silica and purified by column chromatography, eluting with a gradient of DCM/MeOH (0-6%) to afford the pure 47 as a white solid: yield 38 mg, 68%. 1H NMR (CD3OD) δ 8.15 (s, 1H), 4.14 (d, 2H, J=7.7 Hz), 2.48 (quintet, 1H, J=7.5 Hz), 2.37-2.22, 2.08-2.02, 1.89-1.58, 1.37-1.24 (4×m, 22H). LRMS ESI (M+H+) 392.0.

9-Cyclohexylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (48). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49 mg) gave 48 as a white solid: yield 45 mg, 70%. 1H NMR (CD3OD) δ 8.10 (s, 1H), 4.04 (d, 2H, J=7.3 Hz), 2.37-2.22, 2.09-2.03, 1.92-1.54, 1.31-0.96, (4×m, 25H). LRMS ESI (M+H+) 406.3.

9-Cyclobutyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (34 mg) gave 49 as a white solid: yield 18 mg, 45%. 1H NMR (CD3OD) δ 8.32 (s, 1H), 5.03 (m, 1H), 2.72-2.49, 2.38-2.22, 2.04-1.74, 1.64-1.57 (4×m, 20H). LRMS ESI (M+H+) 364.2.

9-Cyclopentyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (473 mg) gave 50 as a white solid: yield 371 mg, 64%. 1H NMR (CD3OD) δ 8.21 (s, 1H), 4.90 (m, 1H), 2.37-2.20, 2.08-1.73, 1.64-1.57 (4×m, 22H). LRMS ESI (M+H+) 378.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propargyl-adenine (51). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (510 mg) gave 51 as a white solid: yield 416 mg, 73%. 1H NMR (CD3OD) δ 8.22 (s, 1H), 5.04 (d, 2H, J=2.6 Hz), 2.98 (t, 1H, J=2.5 Hz), 2.36-2.22, 2.08-2.03, 1.89-1.75, 1.65-1.57 (4×m, 14H). LRMS ESI (M+H+) 348.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(2-hydroxyethyl)adenine (52). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49 mg) gave 52 as a white solid: yield 21 mg, 38%. 1H NMR (CD3OD) δ 8.12 (s, 1H), 4.31 (t, 2H, J=5.2 Hz), 3.87 (t, 2H, J=4.7 Hz), 2.36-2.21, 2.08-2.01, 1.89-1.73, 1.65-1.57 (4×m, 14H). LRMS ESI (M+H+) 354.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(2-hydroxypropyl)adenine (53). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (55 mg) gave 53 as a white solid: yield 37 mg, 57%. 1H NMR (CD3OD) δ 8.13 (s, 1H), 4.32 (t, 2H, J=7.0 Hz), 3.55 (t, 2H, J=5.9, 6.2 Hz), 2.36-2.21, 2.11-2.00, 1.89-1.73, 1.65-1.57 (4×m, 16H). LRMS ESI (M+H+) 368.2.

2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine: Isomer A (60). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-norbornan-2-yl]ethyn-1-yl}adenine (42 mg) gave 60 as a white solid: yield 18 mg, 38%. 1H NMR (CD3OD) δ 8.22 (s, 1H), 5.03 (s, 2H), 2.47-2.51 (m, 1H), 2.19-2.30 (m, 2H), 1.90-2.08 (m, 2H), 1.53-1.66 (m, 1H), 1.27-1.47 (m, 4H). LRMS ESI (M+H+) 308.1.

2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine: Isomer B (61). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-norbornan-2-yl]ethyn-1-yl}adenine (31 mg) gave 61 as a white solid: yield 10 mg, 29%. 1H NMR (CD3OD) δ 8.22 (s, 1H), 5.03 (s, 2H), 2.47-2.51 (m, 1H), 2.19-2.30 (m, 2H), 1.90-2.08 (m, 2H), 1.53-1.66 (m, 1H), 1.27-1.47 (m, 4H). LRMS ESI (M+H+) 308.1.

9-(But-3-ynyl)-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (62). Using the representative procedure for N9-alkylation above 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (52 mg) gave 62 as a white solid: yield 14 mg, 24%. 1H NMR (CD3OD) δ 8.18 (s, 1H), 4.36 (t, 2H, J=6.6 Hz), 2.77 (dt, 2H, J=2.6, 6.6 Hz), 2.36 (t, 1H, J=2.6 Hz), 2.36-2.22, 2.08-2.03, 1.89-1.74, 1.64-1.57 (4×m, 16H). LRMS ESI (M+H+) 362.0.

2-{3-[1-(Methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}-9-propargyladenine (63). Using the representative procedure for N9-alkylation above 2-{3-[1-(methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}adenine (53 mg) gave 63 as a white solid: yield 18 mg, 30%. 1H NMR (CD3OD) δ 8.21 (s, 1H), 5.02 (s, 2H), 4.21-4.09 (m, 2H), 3.66 (s, 3H), 2.94-2.74 (m, 2H), 2.47-2.40 (m, 3H), 1.95-1.74 (m, 3H), 1.38-1.20 (m, 2H). LRMS ESI (M+H+) 353.1.

The compounds in tables 1 to 7, or their pharmaceutically acceptable salts either as single stereoisomers or mixtures are representative examples of the invention.

TABLE 1 Compound (CR1R2)m-Z R6 NC100 Propargyl CH2OH NC101 c-Pentyl CH2OH NC102 Propargyl CO2H NC103 c-Pentyl CO2H NC104 Propargyl CO2Me NC105 c-Pentyl CO2Me NC106 Propargyl CH2OAc NC107 c-Pentyl CH2OAc NC108 Propargyl CH2N(CH3)2 NC109 c-Pentyl CH2N(CH3)2 NC110 Propargyl COOCH2CH2NHBoc NC111 c-Pentyl COOCH2CH2NHBoc NC112 Propargyl COOCH2CH2NH2 NC113 c-Pentyl COOCH2CH2NH2 NC114 Propargyl CONHCH2CH3 NC115 c-Pentyl CONHCH2CH3 NC116 Propargyl CONH2 NC117 c-Pentyl CONH2 NC118 Propargyl CONHMe NC119 c-Pentyl CONHMe NC120 Propargyl Me, cis CO2Me NC121 c-Pentyl Me, cis CO2Me NC122 Propargyl Me, trans CO2Me NC123 c-Pentyl Me, trans CO2Me NC124 Propargyl CH2CH3 NC125 c-Pentyl CH2CH3 NC126 Propargyl H NC127 c-Pentyl H NC128 Propargyl COCH3 NC129 c-Pentyl COCH3 NC130 Propargyl CHCH3(OH) NC131 c-Pentyl CHCH3(OH)

TABLE 2 Compound (CR1R2)m-Z R6 NC132 Propargyl H NC133 c-Pentyl H NC134 Propargyl CO2tBu NC135 c-Pentyl CO2tBu NC136 Propargyl CO2Et NC137 c-Pentyl CO2Et NC138 Propargyl CO2iBu NC139 c-Pentyl CO2iBu NC140 Propargyl CO2iPr NC141 c-Pentyl CO2iPr 63 Propargyl COMe NC142 c-Pentyl COMe NC143 Propargyl COC(CH3)3 NC144 c-Pentyl COC(CH3)3 NC145 Propargyl COCH2(CH3)3 NC146 c-Pentyl COCH2(CH3)3 NC147 Propargyl C(O)N(CH3)2 NC148 c-Pentyl C(O)N(CH3)2 NC149 Propargyl C(O)N(CH3)Et NC150 c-Pentyl C(O)N(CH3)Et NC142 Propargyl C(O)N(CH3)iPr NC143 c-Pentyl C(O)N(CH3)iPr NC144 Propargyl C(O)N(CH3)iBu NC145 c-Pentyl C(O)N(CH3)iBu NC146 Propargyl C(O)NH(CH3) NC147 c-Pentyl C(O)NH(CH3) NC148 Propargyl C(O)NH(Et) NC149 c-Pentyl C(O)NH(Et) NC150 Propargyl C(O)NH(iPr) NC142 c-Pentyl C(O)NH(iPr) NC143 Propargyl C(O)NH(iBu) NC144 c-Pentyl C(O)NH(iBu)

TABLE 3 Compound (CR1R2)m-Z R6 NC151 Propargyl H NC152 c-Pentyl H NC153 Propargyl 2-CH3 NC154 c-Pentyl 2-CH3 NC155 Propargyl 2-C(CH3)3 NC156 c-Pentyl 2-C(CH3)3 NC157 Propargyl 2-C6H5 NC158 c-Pentyl 2-C6H5 2 Propargyl 3-CH3 3 c-Pentyl 3-CH3 NC159 Propargyl 3-(CH3)2 NC160 c-Pentyl 3-(CH3)2 NC161 Propargyl 3-CH2CH3 NC162 c-Pentyl 3-CH2CH3 NC163 Propargyl 3-(CH3)2, 5-(CH3)2 NC164 c-Pentyl 3-(CH3)2, 5-(CH3)2 NC165 Propargyl 4-CH3 NC166 c-Pentyl 4-CH3 NC167 Propargyl 4-C2H5 NC168 c-Pentyl 4-C2H5 NC169 Propargyl 4-C(CH3)3 NC170 c-Pentyl 4-C(CH3)3 NC171 Propargyl 4-C6H5 NC172 c-Pentyl 4-C6H5

TABLE 4 Compound (CR1R2)m-Z R6 NC173 Propargyl H NC174 c-Pentyl H NC175 Propargyl cyclohexyl NC176 c-Pentyl cyclohexyl NC177 Propargyl CO2Et NC178 c-Pentyl CO2Et NC179 Propargyl CO2tBu NC180 c-Pentyl CO2tBu NC181 Propargyl COMe NC182 c-Pentyl COMe NC183 Propargyl CO2iBu NC184 c-Pentyl CO2iBu NC185 Propargyl 2-Pyrimidinyl NC186 c-Pentyl 2-Pyrimidinyl NC187 Propargyl COC(CH3)3 NC188 c-Pentyl COC(CH3)3 NC189 Propargyl COMe NC190 c-Pentyl COMe NC191 Propargyl COCH2(CH3)3 NC192 c-Pentyl COCH2(CH3)3 NC193 Propargyl COCH3 NC194 c-Pentyl COCH3 NC195 Propargyl C(O)N(CH3)2 NC196 c-Pentyl C(O)N(CH3)2 NC197 Propargyl C(O)N(CH3)Et NC198 c-Pentyl C(O)N(CH3)Et NC199 Propargyl C(O)N(CH3)iPr NC200 c-Pentyl C(O)N(CH3)iPr NC201 Propargyl C(O)N(CH3)iBu NC202 c-Pentyl C(O)N(CH3)iBu NC203 Propargyl C(O)NH(CH3) NC204 c-Pentyl C(O)NH(CH3) NC205 Propargyl C(O)NH(Et) NC206 c-Pentyl C(O)NH(Et) NC207 Propargyl C(O)NH(iPr) NC208 c-Pentyl C(O)NH(iPr) NC209 Propargyl C(O)NH(iBu) NC210 c-Pentyl C(O)NH(iBu)

TABLE 5 Compound (CR1R2)m-Z R6 NC211 Propargyl CH2OH NC212 c-Pentyl CH2OH NC213 Propargyl CO2H NC214 c-Pentyl CO2H NC215 Propargyl CO2Me NC216 c-Pentyl CO2Me NC217 Propargyl CO2Et NC218 c-Pentyl CO2Et NC219 Propargyl CH2OAc NC220 c-Pentyl CH2OAc NC221 Propargyl CH2N(CH3)2 NC222 c-Pentyl CH2N(CH3)2 NC223 Propargyl COOCH2CH2NHBoc NC224 c-Pentyl COOCH2CH2NHBoc NC225 Propargyl COOCH2CH2NH2 NC226 c-Pentyl COOCH2CH2NH2 NC227 Propargyl CONHCH2CH3 NC228 c-Pentyl CONHCH2CH3 NC229 Propargyl CONH2 NC230 c-Pentyl CONH2 NC231 Propargyl CONHMe NC232 c-Pentyl CONHMe NC233 Propargyl CH2CH3 NC234 c-Pentyl CH2CH3 NC235 Propargyl COCH3 NC236 c-Pentyl COCH3 NC237 Propargyl CHCH3(OH) NC238 c-Pentyl CHCH3(OH)

TABLE 6 Compound (CR1R2)m-Z R6 NC239 Propargyl CH2OH NC240 c-Pentyl CH2OH NC241 Propargyl CO2H NC242 c-Pentyl CO2H NC243 Propargyl CO2Me NC244 c-Pentyl CO2Me NC245 Propargyl CH2OAc NC246 c-Pentyl CH2OAc NC247 Propargyl CH2N(CH3)2 NC248 c-Pentyl CH2N(CH3)2 NC249 Propargyl COOCH2CH2NHBoc NC250 c-Pentyl COOCH2CH2NHBoc NC251 Propargyl COOCH2CH2NH2 NC252 c-Pentyl COOCH2CH2NH2 NC253 Propargyl CONHCH2CH3 NC254 c-Pentyl CONHCH2CH3 NC255 Propargyl CONH2 NC256 c-Pentyl CONH2 NC257 Propargyl CONHMe NC258 c-Pentyl CONHMe NC259 Propargyl CH2CH3 NC260 c-Pentyl CH2CH3 NC261 Propargyl COCH3 NC262 c-Pentyl COCH3 NC263 Propargyl CHCH3(OH) NC264 c-Pentyl CHCH3(OH)

TABLE 7 Compound (CR1R2)m-Z W W′ R6 NC265 Propargyl CH CH CO2Me NC266 c-Pentyl CH N CO2Me NC267 Propargyl N CH CO2Me NC268 c-Pentyl N N CO2Me NC269 Propargyl CH CH CO2Me NC270 c-Pentyl CH N CO2Me NC271 Propargyl N CH CO2Me NC272 c-Pentyl N N CO2Me NC273 Propargyl CH CH CH2OH NC274 c-Pentyl CH N CH2OH NC275 Propargyl N CH CH2OH NC276 c-Pentyl N N CH2OH NC277 Propargyl CH CH CH2OH NC278 c-Pentyl CH N CH2OH NC279 Propargyl N CH CH2OH NC280 c-Pentyl N N CH2OH NC281 Propargyl CH CH CO2H NC282 c-Pentyl CH N CO2H NC283 Propargyl N CH CO2H NC284 c-Pentyl N N CO2H NC285 Propargyl CH CH CO2H NC286 c-Pentyl CH N CO2H NC287 Propargyl N CH CO2H NC288 c-Pentyl N N CO2H NC289 Propargyl CH CH CH2OAc NC290 c-Pentyl CH N CH2OAc NC291 Propargyl N CH CH2OAc NC292 c-Pentyl N N CH2OAc NC293 Propargyl CH CH CH2OAc NC294 c-Pentyl CH N CH2OAc NC295 Propargyl N CH CH2OAc NC296 c-Pentyl N N CH2OAc NC297 Propargyl CH CH CONH2 NC298 c-Pentyl CH N CONH2 NC299 Propargyl N CH CONH2 NC300 c-Pentyl N N CONH2 NC301 Propargyl CH CH CONH2 NC302 c-Pentyl CH N CONH2 NC303 Propargyl N CH CONH2 NC304 c-Pentyl N N CONH2 NC305 Propargyl CH CH CONHMe NC306 c-Pentyl CH N CONHMe NC307 Propargyl N CH CONHMe NC308 c-Pentyl N N CONHMe NC309 Propargyl CH CH CONHMe NC310 c-Pentyl CH N CONHMe NC311 Propargyl N CH CONHMe NC312 c-Pentyl N N CONHMe NC313 Propargyl CH CH CO2tBu NC314 c-Pentyl CH N CO2tBu NC315 Propargyl N CH CO2tBu NC316 c-Pentyl N N CO2tBu NC317 Propargyl CH CH CO2tBu NC318 c-Pentyl CH N CO2tBu NC319 Propargyl N CH CO2tBu NC320 c-Pentyl N N CO2tBu NC321 Propargyl CH CH CO2Et NC322 c-Pentyl CH N CO2Et NC323 Propargyl N CH CO2Et NC324 c-Pentyl N N CO2Et NC325 Propargyl CH CH CO2Et NC326 c-Pentyl CH N CO2Et NC327 Propargyl N CH CO2Et NC328 c-Pentyl N N CO2Et NC329 Propargyl CH CH CO2iBu NC330 c-Pentyl CH N CO2iBu NC331 Propargyl N CH CO2iBu NC332 c-Pentyl N N CO2iBu NC333 Propargyl CH CH CO2iBu NC334 c-Pentyl CH N CO2iBu NC335 Propargyl N CH CO2iBu NC336 c-Pentyl N N CO2iBu NC337 Propargyl CH CH CO2iPr NC338 c-Pentyl CH N CO2iPr NC339 Propargyl N CH CO2iPr NC340 c-Pentyl N N CO2iPr NC341 Propargyl CH CH CO2iPr NC342 c-Pentyl CH N CO2iPr NC343 Propargyl N CH CO2iPr NC344 c-Pentyl N N CO2iPr NC345 Propargyl CH CH COMe NC346 c-Pentyl CH N COMe NC347 Propargyl N CH COMe NC348 c-Pentyl N N COMe NC349 Propargyl CH CH COMe NC350 c-Pentyl CH N COMe NC351 Propargyl N CH COMe NC352 c-Pentyl N N COMe NC353 Propargyl CH CH COC(CH3)3 NC354 c-Pentyl CH N COC(CH3)3 NC355 Propargyl N CH COC(CH3)3 NC356 c-Pentyl N N COC(CH3)3 NC357 Propargyl CH CH COC(CH3)3 NC358 c-Pentyl CH N COC(CH3)3 NC359 Propargyl N CH COC(CH3)3 NC360 c-Pentyl N N COC(CH3)3 NC361 Propargyl CH CH COCH2(CH3)3 NC362 c-Pentyl CH N COCH2(CH3)3 NC363 Propargyl N CH COCH2(CH3)3 NC364 c-Pentyl N N COCH2(CH3)3 NC365 Propargyl CH CH COCH2(CH3)3 NC366 c-Pentyl CH N COCH2(CH3)3 NC367 Propargyl N CH COCH2(CH3)3 NC368 c-Pentyl N N COCH2(CH3)3 NC369 Propargyl CH CH C(O)N(CH3)2 NC370 c-Pentyl CH N C(O)N(CH3)2 NC371 Propargyl N CH C(O)N(CH3)2 NC372 c-Pentyl N N C(O)N(CH3)2 NC373 Propargyl CH CH C(O)N(CH3)2 NC374 c-Pentyl CH N C(O)N(CH3)2 NC375 Propargyl N CH C(O)N(CH3)2 NC376 c-Pentyl N N C(O)N(CH3)2 NC377 Propargyl CH CH C(O)N(CH3)Et NC378 c-Pentyl CH N C(O)N(CH3)Et NC379 Propargyl N CH C(O)N(CH3)Et NC380 c-Pentyl N N C(O)N(CH3)Et NC381 Propargyl CH CH C(O)N(CH3)Et NC382 c-Pentyl CH N C(O)N(CH3)Et NC383 Propargyl N CH C(O)N(CH3)Et NC384 c-Pentyl N N C(O)N(CH3)Et NC385 Propargyl CH CH C(O)N(CH3)iPr NC386 c-Pentyl CH N C(O)N(CH3)iPr NC387 Propargyl N CH C(O)N(CH3)iPr NC388 c-Pentyl N N C(O)N(CH3)iPr NC389 Propargyl CH CH C(O)N(CH3)iPr NC390 c-Pentyl CH N C(O)N(CH3)iPr NC391 Propargyl N CH C(O)N(CH3)iPr NC392 c-Pentyl N N C(O)N(CH3)iPr NC393 Propargyl CH CH C(O)N(CH3)iBu NC394 c-Pentyl CH N C(O)N(CH3)iBu NC395 Propargyl N CH C(O)N(CH3)iBu NC396 c-Pentyl N N C(O)N(CH3)iBu NC397 Propargyl CH CH C(O)N(CH3)iBu NC398 c-Pentyl CH N C(O)N(CH3)iBu NC399 Propargyl N CH C(O)N(CH3)iBu NC400 c-Pentyl N N C(O)N(CH3)iBu NC401 Propargyl CH CH C(O)NH(Et) NC402 c-Pentyl CH N C(O)NH(Et) NC403 Propargyl N CH C(O)NH(Et) NC404 c-Pentyl N N C(O)NH(Et) NC405 Propargyl CH CH C(O)NH(Et) NC406 c-Pentyl CH N C(O)NH(Et) NC407 Propargyl N CH C(O)NH(Et) NC408 c-Pentyl N N C(O)NH(Et) NC409 Propargyl CH CH C(O)NH(iPr) NC410 c-Pentyl CH N C(O)NH(iPr) NC411 Propargyl N CH C(O)NH(iPr) NC412 c-Pentyl N N C(O)NH(iPr) NC413 Propargyl CH CH C(O)NH(iPr) NC414 c-Pentyl CH N C(O)NH(iPr) NC415 Propargyl N CH C(O)NH(iPr) NC416 c-Pentyl N N C(O)NH(iPr) NC417 Propargyl CH CH C(O)NH(iBu) NC418 c-Pentyl CH N C(O)NH(iBu) NC419 Propargyl N CH C(O)NH(iBu) NC420 c-Pentyl N N C(O)NH(iBu) NC421 Propargyl CH CH C(O)NH(iBu) NC422 c-Pentyl CH N C(O)NH(iBu) NC423 Propargyl N CH C(O)NH(iBu) NC424 c-Pentyl N N C(O)NH(iBu) NC425 Propargyl CH CH CH2OCOCH3 NC426 c-Pentyl CH N CH2OCOCH3 NC427 Propargyl N CH CH2OCOCH3 NC428 c-Pentyl N N CH2OCOCH3 NC429 Propargyl CH CH CH2OCOCH3 NC430 c-Pentyl CH N CH2OCOCH3 NC431 Propargyl N CH CH2OCOCH3 NC432 c-Pentyl N N CH2OCOCH3 NC433 Propargyl CH CH CH2OCOEt NC434 c-Pentyl CH N CH2OCOEt NC435 Propargyl N CH CH2OCOEt NC436 c-Pentyl N N CH2OCOEt NC437 Propargyl CH CH CH2OCOEt NC438 c-Pentyl CH N CH2OCOEt NC439 Propargyl N CH CH2OCOEt NC440 c-Pentyl N N CH2OCOEt NC441 Propargyl CH CH CH2OCOiPr NC442 c-Pentyl CH N CH2OCOiPr NC443 Propargyl N CH CH2OCOiPr NC444 c-Pentyl N N CH2OCOiPr NC445 Propargyl CH CH CH2OCOiPr NC446 c-Pentyl CH N CH2OCOiPr NC447 Propargyl N CH CH2OCOiPr NC448 c-Pentyl N N CH2OCOiPr NC449 Propargyl CH CH CH2OCOiBu NC450 c-Pentyl CH N CH2OCOiBu NC451 Propargyl N CH CH2OCOiBu NC452 c-Pentyl N N CH2OCOiBu NC453 Propargyl CH CH CH2OCOiBu NC454 c-Pentyl CH N CH2OCOiBu NC455 Propargyl N CH CH2OCOiBu NC456 c-Pentyl N N CH2OCOiBu

Evaluation of Novel A2A Antagonists in Four Mouse Models of PD: The A2A Receptor Antagonist ATL-2 Enhances Motor Function in a Dose-Dependent Manner in Normal and Dopamine-Depleted Mice.

In the set of experiments, we perform a dose response study of ATL-2 in stimulating motor activity in normal mice, and then we further extend this to dopamine-depleted mice. Adult male mice are habituated for 120 minutes and treated (i.p.) with saline or varying doses of compound, and their locomotor activity recorded for 120 minutes.

In a second set of experiments, we utilize the MPTP treatment paradigm to create animal model of PD by severely depleting dopamine in mice. We use a single MPTP treatment paradigm (40 mg/kg) which has been reproducibly reducing dopamine to 30-40% of normal dopamine contents in striatum in our previous studies.35,74 Adult male mice (˜25 mg/kg) are treated with single dose of MPTP (40 mg/kg). Thirty minutes after the MPTP treatment, mice are injected (i.p.) with vehicle or compounds of the invention at the same doses discussed above. Their motor activity is recorded for 180 minutes.

Results: Based on our previous experiments with other A2AR antagonists and our pilot study, we observe the maximal stimulant dose as well as sub-threshold doses of ATL compounds in normal and MPTP-treated mice. Without being bound by any theory, it is proposed that motor stimulant effect may manifest best in dopamine-depleted animals than normal animals, indicating that A2AR antagonists preferentially act at the A2AR in a PD condition to stimulate motor activity.

A2A receptor antagonists synergize with L-dopa to stimulate motor activity in dopamine-depleted mice.

We further tested the ability of these compounds to synergistically enhance motor function in conjunction with L-dopa, the standard therapy. Mice are injected (i.p.) with MPTP at a dose (1-2.5 mg/kg) that markedly decreases striatal dopamine levels. Thirty minutes later (when the mice exhibit an immobility), the mice are then randomly assigned to the following different treatment groups (n=10): (1) L-dopa (25 mg/kg); (2) ATL-2 (0.3, 1, 3, and 10 mg/kg), and (3) L-dopa (25 mg/kg)+ATL-2 (0.3, 1, 3, and 10 mg/kg). Locomotor behavior is monitored for 120 min before and after the treatment.

Results: Based on the Preliminary Results and on the known feature of other A2AR antagonists, a synergistic effect of ATL-2 with L-dopa in stimulating locomotor activity in dopamine-depleted mice is observed. This synergistic effect of ATL-2 and L-dopa is exhibited in a left-shift of the dose-response curve.

A2A Antagonists Potently and Specifically Attenuate MPTP-Induced Neurotoxicity by Inhibiting MPTP Metabolism.

C57B1/6 mice (n=10-12 mice per group) are pretreated with the A2A antagonist ATL-2 (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p) 5 min prior to each of four MPTP (40 mg/kg) injections at 2 hr intervals. These doses are selected based on our preliminary results (with CSC) and on motor and neuroprotective effects (against ischemia) by SCH58261 and DPCPX. The specificities for the A2AR in these dose ranges of ATL-2 have been confirmed using A2A KO mice. Seven days after the MPTP (±CSC, SCH58261 or CPA) treatment, the striatum from one side are dissected out and processed for HPLC analysis of dopamine and DOPAC levels. The other half brain is quickly frozen for sectioning coronally through the striatum and substantial nigra. DAT binding density in striatum may be determined by receptor autoradiography using 3H-mazindol as a specific ligand. Quantitation of DAT (3H-mazindol) binding autoradiography may be performed by densitometry analysis. The numbers of dopaminergic neurons may be determined by TH immunohistochemistry in the substantial nigra. Stereological methods may be used to estimate the absolute reduction in TH+ nigral neurons in MPTP-treated WT mice and any attenuation in those pretreated with ATL-2. In the same sections, cell counts may also be performed for TH+ neurons in the more medial VTA, which is less affected in MPTP treated mice as well as in PD.

Results: Guided by our preliminary results, neuroprotection in a dose-dependent manner (at least from 0.5 to 5 mg/kg range) may be observed. The potency of A2A antagonists for neuroprotection may be observed with their potency for motor stimulation and for possible attenuation of behavioral sensitization (see above). Similarly, the potency of CSC or SCH58261 for neuroprotection against MPTP may be compared to that for neuroprotection against ischemic injury and excitoxicity. A significant difference in an A2A antagonist's potency in neuroprotection against MPTP and against ischemia or excitoxicity may suggest different mechanisms and sites of action (e.g. glial versus neuronal compartments which may have different G-protein coupling mechanisms). On the other hand, the same potency of A2A antagonists for motor stimulation, neuroprotection and possibly delayed sensitization to L-dopa would suggest that the same type of A2AR is responsible for all these potential benefits of A2A antagonists in different animal models of PD.

A2A Antagonists Delay and A2A Agonists Accelerate L-Dopa-Induced Locomotor Sensitization in Unilateral 6-OHDA-Lesioned Mice.

The ability of ATL-2 to modify the development of L-dopa-induced locomotor sensitization in hemiparkinsonian mice are tested. C57BL/6 mice (from the Jackson's lab, Bar Harbor, Mich.) are lesioned with 6-OHDA by unilateral intrastriatal using a standard lesioning protocol. Seven days after the 6-OHDA (or MPP+) treatment, mice are injected with L-dopa (2.0 mg/kg, daily) for 14 days. Five min prior to each L-dopa treatment, the mice receive intraperitoneal pretreatment with: (1) vehicle, (2) ATL-2 (3 mg/kg) or (3) ATL-2 (10 mg/kg). In these dose ranges, the selective A2A antagonists have been shown to produce motor stimulant effects (see Preliminary Results). Rotational responses to L-dopa are recorded on the days 1, 3, 5, 7, 10 and 15. Following the behavioral measurement, mice may be sacrificed and their brains sectioned through striatum and substantial nigra. Striatal enkephalin mRNA levels are determined by in situ hybridization histochemistry. Similarly, DAT (3H-mazindol) binding is measured by receptor autoradiography to ensure successful and equivalent lesions among different experimental groups.

Results: Based on our previous study with SCH58261 in this repeated L-dopa-induced sensitization model, ATL-2 delays or prevent the development of locomotor sensitization. The prevention or delayed appearance with L-dopa locomotor sensitization by co-injection of an A2A antagonist indicates an important role of the A2AR in the development of L-dopa-induced behavioral sensitization. Furthermore, this helps exclude the possibility that an attenuated behavioral sensitization to chronic L-dopa observed in A2A KO mice results from a developmental effect of A2AR deficiency. Thus combined genetic and pharmacological approaches provide the clearest assessment of the A2AR's role in the development of behavioral sensitization to L-dopa, and provides insights into its role in L-dopa-induced dyskinesia.

Methods

Animal Treatments and Catalepsy Behavioral Assessments:

WT and A2A KO mice (generated as above) as well as commercially procured C57B1/6 mice (Taconic, N.Y.) may be used for this study. Since our pilot study and other reports [40,88] indicate that animal age is a critical factor in determining the extent of an MPTP lesion, animal body weight around 25-30 grams (corresponding to approximately 10 weeks of age) is tightly controlled. The mice are housed in temperature and humidity-controlled rooms with a 24-hour 1:1 light:dark cycle. Adenosinergic and dopaminergic agents are injected at the volume of 0.1 ml/10 gram body weight of mice. Other adenosinergic and dopaminergic drugs are purchased from RBI (Natick, Mass.). From our previous work, we have adapted a special solvent (15% DMSO, 15% Alkamuls-EL 620 and 70% saline) for dissolving A2A antagonists, including CSC and SCH58261.

Catalepsy behavior may be induced by haloperidol (1 mg/kg, i.p.) or reserpine (5 mg/kg, i.p. see below). Catalepsy score may be determined by the bar and grid tests. For the bar test, both mouse forepaws are placed on a 6 cm-high horizontal bar (diameter 0.7 cm). In the grid test, mice are allowed to cling to a metal-framed vertical grid (1.3 cm squares). The latency from paw placement until the first complete removal of one paw from the support is measured (maximal test duration 180 sec). Upon the completion of behavioral assessment, mice are sacrificed and the brains are processed for neurochemical and histochemical analyses.

Dopamine Depletion by the Treatment with MPTP or 6-OHDA:

a) Intraperitoneal Injection of MPTP: The MPTP administration regimen (20 mg/kg×4 at 2 hr interval) has been shown to produce severe dopamine depletion (consistently greater than ˜80% in our Preliminary Results FIGS. 6 and 7). Naive C57B1/6 mice are pretreated with adenosine antagonists 5 min prior to MPTP treatment.

b) Intrastriatal Injection of 6-OHDA: Wild-type C57B1/6 or A2AR mutant mice are anesthetized with Avertin and positioned in a stereotaxic frame. Three microliters of 6-OHDA (3 μg/μl) are injected into the left striatum (coordinates from bregma: AP+0.0, L+2.5.0, DV−4.4) via a infusion minipump over a 4 min period. Due to its photolability, 6-OHDA is dissolved in 0.01% ascorbic acid and injected under a light-protected environment.

c) Post-treatment Care: Dopamine-depleted mice may be continually monitored, and special care may be taken to maintain mouse body temperature with a heating blanket or warming lights. During the first 48 hours post-operation, mashed food pellets and water are provided to the mice inside the cage at floor-level for easy access.

Neurochemical Analysis:

(a) Measurements of Catecholamines and Indoleamines in Striatum by HPLC: To measure tissue catecholamine and indoleamine levels, mice are decapitated, their brains are removed rapidly, and striata are dissected out and frozen on dry ice. Striata are weighed frozen and then homogenized in 200 μl of 150 mM trichloroacetic acid containing 0.1 mM EDTA and 1 μM epinephrine (as an internal standard). Homogenates are centrifuged for 5 min at 15,000 g. The catecholamines in the supernatant are separated over a reverse-phase hydrophobic interaction C-18 HPLC column (Beckman, 5μ ODS) and measured using an electrochemical detector (ESA Coulochem 5100A) with electrodes set in series at oxidizing (+0.22 V) and then reducing (−0.35 V) potentials. Both the retention time and the ratio of oxidation to reduction currents for given sample peaks are compared against those for external standards to ensure proper identification of analytes.

(b) Stereologic quantitation of neuronal loss in substantia nigra: One week after lesioning, mice may be perfusion-fixed and their brains may be microtome-cut into 40 μm coronal free-floating sections. Every sixth section may be processed for TH immunohistochemistry using a 1:1,000 dilution of a polyclonal rabbit antiserum against rat TH (Eugene Tech. Intl., NJ). Immunostaining is completed using standard avidin-biotin procedures described previously [18,130]. A non-biased stereological technique is employed to quantify the effect of treatment on total TH+ nigra (pars compacta) cell counts as described previously [81]. All counts are performed by a single observer who is unaware of the treatment group at the time of neuronal estimates. Based on our pilot studies in WT mice MPP+ at this dose (3 μg/striatum) produced a ˜40% loss of ipsilateral TH+ nigral neurons.

(c) A2A receptor binding autoradiography: Twenty micron striatal sections are preincubated for 5 minutes with ice-cold buffer (509 mM Tris-HCl, 5 mM KCl and 300 mM NaCl, pH 7.9) and then incubated for 60 minutes in the same buffer containing 6 nM 3H-SCH58261 (provided generously by Dr. E. Ongini) [131]. The slides are washed twice and then air-dried before exposure to Hyperfilm (Amersham, Ill.) for 2-4 weeks. The films are analyzed with a video-based image analysis system (MultiAnalyst; Biorad), and total striatal 3H-SCH58261 binding (fmol/mg tissue) is calculated using a tritium-labeled calibration standard [17,131].

Statistical Analysis

Single statistical comparisons of an A2AR KO group to its WT control are generally performed using a Student's t test, two-tailed. Comparison of more than two factors (e.g. genotype, drug treatment and time course) and their interactions are made using 2-way ANOVA followed by Newman-Keuls post hoc analysis. If data are not normally distributed, non-parametric tests (Kruskal-Wallis or Mann-Whitney U test) are used.

Vertebrate Animals. Mice are the only animals that are be used in experiments. The mice are monitored daily (co-investigators or technician) under the supervision of a staff veterinarian. In the majority of the experiments the mice are kept under SPF conditions with no more than 5 mice/cage of females and 4 mice/cage of males. All husbandry and veterinary care meets NIH and AAALAC standards for humane care for use of laboratory animals. In addition, because of daily observation of all animals, any moribund animal is humanely euthanized by CO2.

Models of PD are used to investigate pre-clinical efficacy and pharmacokinetics of A2AAR antagonist. Because we have used these model in our laboratory, the model is now well characterized and the experimental manipulation of mice for these studies are well established.

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The entire disclosure of all documents cited throughout this application are incorporated herein by reference.

Claims

1. A method for treating cancer, comprising: administering a therapeutically effective amount of an A2A antagonist compound of formula I a mammal in need of such treatment:

wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R1 and R2 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R1 and R2 are independently absent, with the proviso that Ra is not SH or halogen when the R1 or R2 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
R3 is selected from the group consisting of hydrogen, halo, —ORa, SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated, then R3 can be absent;
R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)— or two R6 groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;
R7 and R8 are each independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl aryl(C1-C8)alkylene, heteroaryl, and heteroaryl(C1-C8)alkylene; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;
R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R9 and R10 are independently absent, with the proviso that Ra is not SH or halogen in the case where the R9 or R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
Y is —CR3R4R5 or NR4R5;
Z is selected from the group consisting of halogen, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, (C6-C20)polycyclyl, heterocyclyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —NRaRb, —SRa, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO2Ra, RaC(═O)O—, RaC(═O)—, —OCO2Ra, RaRbNC(═O)O—, RbOC(═O)NRa—, RaRbNC(═O)—, RaC(═O)NRb—, RaRbNC(═O)NRb—, RaRbNC(═S)NRb—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, OS(O2)Ra, OS(═O)ORa, —OS(O2)ORa and —O(SO2)NRaRb;
Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, propargyl, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1-4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRc—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, SRc, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that the point of attachment of Ra or Rb is not a heteroatom when it is attached to another heteroatom;
Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and
m is 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is not halogen, cyano, or nitro or is not attached via a heteroatom, and when n is 0, Y is not —NR4R5; or
a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

2. The method of claim 1, wherein Z is selected from aryl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, or (C6-C20)polycyclyl, wherein the ring atoms are optionally interrupted by 1 to 8 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRa).

3. The method of claim 1, wherein R3 is selected from the group consisting of hydrogen, OH, OCH3, OAc, NH2, NHCH3, N(CH3)2 and NHAc.

4. The method of claim 1, wherein the ring comprising R4 and R5 and the atom to which they are attached is selected from the group consisting of cyclopentane, cyclohexane, piperidine, dihydro-pyridine, tetrahydro-pyridine, pyridine, piperazine, decaline, tetrahydro-pyrazine, dihydro-pyrazine, pyrazine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, imidazole, dihydro-imidazole, imidazolidine, pyrazole, dihydro-pyrazole, pyrazolidine, norbornane and adamantane, each unsubstituted or substituted.

5. The method of claim 4, wherein the ring comprising R4 and R5 and the atom to which they are attached is selected from the group consisting of cyclohexane, piperidine, piperazine, norbornane, adamantane, each unsubstituted or substituted.

6. The method of claim 1, wherein number of R6 groups substituted on the R4R5 ring is from 1 to 4 and each R6 is independently selected from the group consisting of OH, OCH3, methyl, ethyl, t-butyl, —CO2Ra, —CONRaRb, OAc, NH2, NHCH3, N(CH3)2, NHEt and N(Et)2, provided that when the ring comprising R4 and R5 contains a ring heteroatom that is O or S, the ring heteroatom that is O or S is not substituted with R6.

7. The method of claim 1, wherein —NR7R8 is selected from the group consisting of amino, methylamino, dimethylamino, ethylamino, 3-pentylamino, (diphenylethyl)-amino, (pyridylmethyl)-amino, diethylamino and benzylamino.

8. The method of claim 1, wherein R9 is independently selected from the group consisting of hydrogen, fluoro, —OH, —CH2OH, —OCH3, —NH2, —NHCH3, and —N(CH3)2.

9. The method of claim 1, wherein R10 is hydrogen.

10. The method of claim 1, wherein Ra and Rb are each independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C8)alkylene.

11. The method of claim 1, wherein Y is —CR3R4R5 or NR4R5, and is selected from the group consisting of:

wherein q is 0, 1, 2, 3 or 4; R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—; and each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)—, provided that R6 is not halogen or a heteroatom when R6 is attached to a heteroatom.

12. The method of claim 1, wherein Y is —CR3R4R5 or NR4R5 and is selected from the group consisting of:

wherein R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—, and each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)—.

13. A method for treating cancer, comprising: administering a therapeutically effective amount of an A2A antagonist compound of formula II a mammal in need of such treatment:

wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R1 and R2 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R1 and R2 are independently absent, with the proviso that Ra is not SH or halogen when the R1 or R2 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated, then R3 can be absent;
R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic, or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRc—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of hydrogen, halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)—, or two R6 groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;
R7 and R8 are each independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene, heteroaryl, heteroaryl(C1-C8)alkylene-; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;
R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R9 and R10 are independently absent, with the proviso that Ra is not SH or halogen in the case where R9 and R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 and —SCH3;
L is a linker selected from the group consisting of —(C1-C3)alkyl-C≡C—, —C≡C—(C1-C3)alkyl-, —(CH2)1-3—CH═CH—, —CH═CH—(CH2)1-3—, —(CH2)1-2—CH═CH—CH2— and —CH2—CH═CH—(CH2)1-2—;
Y is —CR3R4R5 or NR4R5;
Z is selected from the group consisting of halogen, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, (C6-C20)polycyclyl, heterocyclyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —NRaRb, —SRa, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO2Ra, RaC(═O)O—, RaC(═O)—, —OCO2Ra, RaRbNC(═O)O—, RbOC(═O)NRa—, RaRbNC(═O)—, RaC(═O)NRb—, RaRbNC(═O)NRb—, RaRbNC(═S)NRb—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —OS(O2)Ra, —OS(═O)ORa, —OS(O2)ORa and —O(SO2)NRaRb;
Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, propargyl, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1 to 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—)—S(O)2— and amino (—NRc); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, SRc, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that the point of attachment of Ra or Rb is not a heteroatom when it is attached to another heteroatom;
Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and
m is 0 to 8; n is 0, 1, 2 or 3 provided that when m is 0, Z is not halogen, cyano, or nitro or is not attached via or a heteroatom; or
a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

14. A method for treating cancer, comprising: administering a therapeutically effective amount of an A2A antagonist compound of formula I a mammal in need of such treatment:

wherein:
(CR1R2)m-Z together is selected from the group consisting of —CH2CH═CH2, —CH2C≡CH, —CH2C≡CCH3 or —CH2CH2C≡CH;
Y is —CR3R4R5 or NR4R5;
R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated, then R3 can be absent;
R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)—, or two R6 groups and the atom to which they are attached combine to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;
R7 and R8 are each independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene, heteroaryl, heteroaryl(C1-C8)alkylene-; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;
R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa), or where R9 and R10 are independently absent, with the proviso that Ra is not SH or halogen in the case where the R9 or R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, propargyl, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1-4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRc—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, SRc, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that the point of attachment of Ra or Rb is not a heteroatom when it is attached to another heteroatom;
Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and
n is 0, 1, 2 or 3; or
a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

15. A method for treating cancer, comprising: administering a therapeutically effective amount of an A2A antagonist compound of formula I a mammal in need of such treatment:

wherein
Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl ring optionally substituted with 1 to 4 substituents of Ra;
Y is —CR3R4R5 or NR4R5;
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R1 and R2 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R1 and R2 are independently absent, with the proviso that Ra is not SH or halogen when the R1 or R2 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated, then R3 can be absent;
R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)— or two R6 groups and the atom to which they are attached combine to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;
R7 and R8 are each independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene, heteroaryl, heteroaryl(C1-C8)alkylene-; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;
R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R9 and R10 are independently absent, with the proviso that Ra is not SH or halogen in the case where the R9 or R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, propargyl, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1-4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRc—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, SRc, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that the point of attachment of Ra or Rb is not a heteroatom when it is attached to another heteroatom;
Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and
m is 0 to 8; n is 0, 1, 2 or 3, provided that when n is 0, Y is not —NR4R5; or
a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

16. The method of claim 15, wherein Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, where m is 0 or 1.

17. The method of claim 1, wherein:

Y is selected from the group consisting of
wherein Y optionally comprises 1, 2 or 3 double bonds; each carbon in the ring is optionally replaced by or interrupted by 1 to 6 heteroatoms selected from —O—, —S—, —SO—, —S(O)2—, or amino (—NRa—), and is optionally further substituted with from 1 to 10 R6 groups, provided that the Y ring is not attached at a bridgehead carbon atom or at a trisubstituted carbon atom;
Z is selected from the group consisting of halogen, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, (C6-C20)polycyclyl, heterocyclyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —NRaRb, —SRa, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO2Ra, RaC(═O)O—, RaC(═O)—, —OCO2Ra, RaRbNC(═O)O—, RbOC(═O)NRa—, RaRbNC(═O)—, RaC(═O)NRb—, RaRbNC(═O)NRb—, RaRbNC(═S)NRb—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —OS(O2)Ra, OS(═O)ORa, —OS(O2)ORa and —O(SO2)NRaRb;
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R1 and R2 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R1 and R2 are independently absent, with the proviso that Ra is not SH or halogen when the R1 or R2 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)— or two R6 groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;
R7 and R8 are each independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene, heteroaryl, heteroaryl(C1-C8)alkylene-; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;
R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C9)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R9 and R10 are independently absent, with the proviso that Ra is not SH or halogen in the case where the R9 or R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, propargyl, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1-4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRc—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, SRc, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that the point of attachment of Ra or Rb is not a heteroatom when it is attached to another heteroatom;
Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and
m is 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is not halogen, cyano, or nitro or attached via a heteroatom; or
a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

18. A method for treating cancer, comprising: administering a therapeutically effective amount of an A2A antagonist compound of formula I a mammal in need of such treatment:

wherein:
R1 and R2 are hydrogen, m is 0, 1, 2 or 3 and Z is the moiety derived from the ring selected from the group consisting of furan, dihydro-furan, thiophene, pyrrole, 2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole, dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine, tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane, wherein each Z group is optionally substituted with from 1 to 10 Ra groups;
Y is —CR3R4R5 or NR4R5;
R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated, then R3 can be absent;
R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)— or two R6 groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;
R7 and R8 are each independently hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, aryl or aryl(C1-C8)alkylene, heteroaryl, heteroaryl(C1-C8)alkylene-; or wherein R7 and R8 together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;
R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C8)alkyl, aryl and aryl(C1-C8)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R9 and R10 are independently absent, with the proviso that Ra is not SH or halogen in the case where the R9 or R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, propargyl, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1-4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRc—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, SRC, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that the point of attachment of Ra or Rb is not a heteroatom when it is attached to another heteroatom;
Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and
m is 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is not attached via a heteroatom, and when n is 0, Y is not —NR4R5; or
a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

19. The method of claim 18, wherein R1 and R2 are hydrogen, m is 0 or 1, and Z is the moiety derived from the ring selected from the group consisting of furan, thiophene, pyrrole, 2H-pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole and 1H-tetrazole, wherein each Z group is optionally substituted with from 1 to 3 Ra groups selected from the group consisting of methyl, ethyl, propyl, iso-propyl, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 and —SCH3.

20. A method for treating cancer, comprising: administering a therapeutically effective amount of an A2A antagonist compound of formula I a mammal in need of such treatment:

wherein:
R7 and R8 are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl-, aryl(C1-C8)alkylene-, mono- or bicyclic-, aromatic or nonaromatic ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, and each is optionally substituted with from 1, 2, 3 or 4 Ra groups;
Y is —CR3R4R5 or NR4R5;
Z is selected from the group consisting of halogen, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, (C6-C20)polycyclyl, heterocyclyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —NRaRb, —SRa, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO2Ra, RaC(═O)O—, RaC(═O)—, —OCO2Ra, RaRbNC(═O)O—, RbOC(═O)NRa—, RaRbNC(═O)—, RaC(═O)NRb—, RaRbNC(═O)NRb—, RaRbNC(═S)NRb—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, —OS(O2)Ra, —OS(═O)ORa, —OS(O2)ORa and —O(SO2)NRaRb;
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C9)alkyl, aryl and aryl(C1-C8)alkyl, wherein R1 and R2 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R1 and R2 are independently absent, with the proviso that Ra is not SH or halogen when the R1 or R2 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
R3 is selected from the group consisting of hydrogen, halo, —ORa, —SRa, (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, heterocycle, heterocycle(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, RaS(═O)—, and RaS(═O)2—; or if the ring formed from the group CR3R4R5 is aryl or heteroaryl or partially unsaturated, then R3 can be absent;
R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated, mono-, bi- or tricyclic or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— or amine (—NRa—) in the ring, wherein any ring comprising R4 and R5 is optionally further substituted with from 1 to 14 R6 groups; wherein each R6 is independently selected from the group consisting of halo, —ORa, —SRa, substituted or unsubstituted (C1-C8)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, heterocycle, heterocyclyl(C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, heteroaryl, heteroaryl(C1-C8)alkyl, —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)—, RaRbNC(═S)N(Rb)—, RaOC(═S)—, RaC(═S)—, —SSRa, and RaS(═O)-or two R6 groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;
R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, (C1-C9)alkyl, aryl and aryl(C1-C8)alkyl, wherein R9 and R10 are optionally substituted with 1 to 4 substituents of Ra, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)2— or amino (—NRa—), or where R9 and R10 are independently absent, with the proviso that Ra is not SH or halogen in the case where the R9 or R10 to which Ra is bound is halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3 or —SCH3;
Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, —NH2, —OH, —SH, —NHCH3, —N(CH3)2, —OCH3, —SCH3, propargyl, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3, —OS(O2)OCH3, (C1-C8)alkyl, aryl, aryl(C1-C8)alkyl, (C3-C8)cycloalkyl, (C6-C12)bicycloalkyl, cycloalkyl(C1-C8)alkyl, bicycloalkyl(C6-C12)alkyl, heteroaryl and heteroaryl(C1-C8)alkyl, wherein the alkyl and cycloalkyl are optionally interrupted with 1-4 heteroatoms selected from the group consisting of —O—, —S—, —SO—, —S(O)2— and amino (—NRc—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —ORc, —NRcRc, SRc, cyano, —OS(O2)H, —OS(O2)OH, —OS(O2)CH3 and —OS(O2)OCH3, provided that the point of attachment of Ra or Rb is not a heteroatom when it is attached to another heteroatom;
Rc is selected from the group consisting of hydrogen and (C1-C8)alkyl; and
m is 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is not halogen, cyano, or nitro or is not attached via a heteroatom, and when n is 0, Y is not —NR4R5; or
a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

21. The method of claim 20, wherein R7 is selected from the group consisting of benzyl, phenethyl, phenylpropyl and each is optionally substituted with from 1, 2 or 3 substituents of Ra.

22. The method of claim 1, wherein the compound selected from the group:

9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (1);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenine (2);
9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (3);
9-Cyanomethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (4);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-methoxybenzyl)adenine (5);
9-(3,4-Dichlorobenzyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (6);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-trifluoromethylbenzyl)adenine (7);
9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (8);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-[2-(trifluoromethylphenyl)thiazol-4-ylmethyl]adenine (9);
2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(3-(thiophen-2-yl)prop-2-ynyl)adenine (10);
9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (14);
9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (15);
9-Allyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (16);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(propargyl)adenine (17);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pent-4-ynyl)adenine (18);
9-(2-Chloroethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (21);
9-([1,3]-Dioxolan-2-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (22);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(tetrahydro-pyran-2-ylmethyl)adenine (23);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(isopropylcarboxylate)adenine (24);
9-(Acetic acid ethyl ester)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (25);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-oxo-oxazolidin-5-ylmethyl)-N6-(3-pentyl)adenine (26);
9-Benzyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (27);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pyridin-3-ylmethyl)adenine (28);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-nitrobenzyl)-N6-(3-pentyl)adenine (29);
9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (30);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-methyl-thiazol-5-ylmethyl)-N6-(3-pentyl)adenine (31);
N6-[(S)-(+)-sec-Butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyl-adenine (32);
N6-[(s)-(+)-sec-Butyl]-9-(3,5-dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (33);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(s)-(−)-alpha-napthalen-1-yl-ethyl]-9-(propargyl)adenine (35);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-methoxybenzyl)-9-(propargyl)adenine (36);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(propargyl)-N6-(pyridin-2-ylmethyl)adenine (37);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(methyl)(2-phenethyl)]-9-(propargyl)adenine (38);
9-Cyclopropylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (45);
9-Cyclobutylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (46);
9-Cyclopentylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (47);
9-Cyclohexylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (48);
9-Cyclobutyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49);
9-Cyclopentyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50);
2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propargyl-adenine (51);
2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine;
9-(But-3-ynyl)-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (62); and
2-{3-[1-(Methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}-9-propargyladenine (63); or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.
Patent History
Publication number: 20070244134
Type: Application
Filed: May 14, 2007
Publication Date: Oct 18, 2007
Inventors: Anthony Beauglehole (Charlottesville, VA), Jayson Rieger (Charlottesville, VA), Robert Thompson (Charlottesville, VA)
Application Number: 11/803,312
Classifications
Current U.S. Class: 514/263.200; 514/263.100; 514/263.400
International Classification: A61K 31/52 (20060101); A61P 43/00 (20060101);