US20070244134A1

US20070244134A1 - Selective antagonists of A2A adenosine receptors

Info

Publication number: US20070244134A1
Application number: US11/803,312
Authority: US
Inventors: Anthony Beauglehole; Jayson Rieger; Robert Thompson
Original assignee: Individual
Current assignee: Adenosine Therapeutics LLC; PGxHealth LLC
Priority date: 2004-04-02
Filing date: 2007-05-14
Publication date: 2007-10-18
Also published as: AU2005231440A1; CN1972945A; EP1740587A2; WO2005097140A2; US7217702B2; US20050282831A1; WO2005097140A3; EP1740587A4; AU2005231440B2; CA2563123A1; JP2007531729A; JP2012229231A; IL178365A0; IL178365A; AU2005231440B9; US20080176858A1

Abstract

Selective antagonists of A_2Aadenosine receptors like those of formula I are provided, wherein Y forms a ring.

The novel A_2ABlockers are useful for the treatment of Parkinson's disease and other diseases.

Description

CROSS REFERENCE TO RELATED APPLICATION

The present application is a continuation of “Selective Antagonists of A_2AAdenosine 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 A_2AAdenosine 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 A_2Aadenosine receptor (AR). These compounds are useful as pharmaceutical agents.
Selective antagonists of A_2Aadenosine receptors have proven to be effective for the treatment of Parkinson's disease (PD) both in animal models and in a human trial.¹However, 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.²The 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.³Today, L-dopa continues to be the “Gold Standard” treatment for the motor symptoms of PD.^4,5Despite the considerable symptomatic relief it affords, long-term treatment with L-dopa has major limitations.⁶After five to ten years of treatment with L-dopa, up to 60% of patients experience loss of L-dopa effectiveness and some debilitating complications,^7,8notably, 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.⁹The development of dyskinesia might reflect desensitization of dopamine receptors.¹⁰Most 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.¹²Striatal 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 A_2Aadenosine receptor (A_2AAR) has received increasing attention as a treatment for PD.^13,14This contention is based on our understanding of the role of the A_2AAR in the basal ganglia and on the recent development of new, more selective A_2AAR antagonists. Anatomical, neurochemical and behavioral evidence of adenosine-dopamine interactions underlie this new therapeutic approach.^15-17Anatomically, A_2AAR density is high in the striatum, where receptor mRNA is co-expressed with D₂receptor mRNA in the striatopallidal neurons.^18-20This unique cellular distribution of A_2Areceptors suggests that A_2Areceptor antagonists can selectively modulate the “indirect” striatopallidal pathway to affect motor activity. At the neurochemical level, activation of the A_2AAR reduces the binding affinity of D₂receptors in the striatum,²¹and antagonizes many neurochemical and cellular changes brought about by the activation of striatal D₂receptors, 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 activity^22,23whereas the unselective agonist NECA²⁴inhibits spontaneous locomotor activity as well as motor activity induced by dopamine agonists. Thus, A_2AAR 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 A_2Aantagonists: (1) a direct receptor-receptor (A_2A-D₂) antagonistic interaction,^25,26(2) an opposing but independent of A_2Aand D₂receptor signaling^27-29or (3) A_2AAR modulation of GABA release in the basal ganglia.^30-32These receptors also form A_2AAR-D2 heterodimers,³³but how dimerization affects receptor function is unclear.
A_2AReceptor Antagonists May Offer Multiple Therapeutic Benefits for PD Patients
First, A_2Aantagonists stimulate motor activity in normal as well as dopamine-depleted animals. In rodent models of PD, unselective adenosine antagonists (caffeine and theophylline)^22,34and the A_2AAR-selective antagonists SCH58261, KW6002 and CSC can reverse motor deficits induced by MPTP, 6-hydroxydopamine, haloperidol or reserpine^35-41as well as by genetic deletion of D₂receptors.⁴²More recently, the A_2Aantagonists KW6002 reversed motor deficit in MPTP-treated non-human primates.^43,44Furthermore, A_2Aantagonists can stimulate motor activity when combined with sub-threshold doses of dopaminergic agents such as L-dopa or D₁and D₂agonists such as aporphormine or quinpirole.⁴⁵For 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.^44,46,47Thus, tolerance to the motor stimulant effect of A_2Aantagonists did not develop.
Second, studies of the MPTP-treated monkey model of PD revealed a novel feature of A_2Aantagonists, namely, stimulation of motor activity without dyskinesia.^43,44,48In 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 A_2AAR knockout mice suggest that development of behavioral sensitization by chronic treatment of L-dopa requires activation of the A_2AAR. Genetic inactivation of the A_2Areceptor attenuated L-dopa-induced rotational behavior.⁴⁹This 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.⁵⁰Further studies are warranted to explore the molecular mechanism underlying this novel aspect of A_2AAR function.
Third, accumulating evidence suggests that the specific inactivation of A_2AARs consistently attenuates brain damage induced by ischemia^51-53and excitoxicity,^54,55as well as in animal models of Huntington's disease⁵⁶and Alzheimer's disease.⁵⁷The neuroprotection by A_2AAR antagonists has been recently extended to a rodent model of PD. Co-administration of A_2AAR antagonists, such as CSC, DMPX, SCH58261 and KW6002 (but not the A₁AR antagonist DPCPX) attenuated dopaminergic neurotoxicity in several neurotoxin models of PD.⁵⁸A_2AAR 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.^59,60Likewise, knockout of A_2AARs attenuated MPTP-induced dopaminergic neurotoxicity in mice.⁵⁹Together with the demonstration of neuroprotection by A_2AAR antagonists against a wide range of neuronal injury models. These results raise the possibility that A_2Aantagonists 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 A_2AAR 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 A_2AAR density are normal in PD patients,⁶¹indicating that A_2Aantagonists might remain effective, even in the later stages of PD.
The prospective use of A_2AR 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.⁶²Two 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.⁶³Thus, 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 A_2AAR antagonists and strongly argue that A_2Aantagonists 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.^64,65KW6002 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 A_2AAR antagonists, the 8-styrylxanthines, appeared about ten years ago. This class includes KW-6002, which has low nanomolar affinity for the A_2AAR and >100-fold selectivity for the A_2AAR over the A₁AR. KW-6002, entered clinical trials in 2002 as an agent for the treatment of PD.^1,66SCH58261, 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 A_2AAR in vitro.⁶⁷The 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 A_2AAR in the sub-nanomolar range but less selective, interacting with A_2BAR as well.⁶⁸These potent A_2Aantagonists have been important research tools, greatly facilitating pharmacological investigations of A_2AAR function in vitro as well as in vivo significantly enhancing our understanding of the neurobiology of the A_2AAR. 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.⁶⁹SCH58261 is very poorly soluble and even its second-generation derivatives have marginal bioavailability.⁷⁰As 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-ones⁷¹and 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 A_2AAR antagonists.

SUMMARY OF THE INVENTION

In one aspect, there is provided a compound of the formula I:

wherein R¹and R²are 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 R¹and R²are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R¹and R²are independently absent, with the proviso that R^ais not thio or halogen in the case where R¹and R²to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OMe and —SMe; R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, R^aS(═O)₂—, —NNR^aand —OPO₂R^a; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³can be absent; R⁴and R⁵together 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 (—NR^a—) in the ring, wherein any ring comprising R⁴and R⁵is optionally further substituted with from 1 to 14 R⁶groups; wherein each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, —NNR^aand —OPO₂R^aor two R⁶groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring; R⁷and R⁸are each independently hydrogen, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl or aryl(C₁-C₈)alkylene, heteroaryl, heteroaryl(C₁-C₈)alkylene-; or wherein R⁷and R⁸together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring; R⁹and R¹⁰are 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 R⁹and R¹⁰are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R⁹and R¹⁰are independently absent, with the proviso that R^ais not thio or halogen in the case where R⁹and R¹⁰to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OMe and —SMe; Y is —CR³R⁴R⁵or 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, —NR^aR^b, —OR^a, —SR^a, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)NR^a—, R^aR^bNC(═O)—, R^aC(═O)NR^b, R^aR^bNC(═O)NR^b—, R^aR^bNC(═S)NR^b—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, —NNR^a, —OPO₂R^a, —OS(O₂)R^a, —OS(═O)OR^a, —OS(O₂)OR^aand —O(SO₂)NR^aR^b; R^aand R^bare 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 (—NR^c); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —OR^c, —NR^cR^c, —SR^c, cyano, —NNH, —NNCH₃, —OPO₂H, —OPO₂CH₃, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that R^ais not a heteroatom when it is attached to another heteroatom; R^cis 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)_mtogether 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)_mtogether 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≡CCH₃or —CH₂CH₂C≡CH. In yet another variation, (CR¹R²)_m-Z together is —CH₂C≡CH.
In another variation of the above formulae, R₁and R₂are hydrogen or are absent, m is 2 to 8 and the group (CR¹R²)_moptionally 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, —NR^aR^b, —OR^a, —SR^aand 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, R¹and R²are hydrogen, and the group (CR¹R²)_mis 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 (—NR^a—). 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 R^a. 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 R¹and R²are 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 (—NR^a—), and is optionally further substituted with from 1 to 10 R⁶groups, 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 (—NR^a—), and the ring is optionally substituted with from 1 to 7 R^agroups 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)CH₃and —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, R⁹and R¹⁰are 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 R^agroups 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)CH₃and —S(SO₂)OCH₃.
In another variation of the above, R¹and R²are 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 R^agroups.
In yet another variation, R¹and R²are 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 R^agroups selected from the group consisting of methyl, ethyl, propyl, iso-propyl, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃and —SCH₃. In another variation, Z is selected from the group consisting of —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)NR^a—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)NR^b—, R^aR^bNC(═O)NR^b—, R^aR^bNC(═S)NR^b, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, R^aS(O₂)—, —N═NR^a, —OPO₂R^a, —OS(O₂)R^a, —OS(═O)OR^a, —OS(O₂)OR^aand —OS(O₂)NR^aR^b, wherein m is 1 to 8, and the group (CR¹R²)_mis optionally saturated or partially unsaturated. In yet another variation, Z is selected from the group consisting of —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)NR^a—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)NR^b—, R^aR^bNC(═O)NR^b—, R^aR^bNC(═S)NR^b—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, R^aS(═O)₂—, —N═NR^a, —OPO₂R^a, —OS(O₂)R^a, —OS(═O)OR^a, —OS(O₂)OR^aand —O(SO₂)NR^aR^b, and wherein (R¹R²)_mtogether 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 —CO₂R^a, R^aC(═O)—, R^aR^bN—, —OPO₃R^a, R^aOC(S)—, R^aC(═S)—, R^aS(═O), R^aS(═O)₂—, —OPO₂R^a, —OS(O₂)R^a, —OS(═O)OR^a, —OS(O₂)OR^aor —OS(O₂)NR^aR^b, and wherein (CR¹R²)_mtogether 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 R⁹is independently selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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-, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, R^aS(═O)₂—, —N═NR^aand —OPO₂R^a. In another variation, R¹and R²together with the carbon atom to which they are attached is C═O, C═S or C═NR^c. In yet another variation, R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^a, R^aC(═O)O⁻, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b), R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSRA, R^aS(═O)—, R^aS(═O)₂—, —NNR^aand —OPO₂R^a; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated then R³can be absent. In another variation of the above, R³is selected from the group consisting of hydrogen, OH, OMe, OAc, NH₂, NHMe, NMe₂and NHAc. In a particular variation, R³is hydrogen or OH.
In one particular variation of each of the above; R⁴and R⁵together 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 (—NR^a—) in the ring, wherein any ring comprising R⁴and R⁵is optionally further substituted with from 1 to 14 R⁶groups; wherein each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, —NNR^a, —OPO₂R^a, or two R⁶groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring. In another variation, the ring comprising R⁴and R⁵and 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, R⁶is selected from the group consisting of substituted or unsubstituted (C₁-C₈)alkyl, —OR^a, —CO₂R^a, R^aC(═O)—, R^aC(═O)O—, R^aR^bN—, R^aR^bNC(═O)— and aryl, provided that when the ring comprising R⁴and R⁵contains a heteroatom that is O or S, the heteroatom is not substituted with R⁶. In another variation, R⁶is selected from the group consisting of OH, OMe, methyl, ethyl, t-butyl, —CO₂Ra, —CONR^aR^b, OAc, NH₂, NHMe, NMe₂, NHEt and N(Et)₂, provided that when the ring comprising R⁴and R⁵contains a heteroatom that is O or S, the heteroatom is not substituted with R⁶. In yet another variation, R⁶is selected from the group consisting of methyl, ethyl, —CO₂R^a, —CONR^aR^band OAc, provided that when the ring comprising R⁴and R⁵contains a heteroatom, the heteroatom is not substituted with OAc. In yet another variation, R⁶is selected from the group consisting of —(CH₂)_1-2OR^a, —(CH₂)_1-2C(═O)OR^a, —(CH₂)_1-2OC(═O)R^a, —(CH₂)_1-2C(═O)R^a, —(CH2)_1-2OCO₂R^a, —(CH₂)_1-2NHR^a, —(CH₂)₁₂NR^aR^b, —(CH₂)_1-2C(═O)NHR^aand —(CH₂)_1-2C(═O)NR^aR^b. In yet another variation, R⁶is —CH₂C(═O)OR^a, —CH₂C(═O)OR^a, —CH₂OH, —CH₂OAc, —CH₂NH(CH₃) and —(CH₂)_1-2N(CH₃)₂. In another variation, the number of R₆groups substituted on the R₄R₅ring is from 1 to 4.
In another variation, R⁷and R⁸is 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 (—NR^a—) in the ring, and each is optionally substituted with from 1, 2, 3 or 4 R^agroups. In yet another variation, R⁷is 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 R⁷is hydrogen, methyl or sec-butyl. In another variation, R⁷and R⁸are 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 R⁷and R⁸together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring.
In one particular variation of each of the above, —NR⁷R⁸is selected from the group consisting of amino, methylamino, dimethylamino, ethylamino, pentylamino, diphenylethylamino, pyridylmethylamino, diethylamino and benzylamino. In another variation, —NR⁷R⁸is selected from the group consisting of amino, methylamino, dimethylamino, ethylamino, diethylamino and benzylamino, or wherein —NR⁷R⁸is amino.
In one particular variation of each of the above; R^aand R^bare 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 R^aand R^btogether with the nitrogen to which they are attached, form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; R^cis hydrogen or (C₁-C₆)alkyl; m is 0 to about 8 and p is 0 to 2; and Y is —CR³R⁴R⁵or NR⁴R⁵.
In another variation, R⁷is selected from the group consisting of benzyl, phenethyl, phenylpropyl and each is optionally substituted with from 1, 2 or 3 substituents of R^a. In a particular variation, R⁷is selected from the group consisting of benzyl, phenethyl, phenylpropyl and each is optionally substituted with from 1, 2 or 3 substituents of R^aselected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy and propoxy; or wherein R⁷is benzyl and R^ais methoxy.
In another aspect of the above, R⁹is selected from the group consisting of hydrogen, fluoro, —OH, —CH₂OH, —OMe, —OAc, —NH₂, —NHMe, —NMe₂and —NHAc; or wherein R⁹is hydrogen or OH. In one variation, each R¹⁰is 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, R¹⁰is selected from the group consisting of hydrogen, (C₁-C₈)alkyl, cyclopropyl, cyclohexyl and benzyl; or wherein R¹⁰is hydrogen. In yet another variation of the above, R⁹and R¹⁰and the carbon atom to which they are attached is a C═O group.
In a variation of the above compound, R^aand R^bare each independently selected from the group consisting of hydrogen, (C₁-C₄)alkyl, aryl and aryl(C₁-C₈)alkylene. In a particular variation, R^aand R^bare each independently selected from the group consisting of hydrogen, methyl, ethyl, phenyl and benzyl. In another variation, R^ais (C₁-C₈)alkyl. In yet another variation, R^ais selected from the group consisting of methyl, ethyl, propyl and butyl. In yet another variation, R^ais selected from the group consisting of methyl, ethyl, i-propyl, i-butyl and tert-butyl. In still another variation, R^aand R^bis a ring.
In one variation of each of the above, Y is —CR₃R₄R₅or NR₄R₅, and is selected from the group consisting of:

wherein q is 0, 1, 2, 3 or 4; R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b), R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, R^aS(═O)₂—, —NNR^aand —OPO₂R^a; and each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, —NNR^aand —OPO₂R^a, provided that R⁶is not halogen or a heteroatom when R⁶is attached to a heteroatom.
In another variation, Y is —CR³R⁴R⁵or NR⁴R⁵and is selected from the group consisting of:

wherein R³is selected from the group consisting of hydrogen, halo, —OR^a, SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, R^aS(═O)₂—, —NNR^aand —OPO₂R^a; and each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, —OPO₃R^a, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, —NNR^aand —OPO₂R^a.
In another variation, the ring comprising —C(R³)R⁴R⁵is 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)R⁴R⁵is 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)R⁴R⁵is 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 (—NR^a—). In one variation of the above, R¹and R²are 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 R^agroups. 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 (—NR^a—).
In a particular variation, R¹and R²are 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 R^agroups.
In another aspect, there is provided a compound of the formula:

wherein R⁷and R⁸are 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, R⁸is selected from the group consisting of hydrogen or (C₁-C₄)alkyl; and R¹¹is 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; R¹³is methyl, iso-propyl, iso-butyl, or tert-butyl; and R¹, R²and 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 A_2Aanatagonist 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 A_2Aantagonist 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 A_2Aantagonist 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 A_2Aantagonists 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 A_2AAR antagonists injected into mice.
FIG. 2 sows the effect of A_2AAR 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)NR^a—, for example, it is intended that the corresponding isomeric group that is —OC(═O)— or —NR^aC(═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 R¹and R²are 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)CH₃and —S(SO₂)OCH₃, and the like.

Representative A_2AAR Antagonists:

TABLE 1







Binding Affinity and Selectivity of A_2AAR Ligands^a

Ki, nM

ATL #	R¹²	R⁷	(CR¹R²)_m-Z	A₁AR	A_2AAR	A_2BAR	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 A_2AAR.
Activities expressed as percentage are displacement of radioligand by 1 μM candidate ligand.

Motor Enhancement by the Lipophilic A_2AReceptor 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 A_2AR antagonists, the motor stimulant effect of ATL2 is comparable or stronger than other A_2AR antagonists such as SCH58261 and KW6002.
Absence of Motor Stimulant Effect of ATL-2 in Mice Lacking the A_2AReceptor
We validated that ATL-2 acts on the A_2Areceptor to stimulate motor activity by using A_2AR 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 A_2Areceptor KO and their WT littermates. WT and A_2AKO 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,³⁵but this motor stimulation was absent in A_2Areceptor KO mice.
Experimental
Synthesis of A_2AAR 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 K_i(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

+K_i< 10,000 nM;
++K_i< 1,000 nM;
+++K_i< 500 nM;
++++K_i< 100 nM.

Compound No.	R⁷	(CR¹R²)_m-Z	Human K_i(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	++++

+K_i< 10,000 nM;
++K_i< 1,000 nM;
+++K_i< 500 nM;
++++K_i< 100 nM.

Compound No.	(CR⁹R¹⁰)_n-Y	(CR¹R²)_m-Z	Human K_i(nM)

60		Propargyl	++++

61		Propargyl	++++

63		Propargyl	++++

+K_i< 10,000 nM;
++K_i< 1,000 nM;
+++K_i< 500 nM;
++++K_i< 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 A_2AAntagonists in Four Mouse Models of PD: The A_2AReceptor 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.^35,74Adult 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 A_2AR 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 A_2AR antagonists preferentially act at the A_2AR in a PD condition to stimulate motor activity.
A_2Areceptor 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 A_2AR 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.
A_2AAntagonists Potently and Specifically Attenuate MPTP-Induced Neurotoxicity by Inhibiting MPTP Metabolism.
C57B1/6 mice (n=10-12 mice per group) are pretreated with the A_2Aantagonist 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 A_2AR in these dose ranges of ATL-2 have been confirmed using A_2AKO 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 A_2Aantagonists 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 A_2Aantagonist'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 A_2Aantagonists for motor stimulation, neuroprotection and possibly delayed sensitization to L-dopa would suggest that the same type of A_2AR is responsible for all these potential benefits of A_2Aantagonists in different animal models of PD.
A_2AAntagonists Delay and A_2AAgonists 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 A_2Aantagonists 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 A_2Aantagonist indicates an important role of the A_2AR 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 A_2AKO mice results from a developmental effect of A_2AR deficiency. Thus combined genetic and pharmacological approaches provide the clearest assessment of the A_2AR'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 A_2AKO 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 A_2Aantagonists, 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.

REFERENCES

1. Hauser R A, Hubble J P, Truong D D. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology. 2003; 61:297-303.
2. Lang A E, Lozano A M. Parkinson's disease. Second of two parts. N Engl J. Med. 1998; 339:1130-1143.
3. Agid Y, Cervera P, Hirsch E, Javoy-Agid F, Lehericy S, Raisman R, Ruberg M. Biochemistry of Parkinson's disease 28 years later: a critical review. Mov Disord. 1989; 4 Suppl 1:S126-S144.
4. Lang A E, Lozano A M. Parkinson's disease. Second of two parts. N Engl J. Med. 1998; 339:1130-1143.
5. Lang A E, Lozano A M. Parkinson's disease. First of two parts. N Engl J. Med. 1998; 339:1044-1053.
6. Obeso J A, Olanow C W, Nutt J G. Levodopa motor complications in Parkinson's disease. Trends Neurosci. 2000; 23:S2-S7.
7. Bezard E, Brotchie J M, Gross C E. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001; 2:577-588.
8. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol. 2000; 47:S2-S9.
9. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol. 2000; 47:S2-S9.
10. Jenner P. Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopaminergic treatments. J Neurol. 2000; 247 Suppl 2:II43-II50.
11. Melamed E, Offen D, Shirvan A, Djaldetti R, Barzilai A, Ziv I. Levodopa toxicity and apoptosis. Ann Neurol. 1998; 44:S149-S154.
12. Jenner P. Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopaminergic treatments. J Neurol. 2000; 247 Suppl 2:II43-II50.
13. Chen J F. The adenosine A(2A) receptor as an attractive target for Parkinson's disease treatment. Drug News Perspect. 2003; 16:597-604.
14. Schwarzschild M A, Chen J F, Ascherio A. Caffeinated clues and the promise of adenosine A(2A) antagonists in PD. Neurology. 2002; 58:1154-1160.
15. Ferre S, Fredholm B B, Morelli M, Popoli P, Fuxe K. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 1997; 20:482-487.
16. Richardson P J, Gubitz A K, Freeman T C, Dixon A K. Adenosine receptor antagonists and Parkinson's disease: actions of the A2A receptor in the striatum. Adv Neurol. 1999; 80:111-119.
17. Schwarzschild M A, Chen J F, Ascherio A. Caffeinated clues and the promise of adenosine A(2A) antagonists in PD. Neurology. 2002; 58:1154-1160.
18. Fink J S, Weaver D R, Rivkees S A, Peterfreund R A, Pollack A E, Adler E M, Reppert S M. Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res Mol Brain Res. 1992; 14:186-195.
19. Schiffmann S N, Jacobs O, Vanderhaeghen J J. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J. Neurochem. 1991; 57:1062-1067.
20. Schiffmann S N, Vanderhaeghen J J. Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J. Neurosci. 1993; 13:1080-1087.
21. Ferre S, Rubio A, Fuxe K. Stimulation of adenosine A2 receptors induces catalepsy. Neurosci Lett. 1991; 130:162-164.
22. Ferre S, Fuxe K, Von Euler G, Johansson B, Fredholm B B. Adenosine-dopamine interactions in the brain. Neurosci. 1992; 51:501-512.
23. Fredholm B B, Battig K, Holmen J, Nehlig A, Zvartau E E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999; 51:83-133.
24. Barraco R A, Martens K A, Parizon M, Normile H J. Adenosine A2a receptors in the nucleus accumbens mediate locomotor depression. Brain Res Bull. 1993; 31:397-404.
25. Ferre S, Von Euler G, Johansson B, Fredholm B B, Fuxe K. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci USA. 1991; 88:7238-7241.
26. Fuxe K, Ferre S, Zoli M, Agnati L F. Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia. Brain Res Brain Res Rev. 1998; 26:258-273.
27. Aoyama S, Kase H, Borrelli E. Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J. Neurosci. 2000; 20:5848-5852.
28. Chen J F, Moratalla R, Impagnatiello F, Grandy D K, Cuellar B, Rubinstein M, Beilstein M A, Hackett E, Fink J S, Low M J, Ongini E, Schwarzschild M A. The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice. Proc Natl Acad Sci USA. 2001; 98:1970-1975.
29. Thompson R D, Secunda S, Daly J W, Olsson R A. N6,9-disubstituted adenines: potent, selective antagonists at the A1 adenosine receptor. J Med. Chem. 1991; 34:2877-2882.
30. Mori A, Shindou T, Ichimura M, Nonaka H, Kase H. The role of adenosine A2a receptors in regulating GABAergic synaptic transmission in striatal medium spiny neurons. J Neurosci. 1996; 16:605-611.
31. Richardson P J, Gubitz A K, Freeman T C, Dixon A K. Adenosine receptor antagonists and Parkinson's disease: actions of the A2A receptor in the striatum. Adv Neurol. 1999; 80:111-119.
32. Svenningsson P, Le Moine C, Fisone G, Fredholm B B. Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol. 1999; 59:355-396.
33. Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg S R, Neve K, Fuxe K, Agnati L F, Woods A S, Ferre S, Lluis C, Bouvier M, Franco R. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol. Chem. 2003; 278:46741-46749.
34. Fredholm B B, Battig K, Holmen J, Nehlig A, Zvartau E E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use [Review]. Pharmacol Rev. 1999; 51:83-133.
35. Chen J F, Moratalla R, Impagnatiello F, Grandy D K, Cuellar B, Rubinstein M, Beilstein M A, Hackett E, Fink J S, Low M J, Ongini E, Schwarzschild M A. The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice. Proc Natl Acad Sci USA. 2001; 98:1970-1975.
36. Grondin R, Bedard P J, Hadj T A, Gregoire L, Mori A, Kase H. Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology. 1999; 52:1673-1677.
37. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H, Kuwana Y, Jenner P. Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000; 162:321-327.
38. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H, Kuwana Y, Jenner P. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. 1998; 43:507-513.
39. Kanda T, Tashiro T, Kuwana Y, Jenner P. Adenosine A2A receptors modify motor function in MPTP-treated common marmosets. Neuroreport. 1998; 9:2857-2860.
40. Pinna A, Fenu S, Morelli M. Motor stimulant effects of the adenosine A(2A) receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats. Synapse. 2001; 39:233-238.
41. Pinna A, di Chiara G, Wardas J, Morelli M. Blockade of A2a adenosine receptors positively modulates turning behaviour and c-Fos expression induced by D1 agonists in dopamine-denervated rats. Eur J. Neurosci. 1996; 8:1176-1181.
42. Aoyama S, Kase H, Borrelli E. Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. Journal of Neuroscience. 2000; 20:5848-5852.
43. Grondin R, Bedard P J, Hadj T A, Gregoire L, Mori A, Kase H. Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology. 1999; 52:1673-1677.
44. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H, Kuwana Y, Jenner P. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. 1998; 43:507-513.
45. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H, Kuwana Y, Jenner P. Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000; 162:321-327.
46. Halldner L, Lozza G, Lindstrom K, Fredholm B B. Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist. Eur J. Pharmacol. 2000; 406:345-354.
47. Pinna A, Fenu S, Morelli M. Motor stimulant effects of the adenosine A(2A) receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats. Synapse. 2001; 39:233-238.
48. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H, Kuwana Y, Jenner P. Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000; 162:321-327.
49. Fredduzzi S, Moratalla R, Monopoli A, Cuellar B, Xu K, Ongini E, Impagnatiello F, Schwarzschild M A, Chen J F. Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors. J. Neurosci. 2002; 22:1054-1062.
50. Bibbiani F, Oh J D, Petzer J P, Castagnoli N, Jr., Chen J F, Schwarzschild M A, Chase T N. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease. Exp Neurol. 2003; 184:285-294.
51. Chen J F, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, Moskowitz M A, Fink J S, Schwarzschild M A. A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 1999; 19:9192-9200.
52. Monopoli A, Casati C, Lozza G, Forlani A, Ongini E. Cardiovascular pharmacology of the A2A adenosine receptor antagonist, SCH 58261, in the rat. J Pharmacol Exp Ther. 1998; 285:9-15.
53. Phillis J W. The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil. Brain Res. 1995; 705:79-84.
54. Jones P A, Smith R A, Stone T W. Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist. Brain Res. 1998; 800:328-335.
55. Jones P A, Smith R A, Stone T W. Protection against kainate-induced excitotoxicity by adenosine A2A receptor agonists and antagonists. Neuroscience. 1998; 85:229-237.
56. Popoli P, Pintor A, Domenici M R, Frank C, Tebano M T, Pezzola A, Scarchilli L, Quarta D, Reggio R, Malchiodi-Albedi F, Falchi M, Massotti M. Blockade of striatal adenosine A2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum. J. Neurosci. 2002; 22:1967-1975.
57. Dall'Igna O P, Porciuncula L O, Souza D O, Cunha R A, Lara D R, Dall'Igna OP. Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br J. Pharmacol. 2003; 138:1207-1209.
58. Chen J F, Xu K, Petzer J P, Staal R, Xu Y H, Beilstein M, Sonsalla P K, Castagnoli K, Castagnoli N, Jr., Schwarzschild M A. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci. 2001; 21:RC143.
59. Chen J F, Xu K, Petzer J P, Staal R, Xu Y H, Beilstein M, Sonsalla P K, Castagnoli K, Castagnoli N, Jr., Schwarzschild M A. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci. 2001; 21:RC143.
60. Ikeda K, Kurokawa M, Aoyama S, Kuwana Y. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease. J. Neurochem. 2002; 80:262-270.
61. Martinez-Mir M I, Probst A, Palacios J M. Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease. Neuroscience. 1991; 42:697-706.
62. Ross G W, Abbott R D, Petrovitch H, Morens D M, Grandinetti A, Tung K H, Tanner C M, Masaki K H, Blanchette P L, Curb J D, Popper J S, White L R. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA. 2000; 283:2674-2679.
63. Ascherio A, Zhang S M, Heman M A, Kawachi I, Colditz G A, Speizer F E, Willett W C. Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann Neurol. 2001; 50:56-63.
64. Hauser R A, Hubble J P, Truong D D. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology. 2003; 61:297-303.
65. Bara-Jimenez W, Sherzai A, Dimitrova T, Favit A, Bibbiani F, Gillespie M, Morris M J, Mouradian M M, Chase T N. Adenosine A(2A) receptor antagonist treatment of Parkinson's disease. Neurology. 2003; 61:293-296.
66. Bara-Jimenez W, Sherzai A, Dimitrova T, Favit A, Bibbiani F, Gillespie M, Morris M J, Mouradian M M, Chase T N. Adenosine A(2A) receptor antagonist treatment of Parkinson's disease. Neurology. 2003; 61:293-296.
67. Zocchi C, Ongini E, Ferrara S, Baraldi P G, Dionisotti S. Binding of the radioligand [3H]-SCH 58261, a new non-xanthine A2A adenosine receptor antagonist, to rat striatal membranes. Br J. Pharmacol. 1996; 117:1381-1386.
68. Keddie J R, Poucher S M, Shaw G R, Brooks R, Collis M G. In vivo characterisation of ZM 241385, a selective adenosine A2A receptor antagonist. Eur J. Pharmacol. 1996; 301:107-113.
69. Mori A, Shindou T, Ichimura M, Nonaka H, Kase H. The role of adenosine A2a receptors in regulating GABAergic synaptic transmission in striatal medium spiny neurons. J. Neurosci. 1996; 16:605-611.
70. Todde S, Moresco R M, Simonelli P, Baraldi P G, Cacciari B, Spalluto G, Varani K, Monopoli A, Matarrese M, Carpinelli A, Magni F, Kienle M G, Fazio F. Design, radiosynthesis, and biodistribution of a new potent and selective ligand for in vivo imaging of the adenosine A(2A) receptor system using positron emission tomography. J Med. Chem. 2000; 43:4359-4362.
71. Colotta V, Catarzi D, Varano F, Cecchi L, Filacchioni G, Martini C, Trincavelli L, Lucacchini A. 4-Amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-alpha]-quinoxalin-1-one: a new A_2Aadenosine receptor antagonist with high selectivity versus A1 receptors. Arch Pharm (Weinheim). 1999; 332:39-41.
72. Thompson R D, Secunda S, Daly J W, Olsson R A. N6,9-disubstituted adenines: potent, selective antagonists at the A1 adenosine receptor. J Med. Chem. 1991; 34:2877-2882.
73. Iwasaki K, Kusachi S, Tominaga Y, Kita T, Taniguchi G. Coronary artery spasm demonstrated by coronary angiography in a patient with acute myocarditis resembling acute myocardial infarction; a case report. Jpn J. Med. 1991; 30:573-577.
74. Chen J F, Steyn S, Staal R, Petzer J P, Xu K, Van Der Schyf C J, Castagnoli K, Sonsalla P K, Castagnoli N, Jr., Schwarzschild M A. 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. J Biol. Chem. 2002; 277:36040-36044.

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 A_2Aantagonist compound of formula I a mammal in need of such treatment:

wherein:

R¹and R²are 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 R¹and R²are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R¹and R²are independently absent, with the proviso that R^ais not SH or halogen when the R¹or R²to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃or —SCH₃;

R³is selected from the group consisting of hydrogen, halo, —OR^a, SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, and R^aS(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³can be absent;

R⁴and R⁵together 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 (—NR^a—) in the ring, wherein any ring comprising R⁴and R⁵is optionally further substituted with from 1 to 14 R⁶groups; wherein each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)— or two R⁶groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;

R⁷and R⁸are each independently hydrogen, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl aryl(C₁-C₈)alkylene, heteroaryl, and heteroaryl(C₁-C₈)alkylene; or wherein R⁷and R⁸together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;

R⁹and R¹⁰are 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 R⁹and R¹⁰are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R⁹and R¹⁰are independently absent, with the proviso that R^ais not SH or halogen in the case where the R⁹or R¹⁰to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃or —SCH₃;

Y is —CR³R⁴R⁵or 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, —NR^aR^b, —SR^a, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)NR^a—, R^aR^bNC(═O)—, R^aC(═O)NR^b—, R^aR^bNC(═O)NR^b—, R^aR^bNC(═S)NR^b—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, OS(O₂)R^a, OS(═O)OR^a, —OS(O₂)OR^aand —O(SO₂)NR^aR^b;

R^aand R^bare 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 (—NR^c—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —OR^c, —NR^cR^c, SR^c, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^aor R^bis not a heteroatom when it is attached to another heteroatom;

R^cis 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 (—NR^a).

3. The method of claim 1, wherein R³is selected from the group consisting of hydrogen, OH, OCH₃, OAc, NH₂, NHCH₃, N(CH₃)₂and NHAc.

4. The method of claim 1, wherein the ring comprising R⁴and R⁵and 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 R⁴and R⁵and 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 R⁶groups substituted on the R⁴R⁵ring is from 1 to 4 and each R⁶is independently selected from the group consisting of OH, OCH₃, methyl, ethyl, t-butyl, —CO₂R^a, —CONR^aR^b, OAc, NH₂, NHCH₃, N(CH₃)₂, NHEt and N(Et)₂, provided that when the ring comprising R⁴and R⁵contains 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 —NR⁷R⁸is 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 R⁹is 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 R¹⁰is hydrogen.

10. The method of claim 1, wherein R^aand R^bare 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 —CR³R⁴R⁵or NR⁴R⁵, and is selected from the group consisting of:

wherein q is 0, 1, 2, 3 or 4; R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b), R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, and R^aS(═O)₂—; and each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)—, provided that R⁶is not halogen or a heteroatom when R⁶is attached to a heteroatom.

12. The method of claim 1, wherein Y is —CR³R⁴R⁵or NR⁴R⁵and is selected from the group consisting of:

wherein R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, and R^aS(═O)₂—, and each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)—.

13. A method for treating cancer, comprising: administering a therapeutically effective amount of an A_2Aantagonist compound of formula II a mammal in need of such treatment:

wherein:

R¹and R²are 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 R¹and R²are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R¹and R²are independently absent, with the proviso that R^ais not SH or halogen when the R¹or R²to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃or —SCH₃;

R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, and R^aS(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³can be absent;

R⁴and R⁵together 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 (—NR^c—) in the ring, wherein any ring comprising R⁴and R⁵is optionally further substituted with from 1 to 14 R⁶groups; wherein each R⁶is independently selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)—, or two R⁶groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;

R⁷and R⁸are each independently hydrogen, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl or aryl(C₁-C₈)alkylene, heteroaryl, heteroaryl(C₁-C₈)alkylene-; or wherein R⁷and R⁸together with the nitrogen atom to which they attach form a heterocycle or heteroaromatic ring;

R⁹and R¹⁰are 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 R⁹and R¹⁰are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R⁹and R¹⁰are independently absent, with the proviso that R^ais not SH or halogen in the case where R⁹and R¹⁰to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃and —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 —CR³R⁴R⁵or 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, —NR^aR^b, —SR^a, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)NR^a—, R^aR^bNC(═O)—, R^aC(═O)NR^b—, R^aR^bNC(═O)NR^b—, R^aR^bNC(═S)NR^b—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, —OS(O₂)R^a, —OS(═O)OR^a, —OS(O₂)OR^aand —O(SO₂)NR^aR^b;

R^aand R^bare 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 (—NR^c); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —OR^c, —NR^cR^c, SR^c, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^aor R^bis not a heteroatom when it is attached to another heteroatom;

R^cis 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

14. A method for treating cancer, comprising: administering a therapeutically effective amount of an A_2Aantagonist 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≡CCH₃or —CH₂CH₂C≡CH;

Y is —CR³R⁴R⁵or NR⁴R⁵;

R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a), R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, and R^aS(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³can be absent;

R⁴and R⁵together 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 (—NR^a—) in the ring, wherein any ring comprising R⁴and R⁵is optionally further substituted with from 1 to 14 R⁶groups; wherein each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)—, or two R⁶groups and the atom to which they are attached combine to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;

R⁹and R¹⁰are 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 R⁹and R¹⁰are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a), or where R⁹and R¹⁰are independently absent, with the proviso that R^ais not SH or halogen in the case where the R⁹or R¹⁰to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃or —SCH₃;

R^cis selected from the group consisting of hydrogen and (C₁-C₈)alkyl; and

n is 0, 1, 2 or 3; or

15. A method for treating cancer, comprising: administering a therapeutically effective amount of an A_2Aantagonist 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 R^a;

Y is —CR³R⁴R⁵or NR⁴R⁵;

R⁴and R⁵together 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 (—NR^a—) in the ring, wherein any ring comprising R⁴and R⁵is optionally further substituted with from 1 to 14 R⁶groups; wherein each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)— or two R⁶groups and the atom to which they are attached combine to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;

R^cis 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

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 (—NR^a—), and is optionally further substituted with from 1 to 10 R⁶groups, 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, —NR^aR^b, —SR^a, cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)NR^a—, R^aR^bNC(═O)—, R^aC(═O)NR^b—, R^aR^bNC(═O)NR^b—, R^aR^bNC(═S)NR^b—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, —OS(O₂)R^a, OS(═O)OR^a, —OS(O₂)OR^aand —O(SO₂)NR^aR^b;

R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)— or two R⁶groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;

R⁹and R¹⁰are 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 R⁹and R¹⁰are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R⁹and R¹⁰are independently absent, with the proviso that R^ais not SH or halogen in the case where the R⁹or R¹⁰to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃or —SCH₃;

R^cis 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

18. A method for treating cancer, comprising: administering a therapeutically effective amount of an A_2Aantagonist compound of formula I a mammal in need of such treatment:

wherein:

R¹and R²are 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 R^agroups;

Y is —CR³R⁴R⁵or NR⁴R⁵;

R³is selected from the group consisting of hydrogen, halo, —OR^a, —SR^a, (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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O, R^bOC(═O)N(R^a)—, R^aR^bN, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, R^aS(═O)—, and R^aS(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³can be absent;

R^aand R^bare 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 (—NR^c—); and wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of —OR^c, —NR^cR^c, SRC, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^aor R^bis not a heteroatom when it is attached to another heteroatom;

R^cis 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

19. The method of claim 18, wherein R¹and R²are 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 R^agroups selected from the group consisting of methyl, ethyl, propyl, iso-propyl, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃and —SCH₃.

20. A method for treating cancer, comprising: administering a therapeutically effective amount of an A_2Aantagonist compound of formula I a mammal in need of such treatment:

wherein:

R⁷and R⁸are 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 (—NR^a—) in the ring, and each is optionally substituted with from 1, 2, 3 or 4 R^agroups;

Y is —CR³R⁴R⁵or NR⁴R⁵;

R¹and R²are 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 R¹and R²are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1-4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R¹and R²are independently absent, with the proviso that R^ais not SH or halogen when the R¹or R²to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃or —SCH₃;

R⁴and R⁵together 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 (—NR^a—) in the ring, wherein any ring comprising R⁴and R⁵is optionally further substituted with from 1 to 14 R⁶groups; wherein each R⁶is independently selected from the group consisting of halo, —OR^a, —SR^a, 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, —CO₂R^a, R^aC(═O)O—, R^aC(═O)—, —OCO₂R^a, R^aR^bNC(═O)O—, R^bOC(═O)N(R^a)—, R^aR^bN—, R^aR^bNC(═O)—, R^aC(═O)N(R^b)—, R^aR^bNC(═O)N(R^b)—, R^aR^bNC(═S)N(R^b)—, R^aOC(═S)—, R^aC(═S)—, —SSR^a, and R^aS(═O)-or two R⁶groups and the atom to which they are attached combined to form C═O or C═S, or wherein two R⁶groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;

R⁹and R¹⁰are 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 R⁹and R¹⁰are optionally substituted with 1 to 4 substituents of R^a, wherein the alkyl is optionally interrupted by 1 to 4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^a—), or where R⁹and R¹⁰are independently absent, with the proviso that R^ais not SH or halogen in the case where the R⁹or R¹⁰to which R^ais bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃or —SCH₃;

R^cis selected from the group consisting of hydrogen and (C₁-C₈)alkyl; and

21. The method of claim 20, wherein R⁷is selected from the group consisting of benzyl, phenethyl, phenylpropyl and each is optionally substituted with from 1, 2 or 3 substituents of R^a.

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