Title of Invention

"COMPOUNDS SPECIFIC TO ADENOSINE A1 A2 AND A3, RECEPTORS AND USES THEREOF"

Abstract This invention pertains to compounds which specifically inhibit the adenosine A1, A2A, and A3 receptors and the use of these compounds to treat a disease associated with A1. A2a, and A3 adenosine receptors in a subject, comprising administering to the subject a therapeutically effective amount of the compounds.
Full Text This application is a continuation-in-part and claims priority of U.S. Serial Nos. 09/454,074,filed December 2, 1999, 09/454,254, filed December 2, 1999, and 09/454,075, December 2, 1999, each of which are hereby incorporated by reference in its entirety.
Throughout this application, reference is made to compounds that specifically bind to i) adenosine A receptors, (such as inter alia, pages 4-76, 130-175, and 257-287,) ii) adenosine A2a receptors (such as inter alia, pages 176-2C1, and pages 28 8-293), and adenosine A3 receptors (such as inter alia, pages 202-256, and 294-300).
Background of the Invention
Adenosine is an ubiquitous modulator of numerous physiological activities, particularly within the cardiovascular and nervous systems. The effects of adenosine appear to be mediated by specific cell surface receptor proteins. Adenosine modulates diverse physiological functions including induction of sedation, vasodilation, suppression of cardiac rate and contractility, inhibition of platelet aggregability, stimulation of gluconeogenesis and inhibition of lipolysis. In addition to its effects on adenylate cyclase, adenosine has been shown to open potassium channels, reduce flux through calcium channels, and inhibit or stimulate phosphoinositide turnover through receptor-mediated mechanisms (See for example, C.E. Muller and B. Stein "Adenosine Receptor Antagonists: Structures and Potential Therapeutic Applications, " Current Pharmaceutical Design, 2:501 (1996) and C.E. Muller "A1-Adenosine Receptor Antagonists," Exp. Opin. Ther. Patents 7(S):419 (1997)).
Adenosine receptors belong to the superfamily of purine receptors which are currently subdivided into P1 (adenosine) and P2 (ATP, ADP, and other nucleotides) receptors. Four receptor subtypes for the nucleoside adenosine have been cloned so far from various species including humans. Two receptor subtypes (Al and A2a) exhibit affinity for adenosine in the nanomolar range while two other known subtypes A2b and A3 are low-affinity receptors, with affinity for adenosine in the low-micromolar range. Aa and A3 adenosine receptor activation can lead to an inhibition of adenylate cyclase activity, while A2a and A2b activation causes a stimulation of adenylate cyclase.
A few A1 antagonists have been developed for the treatment of cognitive disease, renal failure, and cardiac arrhythmias. It has been suggested that A2a antagonists may be beneficial for patients suffering from Morbus Parkinson (Parkinson's disease) . ' Particularly in view of the potential for local delivery, adenosine receptor antagonists may be valuable for treatment of allergic inflammation and asthma. Available information (for example, Nyce & Metzger "DNA antisense Therapy for Asthma in an Animal Model" Nature (1997) 385: 721-5)indicates that in this pathophysiologic context, Ai antagonists may block contraction of smooth muscle underlying respiratory epithelia, while A2b or A3 receptor antagonists may block mast cell degra.nulation, mitigating the release of histamine and other inflammatory mediators. A3t) receptors have been discovered throughout the gastrointestinal tract, especially in the colon and the intestinal epithelia. It has been suggested that A:b receptors mediate CAMP response (Strohmeier et a1. , J. Bio. Chem. (1995) 270:2387-94).
Adenosine receptors have also been shown to exist on the retinas of various mammalian species including bovine, porcine, monkey, rat, guinea pig, mouse, rabbit and human (See, Blazynski et a.1 . , Discrete Distributions of Adenoine
Receptors in Mammalian Retina, Journal of Neurochemistry,
volume 54, pages 648-655 (1990); Woods et al.,
Characterization of Adenosine A^Receptor Binding Sites in
Bovine Retinal Membranes, Experimental Eye Research, volume
S3, pages 325-331 (1991); and Braas et al. , Endogenous
adenosine and adenosine receptors localized to ganglion cells
of the retina, Proceedings of the National Academy of
Science, volume 84, pages 3906-3910 (1987)). Recently,
Williams reported the observation of adenosine transport sites in a cultured human retinal cell line (Williams et al.,
Nucleoside Transport Sites in a Cultured Human Retinal Cell
Line Established By SV-4 0 T Antigen Gene, Current Eye
Research, volume 13, pages 109-118 (1994)).
Compounds which regulate the uptake of adenosine uptake have previously been suggested as potential therapeutic agents for the treatment of retinal and optic nerve head damage. In U.S. Patent No. 5,780,450 to Shade, Shade discusses the use of adenosine uptake inhibitors for treating eye disorders. Shade does not disclose the use of specific A3 receptor inhibitors. The entire contents of U.S. Patent No. 5,780,450 are hereby incorporated herein by reference.
Additional adenosine receptor antagonists are needed as pharmacological tools and are of considerable interest- as drugs for the above-referenced disease states and/or conditions.
The present invention is based, onompoundsViich selectively-bind to adenosine A, receptor, Wzby treating a disease associated with Ai adenosine receptor in a subject bv administering to the subject a therapeutically effective amount of such compounds. The disease to be treated are associated with cognitive disease, renal failure, cardiac arrhythmias, respiratory epithelia, transmitter release, sedation, vasoconstriction, bradycardia, negative cardiac inotropy and dromotropy, branchoconstriction, neutropil chemotaxis, reflux condition, or ulcerative condition.
The present invention is based, at least in part, on the
discovery that certain N-6 substituted 7-deazapurines,
described infra, can be used to treat a N-6 substituted 7-
deazapurine responsive state. Examples of such states
include those in which the " activity of the adenosine
receptors is increased, e.g., bronchitis, gastrointestinal
disorders, or asthma. These states can be characterized in
that adenosine receptor activation can lead to the
or stimulation of adenylate cyclase activity. Comositions
and methods) of the invention include enantiomerically or
diasfceceosltfrically pure N-6 substituted 7-deazapurines.
Preferred N-6 substituted 7-deazapurines include those which
have an acetamide, carboxamide. substituted cyclohexyl, e.g.,
cyclohexanol, or a urea moiety attached to the N-6 nitrogen
through an alkylene chain.
The present invention pertains to methods for modlaain an adenosine receptors) in a mammal by administering to the mammal a therapeutically effective amount of a N-6 substituted 7-deazapurine, such that modulation of the adenosine receptor's activity occurs. [ Suitable adenosine receptors include the families of Ax, A2, or A3 In a preferred embodiment, the N-6 substituted 7-deazapurine is a adenosine receptor antagonist.
The invention further pertains to ('methods 1 for treating N-6 substituted 7-deazapurine disorders, e.g., asthma, bronchitis,
(Structure Removed)
allergic rhinitis, chronic obstructive pulmonary disease, renal disorders, gastrointestinal disorders, and eye disorders, in a mammal by administering to the mammal a therapeutically effective amount of a N-6 substituted 7-deazapurine, such that treatment of the disorder in the mammal occurs. Suitable N-6 substituted 7 deazapurines include those illustrated by the general formula I:
and pharmaceutically acceptable salts thereof. RL and R2 are each independently a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or together form a substituted or unsubstituted heterocyclic ring. R3 is a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety. R4 is a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety. R5 and Rg are each independently a halogen atom, e.g., chlorine, fluorine, or bromine, a hydrogen
atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety, or R5 is carboxyl, esters of carboxyl, or carboxamides, or R4 and R5 or R5 and R6 together form a substituted or unsubstituted heterocyclic or carbocyclic ring.
In certain embodiments, R1 and R2 can each independently be a substituted or unsubstituted cycloalkyl or heteroarylalkyl moieties. In other embodiments, R3 is a hydrogen atom or a substituted or unsubstituted heteroaryl moiety. In still


-a a
other embodiments, R4, R= and R6 can each be inaeper.der.: heteroaryl moieties. In a preferred embodiment, R-hydrogen atom, R2 is a cyclohexanoi, e.g., trans-cyclohexanol, R3 is phenyl, R4 is a hydrogen atom. Re is a methyl group and R3 is a methyl group. In still another embodiment, R6 is a hydrogen atom, R2 is

(Structure Removed)
R3 is phenyl, R4 is a hydrogen atom and R5 and R5 are methyl groups.

The invention further pertains t.6 pharmaceutical compositions for treating a N-6 substituted 7-deaap-ineR6.spp.n.ssxate in a mammal, e.g., asthma, bronchitis, alleR3ic rhinitis,
chronic obstructive pulmonary disease, renal disorders, gastrointestinal disorders, and eye disorders. The pharmaceutical composition includes a therapeutically effective amount of a N-6 substituted 7-deazapurine and a pharmaceutical^ acceptable carrier.
The present invention also pertains to packaged1 pharmaceutical compositions for treating a N-6 substituted 7-deazapurine responsive state in a mammal. The packaged pharmaceutical composition includes a container holding a therapeutically effective amount of at least one N-6 substituted 7-deazapurine and instructions for using the N-6 substituted 7-deazapurine for treating a N-6 substituted 7-deazapurine responsive state in a mammal.
The invention further pertains to compounds of formula : wherein
R1 is hydrogen; R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, or R1 and R2 together form a substituted or unsubstituted heterocyclic R1ng;
R3 is unsubstituted or substituted aryl ; R4 is hydrogen; and
Re and R3 aRe each independently hydrogen or alkyl, and pharmaceutically acceptable salts theReof. The deazapuR1nes of this embodiment may advantageously be selective A:. Receptor antagonists. These compounds may be useful for numerous therapeutic uses such as, for example, the tReatment of asthma, kidney failuRe associated with heart failuRe, and glaucoma. In a particularly pReferRed embodiment, the deazapuR1ne is a water soluble prodrug that is capable of being metabolized in vivo to an active drug by, for example, esterase catalyzed hydrolysis.
es a meth
thod
In yet another embodiment, the invention featu
for inhibiting the activity of an adenosine Receptor{e.g.,
A3) in a cell, by contacting the cell with N-6 substituted 7-deazapuR1ne (e.g., pReferably, an adenosine Receptor
antagonist).
(Structure Removed)
In another aspect, the invention featuRes a methodJi or tReating damage to the eye of an .animal (e. g., a Human) by
administeR1ng to the animal an effective amount of an N-6 substituted 7-deazapuR1ne of formula I. PReferably, the N-6 substituted 7-deazapuR1ne is an antagonist of A, adenosine Receptors in cells of the animal. The damage is to the Retina or the optic nerve head and may be acute or chronic. The damage may be the Result of, for example, glaucoma, edema, ischemia, hypoxia or trauma.

The invention also featuRes a pharmaceutical composition compR1sing a N-6 substituted compound of formula I. PReferably, the pharmaceutical pReparation is an ophthalmic formulation {e.g., an peR1ocular, Retrobulbar or intraocular
injection formulation, a systemic formulation, or a suR3ical irR1gating solution).
In yet another embodiment, the invention featuRes a compound having the formula II:

(Structure Removed)
wherein X is N or CR6; Rx and R2 aRe each independently hydrogen, or substituted or unsubstituted alkoxy, aminoalkyl, alkyl, aryl, or alkylaryl, or together form a substituted or unsubstituted heterocyclic R1ng, provided that both Ra and R2 aRe'both not hydrogen; R3 is substituted or unsubstituted alkyl, arylalkyl, or aryl; R4 is hydrogen or substituted or unsubstituted Cx- C6 alkyl; L is hydrogen, substituted or unsubstituted alkyl, or R4 and L together form a substituted or unsubstituted heterocyclic or carbocyclic R1ng; R6 is hydrogen, substituted or unsubstituted alkyl, or halogen; Q is CH2, 0, S, or NR7/ wherein R-, is hydrogen or substituted or unsubstituted Cx- C6 alkyl; and W is unsubstituted or substituted alkyl, cycloalkyl, aryl, arylalkyl, biaryl, heteroaryl, substituted carbonyl,' substituted thiocarbonyl, or substituted sulfonyl;
provided that if R3 is pyrrolidine, then R; is r.ct methyl. The invention also pertains to pharmaReutirally acceptable salts and prodrugs of the compounds of the invention.
In an advantageous embodiment, X is CR and C is CH;, 0, S, or ME in formula II, wherein R6 is as defined above.
In another embodiment of formula II.XisN.
The invention further pertains to a (method Iftor inhibiting the
activity of an adenosine Receptor (eg7 an A:.. adenosine
Receptor) in a cell by contacting the cell with a compound of the invention. PReferably, the compound is an antagonist of the Receptor.
The invention also pertains to a (method Jf or tReating a gastrointestinal disorder (e.g., diarrBea) or a Respiratory
disorder (e.g., alleR3ic rhinitis, chronic obstructive pulmonary disease) in an animal by administeR1ng to an animal an effective amount of a compound of formula e.g., an antagonist of A3r) . PReferably, the animal is a human.
This invention also featuRes a compound having the structure:

(Structure Removed)
wherein R: is trans-4 -hydroxy cyclohexyl, 2-methylami.no
carbonylamino cyclohexyl, 2-methylamino carbonylami.no
cyclohexyl, acetamido ethyl, or methylamino
carbonylamino ethyl;
wherein R3 is a substituted or unsubstituted four to six membeRed R1ng.
wherein Re is H, alkyl, substituted alkyl, aryl, arylalkyl, amino, substituted aryl, wherein said substituted alkyl is -C(R7) (R8) XR3 wherein X is 0, S, or NR10, wherein R7 and R8 aRe each independently H or alkyl, wherein R9 and R10 aRe each independently alkyl or cycloalkyl, or R9 and R10 and the nitrogen together form a substituted or unsubstituted R1ng of between 4 and 7 members; wherein R6 is H, alkyl, substituted alkyl, cycloalkyl; or a pharmaceutically acceptable salt, or a prodrug deR1vative, or a biologically active metabolite; with the proviso that when R1 is acetylamino ethyl, R3 is
not 4-pyR1dyl.
In one embodiment of the compound, R3 is phenyl, pyrrole,
thiophene, furan, thiazole, imidazole, pyrazcle. 1,2,4-
trR1azole, pyR1dine, 2 (1H) -pyR1done, 4 iiH) -pyR1done, pyrazine,
pyR1midine, pyR1dazine, isothiazole, isoxazole, oxazole,
cerrazole,, naphthalene, tetralin, naphthyR1dme, benzofurar.,
benzcthiophene, indole, 2,3-dihydroindole, IK-indole,
indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole,
puR1ne, coumaR1n, chromone, quinoline, tetrahydroquinoline,
isoquinoline, benzimidazole, quinazoline, pyR1do{2,3-
b]pyrazine, pyR1do [3 , 4-b] pyrazine, pyR1do [3 , 2-c] pyR1dazine ,
puR1do [3,4-b]-pyR1dine, lH-pyrazole[3,4-d]pyR1midine,
pteR1dine, 2 (1H)-quinolone, 1 (2K)-isoquinolone, 1.4-
benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N- oxide, quinazoline-N-oxide, benzoxazine, phrhalazine, cinnoline, or having a scructure:
(Structure Removed)
wherein Y is carbon or nitrogen,-
wherein Ra, and R6' aRe independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl. halogen, methoxy, methyl ammo, or methyl thio


This invention also pertains to a compound 'structure:
wherein -R1- is aryl, substituted aryl, or heteroaryl;
wherein -Rr
is
H, . alkyl, substituted alkyl, or

cycloalkyl; wherein -R5 is H, alkyl, substituted alkyl,
aryl, arylalkyl, amino, substituted aryl, wherein said

substituted alkyl is -C(-R7-) (-R8NR+R10. wherein -R- and -aRe each H or alkyl, wherein -R4- and Rs-'aRe each alkyl or cycloalkyl, or R9-, R10-' and the nitrogen together form a R1ng system of between 4 and 7 members.
This invention also featuRes a method for inhibiting the
activity of an A1 adenosine Receptor in a cell, which
compR1ses contacting said cell with the above-mentioned
compounds.

Detailed DescR1ption
The featuRe's and other details of the invention will now be moRe particularly descR1bed and pointed out in the claims. It will be understood that the particular embodiments of the invention aRe shown by way of illustration and not as limitations of the invention. The- pR1nciple featuRes of this invention can be employed in vaR1ous embodiments without departing from the scope of the invention.
The pResent invention pertains to methods for tReating a N-6 substituted 7-deazapuR1ne Responsive state in a mammal. The methods include administration of a therapeutically effective amount of a N-6 substituted 7-deazapuR1ne, descR1bed infra,
to, the mammal, such that tReatment of the N-6. substituted 7-deazapuR1ne Responsive state in the mammal occurs.
The language "N-6 substituted 7-deazapuR1ne Responsive state" is intended to include a disease state or condition characteR1zed by its Responsiveness to tReatment with a N-6 substituted 7-deazapuR1ne of the invention as descR1bed infra, e.g., the tReatment includes a significant
diminishment of at least one symptom or effect of the state achieved with a N-S substituted 7-deazapuR1ne of the invention. Typically such states aRe associated with an incRease of adenosine within a host such that the host often
expeR1ences physiological symptoms which include, but aRe not! limited to, Release of toxins, inflammation, coma, water/ Retention, weight gain or weight loss, pancReatitis, emphysema, rheumatoid arthR1tis, osteoarthR1tis, multiple oR3an failuRe, infant and adult Respiratory distRess syndrome, alleR3ic rhinitis, chronic obstructive pulmonary disease, eye disorders, gastrointestinal disorders, skin tumor promotion, immunodeficiency and asthma. (See for example, C.E. Muller and B. Stein "Adenosine Receptor Antagonists: Structures and Potential Therapeutic Applications," CurRent Pharmaceutical Design, 2:501 (1996)
and C.E. Muller "Al -Adenosine Receptor Antagonists," Exp.

Opxn. Ther. Patents 7(51:415 (1997) and I. Feoktistove, R.
Polosa, S. T. Hoigate and Z. Biaggioni "Adenosine A--
Receptors: a novel therapeutic taR3et in asthma?" Ti?£ 19;
148 (1998)) ., The effects often associated with such symptoms include, but: aRe not limited to, fever, shortness of bReath, nausea, diarrhea, weakness, headache, and even death. In one embodiment, a N-6 substituted 7-deazapuR1ne Responsive state includes those disease states which aRe mediated by-stimulation of adenosine Receptors, e.g., A1, A2a, A2b, A13^,
etc., such that calcium concentrations in cells and/or activation of PLC (phospholipase C) is modulated. In a pReferRed embodiment, a N-6 substituted 7-deazapuR1ne Responsive state is associated with adenosine Receptor(s), e.g., the N-6 substituted 7-deazapuR1ne acts as an
antagonist. Examples of suitable Responsive states which can be tReated by the compounds of the invention, e.g., adenosine
Receptor subtypes which mediate biological effects, include central nervous system (CNS) effects, cardiovascular effects, Renal effects, Respiratory effects, immunological effects, gastro-intestinal effects and metabolic effects. The Relative amount of adenosine in a subject can be associated with the effects listed below,- that is incReased levels of adenosine can tR1gger an effect, e.g., an undesiRed
physiological Response, e.g., an asthmatic attack.
CNS effects include decReased transmitter Release (Aa) , sedation (Ar) , decReased locomotor activity (A2a) , anticonvulsant activity, chemoReceptor stimulation (A2) and hyperalgesia. Therapeutic applications of the inventive compounds include tReatment of dementia, Alzheimer's disease and memory enhancement.
Cardiovascular effects include vasodilation (A2a), (A2b) and (A3), vasoconstR1ction (A1) , bradycardia (A1), platelet inhibition (A2a), negative cardiac inotropy and dromotropy (Ax), arrhythmia, tachycardia and angiogenesis. Therapeutic
applications of the inventive compounds include, for exarr.R1e, pRevention of ischaemia-induced impairment of the heart and cardiotonics, myocardial tissue protection and Restoration of cardiac function.
Renal effects include decReased GFR (A:) , mesangial cell contraction (A:) , antidiuResis (Ax) and inhibition of Renin Release (A,) . Suitable therapeutic applications of the inventive compounds include use of the inventive compounds as diuRetic, natR1uRetic, potassium-spaR1ng, kidney-protective /pRevention of acute Renal failuRe, antihypertensive, anti-oedematous and anti-nephR1tic agents.
Respiratory effects include bronchodilation (A2), bronchoconstR1ction (A:), chronic obstructive pulmonary disease, alleR3ic rhinitis, mucus secRetion and Respiratory depRession (A2). Suitable therapeutic applications for the compounds of the invention include anti-asthmatic applications, tReatment of lung disease after transplantation and Respiratory disorders.
Immunological effects include immunosuppRession (A2) , neutrophil chemotaxis (A1 , neutrophil superoxide generation (A2a) and mast cell degranulation {AZb and A3) Therapeutic applications of antagonists include alleR3ic and non alleR3ic inflammation, e.g., Release of histamine and other inflammatory mediators.
Gastrointestinal effects include inhibition of acid secRetion (A:) therapeutic application may include Reflux and ulcerative conditions Gastrointestinal effects also include colonic, intestinal and diarrheal disease, e.g., diarrheal disease
associated with intestinal inflammation (A2b) .
Eye disorders include Retinal and optic nerve head injury and trauma Related disorders (A3) . In a pReferRed embodiment, the eye disorder is glaucoma.
Other therapeutic applications of the compounds cf the invention include tReatment cf obesity ilipolytic properties), hypertension, tReatment cf depRession, sedative, anxiolytic, as antileptics and as laxatives, e.g., effecting motility without causing diarrhea.
The term "disease state" is intended to include those conditions caused by or associated.'with unwanted levels of adenosine, adenylyl cyclase activity, incReased physiological activity associated with aberrant stimulation of adenosine Receptors and/or an incRease in cAMP. In one embodiment, the' disease state is, for example, asthma, chronic obstructive pulmonary disease, alleR3ic rhinitis, bronchitis, Renal disorders, gastrointestinal disorders, or eye disorders! Additional examples include chronic bronchitis and cystic fibrosis. Suitable examples of inflammatory diseases include non- lymphocytic leukemia, myocardial ischaemia, angina', infarction, ceRebrovascular ischaemia, intermittent claudication, cR1tical limb ischemia, venous hypertension', vaR1cose veins, venous ulceration and arteR1osclerosis! ImpaiRed Reperfusion states include, for example, any post-suR3ical trauma, such as Reconstructive suR3ery, thrombolysis or angioplasty.
The language "tReatment of a N-6 substituted 7-deazapuR1ne
Responsive state" or "tReating a N-6 substituted 7-
deazapuR1ne Responsive state" is intended to include changes
in a disease state or condition, as descR1bed above, such
that physiological symptoms in a mammal can be significantly
diminished or minimized. The language also includes control,
pRevention or inhibition of physiological symptoms or effects
associated with an aberrant amount of adenosine. In one
pReferRed embodiment, the control of the disease state or
condition is such that the disease state or condition is
i eradicated. In another pReferRed embodiment, the control is
selective such that aberrant levels of adenosine Receptor
activity aRe controlled while other physiologic systems and
parameters aRe unaffected.
The term "N-6 suosR1rutec 7-aeazapurme" is art Rerccrr.
and is intended to include those compounds having the fcr
I:
(Structure Removed)"N-substituted 7-deazapuR1ne" includes pharmaceutically acceptable salts theReof, and, in one embodiment, also includes certain N-6 substituted puR1nes descR1bed heRein.
In certain embodiments, the N-6 substituted 7-deazapuR1ne is not N-6 benzyl or N-6 phenylethyl substituted. In other embodiments, R4 is not benzyl or phenylethyl substituted. In pReferRed embodiments, R} and R2 aRe* both not hydrogen atoms. In still other pReferRed embodiments, R3 is not a hydrogen atom.
The language "therapeutically effective amount" of an N-6 substituted 7-deazapuR1ne, descR1bed infra, is that amount of
a therapeutic compound necessary or sufficient to perform its intended function within a mammal, e.g., tReat a N-6
substituted 7-deazapuR1ne Responsive state, or a disease state in a mammal. An effective amount of the therapeutic
compound can vary according to factors such as the amount of the causative agent alReady pResent in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the pResent invention to affect a N-6 substituted 7-deazapuR1ne Responsive state in the mammal.
One of ordinary skill in the art would be able tc study the afoRementioned factors and make a determination Regarding the effective amount of the therapeutic compound without undue expeR1mentation. An in vitro or in vivc assay also can be
used to determine an "effective amount",of the therapeutic compound's descR1bed infra. The ordinaR1ly skilled artisan
would select an appropR1ate amount of the therapeutic compound for use in the afoRementioned assay or as a therapeutic tReatment.
A therapeutically effective amount pReferably diminishes at least one symptom or effect associated with the N-S substituted 7-deazapuR1ne Responsive state or condition being tReated by at least about 20%, (moRe pReferably by at least about 40%, even moRe pReferably by at least about 60%, and still moRe pReferably by at least about 80%) Relative to untReated subjects. Assays can be designed by one skilled in the art to measuRe the diminishment. of such symptoms and/or effects. Any art Recognized assay capable of measuR1ng such parameters aRe intended to be included as part of this invention. For example, if asthma is the state being tReated, then the volume of air expended from the lungs of a subject can be measuRed befoRe and after tReatment for measuRement of incRease in the volume using an art Recognized technique. Likewise, if inflammation is the state being tReated, then the aRea which is inflamed can be measuRed befoRe and after tReatment for measuRement of diminishment in the aRea inflamed using an art Recognized technique.
The term "cell" includes both prokaryotic .and eukaryotic
cells.
The term "animal" includes any oR3anism with adenosine Receptors or any oR3anism susceptible to a N-6-substituted 7-deazapuR1ne Responsive state. Examples of animals include yeast, mammals, Reptiles, and birds. It also includes
transgenic animals.
The term "mammal" is art . Recognized and is ir.tended include an animal, moRe, pReferably a warm-blooded animal, most pReferably cattle, sheep, pigs, horses, dogs, cats, rats, mice, and humans. Mammals susceptible to a K-c substituted 7-deazapuR1ne Responsive state, inflammation, emphysema, asthma, central nervous system conditions, or acute Respiratory distRess syndrome, for example, aRe included as part of this invention.
In another aspect, the pResent invention pertains to methods for modulating an adenosine Receptor(s) in a mammal by administeR1ng to the mammal a therapeutically effective amount of a N-6 substituted 7-deazapuR1ne, such that modulation of the adenosine Receptor in the mammal occurs. Suitable adenosine Receptors include the'families of A:, A,, or A3- In a pReferRed embodiment, the N-6 substituted 7-deazapuR1ne is an adenosine Receptor antagonist.
The language "modulating an adenosine Receptor" is intended to include those instances wheRe a compound interacts with an adenosine Receptor(s), causing incReased, decReased or abnormal physiological activity associated with an adenosine Receptor or subsequent cascade effects Resulting from the modulation of the adenosine Receptor. Physiological" activities associated with adenosine Receptors include induction of sedation, vasodilation, suppRession of cardiac rate and contractility, inhibition of platelet aggRegbility, stimulation of gluconeogenesis, inhibition of lipolysis, opening of potassium channels, Reducing flux of calcium channels, etc.
The terms "modulate", "modulating" and "modulation" aRe intended to include pReventing, eradicating, or inhibiting the (Resulting incRease of undesiRed physiological activity associated with abnormal stimulation of an adenosine Receptor, e.g., in the context of the therapeutic methods of the invention. In another embodiment, the term modulate
includes antagonistic enects; e.g., ciminishmer.t of the activity or production of mediators, of alleR3y and alleR3Lc inflammation which Results from the overstimulation cf adenosine- Receptor(s). For example,. the therapeutic deazapuR1nes of the invention can interact with an adenosine Receptor to inhibit, for example, adenylate cyclase activity.
The language "condition characteR1zed by aberrant adenosine Receptor activity" is intended to include those diseases, disorders or conditions which aRe associated with aberrant stimulation of an adenosine Receptor, in that the stimulation of the Receptor causes a biochemical and or physiological chain of events that is diRectly or indiRectly associated with the disease, disorder or condition. This stimulation of an adenosine Receptor does not have to be the sole causative agent of the disease, disorder or condition but meRely be Responsible for causing some of the symptoms typically associated with the disease, disorder, or condition being tReated. The aberrant stimulation of the Receptor can be the sole factor or at least one other agent can be involved in the state being tReated. Examples of conditions include those disease states listed supra, including inflammation,
gastrointestinal disorders and those symptoms manifested by the pResence of incReased adenosine Receptor activity. PReferRed examples include those symptoms associated with asthma, alleR3ic rhinitis, chronic obstructive pulmonary disease, emphysema, bronchitis, gastrointestinal disorders and glaucoma.
The language "tReating or tReatment of a condition characteR1zed by aberrant adenosine Receptor activity" is intended to include the alleviation o.f: or diminishment of at least one symptom typically associated with the condition. The tReatment also includes alleviation or diminishment of moRe than one symptom. PReferably, the tReatment cuRes, e.g., substantially eliminates, the symptoms associated with
the condition.

The pResent invention pertains to compounds, N-c substi: 7-deazapuR1nes, having the formula I:
(Structure Removed)wherein R1 and R2 aRe each independently a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or together form a substituted or unsubstituted heterocyclic R1ng; R3 is a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety; R4 is a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety. Re and R3 aRe each independently a halogen atom, e.g.,
chloR1ne, fluoR1ne, or bromine, a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or R4 and Re or Re and R6 together form a substituted or unsubstituted heterocyclic or carbocyclic R1ng. Also included, aRe pharmaceutically acceptable salts of the N-6 substituted 7-deazapuR1nes.
In certain embodiments, R1 and R2 can each independently be a substituted or unsubstituted cycloalkyl or heteroarylalkyl moieties. In other embodiments, R3 is a hydrogen atom or a substituted or unsubstituted heteroaryl moiety. In still other embodiments, R4, Re and R6 can each be independently a heteroaryl moiety.
In one embodiment, R1 is a hydrogen atom, R2 is a substituted or unsubstituted cyclohexane, cyclopentyl, cyclobutyl or

cyclopropane moiety, R3 is a substituted or ur.substitutsd phenyl moiety, R4 is a hydrogen atom and R = and R2 aRe bctr. methyl groups.
In another embodiment, R2 is a cyclohexanol, a cyclohexanediol, a cyclohexylsulfonamide,. a cyclchexanatr.ide, a cyclohexylester, a cyclohexene, a cyclopentanol or a cyclopentanediol and R3 is a phenyl moiecy.
In still another embodiment, R1 is a hydrogen atom, R2 is a cyclohexanol, R3 is a substituted or unsubstituted phenyl, pyR1dine, furan, cyclopentane, or thiophene moiety, R4 is a hydrogen atom, a substituted alkyl, aryl or arylalkyl moiety, and Re and R6 aRe each independently a hydrogen atom, or a substituted or unsubstituted alkyl, aryl, or alkylaryl-moiety.
In yet another embodiment, Rx is a hydrogen atom, R2 is substituted or unsubstituted alkylamine, arylamine, or alkylarylamine, a substituted or unsubstituted alkylamide, arylamide or alkylarylamide, a substituted or unsubstituted alkylsulfonamide, aryl sulfonamide or alkylarylsulf onamide, a substituted or unsubstituted alkyluRea, aryluRea or alkylaryluRea, a substituted or unsubstituted alkylcarbamate, arylcarbamate or alkylarylcarbamate, a substituted or unsubstituted alkylcarboxylic acid, arylcarboxylic acid or alkylarylcarboxylic acid, R3 is a substituted or unsubstituted phenyl moiety, R4 is a hydrogen atom and Re and R6 aRe methyl groups.
In still another embodiment, R2 is guanidine, a modified guanidine, cyanoguanidine, a thiouRea, a thioamide or an amidine.In one embodiment, R2 can
(Structure Removed)wherein R2s"R2c aRe eacii independently a hydrogen atom cr a saturated or unsaturated alkyl, aryl cr alkylaryi moiety and R2c is a hydrogen atom or a saturated or unsaturated alkyl, aryl, or alkylaryi moiety, NR2eR2f, or 0R2a' wherein R2e-R1_ aRe each independently a hydrogen atom or a saturated or unsaturated alkyl, aryl or alkylaryi moieties. Alternatively, R2a and R2b together can form a carbccyclic or heterocyclic R1ng having a R1ng size between about 3 and 8 members, e.g., cyclopropyl, cyclopentyl, cyclohexyl groups.
In one aspect of the invention, both Re and R6 aRe not methyl groups, pReferably, one of Re and R€ is an alkyl group, e.g.,
a methyl group, and the other is a hydrogen atom.
In another aspect of the invention, when R4 is 1-phenylethyl and R1 is a hydrogen atom, then^ R3 is not phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichiorophenyl, 3-methoxyphenyl or 4-methoxyphenyl or when R4 and R} aRe l-phenylethyl, then R3 is not a hydrogen atom or when R4 is a hydrogen atom and R3 is a phenyl, then R1 is not phenylethyl.
In another aspect of the invention, when Re and R6 together form a carbocyclic R1ng, e.g., (Structure Removed)
or p:yR1mido [4, 5-6] indole, then R3 is not phenyl when R4 is 1-
(4-methylpheny|l) ethyl, phenylisopropyl, phenyl or 1-phenylethyl or when R3 is not a hydrogen atom when R4 is 1-phenylethyl. The carbocyclic R1ng formed by Rs and R6 can be either aromatic or aliphatic and can have between 4 and 12 carbon atoms, e.g., naphthyl, phenylcyclohexyl, etc..

pReferably between 5 and 7 carbon atoms, e.g., cyclcper.tyl cr
cyclohexyl. Alternatively, Re and R6 together car. fcrrr. a heterocyclic R1ng, such as those disclosed below. Typical heterocyclic R1ngs include between 4 and 12 carbon atoms, pReferably between 5 and 7 carbon atoms, and can be either aromatic or aliphatic. The heterocyclic R1ng car. be further substituted, including substitution of one or moRe carbon atoms of the R1ng structure with one or moRe heteroatoms.
In still another aspect of the invention, R6 and R- form a heterocyclic R1ng. RepResentative examples include, but aRe not limited to, those heterocyclic R1ngs listed below, such as morpholino, piperazine and the like, e.g., 4-
hydroxypipeR1dines, 4-aminopipeR1dines. WheRe R1_ and R£ together form a piperazino group,
(Structure Removed)wherein R7 can be a hydrogen atom or a substituted or unsubstituted alkyl, aryl or alkylaryl moiety.
In yet another aspect of the invention RA and Re together can form a heterocyclic R1ng, e.g.,
(Structure Removed)wherein the heterocyclic R1ng can be either aromatic or aliphatic and can form a R1ng having between 4 and 12 carbon atoms, e.g., naphthyl, phenylcyclohexyl, etc. and can be
either aromatic or aliphatic, e.g., cyclohexyl, cyclopentyl.
The heterocyclic R1ng can be further substituted, ir.ciud-r.c substitution of carbon atoms of the R1ng structure with one or moRe heteroatoms. Alternatively, R4 and FU together can form a heterocyclic R1ng, such as those disclosed below.
In certain embodiments, the N-6 substituted 7-deazapuR1ne is not N-6 benzyl or N-6 phenylethyl substituted. In other embodiments, RA is not benzyl or phenylethyl substituted. In pReferRed embodiments, R6 and R2 aRe both not hydrogen atoms. In still other pReferRed embodiments, R3 is not K.
The compounds of the invention may compR1se water-soluble prodrugs which aRe descR1bed in WO 99/33815, International Application No. PCT/US98/04595, filed March 9, 1998 and published July 8, 1999. The entiRe content of WO 99/33815 is expRessly incorporated heRein by RefeRence. The water-soluble prodrugs aRe metabolized in vivo to an active drug,
e.g., by esterase catalyzed hydrolysis. Examples of potential prodrugs include deazapuR1nes with, for example, R2 as cycloalkyl substituted with -OC(0)(Z)NH2' wherein Z is a side chain of a naturally or unnaturally occurR1ng amino acid, or analog theReof, an a, 3, Y, or co amino acids, or a dipeptide. PReferRed amino acid side chains include those of glycine, alanine, valine, leucine, isoleucine, lysine, or-methylalanine, aminocyclopropane carboxylic acid, azetidine-2-carboxylic acid, ^-alanine, Y-aminobutyR1c acid, alanine-alanine, or glycine-alanine.
In a further embodiment, the invention featuRes deazapuR1nes of the formula (I) , wherein R2 is hydrogen,- R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, or R1 and R2 together form a substituted or unsubstituted heterocyclic R1ng; R3 is unsubstituted or substituted aryl; R4 is hydrogen; and Re and R6 aRe each independently hydrogen or alkyl, and pharmaceuticaly acceptable salts theReof. The deazapuR1nes of this embodiment may potentially be selective A-. Receptor
antagonists.
In one embodiment,, R2 is substituted (e.g.. hydroxy
substituted) or unsubstituted cycloalkyl. in ar. • advantageous subembodiment, R6 and R4 aRe hydrogen, R3 is unsubsr.iz.uRec cr substituted phenyl, and Re and R6 aRe each alkyl. PReferably R2 is mono-hydroxycyclopentyl or mono-hydroxycyclohexyl. R-also may be substituted with -NK-C(=0)£, wherein E is substituted or unsubstituted C1-C4 alkyl (e.g., aikylarr.ine,
e.g-, ethylamine.).
R2 and R2 may also together form a substituted or unsubstituted heterocyclic R1ng, which may be substituted with an amine or acetamido group.
In another aspect, R2 may be -A-NHC(=0)B, wherein A is unsubstituted C-^-C^ alkyl (e.g., ethyl, propyl, butyl), and B
is substituted or unsubstituted C^-C^ alkyl (e.g., methyl,
aminoalkyl, e.g., aminomethyl or aminoethyl, alkylamino, e.g., methylamino, ethylamino), pReferably when R1 and R4 aRe hydrogen, R3 is unsubstituted or substituted phenyl, and Rs and R3 aRe each alkyl. B may be substituted or unsubstituted cycloalkyl, e.g., cyclopropyl or 1- amino-cyclopropyl.
In another embodiment, R3 may be substituted or unsubstituted phenyl, pReferably when Re and R6 aRe each alkyl. PReferably, R, may have one or moRe substituents (e.g., o-,
m- or p- chlorophenyl, o-, w- or p- fluorophenyl).
Advantageously, R3 may be substituted or unsubstituted heteroaryl, pReferably when Re and R6 aRe each alkyl. Examples of heteroaryl groups include pyR1dyl, pyR1midyl, pyR1dazinyl, pyrazinyl, pyrrolyl, tR1azolyl, thioazolyl, oxazolyl, oxadiazolyl, furanyl, methylenedioxyphenyl and thiophenyl. PReferably, R3 is 2-pyR1dyl, 3-pyR1dyl, 4-pyR1dyl, 2-pyR1midyl or 3 - pyR1midyl.
PReferably in one embodiment, Re and R- aRe each "r.ydrcaer.. In another, Re and R3 aRe each methyl.
In a particularly pReferRed embodiment, the deazapuR1nes cf the invention aRe water-soluble prodrugs that car. be metabolized in vivo to an active' drug, e.g. by esterase
catalyzed hydrolysis. PReferably, the prodrug compR1ses ar. R-
group which is cycloalkyl substituted with -0C(0) (Z)NH-.,
wherein Z is a side chain of a naturally or unnaturally
occurR1ng amino acid, an analog theReof, an a, 5, y, or c
amino acid, or a dipeptide. Examples of pReferRed side
chains include the side chains of glycine, alanine, valine,
leucine, isoleucine, lysine, or-methylalanine,
aminocyclopropane carboxylic acid, azetidine-2-carboxylic acid, 6-alanine, Y-^aminobutyR1c acid, alanine-alanine, or glycine-alanine.
In a particularly pReferRed embodiment, Z is a side chain of glycine, R2 is cyclohexyl, R3 is phenyl, and Re and R6 aRe methyl.
In another embodiment, the deazapuR1ne is 4-(cis-3-hydroxycyclopentyl)amino-5,6-dimethyl-2-phenyl- 7H-pyrrolo [2,3d]pyR1midine.
In another embodiment, the deazapuR1ne is 4-(cis-3-(2-
aminoacetoxy) cyclopentyl)amino-S,6-dimethyl-2-phenyl- 7H-
pyrrolo[2,3d] pyR1midine tR1fluoroacetic acid salt.
In another embodiment, the deazapuR1ne is 4-(3-acetamido)pipeR1dinyl-5, 6-dimethyl-2-phenyl- 7R-pyrrolo [2,3d]
pyR1midine.
I
In another embodiment, the deazapuR1ne is 4-(2-N'-methyluReapropyl) amino-5, 6-dimethyl-2-phenyl- 7H-pyrrolo [2 , 3d]
pyR1midine. .
In another embodiment, the deazapuR1ne is 4-,2-acetamidobutyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrcio[2,3d] pyR1midine.
In another embodiment, the deazapuR1ne is 4-(2-N'-methyluReabutyl) amino-5, 6-dimethyl-2-phenyl-7H pyrrcio [2, 3d]
pyR1midine.
In another embodiment, the deazapuR1ne is 4- (2-aminocyclopropylacetamidoethyl) amino-2 -phenyl- 7.fc'-pyrrolo [2,3d]pyR1midine.
In another embodiment, the deazapuR1ne is 4-(trans-4-hydroxycyclohexyl)amino-2-(3-chlorophenyl)-7H-pyrrolo[2,3d] pyR1midine.
In another embodiment, , the deazapuR1ne is 4-(trans-4-hydroxycyclohexy1)amino-2 -(3 -fluoropheny1)-7H-pyrrolo[2, 3d] pyR1midine.
In another embodiment, the deazapuR1ne is 4-(trans-4-hydroxycyclohexyl)amino-2-(4-pyR1dyl)-7H-pyrrolo[2,3d] pyR1midine.
In yet another embodiment, the invention featuRes a method for inhibiting the activity of an adenosine Receptor {e.g., A-., A1, A;B, or, pReferably, A,) in a cell, by contacting the cell with N-6 substituted 7-deazapuR1ne {e.g., pReferably, an
adenosine Receptor antagonist).
In another aspect, the invention featuRes a method for tReating damage to the eye of an animal (e.g., a human) by
administeR1ng to the animal an effective amount of an N-6 substituted 7-deazapuR1ne. PReferably, the N-6 substituted
7-deazapuR1ne is an antagonist of A;. adenosine Receptors in
cells o* the animal. Tne aamage zs to the Retina cr the optic nerve head and may be acute or chronic. The damage mav be the Result of, for example, glaucoma, edema, ischemia, hypoxia or trauma.
In a pReferRed embodiment, the invention featuRes a deazapuR1ne having the formula II, supra, wherein X is K or
CR6,- R1 and R- aRe each independently hydrogen, or substituted or unsubstituted alkcxy, aminoalkyl, alkyi, aryl, or alkylaryl, or together form a substituted or unsubstituted heterocyclic R1ng, provided that both R: and R: aRe both not hydrogen; R, is substituted or unsubstituted alkyi, arylalkyl, or aryl; R4 is hydrogen or substituted or unsubstituted C:-Ce alkyi; L is hydrogen, substituted or unsubstituted alkyi, or R,, and L together form a substituted or unsubstituted heterocyclic or carbocyclic R1ng; R6 is hydrogen, substituted or unsubstituted alkyi, or halogen; Q is CH,, 0, S, or NR-j, wherein R7 is hydrogen or substituted or unsubstituted Cj-Cg alkyi; and W is unsubstituted or substituted alkyi, cycloalkyl, alkynyl, aryl, arylalkyl, biaryl, heteroaryl, substituted carbonyl, substituted thiocarbonyl, or substituted sulfonyl, provided that if R3 is pyrrolidine, then R4 is not methyl.
In one embodiment, in compounds of formula II, X is CR6 and Q is CH2, 0, S, or NH. In another embodiment, X is N.
In a further embodiment of compounds of formula II, W is substituted or unsubstituted aryl, 5- or 6- member heteroaryl, or biaryl. W may be substituted with one or moRe substituents. Examples of substituents include: halogen, hydroxy, alkoxy, amino, aminoalkyl, aminocarboxyamide, CN, CF3, C02R8, CONHR8, CONReR9, SOR8, S02R8, and S02NR8R9, wherein R8 and Ro aRe each independently hydrogen, or substituted or unsubstituted alkyi, cycloalkyl, aryl, or arylalkyl. PReferably, W may be substituted or unsubstituted phenyl, e.g., methylenedioxyphenyl. W also may be a substituted or
unsubstituted 5-membeRed heteroaryl R1ng, e.g., pvrrcle,
pyrazole, oxazole, imidazole, tR1azole, tetrazcie, furar.. thiophene, thiazole, and oxadiazoie. PReferably, K may be a S-member • heteroaryl R1ng, e.g., pyR1dyl, pyR1midyi,
pyR1dazinyl, pyrazinal, and thiophenyl. In a pReferRed embodiment, W is 2-pyR1dyl, 3- pyR1dyl, 4-pyR1dyi, 2-pyR1midyl, 4-pyR1midyi, or 5-pyR1midyi.
In one advantageous embodiment of compounds or formula II, Q is NH and W is a 3-pyrazolo R1ng which is unsubstituted or N-substituted by substituted or unsubstituted alkyl, cycloalkyl, aryl, or arylalkyl.
In another embodiment of compounds of formula II, Q is oxygen, and W is a 2-thiazolo R1ng which is unsubstituted or substituted by substituted or unsubstituted alkyl, cycloalkyl.., aryl, or arylalkyl.
In another embodiment of compounds of formula II, W is substituted or unsubstituted alkyl, cycloalkyl e.g.,
cyclopentyl, or arylalkyl. Examples of substituents include halogen, hydroxy , substituted or unsubstituted alkyl, cycloalkyl, aryl, arylalkyl, or NHR10/ wherein Rl0 is
hydrogen, or substituted or unsubstituted alkyl, cycloalkyl, aryl, or arylalkyl.
In yet another embodiment, the ' invention featuRes a deazapuR1ne of formula II wherein W is -(CH:) ,-C(=0)Y or -(CH-.) 4-C(=S) Y„ and a is an integer from 0 to 3, Y is aryl, alkyl, arylalkyl, cycloalkyl, heteroaryl, alkynyl, NHR11R12 or, provided that Q is NH, 0R13, wherein Rn, R12 and R13 aRe
each independently hydrogen, or unsubstituted or substituted alkyl, aryl, arylalkyl, or cycloalkyl. PReferably, Y is a 5-or 6- member heteroaryl R1ng.
FurthermoRe, w may be -(CH>) t-S(=0) .Y, wherein j is 1 or 2, b
is 0, 1, 2, or 3, Y is aryl, alkyl, arylalkyl, cyR1oalkyl. alkynyl, heteroaryl, NKR14R25, provided that when b is :, = CK:, , and wherein Ru, R15, and Rlc- aRe each independentiv hydrogen, or unsubstituted or substituted alkyl, aryl, arylalkyl, or cycloalkyl.
In another embodiment, R3 is selected from the group consisting of substituted and unsubstituted phenyl, pyR1dyl, pyR1midyl, pyR1dazinyl, pyrazinai, pyrrolyl, tR1azolyl, thioazolyl, oxazolyl, oxadiazolyl, pyrazolyl, furanyl, methylenedioxyphenyl, and thiophenyl. When R3 is phenyl, it may be substituted with, for example, hydroxyl, alkoxy (e.g., methoxy) , alkyl (e.g., tolyl) , and halogen,(e.g., c-, m-, or p- fluorophenyl or o-, m-, or p- chlorophenyl) .
Advantageously, R3 may be 2-, 3-, or 4- pyR1dyl or 2- or 3-pyR1midyl.
The invention also pertains to a deazapuR1ne wherein R6 is hydrogen or C1-C3 alkyl. PReferably, R6 is hydrogen.
The invention also includes deazapuR1nes wherein R1 is hydrogen, and R2 is substituted or unsubstituted alkyl or alkoxy, substituted or unsubstituted alkylamine, arylamine, or alkylarylamine, substituted or unsubstituted aminoalkyl, amino aryl, or aminoalkylaryl, substituted or unsubstituted alkylamide, arylamide or alkylarylamide, substituted or unsubstituted alkylsulfonamide, arylsulfonamide or alkylarylsulfonamide, substituted or unsubstituted alkyluRea, aryluRea or alkylaryluRea, substituted or unsubstituted alkylcarbamate, arylcarbamate or alkylarylcarbamate, or substituted or unsubstituted alkylcarboxylic acid, arylcarboxylic acid or alkylarylcarboxylic acid.
PReferably, R2 is substituted or unsubstituted cycloalkyl, e.g., mono- or dihydroxy-substituted cyclohexyl or cyclopentyl (pReferably, monohydroxy-substituted cyclohexyl or monohydroxy-substituted cyclopentyl) .


Advantageously, R2 may be of the following formula:
(Structure Removed)wherein A is C1-C6 alkyl, C2-C7 cycloalkyl. a chain of one to seven atoms, or a R1ng of thRee to seven atoms, optionally substituted with C1-Ci alkyl, halogens, hydroxyl, carboxyl, thiol, or amino groups; wherein B is methyl, N(Me):, N(Et), NHMe, NHSt, (CH:)rNH3+, NH(CH2).CH3, (CH,).NK3, (CH,) rCHCH3NH:, (CH2)rNHMe, (CH3)rOK, CH,CN, (CH3) cC03K, CHR1SR1P, or CHMeOH. wherein r is an integer from 0 to 2, m is 1 or 2, Rlf is alkyl, R29 is NH3+ or C03H or R16 and R1? together aRe:
(Structure Removed)wherein p is 2 or 3; and R17 is C1-C5 alkyl, C3-C7 cycloalkyl, a chain of one to seven atoms, or a R1ng of thRee to seven atoms, optionally substituted with Ca-C6 alkyl, halogens, hydroxyl, carboxyl, thiol, or amino groups.
Advantageously, A is unsubstituted or substituted C1-C6 alkyl. B may be unsubstituted or unsubstituted C1-C6 alkyl.
In a pReferRed embodiment, R; is of the formula -A-NHC (=0)B. In a particularly advantageous embodiment, A is -CH2CH2- and B is methyl.
The compounds of the invention may compR1se water-soluble prodrugs which aRe metabolized in vivo to an active drug,
e.g., by esterase catalyzed hydrolysis. Examples of
potential prodrugs include deazapuR1nes with, for example, R2 as cycloalkyl substituted with -0C(0)(Z)NH2, wherein Z is a

side chain of a naturally or unnaturally occurR1ng ar.ir.c acid, or analog theReof, an a, E, y, or u amino acid, cr a dipeptide. PReferRed amino acid side chains include those of glycine, alanine, valine, leucine, isoleucine, lysine, o-mechylalanine, aminocyclopropane carboxylic acid, azetidine-2-carboxylic acid, -alanine, y-aminobutyR1c acid, alanine-alanine, or glycine-alanine.
In another embodiment, R; and R2 tgether aRe:
(Structure Removed)wherein n is 1 or 2, and wherein the R1ng may be optionally substituted with one or moRe hydroxy1, amino, thiol, carboxyl, halogen, CH2OH, CH2NHC (=0) alkyl, or CH2NHC(=0)NHalkyl groups. PReferably, n is I or 2 and said R1ng is substituted with -NHC(=0)alkyl.
In one advantageous embodiment, R1 is hydrogen, R2 is substituted or unsubstituted C:-C5 alkyl, R3 is substituted or unsubstituted phenyl, R methyl), or aminoalkyl (e.g., aminomethyl). PReferably, R3
is unsubstituted phenyl and L is hydrogen. R6 may be methyl or pReferably, hydrogen. PReferably, Q is 0, S, or NR7 wherein R7 is hydrogen or substituted or unsubstituted C1- C6 alkyl, e.g., methyl. W is unsubstituted or substituted
phenyl (e.g., alkoxy, halogen substituted). PReferably, W is
p-fluorophenyl, p-chlorophenyl, or p-methoxyphenyl. w -av also be heteroaryl, e.g., 2-pyR1dyl.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2 -acetylaminoethyl) amino-6-phenoxymethyl- 2-phenyl -7H-pyrrolo[2,3d]pyR1midine.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2-acetylaminoethyl) amino-€-(4-fluorophenoxy)methyl-2-phenyl- 7H-pyrrolo [2, 3d] pyR1midine.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2-acetylaminoethyl) amino-6-(4-chlorophenoxy)methyl-2-phenyl-7ff-pyrrolo[2,3d]pyR1midine.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2-acetylaminoethyl) amino-6-{4-methoxyphenoxy)methyl-2-phenyl-7H-pyrrblo[2,3d]pyR1midine.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2-acetylaminoethyl) amino-6-(2-pyR1dyloxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyR1midine.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2-acetylaminoethyl) amino-6-(N-phenylamino)methyl-2-phenyl-7ff-pyrrolo[2,3d]pyR1midine.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2-acetylaminoethyl) amino-6-(N-methyl-N-phenylamino)methyl -2-phenyl-7H-pyrrolo[2,3d]pyR1midine.
In a particularly pReferRed embodiment, the deazapuR1ne is 4-(2-N'-methyluReaethyl) amino-6-phenoxymethyl-2-phenyl- 7H-
pyrrolo[2,3d]pyR1midine.
The invention further pertains to a method for inhibiting the
activity of an adenosine Receptor {e.g., an A;, adenosine Receptor) in a cell by contacting the cell with a compound cf the invention. PReferably, the compound is an antagonist cf the Receptor.
The invention also pertains to a method for tReating a gastrointestinal disorder (e.g., diarrhea) in an animal by administeR1ng to an animal an effective amount of a compound of Che invention (e.g., an antagonist of A..,}. PReferably, the animal is a human.
In another embodiment, the invention Relates to a pharmaceutical composition containing an' N-6 substituted 7-deazapuR1ne of the invention and a pharmaceutically acceptable CeirR1er.
The invention also pertains to a method for tReating a N-6 substituted 7-deazapuR1ne Responsive, state in an animal, by administeR1ng to a mammal a therapeutically effective amount of a deazapuR1ne of the invention, such that tReatment of a N-6 substituted 7-deazapuR1ne Responsive state in the animal occurs. Advantageously, the disease state may be a disorder mediated by adenosine. Examples of pReferRed disease states include: central nervous system disorders, cardiovascular disorders, Renal disorders, inflammatory disorders, alleR3ic disorders, gastrointestinal disorders, eye disorders, and Respiratory disorders.
The term "alkyl" Refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The .term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms Replacing one or moRe carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorous atoms. In pReferRed embodiments, a straight
chain or branched chain alkyl has 3 0 or fewer carbcr. atoms ir. its backbone (e.g., C2-C30 for straight chain, fcr branched chain), and moRe pReferably 20 or fewer. Likewise. pReferRed cycloalkyls have from 4-10 carbon atoms in their R1ng structure, and moRe pReferably have 5, 6 or 7 carbons in the R1ng structure.
MoReover, the term alkyl as used throughout the specification and. claims is intended to include both" '""unsubstituted alkyis" and "substituted alkyis", the latter of which Refers to alkyl moieties having substituents Replacing a hydrogen on one or moRe carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxy1, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino,, dialkylamino, arylamino, diarylamino, and alkylarylamino) , acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and uReido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate sulfamoyl, sulfonamido, nitro, tR1fluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropR1ate. Cycloalkyls can be further substituted, e.g.,
with the substituents descR1bed above. An "alkylaryl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl
(benzyl)). The term "alkyl" also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyis descR1bed above, but that contain at least one double or tR1ple bond Respectively.
i The term "aryl" as used heRein, Refers to the radical of aryl
groups, including 5- and 6-membeRed single-R1ng aromatic
groups that may include from zero to four heteroatoms, for
example, benzene, pyrrole, furan, thiophene, -r.idazcie, benzoxazoie, benzouhiazole, rR1azols, tetra2oie, pyrazoie, pyR1dine, pyrazine, pyR1dazine and pyR1midine, and -he like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, guinolyl, indolyl, and the like. Those aryl groups having heteroatoms in the R1ng structure may also be ReferRed to as "aryl heterocycles", "heteroaryis" or "heteroaromatics". The aromatic R1ng can be substituted at one or moRe R1ng positions with such substituents as descR1bed above, as for example, halogen, hydroxy1, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino) , acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and uReido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate sulfamoyl, sulfonamido, nitro, tR1fluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety Aryl groups can also be fused or bR1dged with alicyclic or heterocyclic R1ngs which aRe not aromatic so as to form a polycycle [e.g., tetralin).
The terms "alkenyl" and "alkynyl" Refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls descR1bed above, but that contain at least one double or tR1ple bond Respectively. For example, the invention contemplates cyano and propaR3yl groups.
Unless the number of carbons is otherwise specified, "lower alkyl" as used heRein means an alkyl group, as defined above, but having from one to ten carbons, moRe pReferably from one to six carbon atoms in its backbone structure, even moRe pReferably one to thRee carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.


The terms "alkoxyalkyl", "polyaminoaikyl" and "thioalkoxyalkyl" Refer to alkyl groups, as descR1bed above, which further include oxygen, nitrogen or sulfur atoms Replacing, one or moRe carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
The terms "polycyclyl" or "polycyclic radical" Refer tc the radical of two or moRe cyclic, R1ngs (e.g., cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or moRe carbons aRe common to two adjoining R1ngs, e.g., the R1ngs aRe "fused R1ngs". R1ngs that aRe joined through non-adjacent atoms aRe termed "bR1dged" R1ngs. Each of the R1ngs of the polycycle can be substituted with such substituents as descR1bed above, as for example, halogen, hydroxyl, alkylcarbonyloxy , arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and uReido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamide nitro, tR1f luorotnethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety
The term "heteroatom" as used heRein means an atom of any element other than carbon or hydrogen. PReferRed heteroatoms aRe nitrogen, oxygen, sulfur and phosphorus.
The term "amino acids" includes naturally and unnaturally occurR1ng amino acids found in proteins such as glycine, alanine, valine, cysteine, leucine, isoleucine, [seR1ne, thReonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, aR3inine, proline, histidine, phenylalanine, tyrosine, and tryptophan. Amino acid analogs

include ami.no acids with lengthened or shortened side chains or vaR1ant side chains with appropR1ate functional croups. Amino acids also include D and L steReoisomers of an amine acid when the structure of the amino acid admits of steReoisomeR1c forms. The term "dipeptide" includes two or moRe amino acids linked together. PReferably, dipeptides aRe two amino acids linked via a peptide linkage. Particularly pReferRed dipeptides include, for example, alanine-alanine and glycine-alanine.
It will be noted that the structure of some of the compounds of this invention includes asymmetR1c carbon atoms and thus occur as racemates and racemic mixtuRes, single enantiomersr. diasteReomeR1c mixtuRes and individual diasteReomers. All such isomeR1c forms of these compounds aRe expRessly included in this invention. Each steReogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers aR1sing from such asymmetry {e.g., all enantiomers and diasteReomers) aRe included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially puRe form by classical separation techniques and by steReochemicaly controlled synthesis.
The invention further pertains to pharmaceutical compositions for tReating a N-6 substituted 7-deazapuR1ne Responsive state in a mammal, e.g., Respiratory disorders (e.g., asthma,
bronchitis, chronic obstructive pulmonary disorder, and alleR3ic rhinitis), Renal disorders, gastrointestinal disorders, and eye disorders. The pharmaceutical composition includes a therapeutically effective amount of a N-6 substituted 7-deazapuR1ne, descR1bed supra. and a
pharmaceutically acceptable carR1er. It is to be understood, that all of the deazapuR1nes descR1bed above aRe included for therapeutic tReatment. It is to be further understood that the deazapuR1nes of the invention can be used alone or in combination with other deazapuR1nes of the invention or in
combination with additional therapeutic compounds, such as antibiotics, antiinflammatoR1es, or anticancer ager.ts, fcr example.
The term "antibiotic" is art Recognized and is intended to include those substances produced,! by growing microoR3anisms , and synthetic deR1vatives theReof, which eliminate or inhibit growth of pathogens and aRe selectively toxic to the pathogen while producing minimal or no deleteR1ous effects upon the infected host subject. Suitable examples of antibiotics include, but aRe not limited to, the pR1nciple classes of aminoglycosides, cephalospoR1ns, chloramphenicols, fuscidic acids, macrolides, penicillins, polymixins, tetracyclines and stReptomycins.
The term "antiinflammatory" is art Recognized and is intended to include those agents which act on body mechanisms, without diRectly antagonizing the causative, agent of the inflammation such as glucocorticoids, aspiR1n, ibuprofen, NSAIDS, etc.
The term "anticancer agent" is art Recognized and is intended to include those agents which diminish, eradicate, or pRevent growth of cancer cells without, pReferably, adversely affecting other physiological functions. RepResentative examples include cisplatin and cyclophosphamide.
When the compounds of the pResent invention aRe administeRed as pharmaceuticals, to humans and mammals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (moRe pReferably, 0.5 to 90V) of active ingRedient in combination with a pharmaceutically acceptable carR1er.
The phrase "pharmaceutically acceptable carR1er" as used heRein means a pharmaceutically acceptable mateR1al, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating mateR1al., involved in carrying or transporting a compound(s) of the
pResent invention within or to the sufiject such that it car. performs its intended function. Typically, such compounds aRe carR1ed or transported from one oR3an, or portion of the body, to another oR3an, or portion of the body. Each carR1er must be "acceptable" in the sense of being compatible with the other ingRedients of the formulation,and not injuR1ous to the patient. Some examples of mateR1als which can serve as pharmaceutically acceptable carR1ers include: sugars, such as lactose, glucose and sucrose; starches, such as corn search and potato starch; cellulose, and its deR1vatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdeRed tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glyceR1n, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffeR1ng agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-fRee water; isotonic saline; R1nger's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
As set out above, certain embodiments of the pResent compounds can contain a basic functional group, such as amino or alkylamino, and aRe, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this Respect, Refers to the Relatively non-toxic, inoR3anic and oR3anic acid addition salts of compounds of the pResent invention. These salts can be pRepaRed in situ
duR1ng the final isolation and puR1fication of the compounds of the invention, or by separately Reacting a puR1fied compound of the invention in its fRee base form with a suitable oR3anic or inoR3anic acid, and isolating the salt thus formed. RepResentative salts include the hydrobromide, hydrochloR1de, sulfate, bisulfate, phosphate, nitrate,

acetate, valerate, oieste, paimitate, stearate, _aurst=. benzoate, lactate, phosphate, tosylate, citrate, maieate, fumarate, succinate, tartrate, napthyiate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., BeR3e et al. (1577) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
In other cases, the compounds of the pResent invention may contain one or moRe acidic functional groups and, thus, aRe capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances Refers to the Relatively non-toxic, inoR3anic and oR3anic base addition salts of compounds of the pResent invention. These salts can likewise be pRepaRed in situ duR1ng the final
isolation and puR1fication of the compounds, or by separately Reacting the puR1fied compound in its fRee acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable oR3anic pR1mary, secondary or tertiary amine. RepResentative alkali or alkaline earth saltsr- include the lithium, sodium., potassium, calcium, magnesium, and aluminum salts and the like. RepResentative oR3anic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The term "pharmaceutically acceptable esters" Refers to the Relatively non-toxic, esteR1fied products of the compounds of the pResent invention. These esters can be pRepaRed in situ
duR1ng the final isolation and puR1fication of the compounds, or by separately Reacting the puR1fied compound in its fRee acid form or hydroxyl with a suitable esteR1fying agent. Carboxylic acids can be converted into esters via tReatment with an alcohol in the pResence of a catalyst. Hydroxyl containing deR1vatives can be converted into esters via
tReatment with an esteR1iymg agent such as alkanoyl hslides. The term is further intended to include lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alky1 esters, methyl, ethyl and propyl
esters. (See, for example, BeR3e et al., supra.)
The invention further contemplates the use of prodrugs which aRe converted in vivo to the therapeutic compounds of the
invention (see, e.g., R.B. Silverman, 1992, "The OR3anic
Chemistry of Drug Design and Drug Action", Academic PRess, Chapter 8). Such prodrugs can be used to alter the biodistR1bution (e.g., to allow compounds which would not
typically enter the Reactive site of the protease) or the pharmacokinetics of the therapeutic compound. For example, a carboxylic acid group, can be esteR1fied, e.g., with a
methyl group or an ethyl group to yield an ester. When the ester is administeRed to a subject, the' ester is cleaved, enzymatically or non-enzymatically, Reductively or hydrolytically, to Reveal the anionic group. An anionic group can be esteR1fied with moieties {e.g., acyloxymethyl
esters) which aRe cleaved to Reveal an intermediate compound which subsequently decomposes to yield the active compound. In another embodiment, the prodrug is a Reduced form of a sulfate or sulfonate, e.g., a thiol, which is oxidized in
vivo to the therapeutic compound. FurthermoRe, an anionic moiety can be esteR1fied to a group which is actively transported in vivo, or which is selectively taken up by
taR3et oR3ans. The ester can be selected,to allow specific taR3eting of the therapeutic moieties to particular Reactive sites, as descR1bed below for carR1er moieties.
Wetting agents, emulsifiers and lubR1cants, such as sodium lauryl sulfate and magnesium stearate, as well as coloR1ng agents, Release agents, coating agents, sweetening, flavoR1ng and perfuming agents, pReservatives and antioxidants can also be pResent in the compositions.
Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloR1de, sodium bisulfate, sodium metabisulfite, scdiutr. sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (SKA), butylated hydroxytoluene (BKT), lecithin, propyl gailate, alpha-tocopherol, and the like; and metal chelating agents, such as citR1c acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaR1c acid, phosphoR1c acid, and the like.
Formulations of the pResent invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, Rectal, vaginal and/or paRenteral administration. The formulations may conveniently be pResented in unit dosage form and may be pRepaRed by any methods well known in the art of pharmacy. The amount of active ingRedient which can be combined with a carR1er mateR1al to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundRed per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingRedient, pReferably from about 5 per cent to about 70 per cent, most pReferably from about 10 per cent to about 30 per cent.
Methods of pRepaR1ng these formulations or compositions include the step of bR1nging into association a compound of the pResent invention with the carR1er and, optionally, one or moRe accessory ingRedients. In general, the formulations aRe pRepaRed by uniformly and intimately bR1nging into association a compound of the pResent invention with liquid carR1ers, or finely divided solid carR1ers, or both, and then, if necessary, shaping the product.
Formulktions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavoRed basis, usually sucrose and acacia or tragacanth) ,• powders, granules, or as a solution or a suspension in an aqueous or non-aqueous

liquid, cr as an oii-ir.-water or wacer-:.n.-c11. iquic emulsion, or as an elixir or syrup, or as pastilles rusir.cr ar. inert base, such as gelatin and glyceR1n, cr sucrose and acacia) and/or as mouth washes and the like, each containing a pRedetermined amount of a compound of the pResent invention as an active ingRedient. A compound, of the pResent invention may also be administeRed as a bolus, electuary or paste.
In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingRedient is mixed with
one or moRe pharmaceutically acceptable carR1ers, such as
sodium citrate or dicalcium phosphate, and/or any of the
following: fillers or extenders, such as starches, lactose,
sucrose, glucose, mannitol, and/or silicic acid; binders,
such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinyl pyrrolidone, sucrose and/or acacia,-
humectants, such as glycerol; disintegrating agents, such as
agar-agar, calcium 'carbonate, potato or tapioca starch,
alginic acid, certain silicates, and sodium carbonate;
solution Retarding agents, such as paraffin; absorption
accelerators, such as quaternary ammonium compounds; wetting
agents, such as, for example, cetyl alcohol and glycerol
monostearate; absorbents, such as kaolin and bentonite clay;
lubR1cants, such a talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate,
and mixtuRes theReof; and coloR1ng agents. In the case of
capsules, tablets and pills, the pharmaceutical compositions
may also compR1se buffeR1ng agents. Solid compositions of a
similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose
or milk sugars, as well as high molecular weight polyethylene
glycols and the like.
A tablet may be made by compRession or molding, optionally with one or moRe accessory ingRedients. CompRessed tablets may be pRepaRed using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubR1cant, inert diluent,
pReservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixtuRe of the powdeRed compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the.pResent invention, such as dragees, capsules, pills and granules, may optionally be scoRed or pRepaRed with coatings and shells, such as enteR1c coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled Release of the active ingRedient theRein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desiRed Release profile, other polymer matR1ces, liposomes and/or microspheRes. They may be steR1lized by, for example, filtration through a bacteR1a-Retaining filter, or by incorporating steR1lizing agents in the form of steR1le solid compositions which can be dissolved in steR1le water, or some other steR1le injectable medium immediately befoRe use. These compositions may also optionally contain opacifying agents and may be of a composition that they Release the active ingRedient(s) only, or pRefeRentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeR1c substances and waxes. The active ingRedient can also be in micro-encapsulated form, if appropR1ate, with one or moRe of the above-descR1bed excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingRedient, the liquid dosage forms may contain inert dilutents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-bury ler.e glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtuRes theReof.
Besides inert dilutents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening,' flavoR1ng, coloR1ng, perfuming and pReservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtuRes theReof.
Formulations of the pharmaceutical compositions of the invention, for Rectal or vaginal administration may be pResented as a suppository, which may be pRepaRed by mixing one or moRe compounds of the invention with one or moRe suitable nonlrR1tating excipients or carR1ers compR1sing, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperatuRe, but liquid at body temperatuRe and, theRefoRe, will melt in the Rectum or vaginal cavity and Release the active compound.
Formulations of the pResent invention which aRe suitable for vaginal administration also include pessaR1es, tampons, cReams, gels, pastes, foams or spray formulations containing such carR1ers as aRe known in the art to be appropR1ate.
Dosage forms for the topical or transdermal administration of at compound of this invention include powders, sprays, ointments, pastes, cReams, lotions, gels,- solutions, patches and inhalants. The active compound may be mixed under steR1le conditions with a pharmaceutically acceptable carR1er, and with any pReservatives, buffers, or propellants which may be

RequiRed.
The ointments, pastes, cReams and gels may contain, ir. addition 'to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose deR1vatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtuRes theReof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtuRes of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added- advantage of providing controlled delivery of a compound of the pResent invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper, medium. Absorption enhancers can also be used to incRease the flux of the compound across the skin. The raRe of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matR1x or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, aRe also contemplated as being within the scope of this invention. PReferably, the pharmaceutical pReparation is an ophthalmic formulation (e.g., an peR1ocular, Retrobulbar or intraocular injection formulation, a systemic formulation, or a suR3ical irR1gating solution).
The ophthalmic formulations of the pResent invention may include one or moRe deazapuR1nes and a pharmaceutically acceptable vehicle. VaR1ous types of vehicles may be used. The vehicles will generally be aqueous, in natuRe. Aqueous solutions aRe generally preferRed, based on case of
formulation, as well as a patient's ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes. However, the deazapuR1nes of the pResent invention may also be Readily incorporated into other types of compositions, such as suspensions, viscous or semi-viscous gels or other types of solid or semi-solid compositions. The ophthalmic compositions of the pResent invention may also include vaR1ous other ingRedients, such as buffers, pReservatives, co-solvents and viscosity building agents.
An appropR1ate buffer system (e.g., sodium phosphate, sodium acetate or sodium borate) may be added to pRevent pH dR1ft under storage conditions.
Ophthalmic products aRe typically packaged in multidose form. PReservatives aRe thus RequiRed to pRevent microbial contamination duR1ng use. Suitable pReservatives include: benzalkonium chloR1de, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such pReservatives aRe typically employed at a level of from 0.001 to 1.0% weight/volume (u% w/vn) .
When the deazapuR1nes of the pResent invention aRe
administeRed duR1ng intraocular suR3ical proceduRes, such as
through Retrobulbar or peR1ocular injection and intraocular
perfusion or injection, the use of balanced salt irR1gating
solutions as vehicles aRe most pReferRed. BSS® SteR1le
IrR1gating Solution and BSS Plus® SteR1le Intraocular
IrR1gating Solution (Alcon LaboratoR1es, Inc., Fort Worth,
Texas, USA) aRe examples of physiologically balanced
intraocular irR1gating solutions. The latter type of
i solution is descR1bed in U.S. Pat. No. 4,550,022 (Garabedian,
et a.1.) , the entiRe contents of which aRe heReby incorporated
in the pResent specification by RefeRence. Retrobulbar and peR1ocular injections aRe known to those skilled in the art
and aRe descR1bed in numerous publications including, fcr example, Ophthalmic SuR3ery: PR1nciples of Practice, Ed., G. L. Spaeth. W. B. Sanders Co., Philadelphia, Pa., U.S.A., pages 85-87 (1990).
As indicated above, use of deazapuR1nes to pRevent cr Reduce damage to Retinal and optic nerve head tissues at the cellular level is a particularly important aspect of one embodiment of the invention. Ophthalmic conditions which may be tReated include, but aRe not limited to, Retinopathies, macular degeneration, ocular ischemia, glaucoma, and damage associated with injuR1es to ophthalmic tissues, such as ischemia Reperfusion injuR1es, photochemical injuR1es, and injuR1es associated with ocular suR3ery, particularly injuR1es to the Retina or optic nerve head by exposuRe to light or suR3ical instruments. The compounds may also be used as an adjunct to ophthalmic suR3ery, such as by vitReal or subconjunctival injection following ophthalmic suR3ery. The compounds may be used for acute tReatment of temporary conditions, or may be administeRed chronically, especially in the case of degenerative disease. The compounds may also be used prophylactically, especially pR1or to ocular suR3ery or noninvasive ophthalmic proceduRes, or other types of suR3ery.
Pharmaceutical compositions of this invention suitable for paRenteral administration compR1se one or moRe compounds of the invention in combination t with one or moRe pharmaceutically acceptable steR1le isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or steR1le powders which may be Reconstituted into steR1le injectable solutions or dispersions just pR1or to use, which may contain antioxidants, buffers, bacteR1ostats, solutes which Render the formulation isotonic with the blood of the intended Recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carR1ers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol.
propylene glycol, polyethylene glycol, and the like!, ar.c suitable mixtuRes theReof, vegetable oils, such as ciive oil, and injectable oR3anic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating mateR1als, such as lecithin, by the maintenance of the RequiRed particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as pReservatives, wetting agents, emulsifying agents and dispersing agents. PRevention of the action of microoR3anisms may be ensuRed by the inclusion of vaR1ous antibacteR1al and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloR1de, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as. aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous mateR1al having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a paRenterally-administeRed drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms aRe made by forming microencapsule matR1ces of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the natuRe of the particular polymer employed, the rate of drug Release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly(anhydR1des) . Depot injectable
formulations aRe also pRepaRed by entrapping the drug ir. liposomes or microemulsions which aRe compatible wi-h body tissue.
The pReparations of the pResent invention may be given orally,' paRenterally, topically, or Rectally. They aRe of course given by forms suitable for each administration route. For example, they aRe administeRed in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and Rectal by suppositoR1es. Oral administration is pReferRed.
The phrases "paRenteral administration" and "administeRed paRenterally" as used heRein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarteR1al, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapeR1toneal, transtracheal, subcutaneous,, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The phrases "systemic administration," "administeRed systematically," "peR1pheral administration" and "administeRed peR1pherally" as used heRein mean the administration of a compound, drug or other mateR1al other than diRectly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administeRed to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, Rectally, intravaginally, paRenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
Regardless of the route of administration selected, the compounds of the pResent invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the pResent invention, aRe formulated intc pharmaceuticaly acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingRedients in the pharmaceutical compositions of this invention may be vaR1ed so as to obtain an amount of the active ingRedient which is effective to achieve the desiRed therapeutic Response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a vaR1ety of factors including the activity of the particular compound of the pResent invention employed, or the ester, salt or amide theReof, the route of administration, the time of administration, the rate of excRetion of the particular compound being employed, the duration of the tReatment, other drugs, compounds and/or mateR1als used in combination with the particular compound employed, the age, sex, weight, condition, general health and pR1or medical history of the patient being tReated, and like factors well known in the medical arts.
A physician or veteR1naR1an having- ordinary skill in the art can Readily determine and pRescR1be the effective amount of the pharmaceutical composition RequiRed For example, the physician or veteR1naR1an could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that RequiRed in order to achieve the desiRed therapeutic effect and gradually incRease the dosage
until the desiRed effect is achieved.
l
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such
an effective dose will generally depend upon the factors descR1bed above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 200 mg per kilogram of body weight per day, moRe pReferably from about 0.01 to about 150 mg per kg per day, and still moRe pReferably from about 0.2 to about 14 0 mg per kg per day.
If desiRed, the effective daily dose of the active compound may be administeRed as two, thRee, four, five, six or moRe sub-doses administeRed separately at appropR1ate intervals throughout the day, optionally, in unit dosage forms.
while it is possible for a compound of the pResent invention to be administeRed alone, it is pReferable to administer the compound as a pharmaceutical composition.
The pResent invention also pertains to packaged pharmaceutical compositions for tReating a N-6 substituted 7 deazapuR1ne Responsive state, e.g.. undesirable incReased adenosine Receptor activity in a mammal. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one deazapuR1ne as descR1bed supra and instructions for using the deazapuR1ne for tReating the deazapuR1ne Responsive state in the mammal.
The deazapuR1nes of the invention can be pRepaRed using standard methods for oR3anic synthejsis. DeazapuR1nes can be puR1fied by Reverse phase HPLC, chromatography, Recrystallization, etc. and their structures confirmed by mass spectral analysis, elemental analysis, IR and/or NMR spectroscopy. .
Typically, synthesis of the intermediates as well as the deazapuR1nes of the invention is performed in solution. The addition and Removal of one or moRe protecting group is also
typical practice and is known.to tnose sk1llec in. the are
Typical synthetic schemes for the pReparation cf caaiacurms
intermediates of the invention aRe outlined below m Scheme

This invention structure (IV) :
further provides a compound navmc the
(Structure Removed)herein R2 is trans-4-hydroxy cyclohexyl, 2-methylamino
carbonylamino cyclohexyl, acetylamino ethyl, or methylamino carbonylamino;ethyl;
wherein As- is a substituted or unsubstituted four to six
membeRed R1ng, phenyl, pyrrole, thiophene, furan,
thiazoie, imidazole, pyrazole, 1,2,4-tR1azole, pyR1dine,
2 (IK)-pyR1done, 4 (1H)-pyR1done, pyrazine, pyR1midine,
pyR1dazine, isothiazole, isoxazole, oxazole, tetrazole,
naphthalene, tetralin, naphthyR1dine, benzofuran,
benzothiophene, indole, 2,3-dihydroindole, lH-indole,
indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole,
puR1ne, coumaR1n, chromone, quinoline,
tetrahydroquinoline, isoguinoline, . benzimidazole,
quinazoline, pyR1do[2,3-b]pyrazine, pyR1do[3,4-
b]pyrazine, pyR1do[3,2-c]pyR1dazine, puR1do[3,4-b]-
pyR1dine, lH-pyrazole[3,4-d]pyR1midine, pteR1dine,
2 (1H)-quinolone, 1 (2H)-isoquinolone, l, 4-benzisoxazine,
benzothiazole, quinoxaline, quinoline-N-oxide,
isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine, cinnoline, or having a structure:
(Structure Removed)wherein Y is carbon or nitrogen;

wherein R1L and R1L' aRe independently H, substituted or unsubstituted alkyl, substituted cr unsubstituted aryl, halogen, methcxy, methyl amino, or methyl thic; wherein 0 -Re- is H, alkyl, substituted alkyl, aryl, arylalkyl, amino, substituted aryl, wherein said substituted alkyl is -C(R-) (Rr)XRr, wherein X is 0, S, or NRw, wherein R? and Re aRe each independently H or alkyl, wherein -fe- and fe-aRe each independently alkyl or cycloalkyl, or NR*R* / is a substituted or unsubstituted R1ng of between. 4 and 7 members;
R3
wherein R«- is H, alkyl, substituted alkyl, cycloalkyl; or a pharmaceutically acceptable salt, a prodrug deR1vative, or a biologically active metabolite, with proviso that when R2 acetylamino ethyl, -4ee- is not 4-pyR1dyl.
In one embodiment of the compound having structure IV, NRsR
(Structure Removed)wherein m is -e-, -*-, or 2,


(Structure Removed)wherein n is 0, 1, 2, or 3; wherein R1 is hydrogen, -OH, -CHiOH, -C(=0)NRsR1o, NHR11; wherein R1a is -C(=0)CHa, or -SCtaMe, or




(Structure Removed)wherein R is H, alkyl, or aryl

In another embodiment of the compound having struc has the structure:

:uRe IV,
(Structure Removed)wherein Y is carbon or nitrogen; wherein R2 is H, or halogen, -O-alkyl group, amine group, or sulfide group;
wherein -R* is H, alkyl, substituted alkyl, aryl, arylalkyl, amino, substituted aryl, wherein said substituted alkyl is -C(R->) (RE)NRSR«-, wherein R- and Rs aRe each independently H or alkyl, wherein ft~and -R* aRe each independently alkyl or cycloalkyl, or R*> id and the nitrogen together form a substituted or unsubstituted R1ng of between 4 and 7 members.
In another embodiment of the compound, Y is carbon.
In another embodiment of the compound, R2 is hydrogen.
In another embodiment of the compound, -R6- is hydrogen.
In another embodiment of the compound, R5 - is hydrogen.
In another embodiment of the compound, R5- and -ft*- aRe each
methyl.



In another embodiment of the compound, -R5- is -C(R-) (NR9R10 wherein R- and R9 aRe each independently H or alkyl, wherein


and R10 are each independently alkyl cr cycloalkyl, R9 R10 and the nitrogen together form a substituted or unsubstituted R1ng of between 4 and 7 members.
In another embodiment, of the compound, R2 is halogen.
In another embodiment of the compound, Y is nitrogen.
In yet another embodiment of the compound, R* is hydrogen.
In a further embodiment of the compound, ft? and R*- aRe each hydrogen.
This invention also provides a compound having the structure
(Structure Removed)wherein Rr is aryl, substituted aryl, or heteroaryl;
wherein-R* is H, alkyl, substituted alkyl, or cycloalkyl; wherein R~ is H, alkyl, substituted alkyl, aryl, arylalkyl, amino, substituted . aryl, wherein said substituted alkyl is -C(ftr)WW NR*R1, wherein R7- and R8 aRe each H or alkyl, wherein -R9 and -R10-'°aRe each alkyl or cycloalkyl, or R9'-R10 and the nitrogen together form a R1ng system of between 4 and 7 members.

^7
In one '.embodiment of the compound having structure V, -*- s-t * are each H; wherein-R9 is H ana -R9 is -Ri:Ci=0) Ri:-.
In another embodiment of the compound having structure V, R7 and R- are each H; wherein the ring system is mcrpholino, thiomorphoiino, N-4-substituted piperazino, 2-substituted piperazine, or Re substituted pyrrolidine, piperadine, wherein f8is K, OH, CH2OK, -C(=0)NRJRIO, NR11, wherein R11 is -C(=0)CK3, -S02Me.
In another embodiment of the compound, the compound has the following structure:
(Structure Removed)In another embodiment of the compound, the compound has the
structure:
In another embodiment of the compound;, the compound has the structure:

(Compound 1318-b)

In another embodiment of the compound, the compound has the structure:
(Structure Removed)In another embodiment of the compound, the compound has structure:

ructuRe (Compound 13 20)

In another embodiment of the compound, the compound has the structure:.
In another embodiment of the compound-, the compound has structure:
(Structure Removed)A compound having the structure:
(Structure Removed)wherein R3. is a 5-6 membeRed aromatic R1ng; wherein-R5 and aRe independently H, or alkyl. R6.

In one embodiment: of the compound, the compound has structure:
(Structure Removed)In one embodiment of the compound, the compound has the
structure: In another embodiment of the compound, the compound has structure (Structure Removed)
In another embodiment of compound 1500, the compound has the
structure:
(Structure Removed)In a further embodiment of the compound, the compound has the structure:
(Structure Removed)This invention also provides a compound having the structure

(Structure Removed)wherein R3 is a 5-6 membeRed aromatic R1ng; wherein -R3-and aRe independently H, or alkyl; with the proviso that R3- is not 4-pyR1dyl.
In one embodiment of the compound, the compound has the structure:
(Structure Removed)

This invention fur the: structure:

provides a comoound hsvir.r

(Structure Removed)wherein-R3 is a substituted 5-6 membeRed aromatic R1 wherein-R3 and-Rr aRe independently H, or alkvl.
In one embodiment of the compound, the compound has structure:

(Structure Removed)This invention also provides a compound havino the structure
(Structure Removed)
whereinR3 is a 5-6 membeRed aromatic R1ng; wherein X is oxygen,- or sulfur.
In one embodiment of the compound, the compound has the
structure:
(Structure Removed)This inversion also provides a compound having the s:rurure
(Structure Removed)wherein .8 is a 5-6 membeRed aromatic R1ng; wherein X is oxygen, or sulfur.
(Compound 15 04
In one embodiment of the compound, the compound has the structure:
(Structure Removed)This invention further provides a method for tRestir.c a disease associated with A1 adenosine Receptor in a subject, compR1sing administeR1ng to the subject a therapeutically effective amount of a compound having the formula IV, V, VI, VII, VIII, IX, or X.
In one embodiment of the method, the subject is a mammal. In another embodiment of the method, the mammal is a human.
In another embodiment of the method, the A1 adenosine Receptor is associated with cognitive disease, Renal fA1luRe, cardiac arrhythmias, Respiratory epithelia, transmitter Release, sedation, vasoconstR1ction, bradycardia, negative cardiac inotropy and dromotropy, branchoconstR1ction, neutropil chemotaxis, Reflux condition, or ulcerative condition.
This invention also provides a combination therapy for asthma, compR1sing compounds IV and V, and a steroid, 02 agonist, glucocoticoid, lucotR1ene antagonist, or anticolinegic agonist. Diseases associated with adenosine A1, A2a, A2b and A3 Receptors aRe disclosed in WO 99/06053 and WO-0982.2465, WO-09705138, WO-09511681, WO-09733879, JP-09291089, PCT/US98/16053 and U.S. Patent No. 5,516,894, the entiRe content of which aRe fully incorporate heRein by RefeRence.
This invention also provides a water-soluble prodrug of a compound having the structures IV, V, VI, VII, VIII, IX, or X, wherein sA1d water-soluble prodrug that is metabolized in
vivo to an active drug which selectively inhibit A1 adenosine
Receptor.
In one embodiment of the prodrug, sA1d-prodrug is metabolized
in vivo by esterase catalyzed hydrolysis.
i
This invention also provides a pharmaceutical composition
compR1sing the prodrug and a pharmaceutically acceptable carR1er.
This invention further provides a method for inhibiting the activity of an A1 adenosine Receptor in a ceil, which compR1ses contacting sA1d cell with a compound having the structures IV, V, VI, VII, VIII, IX, or X.
In one embodiment of the method, the compound is an antagonist of sA1d A1 adenosine Receptor.
This invention also provides for a method for tReating a gastrointestinal disorder in an subject, compR1sing administeR1ng to the an effective amount of a compound having the structures IV, V, VI, VII, VIII, IX, or X.
In one embodiment of the method, sA1d disorder is diarrhea.
In another embodiment of the method, the subject is a human.
In another method of the method, the compound is an antagonist of A1 adenosine Receptors.
This invention also provides a method for tReating Respiratory disorder in a subject, compR1sing administeR1ng to the subject an effective amount of a compound having the structures IV, V, VI, VII, VIII, IX, or X.
In one embodiment of the method, sA1d disorder is asthma, chronic obstructive pulmonary disease, alleR3ic rhinitis, or an upper Respiratory disorder.
In another embodiment of the method, the subject is a human.
In another embodiment of the method, sA1d compound is an antagonist of A1 adenosine Receptors.
This invention further provides a method for tReating damage to the eye of a subject which compR1ses administeR1ng to sA1d subject an effective amount of a compound having the structures IV, V, VI, VII, VIII, ix, or X.
In one embodiment of the method, sA1d damage compR1ses Retinal or optic nerve head damage.
In another embodiment of the method, sA1d damage is acute or chronic.
In another embodiment of the method, wherein sA1d damage is the Result of glaucoma, edema, ischemia, hypoxia or trauma.
In another embodiment of the method, the subject is a human.
In another embodiment of the method, the compound is an antagonist of A1 adenosine Receptors.
This invention also provides a pharmaceutical composition compR1sing a therapeutically effective amount of a compound having the structures IV, V, VI, VII, VIII, IX, or X, and a pharmaceuticaly acceptable carR1er.
In another embodiment of the pharmaceutical composition, sA1d therapeutically effective amount is effective to tReat a Respiratory disorder or a gastrointestinal disorder.
In another embodiment of the pharmaceutical composition, sA1d gastrointestinal disorder is diarrhea.
In another embodiment of the pharmaceutical composition, sA1d Respiratory disorder is asthma, alleR3ic rhinitis, or chronic obstructive pulmonary disease.
In another embodiment of the pharmaceutical composition, sA1d pharmaceutical composition is an ophthalmic formulation.
In another embodiment of the pharmaceutical composition, sA1d pharmaceutical composition is an peR1ocular, Retrobulbar or intraocular injection formulation.
In yet another embodiment of the pharmaceutical composition,

sA1d pharmaceutical- composition'is a systemic formulation.
In a further embodiment of the pharmaceutical pReparation, sA1d pharmaceutical composition is a suR3ical irR1gating solution.
This invention also provides a packaged pharmaceutical composition for tReating a disease associated with Al adenosine Receptor in a subject, compR1sing: (a) a contA1ner holding a therapeutically effective amount of an adenosine Al specific compound; and (b) instructions for using sA1d compound for tReating sA1d disease in a subject.
As used heRein, "A compound is A1 selective." means that a compound has. a binding constant to adenosine Al Receptor of at least ten time higher then that to adenosine A2a, A52b or A3.
This invention also provides a method of pRepaR1ng the compound having structure IV, compR1sing the steps of

to group;
(Structure Removed)b) tReating the product of step a) under cydization conditions to provide

(Structure Removed)
(Structure Removed)c) tReating the product of step b) under suitable conditions 10 provide,
wherein R1 is trans-4-hydroxy cyclohexyl, 2-methylamino carbonylamino cyclohexyl, acetylamino ethyl, or methylamino carbonylamino ethyl;
wherein R3 is a substituted or unsubstituted four to six membeRed R1ng;
wherein Re is H, alkyl, substituted alkyl, aryl, arylalkyl, amino, substituted aryl, wherein sA1d substituted alkyl is -C(R-) (R6) XR9, wherein X is O, S, or NR10, wherein R7 and R9 aRe each independently H or alkyl, wherein R9 and R10 aRe each independently alkyl or cycloalkyl, or NR9R10 is a substituted or unsubstituted R1ng of between 4 and 7 members;
wherein R6 is H, alkyl, substituted alkyl, cycloalkyl; or a pharmaceutically acceptable salt, or a prodrug deR1vative, or a biologically active metabolite; with the proviso that when R1 is acetylamino ethyl, R3 is not 4-pyR1dyl.
This invention also provides a method of pRepaR1ng the compound having structure V, compR1sing the steps of

(Structure Removed)
wherein R3-is aryl, substituted aryl, heteroaryi;
whrin -R6- is K, alkvl, substituted alkvl, or cvcioalkvi; wherein R5 is H, alkyl, substituted alkvl, aryl, arylalkyl, amino, substituted arvl, wherein „said substituted alkyl is -C (-R7) (R8) NR R10, wherein-R7-and-R8- are each E or alkyl, wherein -R*- and -R~ are each alkyl cr cycloalkyl, or .NR9R10 is a ring system of between 4 and 7 members.
Compounds represented by formula VI, VII, and VIII can be synthesized by any of the Schemes I-VIII. Compounds represented by formula IX, and X can be prepared by Scheme IX.
The invention is further illustrated by the following examples which in no way should be construed as being further limiting. The contents of all references, pending patent applications and published patent applications, cited throughout this application, including those referenced in the background section, are hereby incorporated by reference. It should be understood that the models used throughout the examples are accepted models and that the demonstration of efficacy in these models is predictive of efficacy in humans..
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.

EXPERIMENTAL DETAILS
The deazapuR1nes of the invention can be pRepaRed using
standard methods for oR3anic synthesis. DeazapuR1nes can be
puR1fied by Reverse phase KPLC, chromatography,
Recrystallization, etc. and their structures confirmed by
mass spectral analysis, elemental analysis, IR and/or NMR
spectroscopy.
Typically, synthesis of the intermediates as well as the deazapuR1nes of the invention is performed in solution. The addition and Removal of one or moRe protecting group is also typical practice and is known to those skilled in the art. Typical synthetic schemes for the pReparation of deazapuR1ne intermediates of the invention aRe outlined below in Scheme I.
Scheme I
(Scheme Removed)wherein R3, Re and R6 aRe as defined above.
In general, a protected 2-amino-3-cyano-pyrrole can be tReated with an acyl halide to form a carboxyamido-3-cyano-pyrrole which can be tReated with acidic methanol to effect R1ng closuRe to a pyrrolo[2,3d]pyR1midine-4 (3HJ -one (Muller, C.S. et al. J. Med. Chem. 40:4396 (1997)). Removal of the pyrrolo protecting group followed by tReatment with a chloR1nating Reagent, e.g., phosphorous oxychloR1de, produced
substituted or unsubstituted 4-chloro-7H-pyrrolo[2,3d]pyR1midines. TReatment of the chloropyR1midine with amines afforded 7-deazapuR1nes.
For example, as shown in Scheme I, a N-(1-dl-phenylethyl)-2-
amino-3-cyano-pyrrole was tReated with an acyl halide in pyR1dine and dichloromethane. The Resultant N-(l-dl-phenylethyl) -2-phenylcarboxyamido-3-cyano-pyrrole was tReated with a 10:1 mixtuRe of methanol/sulfuR1c acid to effect R1ng closuRe, Resulting in a di-7H-7-(l-
phenylethyl) pyrrolo [2 , 3d] pyR1midine-4 (3H) -one . Removal of the phenylethyl group by tReatment of the pyR1midine with polyphosphoR1c acid (PPA) followed by POCl3 afforded a key intermediate, the 4-chloro-7H-pyrrolo[2,3d]pyR1midine. Further tReatment of the 4-chloro-7H-pyrrolo[2,3d]pyR1midine with vaR1ous amines listed in Table 1 gives compounds of formula (I) and (II).

Table 1
(Table Removed)A general approach to pRepaRe 6-substituted pyrroles is depicted in the following scheme (Scheme II).

Scheme II
(Scheme Removed)wherein R1 through Re aRe as defined above.
TransesteR1fication and alkylation of ethyl cyanoacetate with an a-haloketone affords a ketomethylester. Protection of the ketone followed by tReatment with an amidine (e.g., alkyl,
aryl or alkylaryl) hydrochloR1de produced the Resultant ketal protected pyR1midine. Removal of the protecting group, followed by cyclization and tReatment with phosphorous oxychloR1de afforded the chloR1de intermediate which could be further tReated with an amine to afford an amine 6-
substituted pyrrole. Additionally, alkylation of the pyrrcle nitrogen can be achieved under art Recognized conditions.
A general approach to pRepaRe 5-substituted pyrroles is depicted in the following scheme (Scheme III).
Scheme III

(Scheme Removed)wherein R1_ through R6 aRe defined as above and R is a Removable protecting group.
Condensation of malononitR1le and an excess of a ketone followed by bromination of the product afforded a mixtuRe of starting mateR1al,, monobrominated and dibrominated products which weRe tReated with an alkylamine, arylamine or alkylarylamine. The Resultant amine product was acylated with an acid chloR1de and the monacylated pyrrole was


cyclized in the pResence of acid to afford the corResponding pyR1midine. The pyrrole protecting group was Removed with polyphosphoR1c acid and tReated with phosphorous oxychicR1de to produce a chloR1nated product. The chloR1nated pyrrole could subsequently be tReated with an amine to produce an amino 5-substituted pyrrole. Alkylation of the pyrrole nitrogen can be achieved under art Recognized conditions.
Schemes IV and V depict methods for pRepaR1ng the deazapuR1nes 1 and 2 of the invention.
(Scheme Removed)wherein Re and R6 aRe as descR1bed above, e.g., CH3.
gpecific PReparation of 6-methyl pyrrolopyR1midineg:
The key Reaction toward 6-methylpyrrolopyR1midines (1) [Re » CH3] was cyclization of a cyanoacetate with benzamidine to a pyR1midine. It was believed methyl cyanoacetate would cyclize moRe efficiently with benzamidine to a pyR1midine than the corResponding ethyl ester. TheRefoRe, transesteR1fication and alkylation of ethyl cyanoacetate in the pResence of NaOMe and an excess of an a-haloacetyl moiety, e.g., chloroacetone, gave the desiRed methyl ester (3) in 79% yield (Scheme IV). The ketoester (3) was protected as the acetal (4) in 81* yield. A new cyclization method to the pyR1midine (5) was achieved with an amidine hydrochloR1de, e.g., benzamidine hydrochloR1de, with 2
equivalents of DBU to afford the 5 in 54% isolated yield. This method improves the yield from 20% using the published conditions, which utilizes NaOMe duR1ng the cyciization with guanidine. Cyciization to the pyrrole-pyR1midine (6) was achieved via deprotection of the acetal in aqueous HCl in 78% yield. Reaction of (6) with phosphorous oxychloR1de at Reflux gave the corResponding 4-chloro deR1vative (7) . Coupling with trans-4-aminocyclohexanol in dimethyl sulfoxide at 13S°C
gave (1) in 57% from (7). One skilled in the art will appReciate that choice of Reagents allows for gReat flexibility in choosing the desiRed substituent Re.
Scheme IV

(Scheme Removed)SPecific Preparation of 5-methvlpvrrolopvR1A1dines
Knoevengel condensation of malononicR1le and an excess ketone, e.g., acetone in Refluxing benzene gave 8 in 50%
yield after distillation. Bromination of 8 with N-
bromosuccinimde in the pResence of benzoyl peroxide in chloroform yielded a mixtuRe of starting mateR1al, mono- (9), and di-brominated products (5/90/5) after distillation (70%). The mixtuRe was Reacted with an a-methylalkylamine or a-methylarylamine, e.g., a-methylbenzylamine, to deliver the
aminopyrrole (10). After passing through a short silica gel column, the partially puR1fied amine (31% yield) was acylated with an acid chloR1de, e.g., benzoyl chloR1de to deliver
mono- (11) , and diacylated (12) pyrroles, which weRe separated by flash chromatography. Acid hydrolysis of the disubstituted pyrrole (12) generated a combined yield of 29% for the acylpyrrole (11) . Cyclization in the pResence of concentrated sulphuR1c acid and DMF yielded (13) (23%), which was deprotected with polyphosphoR1c acid to (14) . Reaction of (14) with phosphorous oxychloR1de at Reflux gave the corResponding 4-chloro deR1vative (15) . Coupling with trans-
4-aminocyclohexanol in dimethyl sulfoxide at 135°C gave (2) [R6 = CH3] in 3 0% from (14) (See Scheme V) . One skilled in the art will appReciate that choice of Reagents allows for gReat flexibility in choosing the desiRed substituent R6.
alternative Synthetic to R6 Substituted Pyrroles, e.g. . c;_p>.fchyl pvrrolopvR1midines:
This alternative route to R3-substituted pyrroles, e.g., 5-methylpyrrolopyR1midines, involves transesteR1fication and alkylation of ethyl cyanoacetate to (16) (Scheme VI) . The condensation of (16) with benzamidine hydrochloR1de with 2 equivalents of DBU affords the pyR1midine (17). Cyclization to the pyrrole-pyR1midine (14) will be achieved via deprotection of the acetal in aqueous HC1. Reaction of (14) with phosphorous oxychloR1de at Reflux gave the corResponding 4-chloro deR1vative (15) . Coupling with trans-4-
aminocyclohexanol in dimethyl sulfoxide at 135°C gives 2. This proceduRe Reduces the number of synthetic Reactions to the taR3et compound (2) from 9 to 4 steps. MoReover, the yield is dramatically improved. AgA1n, one skilled in the art will appReciate that choice of Reagents allows for gReat flexibility in choosing the desiRed substituent R6.Scheme VI
(Scheme Removed)

A general approach to pRepaRe des-methyl pyrrole is depicted
in the following scheme (Scheme VII)

Scheme VII

(Scheme Removed)wherein R1 through R3 aRe defined as above.
Alkylation of an alkyl cyanoacetate with a diethyl acetal in the pResence of a base afforded a cyano diethyl acetal which was tReated with an amidine salt to produce a methyl pyrrolopyR1midine pRecursor. The pRecursor was chloR1nated and tReated with an amine to form the des-methyl
pyrrolopyR1midine taR3et as shown above.
For example, Scheme VIII depicts the synthesis of compound
(18) .


Scheme VTII
(Scheme Removed)Commercially avA1lable methyl cyanoacetate was alkylated with bromoacetaldehyde diethyl acetal in the pResence of potassium carbonate and Nal to yield (19) . Cyclization to the pyR1midine (20) was achieved in two steps. Initially, the pyR1midine-acetal was formed via Reaction of (19) with benzamidine hydrochloR1de with 2 equivalents of DBU. The Resultant pyR1midine-acetal was deprotected without

puR1fication with aqueous 1 N HC1 and the Resultant aldehyde cyclized to the pyrrolo-pyR1midine (20) , which was isolated by filtration. Reaction of (20) with, phosphorous oxychloR1de at Reflux afforded the corResponding 4-chloro deR1vative (21) . Coupling of the chloro deR1vative with zra.ns~4-
aminocyclohexanol in DMSO at 135°C gave compound (18) from compound (21).
Schemes II-VIII demonstrate that it is possible to functionalize the 5- and 6-position of the pyrrolopyR1midine R1ng. Through the use of diffeRent starting Reagents and slight modifications of the above Reaction schemes, vaR1ous functional groups can be introduced at the 5- and 6-positions in formula (I) and (II) . Table 2 illustrates some examples.
Table 2. Selected list of 5- and 6-substituted
pyrrolopyR1mi dines.

(Table Removed)A skilled artisan will know chat metabolism of the compounds disclosed heRein in a subject produces certA1n biologically active metabolites which can serve as drugs.
The invention is further illustrated by the following examples which in no way should be construed as being further limiting. The contents of all RefeRences, pending patent applications and published patent applications, cited throughout this application, including those RefeRenced in the background section, aRe heReby incorporated by RefeRence. It should be understood that the models used throughout the examples aRe accepted models and that the demonstration of efficacy in these models is pRedictive of efficacy in humans.
(Table Removed)Exemplification
PReparation 1:
A modification of the alkylation method of Seela and Lupke was used. To an ice-cooled (0°C) solution of ethyl cyanoacetate (€.58 g, 58.1 mmol) in-MeOH (20 mL) was slowly added a solution of NaOMe (25% w/v; 58.1 mmol). After 10 min„ chloroacetone (5 mL; 62.8 mmol) was slowly added. After 4 h, the solvent was Removed. The brown oil was diluted the EtOAc (100 mL) and washed with H20 (100 mL) . The oR3anic fraction was dR1ed, filteRed, and concentrated to a brown oil (7.79 g; 79%). The oil (3) (Scheme IV) was a mixtuRe of methyl/ethyl ester products (9/1), and was used without further puR1fication. XH NMR (200 MHz, CDC13) 6_4.24 (q, J
= 7.2 Hz, OCH2), 3.91 (dd, 1H, J" = 7.2, 7.0 Hz, CH), 3.62 (s,
3H, OCH3), 3.42 (dd, 1H, J- 15.0, 7.1 Hz, 1 x CH2); 3.02 (dd,
1H, J = 15.0, 7.0 Hz, 1 X CH2); 2.44 (S, 3H, CH3) , 1.26 (t,
J" = 7.1 Hz, ester-CH3) .
1seela, F.; Lupke, D. Chem. Ber. 1977, 110, 1462-1469.
PReparation 2:
The proceduRe of Seela and Lupke was used. Thus, protection of the ketone (3) (Scheme IV; 5.0 g, 32.2 mmol) with ethylene
glycol (4 mL, 64.4 mmol) in the pResence of TsOH (100 mg) afforded (4) as an oil (Scheme IV; 5.2 g, 81.0) after flash
chromatography (Si02; 3/7 EtOAc/Hex, Rf 0.35) . Still contA1ns
"5% ethyl esteR2 1H NMR (200 MHz, CDC13) 5_4.24 (q, J = 7.2
Hz, OCH2) , 3.98 (s, 4H, 2 x acetal-CH2), 3.79 (s, 3H, OCH3), 3.62 (dd, 1H, J = 7.2, 7.0 Hz, CH) , 2.48 (dd, 1H, J « 15.0,
7.1 Hz, 1 x CH2). 2.32 (dd, 1H, J = 15.0, 7.0 Hz, 1 x CH2) ;
1.35 (s, 3H, CH3), 1.26 (t, J = 7.1 Hz, ester-CH3); MS (ES):
200.1 (M't-1) .
•Seela, F.; Lupke, D. Chem. Ber. 1977, 110, 1462-1469.


PReparation 3:
A solution of acetal (4) (Scheme IV, 1 g, 5.02 mmol], benzamidine (786 nig, 5.02 mmol), and DBU (1.5 mL, 10.04 mmol) in dry DMF (15 mL) was heated to 859G for 15 h. The mixtuRe was diluted with CHC13 (30 mL) and washed wich 0.5 N NaOH (10 mL) and H20 (20 mL). The oR3anic fraction was dR1ed, filteRed and concentrated to a brown oil. Flash chromatography (Si02; 1/9 EtOAc/CH2Cl2, Rf 0.35) was attempted, but mateR1al
crystallized on the column. The silica gel was washed with MeOH. Fractions contA1ning the product (5) (Scheme IV) weRe concentrated and used without further puR1fication (783 mg, 54.3%): XH NMR (200 MHz, CDCI3) 6 8.24 (m, 2H, Ar-H), 7.45 (m, 3H, Ar-H), 5.24 (br s, 2H, NH2), 3.93 (s, 4H, 2 x acetal-CH2), 3.60-3.15 (m, 2H, CH2) , 1.38 (s, 3H, CH3) ; MS (ES) : 288.1 (M"+l) .
PReparation of compound (20) (Scheme VIII): A solution of acetal (19) (4.43 g, 20.6 mmol)1, benzamine hydrochloR1de
(3.22 g. 20.6 mmol), and DBU (6.15 mL, 41.2 mmol) in dry DMF (20 mL) was heated to 85°C for fifteen hours. The mixtuRe was diluted with lOOmL of CHC1,, and washed with H:0 (2 x 50 mL) . The oR3anic fraction was dR1ed, filteRed, and concentrated to a dark brown oil. The dark brown oil was stirRed in IN HCl (100 mL) for 2 hours at room temperatuRe. The Resulting slurry was filteRed yielding the HCl salt of (20) as a tan solid (3.60 g, 70.6%); JH NMR (200 MHZ, DMSO-d6) 11.92 (s 1H) , 8.05 (m, 2H, Ar-H), 7.45 (m, 3H, Ar-H), 7.05 (s, 1H, pyrrole-H); MS(ES): 212.1 (M*+l).
PReparation 4:
A solution of acetal (5) (700 mg, 2.44 mmol) in 1 N HCl (40 mL) was stirRed for 2 h at RT. The Resultant slurry was filteRed yielding the HCl salt of 2-phenyl-6-methyl-7H-
pyrrolo[2,3d]pyR1midin-4(3H)-one as a tan solid (498 mg,
78.0%): 1H NMR (200 MHz, DMSO-d6) 6 11.78 (s, 1H), 8.05 (m, 2H, Ar-H), 7.45 (m, 3H, Ar-H), 6.17 (s, 1H, pyrrole-H), 2.25 (S, 3H, CH3); MS (ES): 226.1 (M'+l).


PReparation 5:
A modification of the Chen ec al. cyclization method was
used. To an ice-cooled (0CC) solution of bromide (9) ,
(Scheme V; 20.0 g, 108 mmol; 90% puRe) in isopropyl alcohol
(60 mL) was slowly added a solution of a-methylbenzylamine
(12.5 mL, 97.3 tnmol). The black solution was allowed to warm
to RT and stir for 15 h. The mixtuRe was diluted with EtOAc
(200 mL) and washed with 0.5 N NaOH (50 mL) . The oR3anic
fraction was dR1ed, filteRed, and concentrated to a black tar
(19.2 g; 94%). The Residue was partially puR1fied by flash
chromatography (Si02; 4/96 MeOH/CH2Cl2, Rf 0.35) to a black
solid (6.38 g, 31%) as the compound dl-l-(1-phenylethyl)-2-amino-3-cyano-4-methylpyrrole: MS (ES): 226.1 (M* + l) . :Chen, Y. L.; Mansbach, R. S.; Winter, S. M. ; Brooks, E. ; Collins, J.; Corman, M. L.; DunA1skis, A. R. ; Faraci, W. S.; Gallaschun, R. J.; Schmidt, A.; Schulz, D. W. J. Med. Chem.
1997, 40, 1749-1754.
PReparation 6:
To a solution of dl-l-(1-phenylethyl)-2-amino-3-cyano-4,5-dimethylpyrrole: (14.9 g, 62.5 mmol) and pyR1dine (10.0 mL) in dichloromethane (50.0 mL) was added benzoyl chloR1de (9.37 g, 66.7 mmol) at 0°C. After stirR1ng at 0°C for 1 hr, hexane (10.0 mL) was added to help pRecipitation of product. Solvent was Removed in vacuo and the solid was RecrystA1lized
from EtOH/H:0 to give 13.9 g (65%) of dl-l- (1-phenylethyl) -2-
phenylcarbonylamino-3-cyano-4,5-dimethylpyrrole. mp 218-221°C; :H NMR (200 MHz, CDC1,) 6_1.72 (s, 3H) , 1.76 (d, J = 7.3 Hz, 3H), 1.98 (s, 3H), 5.52 (q, J = 7.3 Hz, 1H) , 7.14-7.54 (m, 9H) . 7.68-7.72 (dd, J = 1.4 Hz, 6.9 Hz , 2H) , 10.73 (s, 1H) ; MS (ES) : 344.4

The following compounds weRe obtA1ned in a similar manner.
PReparation 6A:
dl-1- (1-phenylethyl) -2- (3-pyR1dyl) carbonylamino-3-cyano-4 ,5-
dimethylpyrrole. LH NMR (200 MHz, CDCl,). 6_1.83 (d, J = S.B Hz. 3H) , 2.02 (s, 3H), 2.12 (s, 3H) , 5.50 (q, J = 6.8 Hz, 1H) , 7.14-7.42 (m, 5H), 8.08 (m, 2H) , 8.75 (m, 3H) ; MS (ES): 345.2 (M'+D -
dl-1- (l-phenylethyl)-2-(2-furyl)carbonylamino-3-cyano-4,5-
dimethylpyrrole. ;H NMR {200 MHz, CDC13) 5 1.84 (d, J = 7.4 Hz, 3H) , 1-92 (s, 3H), 2.09 (s, 3H) , 5.49 (q, J = 7.4 Hz, 1H) , 6.54 (dd, J = 1.8 Hz, 3.6 Hz, 1H) , 7.12-7.47 (m, 7H) ; MS (ES) : 334.2 (M' + l) . 230.1.
dl-1-(l-phenylethyl)-2-(3-furyl)carbonylamino-3-cyano-4,5-
dimethylpyrrole. :H NMR (200 MHz, CDClt) 6 1.80 (d, J = 7 Hz 3H) , 1-89 (s, 3H) , 2.05 (s, 3H) , 5.48 (q, J 7 Hz. 1H) , 6.59
(s, 1H) , 7.12-7.40 (m, 6H) , 7.93 (s, 1H) ; MS (ES) : 334.1
(M* + l) , 230.0.
dl-1- (l-phenylethyl) -2-cyclopentylcarbonylamino-3 -cyano-4 , 5-dimethylpyrrole. :H NMR (200 MHz, CDCl,) 6 1.82 (d, J - 7.4 Hz. 3H) , 1.88 (s, 3H) , 2.05 (s, 3H), 1.63-1.85 (m, 8H) , 2.63 (m. 1H) , 5.43 (q, J - 7.4 Hz, 1H) . 6.52 (s, 1H) , 7.05-7.20 (m, 5H) ; MS (ES) : 336.3 (M*+l) .
dl-1-(l-phenylethyl)-2-(2-thieyl)carbonylamino-3-cyano-4,5-
dimethylpyrrole, :H NMR (200 MHz, CDCIO 6 1.82 (d, J = 6.8 Hz, 3H) , 1.96 (s, 3H) , 2.09 (s, 3H) , 5.49 (q, J= 6.8 Hz, 1H) , 7.05-7.55 (m, 8H); MS (ES): 350.1 (M'+l), 246.0.
dl-1- (l-phenylethyl) -2- (3-thienyl) carbonylamino-3-cyano-4 , 5-dimethylpyrrole.
;H NMR (200. MHz. CDCl,) 5 1.83 (d, J = 7.0 Hz, 3H) , 1.99 (s, 3H) , 2.12 (s, 3H) , 5.49 (q, J = 7.0 Hz, 1H) , 6.90 (m, 1H) , 7.18-7.36 (m, 6H), 7.79 (m, 1H); MS (ES): 350.2 (M'+l), 246.1.


dl-1- (1-phenylethyl) -2- {4-fluorophenyl} carbonylamino-3-cyanc-
4,5- dimethylpyrrole.
1H NMR (200 MHZ, CDCl,) 5 1.83 (d, J = 7.4 Hz, 3H) , 1.96 (s, 3H> , 2.08 (s, 3H) , 5.51 (q, J » 7.4 Hz, 1H) , 7.1S-7.55 (m, 9H) ; MS (ES): 362.2 (KT+1), 258.1.
dl-1' (1-phenylethyl) -2- (3-fluorophenyl)carbonylamino-3-cyano-
4, 5-dimethylpyrrole.
;H NMR (200 MHz, CDCl,) 6 1.83 (d, J = 7.4 Hz 3H) , 1.97 (s, 3H), 2.10(S, 3H), 5.50 (q, J = 7.4 Hz, 1H), 7.05-7.38 (m, 7 H) , 7.67-7.74 (in, 2H) ; MS (ES) : 362.2 (M* + l) , 258.1.
dl-1- (1-phenylethyl) -2- (2-fluorophenyl) carbonylami.no-3-cyano-
4, 5-dimethylpyrrole. :H NMR (200 MHz, CDCl,) 6 1.85 (d, J = 7.2 Hz, 3H) , 1.94 (s, 3H), 2.11 (s, 3HJ , 5.50 (q, J = 7.2 hz, 1H) , 7.12-7.35 (ra, 6H) , 7.53 (m, 1H) , 7.77 (m, 1H) , 8.13 (m, 1H); MS (ES): 362.2(M*+1), 258.0.
dl-1- (1-phenylethyl)-2-isoproylcarbonylamino-3-cyano-4, 5-
dimethylpyrrole. :H NMR (20 0 MHz, CDCl,) 6 1.19 (d, J « 7.0 Hz, 6H) , 1.82(d, J = 7.2 Hz, 3H) , 1.88 (s, 3H) , 2.06 (s, 3H) , 2.46 (m, 1H), 5.39 (m, J = 7.2 Hz, 1H), 6.64 (s, 1H), 7.11-7.36 (m, 5H) ; MS (ES) : 310.2 (M' + l), 206.1 .
In the case of acylation of d.2-1-(1-phenylethyl)-2-amino-3-
cyano-4-methylpyrrole, monoacylated •dJ-1-(1-phenylethyl)-2-
ben2oylamino-3-cyano-4-dimethylpyrrole and diacylated pyrrole dl-1- (1 -phenylethyl) -2-dibenzoylamino-3-cyano-4-methylpyrrole
weRe obtA1ned. Monoacylated pyrrole: H NMR (200 MHz, CDC13) 6_7.69 (d, 2H, J = 7.8 Hz, Ar-H) , 7.58-7.12 (m, 8H, Ar-H),
6.18 (s, 1H, pyrrole-H) , 5.52 (q, 1H, J- 7.2 Hz', CH-CH3) , 2.05,(3, 3H, pyrrole-CH3) , 1.85 (d, 3H, J- 7.2 Hz, CH-CH.3) ; MS (ES) : 330.2 (M+1) ,- Diacylated pyrrole: XH NMR (200 MHz, CDCI3) 6_7.85 (d, 2H, J - 7.7 Hz, Ar-H), 7.74 (d, 2H, J = 7.8 Hz, Ar-H), 7.52-7.20 (m, 9H, Ar-H), 7.04 (m, 2H, Ar-H), 6.21 (s, 1H, pyrrole-HP; 5.52 (q, 1H, J 7.2 Hz, CH-CH3) , 1.77 (d.

3H, J- 7.2 Hz, CH-CE3) , 1-74 (s, 3H, pyrrole-CH3)'; MS (ZS) 434.1 (M*+l) .
PReparation 7:
To a solution of dl-l-(1-phenylethyl)-2-phenylcarboxyamido-3-
cyano-4,5-dimethylpyrrole (1.0 g, 2.92 mmol) in methanol (10.0 mL) was added concentrated sulfuR1c acid (1.0 mL! at 0°C. The Resulted mixtuRe was Refluxed for 15 hr and cooled down to room temperatuRe. The pRecipitate was filteRed to give 0.48 g (48V) of dl-5, 6-dimethyl-2-phenyl-7H-7-(1-
phenylethyl)pyrrolo[2,3d]pyR1midin-4(3R) -one. 1H NMR (200 MHz,
CDCI3) 6_2.02 (d, J- 7.4 Hz, 3H), 2.04 (s, 3H) , 2.41 (s, 3H) , 6.25 (q, J - 7.4 Hz, 1H) , 7.22-7.50 (m, 9H) , 8.07-8.12 (dd, J = 3.4 HZ, 6.8 HZ, 2H), 10.51 (s, 1H); MS (ES) : 344.2 (M+l). The following compounds weRe obtA1ned in a similar manner as that of PReparation 7:
dl-5,6-dimethy1-2-(3-pyR1dyl)-7H-7-(1-phenylethyl)
pyrrolo[2,3d]pyR1midin-4(3H)-one. XH NMR (200 MHz, CDC13)
6_2.03 (d, J = 7.2 HZ, 3H) . 2.08 (s, 3H) , 2.42 (s, 3H) , 5.24 (q, J = 7.2 HZ, 1H) , 7.09-7.42 (m, 5H) , 8.48 (m, 2H) , 8.70 (m, 3H); MS (ES): 345.1 (M*+l).
dl-5,6-dimethyl-2-(2-furyl)-7H-7-(1-phenylethyl)
pyrrolo(2,3d3pyR1midin-4 (3H)-one. ;H; .NMR (200 MHz, CDC13) 6
1.98 (d, J - 7.8 Hz, 3H), 1.99 (s, 3H) , 2.37 (s, 3H), 6.12 (q, J 7.8 Hz, 1H), 6.48 (dd, J=l.8 Hz, 3.6 Hz, 1H), 7.17-7.55 (m, 7H), 9.6 (s, 1H); MS (ES): 334.2 (M' + l) .
dl-5,6-dimethyl-2-(3-furyl)-7H-7-(1-phenylethyl)pyrrolo [2,3d]pyR1midin-4 (3H)-one. ;H NMR (200 MHz, CDC13) 6 1.99 (d, J = 7 Hz, 3H) . 2.02 (s, 3H) , 2.42 (s, 3H) , 6.24 (q, J = 7 Hz, 1H) , 7.09 (s, 1H) , 7.18-7.32 (m, SH! , 7.48 (s, 1H) , 8.51 (s, 1H) ; MS (ES) : 3 34.2 (M'+l) .
dl-5,6-dirnethyl-2-cyclopentyl-7h-7-(1-phenylethyl)

Tne term "N-6 suDstirutec 7-aeazapurme" is art Recognized and is intended to include those compounds having the fcrrr.ula I:

(Table Removed)N-substituted 7-deazapuR1ne" includes pharmaceutically acceptable salts theReof, and, in one embodiment, also includes certA1n N-6 substituted puR1nes descR1bed heRein.
In certA1n embodiments, the N-€ substituted 7-deazapuR1ne is not N-6 benzyl or N-6 phenylethyl substituted. In other embodiments, R4 is not benzyl or phenylethyl substituted. In pReferRed embodiments, R± and R2 aRe both not hydrogen atoms. In still other pReferRed embodiments, R3 is not a hydrogen atom.
The language "therapeutically effective amount" of an N-6 substituted 7-deazapuR1ne, descR1bed infra, is that amount of
a therapeutic compound necessary or sufficient to perform its intended function within a mammal, e.g., tReat a N-6
substituted 7-deazapuR1ne Responsive state, or a disease state in a mammal. An effective amount of the therapeutic
compound can vary according to factors such as the amount of the causative agent alReady pResent in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the pResent invention to affect a N-6 substituted 7-deazapuR1ne Responsive state in the mammal.
pyrrolo[2,3d]pyrimidin-4 (3H)-one. :H NMR (200 MHz, CDCl) 5 1.95 (d, J = 7.4 Hz, 3H), 2.00 (s, 3H) , 2.33 (s, 3H) , 1.6S-1.88 (m, 8H), 2.97 (m, 1H) , 6.10 (q, J = 7.4 Hz, 1H) , 7.16-7.30 (m. 5H) , .9.29 (s, 1H) ; MS (ES) : 33S.3 (M" + l).
dl -5, 6-dimethy 1-2- (2-thienyl) -7H-7- (1 -phenyl ethyl)
pyrrolo[2,3d]pyrimidin-4 (3) -one. :H NMR (200 MHz, CDC1J
2.02(d, J 7.2 Hz, 3H), 2.06 (s, 3H) , 2.41 (S, 3K), 6.13- (q, J = 7.2 Hz, 1H), 7.12 (dd, J = 4.8, 2.8 Hz, 1H), 7.26-7.32 (m, 5H) , 7.44 (d, J = 4.8 Hz, 1H) , 8.01 (d, J = 2.S Hz, 1H) 11.25 (s, 1H) ; MS (ES): 350.2 (M'+l).
dl-5,6-dimethyl-2- (3-thienyl) -7H-7- (1-phenylethyl) pyrrolo[2,3d]pyrimidin-4 (3tf)-one. :H; NMR (200 MHz, CDCl,) 6
2.00 (d, J = 7.4 Hz, 3H), 2.05 (s, 3H) , 2.43 (s, 3H), 6.24(q,
J = 7.4 Hz, 1H), 7.24-7.33 (m, 5H), 7.33-7.39 (m, 1H), 7.85
(m, 1H), 8.47 (m, 1H), 12.01 (s, 1H); MS (ES): 350.2 (M'+l) .
dl-5,6-dimethyl-2-(4-fluorophenyl)-7H-7-(1-phenylethyl) pyrrolo[2,3d]pyrimidin-4(3H)-one. ;H NMR (200 MHz, CDCl,) 5
2.01 (d, J = 6.8 Hz, 3H), 2.05 (s, 3H), 2.42 (s, 3H) , 6.26
(q, J = 6.8 Hz, 1H) , 7.12-7.36 (m, 7H), 8.23-8.30 (m, 2H) ,
11.82 (s, 1H); MS (ES) : 362.3 (M~+l) .
dl-5,6-dimethyl-2-(3-fluorophenyl)-7-7-(1-phenylethyl) pyrroloi:2,3d]pyrimidin-4 (3if)-one. lK NMR (200 MHz, CDCl,) 5
2.02 (d, J = 7.4 Hz, 3H), 2.06 (s, 3H), 2.44 (S, 3H), 6.29
(q, J = 7.4 Hz, 1H) , 7.13-7.51 (m, 7H) , 8.00-8.04 (m, 2H) ,
11.72 (s, 1H)/ MS (ES): 362.2 (M*+l).
dl-5,6-dimethyl-2-(2-fluorophenyl)-7H-7-(1-phenylethyl)
pyrrolo[2,3d]pyrimidin-4 (2H) Jone. ;H NMR (200 MHz, CDCl,) 5
2.00(d, J = 7.2 Hz, 3H), 2.05 (s, 3H), 2.38 (s, 3H), 6.24 (q, J = 7.2 Hz, 1H), 7.18 - 7.45 (m, 8 H), 8.21 (m, 1H), 9.54 (s, 1H); MS (ES): 362.2 (M+l).
dl-5 , 6 -dimethyl -2 -isopropyl-7-7- (1-phenylethyl) pyrrole [2 , 3d] pyrimidin-4 (3H) -one.
:H NMR (200 MHz, CDC1:.) 6 1.30 (d, J = 6.8 Hz, 3K) , 1.32 (d, J = 7.0 Hz, 3H) , 2.01 (s, 3H), 2.34 (s, 3H), 2.90 (m, IH) , 6.13 (m, IH) , 7.17-7.34 (m, 5H) , 10.16 (s, IH) ; MS (ES) : 310.2 (M*+l) .
Preparation 8:
A solution of dl-1- (1-phenylethyl) -2-benzoylamino-3-cyano-4-
dimethylpyrrole (785 mg, 2.38 mmol) with concentrated H2S04 (1 mL) in DMF (13 mL) was stirred at 13 0°C for 4 8 h. The black solution was diluted with CHC13 (100 mL) and washed with 1 N NaOH (3 0 mL) , and brine (30 mL) . The organic fraction was dried, filtered, concentrated, and purified by flash chromatography (Si02; 8/2 EtOAc/Hex, Rf 0.35) to a brown solid
(184 mg, 24%) as dl-5-methyl-2-phenyl-7H-7- (1-
phenylethyl)pyrrolo [2, 3d]pyrimidin-4 (3H)-one. 1H NMR (200 MHz,
CDCI3) 5_8.18 (m, 2H, Ar-H), 7.62-7.44 (m, 3H, Ar-H), 7.40-7.18 (m, 5H, Ar-H), 6.48 (s, IH, pyrrole-H), 6.28 (q, IH, J
= 7.2 Hz, CH-CH3) , 2:18 (s, 3H, pyrrole - CH3) , 2.07 (d, 3H, J
= 7.2 Hz, CH-CH3); MS ES : 330.2 (M + 1).
Preparation 9:
A mixture of dl-1-(1-phenylethyl)-2-amino-3-cyano-4,5-dimethylpyrrole (9.60 g, 40.0 mmol) and of formic acid (50.0 mL, 98%) was refluxed for 5 hr. After cooling down to room temperature and scratching the sides of flask, copious precipitate was formed and filtered. The material was washed with water until washings showed neutral pH to give dI-5,6-dimethyl-7H-7-(1-phenylethyl)pyrrolo[2,3d]pyrimidin-4(3H) -
one. :H NMR (200 MHz, CDC13) 5 1.96 (d, J - 7.4 hz, 3H) , 2.00 (s, 3H), 2.38 (s, 3H), 6.21 (q, J = 7.4 Hz, IH), 7.11-7.35 (m, 5H), 7.81 (s, IH), 11.71 (s, IH); MS (ES): 268.2 (M*+l).

Preparation 10:
dl-S, 6-dimethyl-2-phenyl-7H-7-(1-phenylethyl) pyrrole [2, 3d]pyrimidin-4 (3H)-one (1.0 g, 2.91 mmol) was suspended in
polyphosphoric acid {30.0 mL) . The mixture was heated at lOO'C for 4 hr. The hot suspension was poured onto ice water, stirred vigorously to disperse suspension, and basified to pK 6 with solid KOH. The resulting solid was filtered and collected to give 0.49 g [S3H) of 5,6-dimethyl-2-phenyl-7H-pyrrolo [2, 3d] pyrimidin-4 (3H)-one. :H NMR (200 MHz, DMSO-dr) 6_2.17 (s, 3H), 2.22 (s, 3H) , 7.45 (br, 3H) , 8.07 (br, 2H, ) , 11.49 (S, 1H), 11.82 (S, 1H); MS (ES) : 344.2 (M + l).
The following compounds were obtained in a similar manner as that of Preparation 10:
5-methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidin-4(3H) -one. MS (ES) : 226.0 (M* + l) .
5, 6-dimethyl-2- (3-pyridyl) -7H-pyrrolo [2, 3d]pyrimidin-4 (3H) -one. MS (ES): 241.1 (M"+l).
5,6-dimethyl-2- (2-furyl) -7H-pyrrolo[2,3d]pyrimidin-4 (3H) -one.
:H NMR (200 MHz, DMSO-d6) 5 2.13 (s, 3H) , 2.18 (s, 3H) , 6.39 (dd, J = 1.8, 3.6 Hz, 1H) , 6.65 (dd, J = 1.8 Hz, 3.6 Hz, 1H) , 7.85 (dd, J = 1.8, 3.6 Hz, 1H, ) , 11.45 (s, 1H) , 11.60 (s, 1H) ; MS (ES) : 230.1 (M+l) .
5, 6-dimethyl-2- (3-furyl) -7H-pyrrolo [2 ,13d] pyrimidin-4 (3H) -one.
:H NMR (200 MHz. DMSO-d6) 6 2 .14 (s, 3H) , 2.19 (s, 3H) , 6.66
(S, 1H) , 7.78 (s, 1H) , 8.35 (s, 1H) , 11.3 (s, 1H) , 11.4 (s,
1H); MS (ES): 230.1 (M'+l). |
I 5, 6-dimethyl-2-cyclopentyl-7H-pyrrolo [2. 3d] pyrimidin-4 (3H) -
one.H NMR (200 MHz, DMSO-d6) 5 1.57-1.91 (m, 8 H) , 2.12 (s, 3H) , 2.16 (s, 3H) , 2.99 (m, 1H) , 11.24 (s, 1H) , 11.38 (s, 1H); MS (ES): 232.2 (M+l).

5 , 6-dimethyl-2- (2-thienyl) -7H-pyrrolo [2, 3d] pyrimidir.-4 (3H) -
one. 1H NMR (200 MHz, DMSO-d6) 6 2.14 (s, 3H) , 2.19 (s, 3H) , 7.14 (dd, J = 3.0. 5.2 Hz, 1H) , 7.70 (d, J . 5.2 Hz 1H) , 8..10 (d, J=3.0 Hz, 1H), 11.50 (S, 1H); MS: (ES): 246.1 (M-+l).
5, 6-dimethyl-2-(3-thienyl)-7H-pyrrolo[2,3d]pyrimidin-4(2H) -one. 1H NMR (200 MHz, DMSO-d6) 5 2.17 (s, 3H) , 2.21 (s, 3H) , 7.66(m, 1H), 7.75 (m, 1H), 8.43 (m, 1H). 11.47 (s, 1H), 11.69 (s, 1H) ; MS (ES) : 246.1 (M- + l) .
5, 6-dimethyl-2-(4-fluorophenyl)-7H-pyrrolo[2,3d]pyrimidin-
4(3H)-one. 1HNMR (200 MHz, DMSO-d65 2.17 (s, 3H) , 2.21 (S,
3H) , 7.31 (m, 2H) , 8.12 (m, 2H) , 11.47 (s, 1H) ; MS (ES) : 258.2 (M'+l).
5,6-dimethyl-2-(3-fluorophenyl)-7H-pyrrolo[3d]pyrimidin-
4(3H)-one.1H NMR (200 MHz, DMSO-d6) 6 2.18 (s, 3H) , 2.21 (s,
3H) , 7.33 (m, 1H) , 7.52 (m, 1H) , 7.85-7.95 (m, 2H), 11.56 (s, 1H) , 11.80 (s, 1H) ; MS (ES) : 258.1 (M- + l) .
5,6-dimethyl-2-(2-fluorophenyl)-7H-pyrrolo[2,3d]pyrimidin-
4(3H)-one. :H NMR (200 MHz, DMSO-d6) 6 2.18 (s, 3H) , 2.22 (s,
3H) , 7.27-7.37 (m, 2H) , 7.53 (m 1H) , 7.68 (m, 1H) , 11.54 (s, 1H), 11.78 (S, 1H); MS (ES): 258.1 (M-+l).
5, 6-dimethyl-2-isopropyl-7H-pyrrolo [2, 3d] pyrimidin-4 (3H) -one.
:H NMR (200 MHz, DMSO-d6) 6 1.17 (d, J- 6.6 Hz, 6H) , 2.11 (s, 3H) , 2.15 (s, 3H) , 2.81 (m. 1H) , 11.20 (s. 1H) , 11.39 (s, 1H) ; MS (ES) : 206.1 (M* + l) .
5,6-dimethyl-7H-pyrrolo[2 , 3d]pyrimidin-4(3H) -one. :H NMR
(200 MHz, lDMSO-d6) 6 2.13 (s, 3H) , 2.17 (s, 3H) , 7.65 (s, 1H) ; MS (ES) : 164.0 (M' + l) .
Preparation 11:
A solution of 5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]
pyrimidin-412 H) -one (1.0 g, 4.2 mmol) in phosphorus oxychloride (25.0 mL) was refluxed for 6 hr and then concentrated in vacuo to dryness. Water was added to the
residue to induce crystallization and the resulting solid was filtered and collected to give 0.90 g (83%) of 4-chloro-5,6-dime thyl-2-phenyl-7H-pyrrolo [2,3d] pyrimidine. :H NMR (200 MH2,
DMSO-dJ 6_2.33 (S, 3H) , 2.33 (s, 3H) , 7.46-7.49 (m, 3H) , 8.30-8.35 (m, 2H) , 12.20 (s, 1H); MS (ES): 258.1 (M' + l). The following compounds were obtained in a similar manner as that of Preparation 11:
4-chloro-5-methyl-2-phenyl-7H-pyrrolo[2, 3d] pyrimidine. MS
(ES): 244.0 (M'+l).
4-chloro-6-methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS
(ES): 244.0 (M' + l)-
4-chloro-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. ;H NMR (200 MHz, DMSO-d6) 8.35 (2, 2H), 7.63 (br s, 1H), 7.45 (m. 3H), 6.47 (br S, 1H); MS (ES): 230.0 (M'+l).
4-chloro-5,6-dimethyl-2-(3-pyridyl)-7H-pyrrolo[2,3d] pyrimidine. MS (ES) : 259.0 (M'+l).
4-chloro-5,6-dimethyl-2- (2-furyl) -7H-pyrrolo [2 , 3d] pyrimidine.
:H NMR (200 MHz, DMSO-dJ 6 2.35 (s, 3H) , 2.35 4 -chloro-5,6-dimethyl-2-(3-furyl)-7H-pyrrolo[2,3d]pyrimidine. :H NMR (200 MHz, DMSO-dJ 6 2.31 (s, 3H) , 2.31 (s, 3H) , 6.62 (S, 1H) , 7.78 (s, 1H) , 8.18 (s, 1H) , 12.02 (s, 1H) ; MS (ES): 248.1 (M'+l) .
4-chloro-5,6-dimethy1-2-cyclopentyl-7H-pyrrolo[2,3d] pyrimidine. 'H NMR (200 MHz, DMSO-dJ 6 1.61- 1.96 (m, 8H) ,
2.27 (s, 3H), 2.27 (s, 3H) , 3.22 (6. 1H) . u.97 (s, 1H) • K= (ES) : 250.1 (M1+l) .
4-chloro-5,6-dimethyl-2-(2-thienyl)-7H-pyrrolo[2,3d] pyrimidine. :H NMR (200 MHz, DMSO-dJ 5 2.29 (s, 3H) , 2.31 (s 3H) , 7.14 (dd, J = 3.1 Hz, 4.0 Hz, 1H) , 7.33 (d, J = 4.9 Hz, 1H6, 7.82 (d, J = 3.1 Hz, 1H), 12.19 (S, iH) ; MS (ES) : 264.1 (M- + 1) .
4-chloro-5„S-dimethyl-2-(3-thienyl)-7H-pyrrolo[2,3d] pyrimidine. :H NMR (200 MHz, DMSO-dg) 5 2.32 (s, 3H) , 2.32 (s, 3H), 7.€2 (dd, J . 3.0, 5.2 Hz, 1H) , 7.75 (d, J = 5.2 Hz, 1H) , 8.20 (d, J = 3.0 Hz, 1H) ; MS (ES) : 264.0 (JT + l) .
4 -chloro-5,6-dimethyl-2 -(4 -fluorophenyl)-7H-pyrrolo[2,3d] pyrimidine. :H NMR (200 MHz, DMSO-dJ 6 2.33 (s, 3H) , 2.33 (s, 3H). 7.30 (m, 2H) , 8.34 (m, 2H) , 12.11 (s, 1H) ; MS (ES) : 276.1. (M"+l) .
4-chloro-S,6-dimethyl-2-(3-fluorophenyl)-7H-pyrrolo[2,3d] pyrimidine. 2H NMR (200 MHz, DMSO-ds) 5 2.31 (s, 3H) , 2.33 (s, 3H) , 7.29 (m, 1H) , 7.52 (m, 1H) , 7.96 (m, 1H) , 8.14 (m, 1H) , 11.57 (s, 1H); MS (ES): 276.1 (M1+l).
4-chloro-5, 6-dimethyl-2- (2-f luorophenyl) -7H-pyrrolo [2, 3d] pyrimidine. :H NMR (200 MHz, DMSO-ds) 6 2.34 (s, 3H) , 2.34 (s, 3H), 7.33 (m, 2H). 7.44 (m, 1H), 7.99 (m, 1H), 12.23 4-chloro-5,6-dimethyl-2-isopropyl-7H-pyrrolo[2,3d]pyrimidine. :H NMR (200 MHz, DMSO-d,) 5 1.24 (d, J = 6.6 Hz, 6H) , 2.28 (s, 3H) , 2.28 js. 3H) , 3.08 (q, J = S.6rHz, 1H) , 11.95 (s, 1H) ; MS (ES): 224.0 (M"+l).
4-chloro-5,6-dimethyl-7H-pyrrolo[2,3d]pyrimidine. 1H NMR (200MHZ, DMSO-ds) 5 2.31 (s, 3H) , 2.32 (s, 3H) . 8.40 (s, 1H) ; MS (ES) : 182.0 (M1 + l) .
dl-4 -chloro-5, 6 -dimethyl-2 -phenyl- 1H-1- (l-phenylethyl) pvrrclc [2, 3d]pyrimidine.
Preparation 12:
To a solution of dl-1,2-diaminopropane (1.48 g, 20.0 mmol) and sodi urn carbonate (2.73 g, 22.0 mmol) in dioxane (10 0.0 mL) and water (100.0 mL) was added di-tert-dicarbonate (4.80 g, 22.0 mmol) at room temperature. The resulted mixture was stirred for 14 hr. Dioxane was removed in vacuo. The precipitate was filtered off and the filtrate was concentrated in vacuo to dryness. The residue was triturated
with EtOAc and then filtered. The filtrate was concentrated in vacuo to dryness to give a mixture of dl-l-amino-2-(1,1-dimethylethoxy) carbonylamino-propane, and dl -2-amino-l- (1,1-
dimethylethoxy) carbonylamino-propane which were not separable by normal chromatography method. The mixture was used for the reaction in Example 8.
Preparation 13:
To solution of Fmoc-(3-Ala-OH (1.0 g, 3.212 mmol) and oxalyl chloride (0.428 g, 0.29 mL, 3.373 mmol) in dichloromethane (20.0 mL) was added a few drops of N,N-dimethylformamide at 0°C. The mixture was stirred at room temperature for 1 hr followed by addition of cyclopropylmethylamine (0.229 g, 0.28 mL, 3.212 mmol) and triethylamine (0.65 g, 0.90 mL, 6.424 mmol) . After 10 min, the mixture was treated with 1 M hydrochloride (10.0 mL) and the aqueous mixture was extracted with dichloromethane (3 x 3 0.0 mL) . The organic solution was concentrated in vacuo to dryness. The residue was treated
with a solution of 20% piperidine in N,N-dimethylforamide (20.0 mL) for 0.5 hr. After removal of the solvent in vacuo, the residue was treated with 1 M hydrochloride (20.0 mL) and ethyl acetate (20.0 mL) . The mixture was separated and the aqueous layer was basified with solid sodium hydroxide to pH = 8. The precipitate was removed by filtration and the aqueous solution was subjected to ion exchange column eluted
with 20% pyridine to give 0.262 g (57%) of N-cyclopropylmethyl 3-alanine amide. ;K NMR (200 MHz, CD,OB) 6_0.22 (m, 2H), 0.49 (m, 2H) , 0.96 (m, 2H) , 2.40 (t, 2K) . 2.92 (t, 2H). 3.05 (d, 2H) ; MS (ES) : 143.1 (H1+l).
Preparation 14:
N- tert-butoxycarbonyl- trans-1, 4-cyclohexyldiamine .
crans-1,4-cyclonexyldiamine (6.08 g, 53.2 mmol) was dissolved
in dichloromethane (lOOmL) . A solution of di-t-butyldicarbonate (2.32 g, 10.65 mmol in 40 mL dichloromethane) was added via cannula. After 20 hours, the reaction was partitioned between CHCl, and water. The layers were separated and the aqueous layer was extracted with CHC1:. (3x). The combined organic layers were dried over MgS04, filtered and concentrated to yield 1.20 g of a white solid (53%). :H-NMR (200MHz, CDCl3) : 6 1.0-1.3 (m, 4H) , 1.44 (s, 9H) , 1.8 -2.1 (m, 4H), 2.62 (brm, 1H), 3.40 (brs, 1H), 4.37 (brs, 1H0; MS (ES) : 215.2 (M1+l) .
4 - (N-acetyl) -N- Cert-butoxycarbonyl- trans-1, 4 -cyclohexyl diamine.
N- tert-butoxycarbonyl -trans-1, 4 -cyclohexyldiamine (530 mg,
2.47 mmol) was dissolved in dichloromethane (20 mL) . Acetic
anhydride (250 mg, 2.60 mmol) was added dropwise. After 16
hours, the reaction was diluted with water and CHC13. The
layers were separated and the aqueous layer was extracted
with CHC1; (3x). The combined organic layers were dried over
MgSO,, filtered and concentrated. Recrystallization
(EtOH/H,0) yielded 190 mg of white crystals (30%) . lH NMR
(200 MHz, CDCl3) : 6 0.9 - 1.30 (m, 4H) , 1.43 (s, 9H) , 1.96-
2.10 (m, 7H) , 3.40 (brs, 1H) , 3.70 (brs, 1H), 4.40 (brs, 1H) ,
4.40 (brs, 1H) ; MS (ES) : 257.2 (M- + 1), 242.1 (M" - 15), 201.1
(M" - 56).
4 - (4-crans-acetamidocyclohexyl)amino-5,6-dimethyl-2-phenyl-
7H-(1-phenylethyl) pyrrolo[2,3d]pyrimidine.
4-(N-acetyl)-N-tert-butoxycarbonyl-crans-1,4-
cyclohexyldiamine (190 mg, 0.74 mmol), was dissolved ir. dichloromethane (5 mL) and diluted with TFA (6 ml) . After 16 hours, the reaction was concentrated., The crude solid, DMSC (2mL) , NaHCO, (200 mg, 2.2 mmol) and 4-chloro-5,6-dimethyi -2-I phenyl-7H-pyrrolo[2,3d]pyrimidine (35 mg, 0.14 mmol) were combined in a flask and heated to 130 °C. After 4.5 hours, the reaction was cooled to room tempetature and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over MgS04, filtered and concentrated. Chromatography (silica preparatory plate,- 20:1 CHC1:. :EtOH) yielded 0.3 mg of a tan solid (1% yield). MS (ES) : 378.2 (M1+l) .
4 -(N-methanesulfonyl)-N-tert-butoxycarbonyl- trans-1,4-
cyclohexyldiamine.
trans-1,4 -cyclohexyl diamine (530 mg, 2.47 mmol) was dissolved
in dichloromethane (20 ml) and diluted, with pyridine (233 mg, 3.0 mmol). Mechanesulfonyl chloride (300 mg, 2.60 mmol) was added dropwise. After 16 hours, the reaction was diluted with water and CHC1:.. The layers were separated and the aqueous layer was extracted with CHC1: (3x) . The combined organic layers were dried over MgSO«, filtered and concentrated, recrystallization (EtOH/H:0) yielded 206 mg of white crystals (29V). ;H-NMR (200MHz, .CDC13) : 6 1.10-1.40 (m, 4H) , 1.45 (s, 9H) , 2.00-2.20 (m, 4H) , 2.98 (s, 3H) , 3.20-3.50 (brs, 2H) , 4.37 (brs, 1H) ; MS (ES) 293.1 (M1+l). 278.1 (M--15), 237.1 (M1-56).
4- (4-crans-methanesulfamidocyclohexyl)amino-5,6-dimethyl-2-
phenyl-7H- (l-phenylethyl)pyrrolo [2 , 3d]|pyrimidine .
4- (N-sulfonyl) -N- tert-butoxycarbonyl- trans-1,4-
cyclohexyldiamine (206 mg, 0.71 mmol), was dissolved in
dichloromethane (5ml) and diluted with TFA (6 ml) . After 16
hours, the reaction was concentrated. The crude reaction
mixture, DMSO (2 ml), NaHCO, (100 mg, 1.1 mmol) and 1-chloro-
5, 6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine were
combined in a flask and heated to 130 °C. After 15 hours, the reaction was cooled to room temperature, and diluted with EtOAc (3x). The combined organic layers were dried over MgSO, filtered and concentrated. Chromatography (silica preparatory plate, 20:1 CHCl3/EtOH5 yielded 2.6 mg of a tan solid (5% yield) .. MS (ES) : 414.2 (M1+l) .
Example 1:
A solution of 4-chloro-5,6-dimethyl-2'-phenyl-7H-pyrrolo [2,3d] pyrimidine (0.50 g, 1.94 mmol) and 4-trans-hydroxy eyelohexylamine (2.23 g, 19.4 mmol) in methyl sulfoxide (10.0 mL) was heated at 130°C for 5 hr. After cooling down to room temperature, water (10.0 mL) was added and the resulted aqueous solution was extracted with EtOAc (3 xlO.O mL) . The combined EtOAc solution was dried (MgS04) and filtered, the filtrate was concentrated in vacuo to dryness, the residue
was chromatographed on silica gel to give 0.49 g (75%) of 4-(4-crans-hydroxycyclohexyl)amino-5,6-dimethyl-2-phenyl-7H-
pyrrolo [2,3d]pyrimidine. mp 197-199°C; :H NMR (200 MHz, CDClj) 6_1.25-1.59 (m, 8H), 2.08 (s, 3H) , 2.29 (s, 3H) , 3.68-3.79 (m, 1H), 4.32-4.38 (m, 1H), 4.88 (d, J = 8 Hz, 1H). 7.26-7.49 (m, 3H) , 8.40-8.44 (dd, J = 2.2, 8 Hz, 2H) , 10.60 (s, 1H) ; MS (ES): 337.2 (M1+l).
The following compounds were obtained!; in a similar manner to that of Example 1:
4- (4 -trans-hydroxycyclohexyl)amino-6-methyl-2-phenyl-7H-
pyrrolo [2.3d] pyrimidine. lH NMR (200 MHz, CDC13) 6_11.37 (s, 1H, pyrrole-NH), 8.45 (m, 2H, Ar-H), 7.55 (m, 3H, Ar-H), 6.17 (s, 1H, pyrrole-H) , 4.90 (br d, 1H, NH) , 4.18 (m, 1H, CH-O) , 3.69 (m, 1H, CH-N) , 2.40-2.20 (m, 2H) , 2.19-1.98 (m. 2H) , 2.25 (S, 3H, CH3) 1.68-1.20 (m, 4H); MS (ES): 323.2 (M1+l).
4 - (4 - trans-hydroxycyclohexyl)amino'5-methyl-2-phenyl-1H-
pyrrolo [2,3d] pyrimidine.1H NMR (200 MHz, CDC13) 6_I1.37 (s, 1H, pyrrole-NH), 8.40 (m, 2H, Ar-H), 7.45 (m, 3H, Ar-H), 5.96
(s, 1H, pyrrole-H), 4.90 (br d. 1H, NH) , 4.18 (m, 1H, CK-C) , 3.69 (m, 1H. CK-N) , 2.38-2.20 (m, 2H) , 2.18-1.98 (m, 2K) , 2.00 (s, 3H, CH3) 1.68-1.20 (m, 4H) ; MS (ES) : 323.2 (M1 + l).
4- (4 - crans-hydroxycyclohexyl) amino-2-phenyl-7H-pyrrolo [2,3d] pyrimidine. mp 245.5-246.5°C; ;H NMR (200MHz, CD,OD) 5 8.33 (m, 2H, Ar-H), 7.42 (m, 3H, Ar-H) , 7.02 (d, 1H, J=3.6 Hz. pyrolle-H), 6.53 (d, 1H, J=3.6 Hz, pyrolle-H), 4.26 (m. 1H, CH-O) , 3.62 (m,lH, CH-N) , 2.30-2.12 (m, 2H) , 2.12-1.96 (m, 2H) , 1.64-1.34 {m, 4H) ; MS, M+l=309.3; Anal (Ci?H:,N,0) C, H, N.
4 -(4 - trans-hydroxycyclohexyl)amino-5,6-dimethyl-2-(3 -pyridyl) -7H-pyrrolo [2,3d] pyrimidine. :H NMR (200 MHz, CDClj) 6_1.21-1.54 (m, 8H); 2.28 (s, 3H); 2.33 (s, 3H); 3.70 (m, 1H) , 4.31(m, 1H) , 4.89 (d, 1H), 7.40 (m, 1H) , 8.61 (m, 2H), 9.64 (m, 1H); MS (ES): 338.2 (M- + l) .
4- (4- crans-hydroxycyclohexyl)amino-5, 6-dimethyl-2- (2-furyl) -
7H-pyrrolo [2,3d] pyrimidine. :H NMR (200 MHz, CDCl;.) 6 1.26-
1.64(m, 8H), 2.22 (s. 3H), 2.30 (s, 3H), 3.72(m, 1H), 4.23 (m, 1H), 4.85 (d, 1H), 6.52(m, 1H), 7.12 (m, 1H), 7.53 (m, 1H) , 9.28 (s, 1H) ;• MS (ES) : 327.2 (M1) .
4- (4- trans-hydroxycyclohexyl) amino-5, 6-dimethyl-2- (3-furyD-
7H-pyrrolo [2.3d] pyrimidine. ;H NMR (200 MHz, CDC1?) 6 1.25-
1.63 (m, 8 H), 2.11 (s, 3H), 2.27 (s, 3H), 3.71(m, 1H), 4.20 (m, 1H) , 4.84 (d, 1H) , 7.03 (m, 1H) , 7.45 (m, 1H) , 8.13 (m, 1H), 10.38 (m, 1H); MS (ES): 327.2 (M1+l).
4- (4-trans-hydroxycyclohexyl)amino-5,6-dimethyl- 2 -
cyclopentyl-7H-pyrrolo [!2,3d] pyrimidine. :H NMR (200 MHz,
CDC1J 6 1.26-2.04 (m, ' 16 H) , 2.26 (s, 3H) , 2.27 (s, 3H) , 3.15 (m, 1H) , 3.70 (m. 1H) , 4.12 (m, 1H) , 4.75 (d, 1H) ; MS (ES): 329.2 (M-+l).
4- (4- trans-hydroxycyclohexyl)amino-5,;6-dimethyl-2- (2-rhienyi.1 -7H-pyrrolo[2,3d]pyrimidin-4-amine. :H NMR (200 MHz, CDC1.) 5
1.28-1.59 (m, 8H), 2.19 (s, 3H) , 2.29 (s, 3H). 3.74 (m, 1H) , 4.19 (ra, 1H), 4.84 (d, 1H) , 7.09 (m, 1H) , 7.34 (m, 1H) , 7.85 (m, 1H), 9.02 (S, 1H); MS (ES): 343.2 (M1+l).
4 - (4 -trans-hydroxycyclohexyl)amino-5,6-dimethyl-2- (3 -thienyl) -7H-pyrrolo[2,3d]pyrimidine. ;H NMR (200 MHz, CDC1;) 6 1.21-1.60 (m, 8H), 1.98 (s, 3H) , 2.23 (s, 3H) , 3.66 (m, 1H) , 4.22 (m, 1H), 7.27 (m, 1H) , 7.86 (m, 1H) , 8.09 (m, 1H) , 11.23 (S, 1H); MS (ES): 343.2 (M1+l).
4 -(4-trans-hydroxycyclohexyl)amino-5,6-dimethyl-2 -(4-
fluorophenyl) -7H-pyrrolo[2,3d]pyrimidine. ;H NMR (200 MHz,
CDCl3) 6 1.26- 1.66 (m, 8H), 1.94 (s, 3H) , 2.28 (s, 3H) , 3.73 (m, 1H), 4.33 (m, IK), 4.92 (d, 1H) , 7.13 (m, 2H) , 8.41 (m, 2H) , 11.14 (s, 1H) ; MS (ES) : 355.2 (M- + l) .
4 -(4 -trans-hydroxycyclohexyl)amino-5,6-dimethyl-2 - (3 -
fluorophenyl) -7H-pyrrolo [2, 3d]pyrimidine. ;H NMR (200 MHz,
CDC13) 6 1.26-1.71 (m, 8H), 2.06 (s, 3H) , 2.30 (s, 3H) , 3.72 (m, 1H), 4.30 (m, 1H) , 4.90 (d, 1H) , 7.09 (m, 1H), 7.39 (m, 1H) , 8.05 (m, 1H) , 8.20 (m, 1H) , 10.04 (s. 1H) ; MS (ES) : 355.2 (M-+l) .
4 -(4 - trans-hydroxycyclohexyl)amiho-5,6-dimethyl-2-(2-
fluorophenyl)-7H-pyrrolo[2,3d]pyrimidine. ;H NMR (200 MHz,
CDCI3) 6 1.30-1.64 (m, 8H), 2.17 (s, 3H), 2.31 (s, 3H), 3.73 (m, 1H), 4.24 (m, 1H) , 4.82 (d, 1H) , 7.28 (m, 2H) , 8.18 {m, 1H), 9.02 (m. 1H), 12.20 (s, 1H); MS (ES): 355.3 (M1+l). 4- (4- trans -hydroxycyclohexyl) amino-5 , 6-dimethyl-2-isopropyl-
7H-pyrrolo [2.3d] pyrimidine :H NMR (200 MHz, _CDC13) 5 1.31 (d,
J = 7.0 Hz, 6H) , 1.30-1.65 (m, 8H) , 2.27 (s, 3H) , 2.28 3H) , 3.01 (m, J = 7.0 Hz, 1H) , 3.71 (m, 1H) , 4.14 (m, 1H) ,
4.78 (d, 1H); MS (ES): 303.2.
dl-4 -(2-craas-hydroxycyclohexyl)amino-5,6-dimethyl-~-
isopropyl-7H--pyrrblo [2, 3d]pyrimidine, iH NMR (200 MHz, C2Z1-.'-
d 1.31-1.42 (br, 4H) , 1.75-1.82 (br, 4H), 2.02 (s, 3H) , 2.2 = (s, 3H), 3.53 (m, 1H) , 4.02 (m, 1H), 5.08 (d, 1H) , 7.41-7.48 (m, 3H) , 8.30 (m, 2H) , 10.08 (s, 1H) ; MS (ES) : 337.2 (M1-l).
4- (3 , 4- trans-dihydroxycyclohexyl) amino-5, 6 -dimethyl-2-phenyl -7H-pyrrolo[2,3d]pyrimidine. MS (ES) : 353.2 (M++l) .
4- (3,4-cis-dihydroxylcyclohexyl) amino-5, 6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS (ES) : 353.2 (M%1).
4 -(2-acetylaminoethyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo [2,3d]pyrimidine.
mp 196-199°C; aH NMR (200 MHz, CDC1,) 5_1.72 (s, 3H) , 1.97 (s, 3H), 2.31 (s, 3H) , 3.59 (m, 2H) , 3.96 (m, 2H) , 5.63 (br, 1H) , 7.44-7.47 (m, 3H) , 8.36-8.43 (dd, J = 1 Hz, 7 Hz, 2H), 10.76 (s, 1H); MS (ES): 324.5 (M- + l) .
di-4- (2-trans-hydroxycyclopentyl) amino-5, 6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine.:
•H NMR (200 MHz, CDCl3) 6_1.62 (m, 2H) , 1.79 (br, 4H) , 1.92 (s, 3H) , 2.29 (s, 3H) , 4.11 (m, 1H) , 4.23 (m, 1H) , 5.28 (d, 1H) , 7.41-7.49 (m, 3H) , 8.22 (m, 2H) ,■ 10.51 (s, 1H) ; MS (ES) : 323.2 (M-+l). 1 For preparation of 2-crans-hydroxycyclopentylamine, see PCT
9417090.
dl-4- (3- trans-hydroxycyclopentyl) amino-5, 6-dimethyl-2-phenyl-
1H-pyrrolo [2,3d]pyrimidine.:
:H NMR (200 MHz, CDC1:.) 6_1.58-1.90 (br, 6 H,), 2.05 (s, 3H) , 2.29 (S, 3H) , 4.48-4.57 (m, 1H) , 4.91-5.01 (m, 2H) , 7.35-7.46 (m, 3H) , 8.42-8.47 (m, 2H) , 10.11 (s, 1H) ; MS (ES): 323.2 (M1 + l) .

: For preparation of 3-trans-hydroxycyclopentylamine, see E?-A-322242.
dl-4- (3-cis-hydrcxycyclopentyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine.:
:H NMR (200 MHz, CDClO 6_1.82-2.28 (br, 6H) , 2.02 (s, 3H) , 2.30 (s, 3H), 4.53-4.60 (m, 1H), 4.95-5.08 (m, 1H). 5.85-5.93 (d, 1H) , 7.35-7.47 (m, 3H), 8.42-8.46 (m, 2H) , 10.05 (s, 1H> ; MS (ES) : 323.2 (M1+l) .
: For preparation of 3-cis-hydroxycyclopentylamine, see EP-A-322242.
4 - (3,4- trans-dihydroxycyclopentyl) amino- 5, 6 -dimethyl - 2 -phenyl
-7H-pyrrolo [2, 3d] pyrimidine.: :H NMR (200 MHz, CDC1,) 6_1.92-
1.99 (br, 2H) , 2.14 (s, 3H) , 2.20 (br, 2H) , 2.30 (s, 3H) , 2.41-2.52 (br, 2H), 4.35 (m, 2H), 4.98 (m, 2H), 7.38-7.47 (m, 3H), 8.38-8.42 (m, 2H) , 9.53 (s, 1H); MS (ES): 339.2 (M1+l). : For preparation of 3,4-trans-dihydroxycyclopentylamine, see
PCT 9417090.
4 - (3 -amino-3 -oxopropyl) amino- 5 , 6 -dimethyl -2-phenyl- "7H-
pyrrolo[2,3d]pyrimidine.
;H NMR (200 MHz, CDC1,} 6_2.02 (s, 3H), 2.29 (s, 3H) , 2.71 (t, 2H) , 4.18 (m, 2H) , 5.75-5.95 (m, 3H) , 7.38-7.48 (m, 3H) , 8.37-8.41 (m, 2H) , 10.42 (s, 1H) ; MS, (ES) : 310.1 (M1 + l) .
4- (3-N-cyclopropylmethylamino-3-oxoprppyl) amino-5, 6-dimethyl-2-phenyl-7i/-pyrrolo [2, 3d] pyrimidine. :H NMR (200 MHz, CD,OD)
6_0.51 (q, 2H) , 0.40 (q, 2H) , 1.79-1.95 (br, 1H) , 2.36 (s, 3H) , 2.40 (s, 3H) , 2.72 (t, 2H) , 2.99 (d, 2H) , 4.04 (t, 2H) , 7.58-7.62 (m, 3H) , 8.22-8.29 (m, 2H) ; MS (ES): 364.2 (M--t-l).
4-(2-amino-2-oxoethyl)amino-5,6-dimethyl-2-phenyl-1H-pyrrolo [2,3d] pyrimidine ;H NMR (200 MHz, CD,OD) 6 2.31 (s, 3H) , 2.38 (s, 3H) , 4.26 (s,"2H), 7.36 (m, 3H) , 8.33 (m, 2H) ; MS (ES): 396.1 (M1V1).
4 -(2-N-methylamino-2-oxoethyl)amino-5, S-dimethyl- 2-phenyl-7H-pyrrolo[2,3d]pyrimidine. :H NMR (20)0 MHz, CDCi:) 6_1.95 (s, 3H) , 2.17 .(s, 3H), 2.82 4- (3- tert-butyloxyl-3-oxopropyl) amino-5, 6-dimethyi-2-phenyl-7H-pyrrolo[2, 3d]pyrimidine. ;H NMR (200 MHz, CDC10 6_l.4S (s, 9H) , 1.96 (s, 3H) , 2.29 (s, 3H) , 2.71 (t, 2H) , 4.01 (q, 2H) , 5.78 (t, 1H) , 7.4.1-7.48 (ffl, 3H) , 8.22-8.29 (m, 2H) ; MS (ES) : 367.2 (MM) .
4-(2-hydroxyethyl)amino-5,6-dimethyl-2-phenyl-7H-
pyrrolo[2,3d]pyrimidine. :K NMR (200 MHz, CDC16) 5 1.92 (s, 3H), 2.29 (s, 3H) , 3.81-3.98 (br, 4H) , 5.59 (t, 1H), 7.39-7.48 (m, 3H) , 8.37 (m, 2H) , 10.72 (s, 1H) ; MS (ES) : 283.1 (M1+l) .
4 - (3 -hydroxypropyl) amino-5 , 6-d;imethyl-2-phenyl-7H-
pyrrolo [2,3d] pyrimidine. :H NMR (200 MHz, CDC1:.) 6 1.84 (m,
2H) , 1.99 (s, 3H), 2.32 (s, 3H), 3.62 (t, 2H) , 3.96 (m, 2H) ,
3.35 (t, 1H) , 7.39-7.48 (m, 3H) , 8.36 (m, 2H) , 10.27 (s, 1H) ;
MS (ES) : 297.2 (M- + l) .
4 -(4-hydroxybutyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo
[2,3d]pyrimidine. :H NMR (200 MHZ, CD$1,) 6 1.71-1.82 (m, 4H) , 1.99 (s, 3H), 2.31 (s, 3H), 3.68-3.80 (m, 4H), 5.20 (t, 1H), 7.41-7.49 (m, 3H), 8.41(m, 2H), 10.37 (s, 1H); MS (ES): 311.2
(M- + l) .
4-(4-trans-acetylaminocyclohexyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine.
4 - (4- trans-me thy lsulfonylaminocyclohexyl) amino- 5, 6-dimethyl-
2-phenyl-7H-pyrrolo[2,3d]pyrimidine.
4 - (2 -acetylaminoethyl)amino-5,6-dimethyl-2-phenyl-7H- 7 -{i-phenylethyl) pyrrolo [2,3d] pyrimidine.
4- (4 - trans-hydcxycyclohexyl) amino-5,6-dimethyl-2-phenyl-7H-1 -phenylethyl) pyrrolo [2,3d] pyrimidine .
4-(3-pyridylmethyl)amino-5,6-dimethyl-2-phenyl-7H-7-(i-phenylethyl) pyrrolo [2 , 3d] pyrimidine .
4 - (2-methylpropyl)amino-5,6-dimethyl-2-phenyl-7H-7-(l-phenylethyl) pyrrolo [2 , 3d] pyrimidine.
Example 2:
To a stirred suspension of triphenylphosphine (0.047 g, 0.179 mmol) and benzoic acid (0.022 g, 0.179 mmol) in THF (1.0 mL) cooled to 0°C was added 4-(4-trans-hydroxycyclohexyl)amino-
5, 6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine (0.05 g,
0.149 mmol) at 0°C. Diethyl azodicarboxylate (0.028 ml, 0.179 mmol) was then added dropwise over 10 minutes. The reaction was then allowed to warm to room temperature. After reaction was complete by TLC the reaction mixture was quenched with aqueous sodium bicarbonate (3.0 mL). The aqueous phase was separated and extracted with ether (2 X 5.0 mL) . The organic extracts were combined, dried, and concentrated in vacuo to
dryness. To the residue was added ether (2.0 mL) and hexane (5.0 mL) whereupon the bulk of the triphenylphosphine oxide was filtered off. Concentration of the filtrate gave a viscous oil which was purified by column .chromatography (hexane:ethyl acetate=4:l) to give 5.0 mg (7.6V) of 4-(4-cis-benzoyloxycyclohexyl)amino-5,€-dimethyl-2-phenyl-7H-
pyrrolo [2, 3d] pyrimidine. MS. (ES) : 441.3 (M--t-l) . The reaction also produced 50.0 mg (84V) of 4-(3-cyclohexenyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo [2, 3d] pyrimidine. MS (ES) : 319.2
(M1 + l) .
Example 3:
To a solution of 4- (4-cis-benzoyloxycyclohexyl)amino-.5 ,6 -dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine (5.0 trig, 0.0114 mmol) in ethanol (1.0 mL) was added 10 drops of 2M sodium hydroxide. After 1 hr, the reaction mixture was extracted with ethyl acetate (3 x 5.0 mL) and the organic layer was dried, filtered and concentrated in vacuo to dryness. The residue was subjected to column chromatography (hexane:ethyl acetate«4:l) to .give 3.6 mg (94%) of 4-(4-cis-hydroxycyclohexyl)amino-5, 6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS (ES): 337.2 (M-+l).
The following compounds were obtained in a similar manner as that of Example 3:
4- (3 -N,N-dimethyl-3-oxopropyl) amino-5, 6-dimethyl-2-phenyl-7.ff-pyrrolo[2,3d]pyrimidine. :H NMR (200 MHz, CDC1-.) 6 2.01 (s, 3H), 2.31 (s, 3H) , 2.73 (t, 2H) , 2.97 (s, 6H) , 4.08 (m, 2H), 6.09 (t, 1H), 7.41-7.48 (m, 3H) , 8.43 (m, 2H), 10.46 (s, 1H) ; MS (ES) : 338.2 (M1+l).
4 - (2 -formylaminoethyl)amino-5 , 6-dimethyl- 2-phenyl-7H-
pyrrolo[2,3d]pyrimidine. lH NMR (200 MHz, CDC15) 6 2.26 (s, 3H) . 2.37 (s, 3H) , 3.59-3.78 (m, 2H) , 3.88-4.01 (m, 2H) , 5.48-5.60 (m, 1H) . 7.38-7.57 (m, 3H) , 8.09 (s, 1H), 8.30-8.45 (m, 2H), 8.82 (s, 1H); MS (ES): 310.1 (M1+l).
4 - (3-acetylaminopropyl)amino-5,6-dimethyl- 2 -phenyl-7H-pyrrolo[2,3d]pyrimidine. MS (ES): 338.2 (M1+l).

Example 4:
4- (3- terc-butyloxy-3-oxopropyl)amino-5,6-dimethyl-2-phenvI-7H-pyrrolo [2,3d] pyrimidine (70.0 mg, 0.191 mmol) ) was
dissolved in trifluoroacetic acidrdichloromethane (1:1, 5.0 mL) . The resulting solution was stirred at room temperature for 1 hr. and then refluxed for 2 hr. After cooling down to room temperature, the mixture was concentrated in vacuo to dryness. The residue was subiected to preparative thin layer chromatography (EtOAc:hexane: AcOH=7:2.5:0.5) to give 4 0.0 mg (681%) of. 4- (3-hydroxy-3-oxopropyl)amino-5,6-dimethyl-2-phenyl-7Hrpyrrolo [2,3d]
pyrimidine. :H NMR (200 MHz, CD,OD) 6 2.32 (s, 3H) , 2.38 (S, 3H), 2.81 (t, 2H), 4.01 (t, 2H), 7.55 (m, 3H), 8.24 (m, 2H); MS (ES): 311.1 (M1+l).
The following compound was obtained in a similar manner as that of Example 4:
4- (3-aminopropyl) amino-5, 6-dintethyl-2-phenyl-7H-pyrrolo [2, 3d] pyrimidine. MS (ES) : 296.1 (M-+l) , 279.1 (M1-NH3) .
Example 5:
4- (3-hydroxy-3-oxopropyl) amino-5, 6-dimethyl -2 -phenyl -7H-
pyrrolo[2,3d]pyrimidine .(50.0 mg, 0.161 mmol) was dissolved in a mixture of N,N-dimethylformamide (0.50 mL) , dioxane (0.50 mL) and water(0.25 mL) . To this solution was added methylamine (0.02 mL, 40% wt in water, 0.242 mmol), triethylamine (0.085 mL) and N,N,N'N'-tetramethyl uronium tetrafluoroborate (61.2 mg, 0.203 mmol). After stirring at room temperature for 10 min, the solution was concentrated and the residue was subjected to preparative thin layer chromatography (EtOAc) to give 35.0 mg (67%) of 4-(3-N-methyl-
!
3-oxopropyl) amino-5 , 6 -dimethyl- 2 -phenyl-7H-
pyrrolo [2,3d] pyrimidine. :H NMR (200 MHz, CDC1,) 6 1.92 (s, 3H) , 2.30 (s, 3H) , 2.65 (t, 2H), 4.08 (t, 2H) , 5.90 (t, 1H), 6.12 (m, 1H) , 7.45 (m, 3H) , 8.41 (m, 2H) , 10.68 (s, 1H) ; MS

(ES) : 311.1 (M1+l) .
The following compounds were obtained in a similar manner as that of Example 5:
I 4- (2-cyclopropanecarbonylaminoethyl) amino-5, 6-dimethyl-2-phenyl-7H-pyrrolof2,3d]pyrimidine. MS (ES) : 350.2 (M-+i) .
4-(2-isobutyrylaminoethyl)amino-5,6-dimethyl-2-phenyl-1H-' pyrrolo [2,3d] pyrimidine. MS (ES) : 352.2 (M-+l) .
4- (3-propionylaminopropyl) amino-5, £*-dimethyl-2-phenyl-7H-
pyrrolo [2,3d]pyrimidine. ;H NMR (200 MHz, CDCIO 5 1.00-1.08
(t, 3H) , 1.71-2.03 (m, 4H), 2.08 (s, 3H) , 2.37 (s, 3H), 3.26-
3.40 (m, 2H), 3.79-3.96 (m, 2H), 5.53-5.62 (m, 1H),_6.17-6.33
(m, 1H) , 7.33-7.57 (m, 3H), 8.31-8.39 (m, 2H) , 9.69 (s, 1H) ;
MS (ES): 352.2 (M1+l).
4- (2 -methylsulf onylaminoethyl) amino-5 , pyrrolo [2,3d]pyrimidine. "H NMR (200 MHz, CDC13) 6 2.18 (s, 3H), 2.27 (s, 3H), 2.92 (s, 3H) , 3.39-3.53 (m, 2H) , 3.71-3.88 (m, 2H) , 5.31-5.39 (m, 1H), 6.17-6.33 (m, 1H) , 7.36-7.43 (m, 3H), 8.20-8.25 (m, 2H) , 9.52 (s, 1H); MS (ES): 360.2 (M1+l).
Exajaple 6:
A mixture of 4-chloro-5, 6-dimethyl-2-:phehyl-7H-pyrrolo [2 , 3d] pyrimidine (0.70 g, 2.72 mmol) and 1,2-diaminoethane (10.0 mL, 150 mmol) was refluxed under inert atmosphere for 6 hr. The excess amine was removed in vacuo, the residue was washed sequentially with ether and hexane to give 0.75 g (98%) of 4-(2-aminoethyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo [2,3d] pyrimidine. MS (ES) ; 282.2 (M-+l) , 265.1 (M1-NH3) .
I Example 7:
To a solution of 4-(2-aminoechyl)amino-5,6-dimechyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine (70.0 mg, 0.24 9 mmol) and
triethylamine (50.4 mg, 0.498 mmol) in dichloromethane (2.0

mL) was added propionyl chloride (25.6 mg, 0.024 mL, C.27-. mmol) at 0°C. After 1 hr, the mixture was concentrated z~ vacuo and the residue was subjected to preparative thin layer chromatography (EtOAc) to give 22.0 mg (26%) of 4-(2-propionylaminoethyl)amino-5,6-dimethyl-2-phenyl -7H-pyrrolo[2,3d]pyrimidine. MS (ES) : 338.2 (M1+l) .
The following compounds were obtained in a similar manner as that of Example 7:
4-(2-N'-methylureaethyl)amino-5,6-dimethyl-2-phenyl-1H-pyrrolo [2,3d]pyrimidine. ;H NMR (2 00 MHz, CDC1?) 5 2.13 (s, 3H) , 2.32 (s, 3H), 3.53 (d, 3H), 3.55 (m, 2H), 3.88 (m, 2H) , 4.29 (m, 1H), 5.68 (t, 1H) , 5.84 (m, 1H) , 7.42 (m, 3H), 8.36 (dd, 2H), 9.52 (s, 1H); MS (ES): 339.3 (M- + l).
4- (2-N' -ethylureaethyl) amino-5 , 6 --dimethyl -2 -phenyl- 1H-pyrrolo[2,3d]pyrimidine. MS (ES): 353.2 (M1+l).
Example 8:
To a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (41.1 mg, 0.215 mmol), dimethylamino-pyridine (2.4 mg, 0.020 mmol) and pyruvic acid (18.9 mg, 0.015 mL, 0.215 mmol) in dichloromethane (2.0 mL) was added 4- (2-aminoethyl) amino-5, 6-dimethyl-2-phenyl-7H-pyrrolo [2, 3d] pyrimidine (55.0 mg, 0.196 mmol). The; mixture was stirred at room temperature for 4 hr. Usual workup and column chromatography (EtOAc) then gave 10.0 mg (15%) of 4-(2'-pyruvylamidoethyl)amino-5,6-dimethyl-2-phenyl-7Jf-
pyrrolo[2,3d]pyrimidine.. MS (ES): 352.2 (M-+l).
Example 9:
To a solution of 4 -(2-aminoethyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine (60.0 mg, 0.213 mmol) in
dichloromethane (2.0 mL) was added N-trimethylsilyl isocyanate (43.3 mg, 0.051 mL, 0.320 mmol). The mixture was
stirred at room temperature for 3 hr followed by addition of aqueous sodium bicarbonate. After filtration through small amount of silica gel, the filtrate was concentrated in vacuo ro dryness to give 9.8 mg (14%) of 4- (2-ureaethyl) amino-3, 6-dimethyl-2-phenyl-7H-pyrrolo [2, 3d]pyrimidine. MS (£S) : 325.2 (M-+l) .
The following compounds were obtained in a similar manner as that of Example 9:
dJ-4- (2-acetylaminopropyl)amino-5, 6-dimethyl-2 -phenyl-7H-
pyrrolo[2,3dJpyrimidine. :H NMR (200 MHz, CDCl,) 5 1.28-1.32 (d, J=8 Hz, 3 H), 1.S6 (s, 3H) , 1.96 (s, 3H5 , 2.30 (s, 3H) 3.76-3.83 (m, 2H), 4.10-4.30 (m, 1H) , 5.60-5.66 (t, J=6 Hz, 1H) , 7.40-7.51 (ra,. 3H) , 8.36-8.43 (m, 2H) , 10.83 (s, 1H) ; MS (ES): 338.2 (M-+l).
(R)-4-(2-acetylaminopropyl)amino-5, 6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. :H NMR (200 MHz, CDC13) 6 1.31 (d, 3H), 1.66 (s, 3H) 1.99 (s, 3H) , 2.31 (s, 3H), 3.78-3.83 (m, 2H) , 4.17-4.22 (m, 1H), 5.67 (t, 1H) , 7.38-7.5 (m, 3H) , 8.39
(m, 2H), 10.81 (s, 1H); MS (ES): 338.2 (M-+l).
(R) -4 - (1-methyl- 2-acetylaminoethyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. :H NMR (200 MHz. CDCl,) 6 1.41 (d, 3H), 1.68 (s, 3H) , 2.21 (s,3H), 2.34 (s, 3H), 3.46-3.52 (br, m, 2H), 4.73 (m, 1H) , 5.22 (d, 1H), 7.41-7.46 (m, 3H) . 8.36-8.40 (tn, 2H) , 8.93 (s, 1H) ; MS (ES) : 338.2 (M-+l).
(S)-4-(2-acetylaminopropyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. ;H NMR (200 MHz, CDC13) 6 1.31 (d, 3H) , 1.66 (s, 3H) 2.26 (s, 3H) , 2.35 (s, 3H) , 3.78-3.83 (m, 2H) , 4.17-4.22 (m. 1H) , 5.67 (t, 1H) , 7.38-7.5 (m, 3H) , 8.39 (m, 2H), 8.67(s, 1H); MS (ES): 338.2 (M-+l).
(S)-4-(l-methyl-2-acetylaminoechyl)amino-5,6 -dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. :H NMR (200 MHz, CDC10 6

1.41 (d, 3H) , 1.68 (s, 3H), 2.05 (s, 3H) , 2.32 is, 3KJ , 3.46-3.52 (m, 2H), 4.73 (m, 1H) , 5.22 (d, 1H), 7.41-7.46 Cm, 3K: . 8.36-8.40 (m, 2K) , 10.13 (s, 1H) ; MS (ES) : 338.2 (M^l).
gxanple 10:
Reaction of 4-chloro-5,6-dimethyl-2-phenyl-7H-pyrrolo [2,3d] pyrimidine with the mixture of dl-l-amino-2- (1,1 -dimethyl
ethoxy)carbonylamino-propane and dl-2-amino-1- (1,1-dimethyl
ethoxy) carbonyl amino-propane was run in a similar manner as that of Example 1. The reaction gave a mixture of c?2-4-(l-
methyl-2- (1,1-dimethylethoxy)carbonylamino)ethylamino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2, 3d]pyrimidine and dI-4-{2-
methyl-2-(1,1-dimethylethoxy)carbonylamino)ethylamino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine which were separated by column chromatography ('EtOAc.-hexanes=l: 3) . The first fraction was dl -4-(l-methyl-2-(1,1-dimethylethoxy)
carbonylaminoethyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo [2,3d]pyrimidine: :H NMR (200 MHz, CDCl,) 6 1.29 - 1.38
(m, 12 H) , 1.95 (s, 3H) , 2.31 (s, 3H) 3.34-3.43 (m, 2H) , 4.62-4.70 (m, 1H), 5.36-5.40 (d, J.8 Hz, 1H), 5.53 (br, 1H) , 7.37-7.49(m, 3H), 8.37-8.44(m, 2H), 10.75 (s, 1H). MS 396.3
(M1+l) ,- The second fraction was dl -4 - (2- (1,1-
dimethylethoxy)carbonylaminopropyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo [2. 3d] pyrimidine: : Hi NMR (200 MHz, CDC1J 5 1.26-1.40 (m, 12 HK 2.00 (s. 3H) , 2.3.1 (s. 3H) 3.60-3.90 (m. 2H), 3.95-4.10 (m, 1H), 5.41-5.44 (d, J=6.0Hz, 1H), 5.65Cbr, 1H) , 7.40-7.46(m, 3H) , 8.37-8.44 (m, 2H) , 10.89 (s, 1H) ; MS (ES) : 396.2 (M1*l) .
The following compounds were obtained in a similar manner as that of Example 10:
!
(S,S)-4-(2-acetylaminocyclohexyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo [2,3d] pyrimidine. :K NMR (200 MHz, CDC13) 6_1.4 3 (m, 4 H) , 1.60 (s, 3 H), 1.83 (m, 2 H) , 2.18 (s, 3 H) . 2.30 (m, 2 H) , 2.32 (s, 3 H), 3.73 (br, 1H), 4.25 (br, 1H), 5.29 (d, 1H) , 7.43-7.48 (m, 3H) , 8.35-8-40 (m, 2H) , 9.05 (s, 1 H) .
4- (2-methyl-2-aeetylaminopropyl) amino-S, 6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. :H NMR (200 MHz, CDCIO 5_1.5l (s, 6H) , 1.56 (S, 3H) , 2.07 (s, 3H) , 2.36 (s. 3H), 3.76 (d, 2K) , 5.78 (t, 1H), 7.41-7.48 (m, 3H) , 7.93 (s, 1H) , 8.39 (m, 2H) , 10.07 (s, 1H); MS (ES): 352.3 (M-+l).
Example 11:
dl-4-(l-methyl-2-(1,l-dimethylethoxy) carbonyl aminoethyl)
amino-5, 6-dimethyl-2-phenyl-7H-pyrrolo [2, 3d] pyrimidine (60 .6 mg, 0.153 mmol) was treated with trifluoroacetic acid (0.5 mL) in dichloromethane (2.0 mL) for 14 hr. The organic solvent was removed in vacuo to dryness. The residue was
dissolved in N,N-dimethylformamide (2.0 mL) and triethylamine (2.0 mL) . To the solution at 0°C was added acetic anhydride (17.2 mg, 0.016, 0.169 mmol). The resulted mixture was stirred at room temperature for 4 8 hr and then concentrated in vacuo to dryness. The residue was subjected to preparative
thin layer chromatography (EtOAc) to give 27.0 mg (52%) of dl-4-(l-methyl-2-acetylaminoethyl)amino-5,6-dimethyl-2-
phenyl-7H-pyrrolo [2,3d]pyrimidine. :H NMR (200 MHz, CDCIO 6 1.38-1.42 (d, J=8 Hz, 3 H) , 1.69 (s, 3H), 2.01 (s, 3H) , 2.32 (s, 3H) 3.38-3.60 (m, 2H), 4.65-4.80 (m, 1H), 5.23-5.26 (d, J=6 HZ, 1H), 7.40-7.51(m, 3H), 8.37-8.43(m, 2H), 10.44 (s, 1H); MS (ES): 338.2 (M1+l).
Example 12:
(R,R) -4- (2-aminocyclohexyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo [2,3d] pyrimidine, prepared in a similar manner as that of Example 1 from 4-chloro-5,6-dimethyl-2-phenyl-7H-
pyrrolo[2,3d]pyrimidine (0.15 g, 0.583 mmol) and (1R, 2R)- (-)-1,2-diaminocyclohexane (0.63 g, 5.517 mmol), was treated with triethylamine (0.726 g, 7.175 mmol) and acetic anhydride (0.325 g, 3.18 mmol) in N,N-dimethylformamide (10.0 mL) at room temperature for 2 hr. After removal of solvent in vacuo,
ethyl acetate (10.0 mL) and water (10.0 mL) were added to the residue. The mixture was separated and the aqueous layer was

oxohexyl)amino-5, 6-dimethyl-2-phenyl-7H-pyrrcio [2. 3d; pyrimidine. MS (ES) : 353.2 (M1+l) .
Example 15:
A solution of 4-(2-aminoethyl)amino75,6-dimethyl-2-phenyi-7H-
pyrrolo[2,3d]pyrimidine (70.0 mg, 0.249 mmol) and succinic anhydride (27.0 mg, 0.274 mmol) in dichloromethane (4.0 mL) with r-drop of N,N-dimethylf ormamjide was stirred at room temperature for 4 hr. The reaction mixture was extracted with 20% sodium hydroxide (3 x 5.0 mL) . The. aqueous solution was acidified with 3 M hydrochloride to pH = 7.0. The whole mixture'was extracted with ethyl acetate (3 x 10 mL) . The combined organic solution was dried UMgSOJ and filtered. The filtrate was concentrated in vacuo to dryness to give 15.0 mg
(16%) of 4-(7-hydroxy-3-aza-4,7-dioxoheptyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS (ES) : 382.2 (M1+l) .
Example 16:
To 10 mL of dime thy lformamide (DMF) at room temperature were added 700 mg of ,4-cis-3-hydroxycyclopentyl) amino-2-phenyl-
5, 6-dimethyl-7H-pyrrolo [2. 3d] pyrimidine followed by 455 mg of N-Boc glycine, 20 mg of N,N-dimethylatninopyridine (DMAP) , 293 mg of hydroxybenzotriazole (HOBT) and 622 mg of l-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (EDCl). The reaction mixture was left stirring overnight. DMF was then removed under reduced pressure and the reaction mixture was partitioned between 20mL of ethyl acetate and 50mL of water. The aqueous portion was extracted further with 2x2OmL of ethyl acetate and the combined organic portions were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification on silica gel, eluting Iwith ethyl acetate/hexane gave 410 mg of the desired product : 4-(cis-3-(N-t-butoxycarbonyl- 2-aminoacetoxy) cyclopentyl) amino-2-phenyl-5 , 6,-dimethyl-7H-pyrrolo[2,3d] pyrimidine, MS (ES) (M1+l)=480.2. The1 ester was then treated

with 5 mL of 20% trifluoroacetic acid in dichloromethane at room temperature, left over night and then concentrated. Trituration, with ethyl acetate gave 300 rag of an off white solid; 4- (cis-3- (2-aminoacetoxy)cyclopentyl) aminc-5, 6-dimethy 1-2-phenyl-7H-pyrrolo[2,3d]pyrimidine trifluoroacetic acid salt, MS (ES) (M-+l)-380.1.
One skilled in the art will appreciate that the following compounds can be synthesized by the6methods disclosed above:
4-(cis-3-hydroxycyclopentyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d] pyrimidine MS (ES) (MT+1)= 323.1.
4-(cis-3-(2-aminoacetoxy)cyclopentyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2, 3d] pyrimidinetrifluoroacetic acid salt MS (ES) (M1+i) = 380.1.
4- (3-acetamido)piperidinyl-5, 6-dimethyl - 2-phenyl-7H-pyrrolo[2,3d]pyrimidine MS (ES) (M- + l) = 364.2.
4-(2-N'-methylureapropyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2, 3d] pyrimidine, MS (ES) (M1+I)-353.4 .
4- (2-acetamidobutyl)amino-5,6 - d« 352.4.
4-(2-N'-methylureabutyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine MS (ES) (M1+D- 3 67.5
4 - (2-aminocyelopropylacetamidoethyl)amino-2-phenyl-7H-pyrrolo[2,3d] pyrimidine MS (ES) (M- + l) = 309.1.
4-(crans-4-hydroxycyclohexyl)amino-2-(3-chlorophenyl)-7H-
pyrrolo [2,3d] pyrimidine MS (ES) (M1 + l} =342 . 8 .
4~(trans-4-hydroxycyclohexyl)amino-2-(3-fluorcphenyl) -7H-pyrrolo [2,3d] pyrimidine MS (ES) (M1 + l) =327 . 2 .
4 -'( trans-4 -hydroxycyclohexyl) amino-2 - (4 -pyridyl) - 7-H-pyrrolo [2, 3d] pyrimidine MS (ES) (M- + l)-310.2.
Example 17
Scheme IX

(Scheme Removed)The pyrrole nitrogen of (7) (Scheme IX) was protected with di-c-butyldicarbonate under basic conditions to yield the
corresponding carbamate (22). Radical bromination of (22)
i proceeded regioselectively to yield bromide (23). In
general, compound (23) served as a key electrophilic
intermediate for various nucleophilic coupling partners.
Displacement of the alkyl bromide with sodium phenolate
trihydrate yielded compound (24). Subsequent displacement of

the aryl chloride and removal of protecting group occurred in one compound (25)...
the t-butyl carbamate step yielding desired
Detailed Synthesis of Confounds (22)-(25) in Accordance with
Scheme XX(Scheme Removed)Di-t-butyl dicarbonate (5.37 g, 24.6 mmol) and dimethyl aminopyridine (1.1.3 g, 9.2 mmol) were added to a solution containing (7) (1.50 g, 6.15 mmol) and pyridine (30 mL) . After 20 h the reaction was concentrated and the residue was partitioned between' CH^Cl, and water. The CH:C1: layer was separated, dried over MgSO,, filtered and concentrated to yield a black solid. Flash chromatography (Si02; 1/9 EtOAc/Hexanes, Rf 0.40) yielded 1.70 g (80%) of a white solid (225. XH NMR (200 MHz, CDC13) 5_8.50 (m, 2H, Ar-H) , 7.45 (m, 3H, Ar-H), 6.39 Is, 1H, pyrrole-H), 2.66 (s, 3H,pyrrole-CH3) , L.76 (s, 9H, :arbamate-
N-Bromosuccinimide (508 mg, 2.86 mmol) and AIBN (112 mg, C.cS mmol) were added to a solution containing (22) (935 mg, 2.71 mmol) and CC14 (50 mL) . The solution was heated to reflux. After 2 h the reaction was cooled to room temperature and concentrated in vacuo to yield a. white solid. Flash chromatography (SiO2; 1/1 CHrCl:/Hexanes, Rf 0.30) yielded 960
mg (84%)of a white solid (23). XH NMR (200 MHz, CDC13) 5__8.52
(m, 2H, Ar-H), 7.48 (m, 3H, Ar-H), 6.76 (s, 1H, pyrrole-H) ,
4.93 (s, 2H, pyrrole- CH&r) , 1.79 (s, 9H, carbamate- CH:.) ; MS,
M * 1 « 423.9; Mpt = 155-157°C.
(Formula Removed)Sodium phenoxide trihydrate (173 mg, 1.02 mmol) was added in one portion to a solution of bromide (23); (410 mg, 0.97 mmol) dissolved in CH,Cl: (5 mL) and DMF (10 mL) . After 2 h the reaction solution was partitioned between CH;C1: and water. The water layer was extracted with CH:C1;. The combined CH;C1: layers were washed with water, dried over MgS04, filtered and concentrated to yield a yellow solid. Flash chromatography (Si02; 1/6 EtOAc/Hexanes, Rf 0.30) yielded 210 mg (50%) of a
white solid (24). LH NMR (200 MHz, CDC13) 6_8.53 (m, 2H, Ar-
H) , 7.48 (m, 3H, Ar-H), 7.34 (m, 2H, Ar-H), 7.03 (m. 3H, Ar-
H) , 6.83 (s, 1H, 'pyrrole-H), 5.45 (s, 2H, ArCH:0) , 1.76 9H, carbamate-CH2) ,- MS, M- = 436.2.
(Formula Removed)A solution containing (24) (85 mg, 0.20 mmol), N-acetylethylenediamine (201 mg, 1.95 mmol) and DMSO (3 mL) was heated to 100°C. After 1 h the temperature was raised to 13 0GC. After 3 h the reaction was cooled to room temperature and partitioned between EtOAc and water. The water layer was extracted with EtOAc (2x). The combined EtOAc layers are washed with water, dried over MgSO-, filtered and concentrated. Flash chromatography (Si02; 1/10 EtOH/ CHCl,, Rf 0.25) yielded 73 mg (93%)of a white foamy solid (25). 1H
NMR (200 MHz, DMS0-d6) 6 11.81 (br s, 1H, N-H) , 8.39 (m,' 2H, Ar-H), 8.03 (br t, 1H, N-H), 7.57 (br t, 1H, N-H), 7.20 -7.50 (m, 5H, Ar-H), 6.89 - 7.09 (m, 3H. Ar-H), 6.59 (s, 1H, pyrrole-H) , 5.12 (s, 2H, ArCtf,0) , 3.61 (m, 2H, NOT-), 3.36 (m, 2H, NCH:) , 1.79 (s, 3H,COCH,); MS, M+ 1 = 402.6
The following compounds were obtained in a manner similar to that of Example 17:
4 - (2-acetylaminoethyl)amino-6-phenoxymethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. mp 196-197°C; MS (ES) .- 401.6 (M1+l).
4 - (2-acetylaminoethyl)amino-6- (4 -fluorophenoxy)methyl-2-phenyl-7H-pyrrolo[2, 3d]pyrimidine. MS(ES): 420.1 (M- + l).
4- (2-acetylaminoethyl) amino-6- (4-chlorophencxy . r.er_yl- z ' phenyl-7H-pyrrolo [2,3d] pyrimidine. MS(ES): 43S.1 .
4 -(2-acecylaminoethyl)amino-6-(4-mechoxyphencxy:methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS(ES): 432.1 (M--i).
4-(2-acetylaminoethyl)amino-6-(N-pyridin-2-one)methyl-2-phenyl-7H-pyrrolo [2,3d]pyrimidine. MS(ES): 403.1 (M-+l).
4- {2-acetylarninoechyl) amino-6- (N-phenylatriino) methyl-2-phenyl-7H-pyrrolo[2,3]pyrimidine. MS(ES): 400.9 (M1+l).
4- (2-acetylaminoethyl) amino-6- (N-methyl-N-phenyiamino)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS(ES): 414.S (M1*i).
4-(2-N1-methylureaethyl)amino-6-phenoxymethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS (ES) : 41S.9 (M1 + l) .
Example 18: Synthesis of adenosine Aj Antagonists.
Compound 1319 and Compound 1320 (Table 13 below) can be synthesized by the general procedures herein.
(Formula Removed)Compound 1319 (81%) ^H-NMR (d,-DMSO) d 1.37 (m, 4H) , 1.93 (m, 2H) , 2.01 (m, 2H) , 4.11 (brs, 1H) , 4.61 (d, 1H, J = 4.4 Hz), 6.59 (m, 1H) , 7.09
Compound 1320 (31%) MS (ES) : 342.1 (M1+l) .
Example 15: Synthesis of adenosine AL Antagonist.
Compound 1321 (Table 13 below) can be synthesized by the oeneral procedures given below.
(Formula Removed)
Compound 28 (10.93g, 50.76 mmol) was dissolved in DMF (67 mL). 4-Amidinopyridine hydrochloride (8.0g, 50.76 mmol) and DBU (15.4 g, 101.5 mmol) were added sequentially and the reaction was heated to 85°C. After 22 hours, the reaction was cooled to room temperature and the DMF was removed in vacuo. The dark oil was diluted with 2M HCl (80 mL) . The reaction was allowed to stand. After 2 hours, the solution was coaled to 10°C and filtered. The solid was washed with cold water and dried to yield 7.40g of a yellow solid, Compound 29 (69*). ;H-NMR (200MHz, d£-DMSO) d 6.58 (s, 1H) , 7.27 (s, 1H) , 8.53 (d, 2H, J - 5.6), 9.00 (d, 2H, J --5.2Hz). 12.35 (brs, 1H). MS (ES): 212.8 (M-+l).
Compound 29 (7.4 mmol, 29.8 mmol) was diluted with POCl, and heated to 105°C. After 18 hours, the reaction is cooled to room temperature and the P0C1? is removed in vacuo. The thick dark oil is diluted with MeOH (75mL) followed by ether (l20mL) . The amorphous red solid is filtered and washed with ether to yield 3.82 g of a red solid. The crude solid is approximately 8.0% pure and used without further purification in the next reaction. MS (ES) : 230.7 (M- + l) .
concentrated. Ethyl ether was added to the crude sample ar.d the resulting solid was filtered to yield lOOtng of a white solid, 32(62%). 'HNMR (200MHz, CDC1,) d 1.75 (s, 9H) , 2.6c (brs, 2H) , 2.79 (brs, 2HJ . 3.86 is, 2H) , 7.46 (rr., 3K) , 6.50 (m, 2K) .
Compound 32 was -combined with . DMSO (3mL) and trans-4-aminocyclohexanol (144mg, 1.25 mmol) and heated to 13 0°C for 4 hours. The reaction was cooled to room temperature, and diluted with EtOAc and H:0. The layers were separated and the aqueous layer was extracted with EtOAc (2x) . The combined organic layers were washed with H:0 and brine, dried over MgS04, filtered and concentrated. Chromatography' (silica, 8:1 CHCl3/EtOHi) yields 32 mg of a tan oil. Ethyl ether was added and the resulting solid was filtered to yield 5 mg of a white solid (9%).OSIC-148265: ;H-NMR (2 00MHz, CD?OD) : d 1.44 (brm, 4H) , 2.03 (brm, 2H) , 2.21 (bx-m, 2H) , 2.70 {brm, BH) , 3.63 (m, 4H) , 3.92 (m, 1H) . 4.26 (brs, 1H) , 6.42 (s, 1H), 7.42 (m, 3H) , 8.33 (m. 2H) .
Example 21 Synthesis of adenosine A1 Antagonist.
Compound 1503 (Table 15 below) can be synthesized by the general procedures given below.
(Formula Removed)Th'e bromide, compound 31 (220 mg, 0.47 mmol) was dissolved in 1:1 DMF:Dichloromethane (5 mL) . To this was added K,CO, (71 mg, 0.52 mmol) and morpholine (0.047 mL, 0.47 mmol). The mixture was allowed to stir at room temperature overnight. Solvents were removed in vacuo and the residue was partitioned between H;0 and dichloromethane. The organic layer
was dried with MgSO, filtered, and concentrated tc give ar. off white solid :which upon trituration with ether/hexanes gave 175mg of a white solid, 33 (84%). :K-NMR (200MHz, CDC13) : ( 1-9 (9H, s), 2.54 (4H. s) , 3.65 (4H, s), 3.85 (IK. s) , 6-59 (1H, s), 7.45 Compound 33 (50 mg, 0.11 mmol) and trans-4-aminocyciohexanol (105 mg, 0.91 mmol) were taken up. in DMSO (2mL) . The resultant solution was sparged with N;: and then heated to lOO^C in an oil bath and stirred overnight. The crude reaction mixture was poured into water and extracted twice with ethyl acetate (50mL) . The combined organic layers were washed with H:0. After drying with MgSO, and filtering, the organic layer was concentrated in vacuo to give an orange solid. Chromatography (silica, 10V CH3OH in CHrCl:) yielded 15mg (33%). :H-NMR ( 200 MHz, CDCl3) : ( 1.24 - 1.62 (4H, m) , 1.85 (2H6 m) , 2.10 (2H, m) , 2.26 (4H, m), 3.53 (4H, m) , 4.22 (1H, rn) , 4.73 (1H, m),i:5.85 (1H, d) , 6.15 (1H, s) , 7.25 (3H, m) , 8.42 (2H, M), 10.0 (1H, s). MS (ES) : 408 (M1 + 1).
Compounds 1500, 1501, and 1502 can be synthesized using similar preparation steps of Example 20 by treating compound 32 with an appropriately substituted amine.
well microtiter plates, such that a final concentration of 2% DMSO was achieved: in all wells. For primary screening, 1-2 concentrations of jtest compounds were utilized (10 µM, lM ) . For compound profiling, 8 concentrations were tested (10000, 1000, 500, 100, 50, 10, 1 and 0.1 nM) . To each microtiter plate, 10 ul of 20% DMSO was added to "Control" and "Total" wells while 10 ul of Test Compound (in 20% DMSO) was added to "Unknown" wells. Subsequently., 10 ul of NECA (5 uM for A:R, 1 uM for A2aR) were added to "Total" and "Unknown" wells; 10 ul of PBS was added, to the "Control" wells. In the final addition, 80 ul of yeast strain, CY83S2 or CY126S0, were added to all wells. All plates were then agitated briefly (LabLine orbital shaker 2-3 min) and allowed to incubate for 4 hrs. at 3 0°C; in a dry oven.
(S-Galactosidase activity can be quantitated using either colorimetric (e.g.,;0NPG, CPRG), luminescent (e.g., Galacton-Star) or fluorometric substrates (e.g., FDG, Resorufin) substrates. Currently, fluorescence detection is preferred on the basis of superior signal:noise ratio, relative freedom from interference and low cost. Fluorescein digalactopyranoside (FDG, Molecular Probes or Marker Gene Technologies) , a fluorescent (3-Galactosidase substrate, was added to all wells: at 20 ul/well (final concentration = 80 uM). Plates were shaken for 5-6 sec (LabLine orbital shaker) and then incubated at 37°C for 90 min (95% 0:/5% C0: incubator). At the end of the 90 min incubation period, 3-Galactosidase activity was stopped using 20 ul/well of IM Na:C03 and all plates shaken for 5-6 sec. Plates were then agitated for 6 sec and relative fluorescence intensity determined using a fluorometer (Tecan Spectrafluor; excitation = 485 nm, emission = 535 nm).
Calculations: Relative fluorescence values for "Control" wells were interpreted as background and subtracted from "Total" and "Unknown" values. Compound profiles were analyzed via logarithmic transformation (x-axis: compound concentration) followed by one site competition curve fitting to calculate
ICcC. values (GraphPad Prism) .
Yeast strains: Saccharomyces cerevisiae strains CY12 66 0 farl1442 tbtl-l fusl-HIS3 canl ste4 : :trpl: :LYS2 ste3*H5c
gpal (41)-Gai3 lys2 ura3 leu2 trpl: his3; LEU2 PGKp-
MfalLeader-hAlR-PH05term 2mu-orig REP3 Ampr] and CY8362 fgpalp-rGasElOK farl*1442 tbtl-l fusl-HIS3 canl stel4::trpl:
LYS2 ste3*115S lys2 ura3 leu2 trpl his3; LEU2 PGKp-hA2aR 2mu-
ori REP3 Ampr] were developed.
LT Media: LT (Leu-Trp supplemented) media is composed of lOOg DIFCO yeast nitrogen base, supplemented with the following: l.Og valine, : 1.Og aspartic acid, 0.75g phenylalanine, 0. 9g lysine, 0.45g tyrosine, 0.45g isoleucine, 0.3g methionine, 0.6g adenine,, 0.4g uracil, 0. 3g serine, 0.3g proline, 0.3g cysteine, 0.3g arginine, 0. 9g histidine and l.Og threonine.
Construction of Yeast Strains Expressing Human A1 Adenosine
Receptor
In this example, the construction of yeast strains expressing a human A: adenosine receptor functionally integrated into the yeast pheromone system pathway is described.
I- Expression Vector Construction
To construct a yeast expression vector for the human Ax adenosine receptor, the A: adenosine receptor cDNA was obtained by reverse transcriptase PGR of human hippocampus mRNA using primers; designed based on the published sequence of the human A: adenosine receptor and standard techniques. The PCR product was subcloned into the Ncol and Xbal sites of the yeast expression plasmid pMP15.
The pMP15 plasmid was created from pLPXt as follows: The Xbal site of YEP51 (Broach, J.R. et al. (1983) "Vectors for high-level, inducible expression of cloned genes in yeast" p. 83-117 in M. Inouye1 (ed.), Experimental Manipulation of Gene Expression. Academic Press, New York) was eliminated by

digestion, end-fill and religation to, 1create Yep51Ncc£Xba.
Another Xbal.site was created at the, BamKI site by digestion
with BamHI, end-fill, linker (New England Biolabs, H 1081)
ligation, Xbal digestion and re-ligation to generate
YEP51NcoXt. This plasmid was digested with Esp31 and NccI
and ligated to Leu2 and PGKp fragments generated by PCR. The
2 kb Leu2 PCR product was generated by amplification from
YSPSlNco using primers containing Esp31. and Bglll sites. The
660 base pair PGKp PCR product was generated by amplification
from pPGKas (Rang, Y.-S. et al. (1990) Mol. Ceil. Biol.
U2:2582-2590) with PCR primers containing Bglll and Ncol
sites. The resulting plasmid is called pLPXt. , pLPXt was
modified by inserting the coding region of the a-factor pre-
pro leader into the Ncol site. The prepro leader was
inserted so that the Ncol cloning site was maintained at the
31 end of the leader, but not regenerated at the 51 end. In
this way receptors; can be cloned by digestion of the plasmid
with Ncol and Xbal. The resulting plasmid is called pMPlS.
The pMP15 plasmid into which was inserted the human Ai adenosine receptor cDNA was designated p5095. In this vector, the receptor cDNA is1 fused to the 3 1 end of the yeast a-factor prepro leader. During protein maturation the prepro peptide sequences are cleaved to generate mature full-length receptor. This occurs during processing of the receptor through the yeast secretory pathway. This plasmid is maintained by Leu selection (i.e., growth on medium lacking leucine) . The sequence of the cloned coding region was determined and found to be equivalent to that in the published literature (GenBank accession numbers S4 523 5 and S56143) .
II. Yeast Strain Construction
To create a yeast strain expressing the human A, adenosine receptor, yeast strain CY7967 was used as the starting parental strain. The genotype of CY7967 is as follows:
MATa gpaD1163 gpal(41)Gai3 farlD1442 tbt-1 FUS1-HIS3

'canl stel4 : :trpl,: :LYS2 sce3D1156 lys2 ura3 leu2 :r?: his3
The genetic markers are reviewed below:
MATa" Mating type a.
gpalDH63 The endogenous yeast G-protein GPAl has
been deleted.
gpal (41)Gcri3...... gpal (41) -Gai3 was integrated into the
i 7. yeast genome. This chimeric Ga protein is
composed of the first 41 amino acids of the endogenous yeast |Ga subunit GPAl fused to the mammalian G-protein Gai3 in which the cognate N-terminal amino acids have been deleted.
farlD1442 FAR1 gene (responsible for cell cycle
arrest) has been deleted (thereby preventing cell cycle; arrest upon activation of the pheromone response pathway).
tbt-l strain with high transformation efficiency
by.electroporation.
FUS1-HIS3 a fusion between the FUS1 promoter and the
HIS3 coding region (thereby creating a
pheromone inducible HJS3 gene).
can 1 arginine/canavinine permease.
stel4::trpl::L gene disruption of STE14, a C-farnesyl
YS2.... methyltransferase (thereby lowering basal
signaling through the pheromone pathway).
ste3D1156.- endogenous yeast STR, the a factor
pheromone receptor (STE3) was disrupted.
Iys2.....~ defect in 2-aminoapid4te reductase, yeast
need lysine to grow. •
ura3 ~. . defect in orotidine-5•-phosphate
decarboxylase, yeast need uracil to grow
leu2.— defect in b-isopropylrrialate dehydrogenase,
yeast need leucine to .grow.
trpl —.. . defect in phosphoribosylanthranilate,
yeast need tryptophan to grow.
his3 defect in imidazoleglyicerolphosphate
dehydrogenase, yeast need histidine to
•grow.

Two plasmids were transformed into strain CY7957 by electroporation: ^plasmid p5095 (encoding human A: adenosine receptor; described above) and plasmi1d pI584, which is a FUSl-3-galactosidase reporter gene plasmid. Plasmid p!584 was derived from plasmid pRS426 (Christianson, T.w. et al. (1992) Gene 1JLQ:,119-1122) . Plasmid pRS425 contains a polylinker site at nucleotides 2004-2016. A fusion between the FUSl promoter and the 3-galactosidase gene was inserted at the restriction sites EagI and Xhol to create plasmid p!584. The pl584; plasmid is maintained by Trp selection (i.e., growth on medium lacking leucine).
The resultant strain carrying p5095 and pl584, referred to as CY12660, expresses1the human Ax adenosine receptor. To grow this strain in liquid or on agar plates, minimal media lacking leucine and tryptophan was used. To perform a growth assay on plates (assaying FUS1-HIS3) , the plates were at pH 6.8 and contained 0.5-2.5 mM 3-amino-l,2,4-triazole and lacked leucine, tryptophan and histidine. As a control for specificity, a comparison with one or more other yeast-based seven transmembrane receptor screens was included in all experiments.
Construction of Yeast Strains Expressing Human A2a Adenosine
Receptor
In this example, the construction of yeast strains expressing
a human A2a adenosine receptor functionally integrated into
the yeast pheromone system pathway is described.
I. Expression Vector Construction
To construct a yeast expression vector for the human A2a adenosine receptor, the human A2a receptor cDNA was obtained from Dr. Phil Murphy (N1H) . Upon receipt of this clone, the A2a receptor insert was sequenced and :found to be identical to the published sequence (GenBank accession H S4S950) . The receptor cDNA was; excised from the plasmid by PCR with VENT polymerase and cloned into the plasmid pLPBX, which drives receptor expression by a constitutive: Phosphoglycerate Kinase (PGK) promoter in yeast. The sequence of the .entire insert was once again sequenced and found to be identical with the published sequence. However, by virtue of the cloning strategy employed1there were three amino acids appended to the carboxy-terminus of the receptor, GlySerVal.
II. Yeast Strain Construction
To create a yeast strain expressing the human A2a adenosine receptor, yeast strain CY8342 was used as the starting parental strain. The genotype of CY8342 is as follows: MATa farlD1442 tbtl-1 lys2 ura3 leu2 trpl his3 fusl-HIS3 canl ste3D1156 gpaDll63 stel4::trpl::LYS2 gpalp-rGasElOK (or gpalp-rGasD229S or gpalp-rGasE10K+D229S)
The genetic markers are as described in Example 1, except for the G-protein variation. For human A2a receptor-expression, yeast strains were utilized in which the endogenous yeast G protein GPA1 had been deleted and replaced by a mammalian Gas. Three rat Gas mutants were utilized. These variants contain one or two point mutations which convert them into proteins which couple efficiently to yea1st 3v. They are identified as G3,E10K (in which the glutamic acid ,at position ten is
replaced with lysine) , G3.D229S (in which the aspartic acid sz position 229,is replaced wich serine) and G5E10K+D22?S (which contains both point mutations).
Strain CY8342 (carrying one of the three mutant rat 1 Gas proteins) was transformed with either the parental vector pLPBX (Receptor") or with pLPBX-A2a (Receptor"). A plasmid with the FUS1 prompter fused to (3-galactosidase coding sequences (described in above) was added to assess the magnitude of activation of the pheramone response pathway.
Functional Assay .using Yeast Strains Expressing Human A; Adenosine Receptor
In this example, the development of a functional screening assay in yeast for modulators of the human A: adenosine receptor is described.
I. Ligands Used in Assay
Adenosine, a natural agonist for this receptor, as well as two other synthetic: agonists were utilized for development of this assay. Adenosine, reported to have an EC5C of approximately 75 nM, and (-)-N6-(2-phenylisopropyl)-adenosine (PIA) with a reported affinity of approximately 50 nM were used in a subset of experiments. 51-N-ethylcarboxamido-adenosine (NECA) was used in all growth assays. To prevent signaling due to the presence of adenosine in the growth media, adenosine deaminase (4U/ml) was added to all assays.
II. Biological Response in Yeast
The ability of the A: adenosine receptor to functionally couple in a heterologous yeast system was assessed by
introducing the A-^ receptor expression vector (p5095, described above) anto a sjeries of yeast strains that expressed different G protein subunits. The majority of these transformants expressed Ga subunits of the Gai or G00 subtype. Additional Ga proteins were also tested for the possible identification of promiscuous receptor-Ga protein coupling. In various strains, a STE18 or a chimeric STE18-
Gy2 construct was integrated into the genome cf the yeast. The yeast strains harbored a defective HIS3 gene and an integrated copy of FUS1-KIS3, thereby allowing for selection in selective media containing 3-amino-l,2,4-triazole (tested at 0.2, 0.5 and 1.0 mM) and lacking histidine. Transformants were isolated and monolayers were prepared on media containing 3-amino-l,2,4-triazole, 4 U/ml adenosine deaminase .and lacking histidine. Five microliters of various concentrations of ligand (e.g., NECA at 0, 0.1, 1.0 and 10 mM) was applied. Growth was monitored for 2 days. Ligand-dependent growth responses were tested in this manner in the various yeast strains. The results are summarized in Table 1 below. The symbol (-) indicates that ligand-dependent receptor activation was not detected while ( + ) denotes ligand-dependent response. The term "LIRMA" indicates ligand independent receptor mediated activapion.
(Table Removed)
As indicated in Table 3, the most robust signaling was found to occur in a yeast strain expressing che GPA: (41) -GQi3 chimera.
III. fusl-La.eZ Assay
To characterize activation of the pheromone response pathway more fully, synthesis of 3-galactosidase through fuslLacZ in response to agonist,-stimulation was measured. To perform the 0-galactosidase assay, increasing concentrations of ligand were added to mid-log culture of human A, adenosine receptor
expressed in a yeast strain co-expressing a Stel6-Gv2 chimera and GPA41-Gsi3. Transformants were isolated and grown overnight in the presence of histidine and 4 U/ml adenosine deaminase. After five hours of incubation with 4 U/ml adenosine deaminase and ligand, induction of 3-gaiactosidase was measured using CPRG as the substrate for 3-galactoside. 5 x 10 cells were used per assay.
The results obtained with NECA stimulation indicated that at a NECA concentration of 10 M approximately 2-fold stimulation of 3-galactosidase activity was achieved. Moreover, a stimulation index of approximately 10-fold was observed at a NECA concentration of 10~ M.
The utility of this assay was extended by validation of the activity of antagonists on this strain. Two known adenosine antagonist, XAC and DPCPX, were tested for their ability to compete against NECA (at 5 mM) for activity in the 3-galactosidase assay. In these assays, 3-galactosidase induction was measured using FDG as the substrate and 1.6 x 10 cells per assay. The results indicated that both XAC and DPCPX served as potent antagonists of yeast-expressed A1 adenosine receptor, with IC50 values of 44 nM and 49 nM, respectively.
In order to determine if this inhibitory effect was specific to the A1 subtype, a series of complementary experiments were performed with theyeast-based A2a receptor assay (described in Example 4). Results obtained with the A2a yeast-based assay indicated that XAC was a relatively effective A2i receptor antagonist, consistent with published reports. In contrast, DPCPX was relatively inert at this receptor, as expected from published reports.
IV. Radioligand Binding
The A1 adenosine receptor assay was further characterized by measurement of the receptor1s radioligand binding parameters. Displacement binding of [ H]CPX by several adenosine receptor
reference compounds, XAC, DPCPX, and CGS, was analyzed using membranes prepared from yeast expressing the human .V adenosine receptor. The results with yeast membranes expressing the human Ax adenosine receptor were compared to those from yeast membranes expressing the human A2a adenosine receptor or the human A3 receptor to examine the specificity of binding. To perform the assay, fifty mg of membranes were incubated with 0.4 nM ["H]CPX and increasing concentrations of adenosine receptor ligands. Incubation was in 50 mM Tris-HCl, pH 7.4, 1 mM EDTA, 10 mM MgCl2, 0.25 % BSA and 2 U/ml adenosine deaminase in the presence of protease inhibitors for SO minutes at, room temperature. Binding was terminated by addition of ice-cold 50 mM Tris-HCl, pH 7.4 plus 10 mM MgCl2/, followed by rapid filtration over GF/B filters previously soaked with 0.5 % polyethyenimine, using a Packard 96-well' harvester. Data were analyzed by nonlinear least square curve fitting procedure using Prism 2.01 software. The IC50 values obtained in this experiment are summarized in Table 4, below:
Table 4
(Table Removed)These data indicate that the reference compounds have affinities consistent with those reported in the literature. The data further indicate that the yeast-based assays are of sufficient s«:nsit:ivity to discriminate receptor subtype specificity.

Functional Assay using Yeast Strains Expressing Kumar. A2a
Adenosine Receptor
In this example, the development of „a functional screening assay in yeast , for modulators of the human A; adenosine receptor is described.
I. Ligands Used in Assay
The natural ligand adenosine, as well as- -other thoroughly characterized and commercially available ligands were used for study of.the human A2a receptor functionally expressed in yeast-. Three ligands have been used in the establishment of this assay. They include:
T.-igand Reported Ei Function
Adenosine 500 nM agonist
51 ~N-ethylcarboxamidoadenosine 10-15 nM agonist
(NECA) (-)-N6-(2-
phenylisopropyl)-adenosine 100-125 nM agonist
(PIA)
To prevent signaling due to the presence of adenosine in- the growth media, adenosine deaminase (4D/ml) was added to all assays.
II. Biological Response in Yeast
A2a receptor agonists were tested for the capacity to stimulate the pheromone response pathway in yeast transformed with the A2a receptor expression plasmid and expressing either GasE10K, GasD229S or GasEl0K*D:229S. The ability of ligand to stimulate the pheromone response pathway in a receptor dependent manner was indicated by an alteration in the yeast phenotype. Receptor activation modified the phenotype from histidine auxotrophy to;histidine prototrophy (activation of fusl-HIS3). Three independent transformants were isolated atnd grown overnight in the presence of histidine. Cells were washed to remove histidine and diluted to 2 x 10 cells/ml. 5 µ1 of each transformant was spotted onto nonselective media (including histidine) or selective

to S x 10e cells/ml. 1 x 10 "cells were spread onto selective plates°containing 4 U/ml adenosine deaminase and 0.5 or 1.0 mM 3-amino-l, 2,4-triazole (AT) and allowed to dry for 1 hour. 5µ1 of the following reagents were applied to the monolayer: 10 mM adenosine, 38.7 mM histidine, dimethylsulfoxide (DMSO) , 10 mM PIA or 10 mM NECA. Cells were grown 24 hours at 3 0°C. The results showed that cells without receptor could only grow when histidine was added to the media. In contrast, R1 cells only grew in areas where the A2a receptor; ligands PIA and NECA had been spotted. Since the plates contained adenosine deaminase, the lack of growth where adenosine had been spotted confirmed that adenosine deaminase was active.
III. fusl LacZ Assay
To quantitate activation of the yeast mating pathway, synthesis of [3-galactosidase through: fuslLacZ was measured.
Yeast strains expressing aE10K, G„D229S or CXSE10K+D229S were transformed with a plasmid encoding the human A2a receptor (R+) or with a plasmid lacking; the receptor (R-) . Transformants were isolated and grown overnight in the presence of histidine and 4 U/ml adenosine deaminase. 1 x 10 cells were diluted to 1 x 10 cells/ml and exposed to increasing concentrations of NECA for 4 hours, followed by determination of the 3-galactosidase activity in the cells. The results demonstrated that essentially no (3-galactosidase activity was detected in R- strains, whereas increasing amounts of 3-galactosidase activity were detected in R+ strains expressing teither G„E10K, G3.D229S or G3JE10K+P229S as the concentration of NECA increased, indicating a dose dependent increase in units of B-galactosidase detected in response to exposure to increased ligand concentration. This dose dependency was? only observed in cells expressing the A2a receptor. Furthermore the most potent 1 G,„ construct for the A2a receptor was GOJE10K. The GOID22 9S construct was the second-most potent Gai construct for the A2a receptor, while the GOJE10K+D229S construct was the least potent of the three


G33 constructs tested, although even the G3JElOK-rD229S construct stimulated readily detectable amounts of 5-galactosidase activity.
For a further description of the assays identified, see U.S. Application Serial No. 09/088985, entitled "Functional Expression of Adenosine Receptors in,Yeast", filed June 2, 1998 (Attorney Docket No. CPI-093) , the entire contents of which are hereby incorporated herein by reference.
Pharmacological Characterization of the Human Adenosine Receptor Subtypes
Material and Methods
Materials. [ H] -DPCPX [Cyclopentyl-1,3-dipropylxantine, 8-
[dipropyl-2,3-3H(N)] (120.0 Ci/mmoi); [3H]-CGS 21680, [carboxyethyl-3H (N) ] (30 Ci/mmol)! and [l"I] -AB-MECA { [ I]-4-Aminobenzyl-51-N-Methylcarboxamideoadenosine) (2,200 Ci/mmol) were purchased from New England Nuclear (Boston, MA). XAC (Xantine amine congener); NECA (51-N-Ethylcarboxamidoadenosine); and I3-MECA from Research Biochemicals International (RBI, Natick, MA) . The Adenosine Deaminase and Complete protease inhibitor cocktail tablets were purchased from Boehringer Mannheim Corp. (Indianapolis, IN). Membranes from HEK-293 cells stably expressing the human Adenosine 2a [RB-HA2a] ; Adenosine 2b [RB-HA2b] or Adenosine 3 [RB-HA3] receptor subtypes, respectively were purchased from Receptor Biology (Beltsville, MD). Cell culture reagents were from Life Technologies (Grand Island, NY) except for serum that was from Hyclone (Logan, UT).
yeast strains: Saccharomyces cerevisiae strains CY12660
[farl*1442 tbtl-1 fusl-HIS3 canl ste14::trpl::LYS2 ste3*1156 gpal (41) -Gori3 lys2 ura3 leu2 trpl: his3; LEU2 PGKp-MfalLeader-hAlR-PH05term 2mu-orig REP3 Ampr] and CY8362
[gpalp-rGasElOK farl*1442 tbtl-1 fusl-HIS3 canl stel4::trpl: LYS2 ste3*1156 lys2 ura3 leu2 trpl his3,- LEU2 PGKp-hA2aR 2mu-


ori REP3 Ampr] were developed as described above.
Yeast culture: Transformed yeast were grown in Leu-Trp [LT]
media (pH 5.4) supplemented with 2 glucose. For the preparation of membranes 250 ml of LT medium were inoculated with start titer of 1-2 x 10 cells/ml from a 30 ml overnight culture and incubated at 30°C under permanent oxygenation by rotation. After 16 h growth the cells were harvested by centrifugation and membranes were prepared as described below.
Mammalian Tissue Culture: The HEK-293 cells stably expressed
human Adenosine 2a receptor subtype (Cadus clone H 5) were grown in Dulbeco1s minimal essential media (DMEM) supplemented with 10% fetal bovine serum and IX penicillin/streptomycin under selective pressure using 500 mg/ml G418 antibiotic, at 3 7°C in a humidified 5% C02 atmosphere.
Yeast Cell Membrane Preparations: 250 ml cultures were
harvested after overnight incubation by centrifugation at 2,000 x g in a Sorvall RT6000 centrifuge. Cells were washed in ice-cold water, centrifuged at 4°C and the pellet was resuspended in 10 ml ice-cold lysis buffer [5 mM Tris-HCl, pH 7.5; 5 mM EDTA; and 5 mM EGTA] supplemented with Protease inhibitor cocktail tablets (1 tablet per 25 ml buffer). Glass beads (17 g; Mesh 4 00-6 00; Sigma) were added to the suspension and the cells were broken by vigorous vortexing at 4°C for 5 min.. The homogenate was diluted with additional 3 0 ml lysis buffer plus protease inhibitors and centrifuged at 3,000 x g for 5 min. Subsequently the membranes were peleted at 3S,000 x g (Sorvall RC5B, type SS34 rotor) for 45 min. The resulting membrane pellet was resuspended in 5 ml membrane buffer [50 mM Tris-HCl, pH 7.5; 0.6 mM EDTA; and 5 mM MgCl2l supplemented with Protease inhibitor cocktail tablets (1 tablet per 50 ml buffer) and stored at -80 °C for further experiments.
Maxnmalian Cell Membrane Preparations: ;HEK-293 cell membranes were prepared as described previously (Duzic E ez al. .- J. Biol. Cheat., 2S7, 9844-9851, 1992) Briefly, cells were washed with PBS and harvested with a rubber policeman. Cells were pelted at 4°C 200 x g in a Sorvall RT6000 centrifuge. The pellet was resuspended in 5 ml/dish of lysis buffer at 4CC (5 mM Tris-HCl, pH 7.5; 5 mM EDTA; 5 mM EGTA; 0.1 mM Phenylmethylsulfonyl fluoride, 10 mg/ml pepstatin A; and 10 mg/ml aprotinin} and homogenized in a Dounce homogenizer. The cell lysate was then centrifuged at 36,000 x g (Sorvall RC5B, type SS34 rotor) for 4 5 min and the pellet resuspended in 5 ml membrane buffer [50 mM Tris-HCl, pH 7.5; 0.6 mM EDTA; 5 mM MgCl2; 0.1 mM Phenylmethylsulfonyl fluoride, 10 mg/ml pepstatin A; and 10 mg/ml aprotinin) arid stored at -80 °C for further experiments.
The Bio-Rad protein assay kits, based on the 3radford dye-binding procedure, (Bradford, M. : Anal. Biochem. 72:248
(1976)) were used to determine total protein concentration in yeast and mammalian membranes.
Adenosine 1 receptor subtype saturation and competition
radioligand binding: Saturation and competition binding on
membranes from yeast cell transformed with human A1 receptor subtype were carried out using antagonist [ H] DPCPX as a radioactive ligand. Membranes was diluted in binding buffer [50 mM Tris-HCl, pH 7.4; containing 10 mM MgCl2; 1.0 mM EDTA; 0.25% BSA; 2 U/ml adenosine deaminase and 1 protease inhibitor cocktail tablet/50 ml] at concentrations of 1.0 mg/ml.
!
In saturation binding membranes (50 ^g/well) were incubate with increasing concentrations of [ H] DPCPX (0.05 - 25 nM) in a final volume of 100µl of binding buffer at 25°C for 1 nr in the absence and presence of 10 MM unlabeled XAC in a 96-well microtiter. plate.

In competition binding membranes (50 jig/well) were incubate with [ H] DPCPX (1.0 nM) in a final volume of 100 mi of binding buffer at 25°C for 1 hr in the absence and presence of 10 µM unlabeled XAC or increasing concentrations of competing compounds in a 96-well microtiter plate.
Adenosine 2a receptor subtype competition radioligand binding: Competition binding on membranes from HEK293 cell-stably expressing the human A2a receptor subtype were carried out using agonist [ H] CGS-21680 as a radioactive ligand. Membranes was diluted in binding buffer [50 mM Tris-HCl, pH 7.4; containing 10 mM MgCl2; 1.0 mM EDTA; 0.25% BSA; 2 U/ml adenosine deaminase and 1 protease inhibitor cocktail tablet/50 ml] at concentrations of 0.2 mg/ml. Membranes (10 fig/well) were incubate with [ H] CGS-21680 (100 nM) in a final volume of 100 ml of binding buffer at 25°C for 1 hr in the absence and presence of 50 µM unlabeled NECA or increasing concentrations of competing compounds, in a 96-well microtiter plate.
Adenosine 3 receptor competition radioligand binding:
Competition binding on membranes from HEK293 cell stably
expressing the human A3 receptor subtype were carried out
12 5 using agonist [ I] AB-MECA as a radioactive ligand.
Membranes was diluted in binding buffer [50 mM Tris-HCl, pH
7.4; containing 10 mM MgCl2; 1-0 mM EDTA; 0.25% BSA; 2 U/ml
adenosine deaminase and 1 protease inhibitor cocktail
tablet/50 ml] at concentrations of 0.2 mg/ml. Membranes (10
jig/well) were incubate with [125I] AB-MECA (0.75 nM) in a
final volume of 100 µ1 of binding buffer at 25°C for 1 hr in
the absence and presence of 10 µM unlabeled IB-MECA or
increasing concentrations of competing compounds in a 96-well
microtiter plate.
At the end of the incubation, the A1H A2a and A3 receptor subtypes radioligand binding assays was terminated by the addition of ice-cold 50 mM Tris-HCl (pH 7.4) buffer
supplemented with 10 mM MgCl2, followed by rapid µ1tration over glass fiber µ1ters (96-well GF/3 UniFilters, Packard! previously presoaked in 0.5% polyethylenimine in a Filtermate 196 cell harvester (Packard). The µ1ter plates were dried coated with 50 µ1 /well scintillation1fluid (MicroScint-20, Packard) and,counted in a TopCount (Packard). Assays were performed in triplicate. Non-specific binding was 5.6 = 0.5%, 10.8 * 1.4% and 15.1 ± 2.6% of the total binding in a AIR, A2aR and A3R binding assay, respectively.
Adenosine 2b receptor subtype competition radioligand binding: Competition binding on membranes from KEK293 cell
stably expressing the human A2b receptor subtype .were carried out using A1 receptor antagonist [ H] DPCPX as a radioactive ligand. Membranes was diluted in binding buffer [10 mM Hepes-KOH, pH 7.4; containing 1.0 mM EDTA; 0.1 mM Benzamidine and 2 U/ml adenosine deaminase] at concentrations of 0.3 mg/ml. Membranes (15µg/well) were incubate with [ H] DPCPX (15 nM) in a final volume jof 100 µ1 of binding buffer at 25°C for 1 hr in the absence and presence of 10 µM unlabeled XAC or increasing concentrations of competing compounds in a 96-well microtiter plate. At the end of the incubation, the assay was terminated by the addition of ice-cold 10 mM Hepes-KOH (pH 7.4) buffer followed by rapid µ1tration over glass fiber µ1ters (96-well GF/C UniFilters, Packard) previously presoaked in 0.5% polyethylenimine in a Filtermate 196 cell harvester (Packard). The µ1ter plates were dried coated with 50 µI/well scintillation fluid (MicroScint-20, Packard) and counted in a TopCount (Packard) . Assays .were performed in triplicate. Non-specific binding was 14.3 + 2.3% of the total binding.
Specific binding of [3H] DPCPX; [3H] CGS-21680 and [125I] AB-MECA was defined as the difference between the total binding and non-specific binding. Percent inhibition of the compounds was calculated against total binding. Competition data were analyzed by iterative curve fitting to a one site model, and
KT values were calculated from IC50 values (Cheng and Pruscf, Biochem. Pharmacol. 22, 3099-3109, 1973) using the GraphPai Prizm 2.01 software.
Results
A primary function of certain cell surface receptors is to recognize appropriate ligands. Accordingly, we determined ligand binding affinities to establish the functional integrity of the Adenosine 1 receptor subtype expressed in yeast. Crude membranes prepared from Saccharomyces
cerevisiae transformed with human Adenosine 1 receptor
subtype construct exhibited specific saturable binding of [ H] DPCPX with a KD of 4(O ± 0.19 nM. The KD and Bmax value were calculated from the saturation isotherm and Scatchard transformation of the data indicated a single class of binding sites. The densities of adenosine binding sites in the yeast membrane preparations were estimated to 716.8 43.4 fmol/mg membrane protein.
The pharmacological subtype characteristics of the recombinant yeast cells transformed with human1 A1 receptor subtype were investigated with subtype selective adenosine ligands (XAC. DPCPX; CGS-15943; Compound 600; Compound 1002; NECA, (R)-PIA; IB-MECA and Alloxazine) that competed with [3H] DPCPX in the expected rank order. Displacement curves recorded with these compounds show the typical steepness with all the ligands, and the data for each of the ligands could be modeled by a one-site fit. The apparent dissociation constants estimated for the individual compound from the curves (Table 5) are consistent with value published for the receptor obtained from other sources.
Table 5 Ki values for membranes from yeast cells transformed with human A1 receptor subtype
(Table Removed)Tables 6 through 12 demonstrate the efficacy and structure activity proµ1es of deazapurines of the invention. Tables 13 and 14 demonstrate selectivity can be achieved for human adenosine receptor sites by modulation of the functionality about the deazapurine structure. Table1 14 also demonstrates the surprising discovery that the compounds set forth therein have subnanomolar activity and higher selectivity for the A,„ receptor as compared to the compounds in Table 13.
TABLE 6
TABLE 7
(Table Removed)Effect of Cµ-Subsiiiuent


(Table Removed)TABLE 8
Effect of Pmoie Rine Substkueni
(Table Removed)TABLE 9


(Table Removed)TABLE 10
Effect of Nµ-Subsriruent
(Table Removed)Effecr of Ng-Subsiiru«r.
TABLE11; "Reiro-Amide" Anaioeues
(Table Removed)TABLE 13
Proµ1e ofSelective Adenosine Antagonists


(Table Removed):2-thienyl-2-yi; -C5-H;-" water soluble:4 R, and R, are hydrogen:1 Rj is 3-fluorbprienyl: • R, is 3-chlorophenyl;r R, is 4-pyridyl:* % activity :2> 10 µµM

(Table Removed)Table 14: Proµ1e of Selective AJb Antagonists
(Table Removed)TABLE 15. Adenosine A1 Receptor Selective Compounds * at least 10 times more selective than other three subtvpes.


independently alkyl or cycloalkyl, or 4**., -ft* and the nitrogen together form.a substituted or unsubstituted ring of between 4 and 7 members.
ft.
wherein -% is wherein Rj is- K, alkyl,: substituted alkyl, or
cycloalkyl;
with the proviso that NR1R2 is not 3-acetamido piperadino, 3-hydroxy pyrrolidine 3-methyloxy carbonylmethyl pyrrolidine, 3-aminocarbonylmethyl, or pyrrolidino; with the proviso that NR;R: is 3-hydroxymethyl piperadino only when A1is 4-pyridyl.
This invention also features a method for inhibiting the
activity of an A2a adenosine receptor in a cell, which
comprises contacting said cell with the above-mentioned
compounds. :
This invention also provides a compound having the structure:

[VI)
wherein NRjR, is a substituted 1or unsubstituted 4-8
membered ring; I
I
wherein Az is a substituted or unsubstituted four to six
(Formula Removed)
membered ring;
wherein -R«- is H, alkyl, substituted aikyl, aryl,
arylalkyl, amino, substituted1 aryl, wherein said
/?7 R% K Nft*-, wherein--Re- and -Re- are each independently H or alkyl,
wherein R1 and -Rr are each independently alkyl or
cycloalkyl, or £*-, -R6 and the nitrogen together form a
substituted or unsubstituted ring of between 4 and 7
members.
wherein -Rs- is H, alkyl, substituted alkyl, or cycloalkyl;
with the proviso that NR1R2 is not G-acetamido piperadino, 3-hydroxy pyrrolidine, 3-methyloxy carbonylmethyl pyrrolidine 3-aminocarbonylmethyl, or pyrrolidino; with the proviso that NR1R2 is 3-hydroxymethyl piperadino only when As is 4-pyridyl.
In one embodiment of the compound, -A*- is a substituted or unsubstituted four to six membered ring, phenyl, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2 (1H)-pyridone, 4 (1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, tetrazole, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindoie, lH-indole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquin1oline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-bjpyrazine, pyrido[3,2-c]pyridazine , purido[3,4-b]-pyridine, lH-pyrazole [3,4-d]pyrimidine, pteridihe, 2(1H)-quinolone, 1 (2H)-isoquinolone, 1, 4-benzisoxazi1ne, benzothiazole ,
cuinoxaline, quinoline-N-oxide, :1 isoquinoline-N-oxide,
quinoxaline-N-oxide, quinazoline-N-oxide, -benzoxazine,
phthalazine, cinnoline, or having a structure:
wherein Y is carbon or nitrogen;
(Formula Removed)
wherein R3 is ;H, substituted or .. unsubstituted alkyl,
substituted or unsubstituted arylr halogen, methoxy, methyl amino, methyl thio;
In another embodiment of the compound; the compound has the structure:
(Formula Removed)
wherein m is 1 or 2; wherein RA and RB are each independently be H, -0H./-CH20H, -CH2CH2OH, -C(=0)NH2,1a heteroatom, or -C(0)NRjSV; wherein, -% is aryl, substituted aryl, or heteroaryl; wherein -JV is alkyl, or X-ftt" , wherein X is O, or N and -ft" is substituted alkyl or aryl.
In another embodiment of the compound, R1R2N is (D)-2-aminocarbonyl pyrrolidino, (D)-2-hydroxymethyl pyrrolidine

(D;-2-hydroxymethyl-£ra.ns—4-hydroxy pyrrolidine, piperazino, or 3-hydroxymethyl piperadino.
In another embodiment of the compound, the compound has the
structure:

(Formula Removed)

wherein m is 0, 1, 2, or 3; wherein Y is 0, S, or NR, wherein
R is RA or RB; wherein RA and RB are each independently be H, -
OH, -CH2OH, -CH,CK,OH, -C(=0)NH2, a heteroatom, or
-C (=0) N-RjR-5µ-; wherein/-Rj "is aryl, substituted aryl, or
*?„ Kit
heteroaryl; wherein -R-µ is alkyl, or X-R3", wherein X is 0, or
N and 9fµf is substituted alkyl or aryl.
In another embodiment of the compound, ;the compound has the structure:
(Structure Removed)

In another embodiment of the compound, : the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:


(Structure Removed)


In another embodiment of the compound,; the compound has the structure:


(Structure Removed)

In another embodiment of the compound, the compound has the structure:

In another embodiment of the compound, \ the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
In another embodiment of the compound, the compound has the structure:


(Structure Removed)
In yet another embodiment of the compound; the compound has the structure:

(Structure Removed)

In a further embodiment of the compound, •, the compound has the structure:


(Structure Removed)

This invention further provides a compound having the structure (V) ;
(Structure Removed)
wherein -R- is H, or methyl.
In one embodiment of the compound V, the compound has the structure:
(Structure Removed)

In another embodiment of the compound V; the compound has the structure:
(Structure Removed)
This invention also provides a method for treating a disease associated with.A2a adenosine receptor in a subject, comprising administering to the subject a therapeutically effective amount of compounds IV, or V.
In one embodiment of the method, the compound treats said diseases by stimulating adenylate cyclase.
In another embodiment of the method, the subject is a mammal.
In another embodiment of the method, the1mammal is a human.
In another embodiment of the method, said A2a adenosine receptor is associated with Parkinson1s disease and diseases associated with locomotor activity, vasodilation, platelet inhibition, neutrophil superoxide generation, cognitive disorder, or senile
dementia.
Diseases associated with adenosine Ai, A2a, A2b and A3 receptors are disclosed in WO 99/06053 and WO-09822465, WO-09705138, WO-
09511681, WO-09733879, JP-09291089, PCT/US98/16053 and U.S. Patent No. 5,516,894, the entire content of which are fully incorporate herein by reference.
This invention also provides a water-soluble prodrug of compounds IV, or V; wherein said water-soluble prodrug that is metabolized in vivo to produce an active drug which selectively inhibit A2a adenosine receptor.
In one embodiment of the prodrug, said prodrug is metabolized in vivo by esterase catalyzed hydrolysis.
This invention also provides a pharmaceutical composition comprising the prodrug and a pharmaceutically acceptable carrier.
This invention also provides a method for inhibiting the activity of an A2a adenosine receptor in a cell, which comprises contacting said cell with compounds IV, or V.
In one embodiment of the method, the compound is an antagonist of said A2a adenosine receptor.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is an ophthalmic formulation.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is an periocular, retrobulbar or intraocular injection formulation.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is a systemic; formulation.
This invention also provides a method for treating a gastrointestinal disorder in an 1. subject, comprising administering to the an effective amount of compounds IV, or V.
In one embodiment of the method, said disorder is diarrhea.
In another embodiment of the method, the subject is a human.
In another embodiment of the method, ;: the compound is an antagonist of A2a adenosine receptors.
This invention further provides a method for treating respiratory disorder in a subject, comprising administering to the subject an effective amount of compounds IV, or V.
In one embodiment of the method, said; disorder is asthma, chronic obstructive pulmonary disease, allergic rhinitis, or an upper respiratory disorder.
In another embodiment of the method, the subject is a human.
In another embodiment of the method, .said compound is an antagonist of A2a adenosine receptors.
This invention also provides a method for treating damage to the eye of a subject which comprises administering to said subject an effective amount of compounds;IV, or V.
In one embodiment of the method, said damage comprises retinal
or optic nerve head damage. ,
In another embodiment of the method, said damage is acute or chronic.
In another embodiment of the method, said damage is the result of glaucoma, edema,, ischemia, hypoxia or. trauma.
In another embodiment of the method, the- subject is a human.
In another embodiment of the method, the compound is an antagonist of A2a adenosine receptors.
This invention also provide a pharmaceutical composition comprising a therapeutically effective amount of compounds IV, or V and a pharmaceutically acceptable carrier.
In one embodiment of the pharmaceutical composition, said therapeutically effective amount is :effective to treat
Parkinson1s disease and diseases associated with locomotor
i
activity, vasodilation, platelet inhibition, neutrophil superoxide generation, cognitive disorderµ or senile dementia.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is an ophthalmic formulation.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is an periocular, retrobulbar or intraocular injection formulation.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is a systemic,formulation.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is a surgicalirrigating solution.
This invention also provides a combination therapy for Parkinson1s disease comprising compounds; IV and V, and any of
the dopamine enhancers.
This invention further provides a combinational therapy for cancer comprising compounds IV and V, arid any of the cytotoxic agents.
This invention further provides a combinational therapy for glaucoma, comprising compounds IV or V;, and a prostaglandin agonist, a muscrinic agonist, or a R-2 antagonist.
This invention also provides a packaged pharmaceutical composition for treating a disease associated with A2a adenosine receptor in a subject, comprising: (a) a container holding a therapeutically effective amount of compounds IV, or V; and (b) instructions for using said compound for, treating said disease in a subject.
This invention also provide a method of preparing compound IV, comprising the steps of
(Structure Removed)
wherein P is a removable protecting group;
b) treating the product of step a) under cyclization conditions to provide
(Structure Removed)
c) treating the product of step b) under suitable conditions to provide
d) treating the chlorinated product of step c) with NHR1R2 to provide (Structure Removed)

wherein NRjR, is a substituted or unsubstituted 4-8 membered ring;
wherein ft* is a substituted or unsubstituted four to six membered ring;
wherein fir-is H, alkyl, substituted alkyl, aryl, arylalkyl, amino, substituted aryl, wherein said substituted alkvl is
(Structure Removed)
-C (-fir) (-Rs-JXR1, wherein X is 0, S, or ;NR-, wherein -ft*- and -R6-are each independently H or alkyl, wherein -R«- and -R1 are each independently alkyl or cycloalkyl, or-R1-, R1 and the nitrogen together form a substituted or unsubstituted ring of between A arid 7 members. [
wherein ft* is H, alkyl, substituted alkyl, or cycloalkyl;
with the proviso that NR1R2 is not 3-*acetamido piperadino, 3-hydroxy pyrrolidino, 3-methyloxy carbonylmethyl pyrrolidino, 3-aminocarbonylmethyl, 1 or pyrrolidino; with the proviso that NR1R2 is 3-hydroxymethyl piperadino only when A*- is 4-pyridyl. *3
This invention further provides a method of preparing compound
V, comprising the steps of
(Structure Removed)
b) treating the product of step a) under cyclization conditions to provide
c) treating the product of step b) under suitable conditions to provide
(Structure Removed)
d) treating the chlorinated product of step c) first with dimethylamine and formaldehyde,
then with N-methyl benzyjamine and finally with NH2R1 to provide
(Structure Removed)



wherein R1 is acetpmido ethyl; wherein -R3 is 4-pyridyl; wherein-R-is H, or methyl; wherein-R6- is N-methyl-N-benzyl aminomethyl.

As used herein, "A compound is A2a selective." means that a compound has a binding constant to adenosine A2a receptor of at least five time higher then that to adenosine A1, A2b, or A3.
The invention is further illustrated by the following examples which in no way should be construed as being further limiting. The contents of all references, pending patent applications and published patent applications, cited throughout this application, including those referenced in the background section, are hereby;incorporated by reference. It should be understood that the models used throughout the examples are accepted models and that the demonstration of efficacy in these models is predictive of efficacy in humans.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Example 22: Synthesis of Adenosine A?. Antagonists, compounds 1601, 1602, and 1603.

Compound 26 (10.93g, 50.76 mmol) was dissolved in DMF (67 mL) . 4-Amidinopyridine hydrochloride (8.0g, 50.76 mmol) and DBU (15.4 g, 101.5 mmol) were added sequentially and the reaction was heated to 85°C. After 22 hours, the reaction was cooled to room temperature and the DMF was removed in vacuo. The dark oil was diluted with 2M HC1 (80 mL). The reaction was allowed to stand. After 2 hours, the solution was cooled to 10°C and µ1tered. The solid was washed with cold water and dried to yield 7.40g of a yellow solid, compound 27 (69%). XH-NMR (200MHz, d6-DMSO) d 6.58 (s, 1H) , 7.27 (I, 1H), 8.53 (d, 2H, J = 5.6), 9.00 (d, 2H, J = 5.2Hz), 12.35 (brs, 1H) . MS (ES) : 212.8 (M-+l) .
Compound 27 (7.4 mmol, 29.8 mmol) was diluted with P0C13 and heated to 105°C. After 18 hours, the reaction is cooled to room temperature and the P0C13 is removed in vacuo. The thick dark oil is diluted with MeOH (75mL) followed by ether (120mL). The amorphous red solid is µ1tered and washed with ether to yield 3.82 g of a red solid. The crude solid, compound 28, is approximately 80% pure and used without further purification in the next reaction. JH-NMR (200MHz, d6-DMSO) d 6.58 (s, 1H), 7.27 (s, 1H), 8.53 (d, 2H, J = 5.6), 9.00 (d, µ2H, J = 5.2Hz), 12.35 (brs, 1H). MS (ES) : 212.8 (M1+l) .
Compound 1601: DMSO (5 mL) and D-prolinol (500mg, 4.94 mmol) were added to compound 28 (500mg, 2.17 mmol) was added. The reaction was heated to 120°C. After 18 hours, The reaction was cooled to room temperature and diluted with EtOAc and H20. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed] with HzO (2x) , brine, dried ..over MgSO,,, µ1tered and concentrated to yield 200mg of a tan solid. The solid was recrystallized from
EtOAc to yield 82 mg of a tan solid (13%) . XH-NMR (200 MHz, d6-DMSO) d 2.05 (m, 4H), 3.43 (m, 1H) , 3.70 - 4.00 (m, 3H), 4.50
(brs, 1H), 4.92 (brs, 1H), 6.62 (m, 1H); 7.22 (m, IK), 8.22 (d, 2H, J = 6.0 Hz), 6.64 (d, 2H, J = 6]2 Hz), MS (ES): 296.0
(!vr+l), mp = 210 - 220°C (decomp.).
Compound 1602: Chromatography (silica, |9:1 CHC13/MeOH) yielded 10 mg of a tan solid (2%).1H-NMR (d6-DMSO) d 2.00 - 2.50 (m, 4H) , 4.05 (ra, 1H), 4.21 (m, 1H) , 6.71 (d, 1H, J - 3.2 Hz), 7.18 (d, 1H, J = 3.2 Hz), 8.37 (d, 2H, J = Compound 1603. Chromatography (silica, 20:1 Hexanes /EtOAc) yielded 135 mg of a tan solid (53%). ?H-NMR (d6-DMSO) d 2.00 (m, 4H) , 3.43 (brs, 1H) , 3.74 (brs, 2H);, 3.87 (brs, 1H) , 4.49 (brs, 1H) , 4.93 (m, 1H) , 6.56 (m, 1H) , 7.12 (m, 1H) , 7.40 (m, 3H), 8.34 (m, 2H) , 11.62 (brs, 1H) . MS*(ES): 295.1 (M- + l).
Compound 1605. Into a 50mL RBF 60mg of 2-(41-pyridyl)-4-Chloropyrimidinopyrrole HC1 salt was dissolved in 2mL anhydrous DMSO. 3-(R)-Hydroy-(D)-prolinol TFA salt (380mg) and 500mg sodium bicarbonate were added thereto.1 The mixture was then flashed with nitrogen gas for 5min and heated to 130°C. After 2 hours, the reaction was cooled to room temperature and the DMSO was removed in vacuo. The residue was partitioned between EtOAc (15mL) and saturated sodium bicarbonate aqueous solution (15mL). The organic layer was separated!and washed with brine (15mL) and dried over Na2SO,. After removal of solvent, the crude product was purified by preparative TLC (CH2Cl2/MeOH = 95/5) to yield 35 mg (50%). XH-NMR (200MHz, CDC13) ( 2.3-2.5 (1H), 3.J4-3.8 (3H), 4.4-4.6 (2H) , 6.4 (1H); 7.1 (1H); 8.2 (d, 2H); 8.7 (d, 2H); 11.0 (1H). MS (ES): 312 (M1+l).

Example 23: Synthesis of Adenosine A2, Antagonist, compound
(Structure Removed)
Compound 28 (200mg) was treated with DMF (30mL), (, (-dimethylglycine methyl ester (73mg HClsalt in 2mL water) and 500mg sodium bicarbonate. After 18 hours, the DMF was removed in vacuo. The residue was partitioned between EtOAc (30mL) and saturated sodium bicarbonate aqueous "solution (15mL). The organic layer was washed with brine (15mL), dried over sodium sulfate, filtered and concentrated. Chromatography (silica, 10:4 hexanes/EtOAc) yielded 150mg of pure product, compound 29 (69%).H-NMR (200MHz, CDCl3) , ( 1.4 (s, ,6H) , 3.8 (s, 3H) ; 3.9 (s, 2H); 6.4 (s, 1H) ; 7.4-7.5 (m, 3H);'8.4 (m, 2H) ; 9.8 (s, 1H) .
Compound 1606:
Procedure is the same as Compound 1605 (72%) . JH-NMR (200MHz, CDC13>, ( 1.3 (s, 6H), 1.7-1.9 (m, 2Hf.; 2.05-2.30 (m, 2H) ; 3.6-4.1 (m, 11H); 4.80-4.95 (m, 1H) ; 6.4 (s, 1H); 7.4-7.6 (m, 3H); 8.3-8,4 (d, J- 8.5 Hz, 2H), 10 (s, 1H). MS (ES): 424.0 (M'+l).
The following compounds can be synthesized in the same manner. Compound 1600: (51%). MS (ES): 326.0 (M+l).
Compound 1607:-lH-NMR (200MHz, CDC1-,) , ( 1.40 - 1.80 (m, 5H) , 2.80 - 3.50 (m, 3H) , 4.60 - 4.80 (m, 3H) , 6.66 (d, 1H, J = 6.2Hz), 7.26 (m, 1H) , 8.21 (d, 2H, J = 6.3Hz), 8.65 (d, 2H, J = 5.8Hz), 11.90 (s, 1H). MS (ES): 310.1 Compound 1608: (64%). aH-NMR (200MHz, d6-DMSO) , ( 1.75 (s, 3H), 2.11 (s, 3H), 2.29 (s, 3H) , 3.56 (m, 6H) , 7.23 - 7.41 (m, 5H), 8.00 (brs, 1H), 8.23 (d, 2K, J = 6.0Hz), 8.63 (d, 2H, J = 5.4 Hz), 8.82 (brs, 1H), 11.56 (brs, 1H). MS (ES): 444.0 (M~+l).
Compound 1604: ^-NMR (200MHz, CD3OD) ( 3.40 (m, 4H) , 4.29 (m, 4H), 6.99 (s, 1H), 7.5 - 7.2 (m, 3H), 7.90 (d, 2H), 8.39 (d, 2H), 8.61 (d, 2H). MS (ES): 357.0 (M+ +1).
TABLE 16. Adenosine A2a Receptor Selective Compounds(Table Removed)
(Table Removed)
Pages 202-256 relate to compounds specific to the A3 receptor
Summary of the Invention
The present invention is also based on compounds which
selectively bind to adenosine A3 receptor, thereby treating a
disease associated with A3 adenosine receptor in a subject by
administering to the subject a therapeutically effective amount
of such compounds. The disease to be treated are associated
with, for example, asthma, hypersensitivity, rhinitis hay
fever, serum sickness, allergic vasculitis, atopic dermapititis,
dermamtitis, psoriasis, eczema, idiopathic pulmonary fibrosis,
eosinophil/ic chlorecystitis, chronic airway inflammation,
hypereosinophilic syndromes, eosinophilic gastroenteritis,
edema, urticaria, eosinophilic myocardial disease, episodic
angioedema with eosinophilia, inflammatory bowel disease,
ulcerative colitis, allergic granulomatosis, carcinomatosis,
eosinophilic granuloma, familial histiocytosis, hypertension,
mast cell degranulation, tumor, cardiac hypoxia, cerebral
ischemia, diuresis, renal failure,, neurological disorder,
mental disorder, cognitive disorder, myocardial ischemia,
bronchoconstriction, arthritis, autoimmune disease, Crohn's
disease, Grave's disease, diabetes, multiple sclerosis,
anaemia, psoriasis, fertility disorders, lupus erthyematdsus,
reperfusion injury, brain arteriole .diameter, the release of
allergic mediators, scleroderma, stroke, global ischemia,
central nervous system disorder, cardiovascular disorder,
renal disorder, inflammatory disorder, gastrointestinal
disorder, eye disorder, allergic disorder, respiratory
disorder, or immunological disorder.
This invention also features a compound having the structure:
(Structure Removed)
wherein R1 is H and R2 is cyclopropyi methylamino
carbonylethyl, cis-3-hydroxy cyclopentyl, acetamido butyl,
methylamino carbonylamino butyl,: ethylamino carbonylamino
propyl, methylamino carbonylamino propyl, 2-acetyl amino-
3-methyl butyl, N,N-diethylamino carbonylamino ethyl,
thioacetamido ethyl, 3-amino acetyloxy cyclopentyl, 3-
hydroxy cyclopentyl, 2-pyrrolyl carbonyl aminoethyl, 2-
imidazolidinone ethyl, l-aminocarbonyl-2-methyl propyl, 1-
aminocarbonyl-2-phenyl ethyl, 3-hydroxy azetidino, 2-
imidazolyl ethyl, acetamido ethyl, 1-(R)-phenyl-2-
hydroxyethyl, N-methylaminocarbonyl pyridyl-2- methyl,
or R1, R2 and the nitrogen together are 3-acetamido
piperadi.no, 3-hydroxy pyrrolidine 3-methyloxy
carbonylmethyl pyrrolidine' 3-aminocarbonylmethyl
pyrrolidino, or 3-hydroxymethyl piperadino.
wherein R3 is a substituted or unsubstituted four to six
menbered ring, pyrrole, thiophene, furan, thiazole,
imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-
pyridone, 4 (1H) -pyridone, pyrazjine, pyrimidine,
pyridazine, isothiazole, isoxazole, cxazole, tetrazple,
naphthalene, tetralin, naphthyridine, benzofuran,
benzothiophene, indole, ;2, 3-dihydroindole, IH-indole,
indoline, benzopyrazole, 1,2-ber.rodioxole, benzoxazcie,
purine, coumarin, chromone, quincline,
tetrahydroquinoiine, isoquinoline, benzimidazole,
quinazoline, pyrido[2, 3-b]pyrazine, pyrido[3, 4-bjpyrazine,
pyrido[3,2-c]pyridazine, purido[3, 4-b]-pyridine, 1H-
pyrazole [3, 4-d] pyrimidine, ; pteridine, 2 (1H) -quinol'one, 1 (2H)-isoquinclone, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine, or cinnoline.
wherein R6 is H, alkyl, substituted alkyl, or cycloaldcyl;
wherein R5 is H, alkyl, substituted alkyl, aryl, or substituted aryl.
This invention also features a method for inhibiting the activity of an A3 adenosine receptor in a cell, which comprises contacting said cell with the above-mentioned compounds.
typical practice and is known to those skilled in the art. Typical synthetic schemes for the preparation of deazapurine intermediates of the invention are outlined below in Scheme I.
This invention also provides a method of preparing compound IV,
comprising the steps of
a) (Structure Removed)
to provide
(Structure Removed)
wherein P is a removable protecting group;
b) treating the product of step a) under cyclization conditions to provide
(Structure Removed)
c) treating the product of step b) under suitable conditions to provide
(Structure Removed)
wherein R1 is H and R1 is cyclopropyl methylaminc
carbonylethyl, cis-3-hydroxy cyclopentyl, acetamido butyl,
methylamino carbonylaminc butyl, ethylamino carbonylaitino
propyl, methylamino carbonylaminc propyl, 2-acetyl aminc-
3-methyl butyl, N,N-diethylamino carbonylamino ethyl,
thioacetamido ethyl, 3-amino acetyloxy cyclopentyl, 3-
. hydroxy cyclopentyl, 2-pyrrolyl carbonyl aminoethyl, 2-
imidazolidinone ethyl, l-aminocarbonyl-2-methyl propyl, 1-
aminocarbonyl-2-phenyl ethyl, 3-hydroxy azetidino, 2-
imidazolyl ethyl, acetamido ethyl, 1-(R)-phenyl-2-
hydroxyethyl, N-methylaminocarbonyl pyridyl-2- methyl,
orR1, R2 and the nitrogen together are 3-acetamido
piperadino, 3-hydroxy pyrrolidino, 3-methyloxy
carbonylmethyl pyrrolidino, 3-aminocarbonylmethyl
pyrrolidino, or 3-hydroxymethyl- piperadino.
wherein R3 is a substituted or unsubstituted four to six membered ring;
wherein R6 is H, alkyl, substituted alkyl, or cycloalkyl;
wherein R5 is H, alkyl, substituted alkyl, aryl, or substituted aryl.
This invention also provides a method of preparing compound of V, comprising the steps of

a) reacting
(Structure Removed)
to provide (Structure Removed)
wherein P is a removable protectinggroup;
b) treating the,product of step a) under cyclization conditions to provide
(Structure Removed)
c) treating the product of step b) under suitable conditions to provide
(Structure Removed)
d) treating the chlorinated product of step c) with N:H2CH2(CH2)mCH2NHC(-0)R1 to provide
(Structure Removed)
wherein m is 0, 1, or 2;
wherein R1 is cyclopropyl methyl, methyl, methylamino, or aminomethyi;
wherein R3 is aryl, substituted aryl, heteroaryl;
where in R6 is H, alkyl, substituted alkyl, or cycloalkyl;
wherein R5 is K, alkyl, substituted alkyl, aryl,
arylalkyl, amino, substituted aryl, wherein said

substituted alkyl is -C (R7) (R8) NR9R10, wherein R7 and R8 are each H or alkyl, wherein R9 and R10 are each alkyl or cycloalkyl, or R9, R10 and the nitrogen together form a ring system of between 4 and 7 members. This invention further provided a method of preparing compound VI, comprising
a) reacting
(Structure Removed)
wherein P is a removable protecting group;
b) treating the product of step a) under cyclization conditions to provide
(Structure Removed)
c) treating the product of step b) under suitable conditions to provide
(Structure Removed)
d) treating the chlorinated product of step c) with HN
(Structure Removed)
to provide
(Structure Removed)
wherein R3 is unsubstituted aryl.
wherein R6 is H, alkyl, substituted aikyl, or cycloalkyi;
wherein R5 is H, aikyl, substituted alkyl, aryl, arylalkyl,
amino, substituted aryl, wherein said substituted alkyl is
-C (R7) (R8)NR9R10, wherein R7 and R8. are each H or aikyl,
wherein R9 andR10are each alkyl or cycloalkyi, or -ft-*-, Re
and the nitrogen together form a ring system of between 4
and.7 members.
This invention also provides a compound having the structure:
(Structure Removed)

wherein R1 is H and R2 is cyclopropyl methylamino
carbonylethyl, cis-3-hydroxy cyclopentyl, acetamido butyl,
methylamino carbonylamino butyl, ethylamino carbonylamino
propyl, methylamino carbonylamino propyl, 2-acetyl amino-
3-methyl butyl, N,N-diethylamino carbonylamino ethyl,
thioacetamido ethyl, 3-amino acetyloxy cyclopentyl, 3-
hydroxy cyclopentyl, 2-pyrrolyl carbonyl aminoethyl, 2-
imidazolidinone ethyl,.l-aminocar.bonyl-2-methyl propyl, 1-
aminocarbonyl-2-phenyl ethyl, 3-hydroxy azetidino, 2-
imidazolyl ethyl, acetamido ethyl, ' 1-(R)-phenyl-2-
hydroxyethyl, N-methylaminocarbonyl pyridyl-2- methyl,
or R1, R2 and the nitrogen together are 3-acetamido
piperadino, 3-hydroxy pyrrolidine, 3-methyloxy
carbonyimethyl pyrrolidine 3-aminocarbonylmethyl
pyrrolidine, or 3-hydroxymethyl piperadino.
wherein R3 is a substituted or unsubstitutec benzene,
pyrrole, thiophene, furan, thiazole, imidazole, pyrazoie,
1,2,4-triazole, pyridine, 2 (IH)-pyridone, 4 (IH)-pyridone,
pyrazine, pyrimidine, pyridazine, isothiazole, isoxazcle,
oxazole, tetrazole, naphthalene, tetraiin, naphthyridine,
benzofuran, benzothiophene, indole, 2,3-dihydroindole; 1H-
indole, indoline, benzopyrazole, 1,3-benzodioxole,
benzoxazole, purine, coumarin, chromone, quinoline,
tetrahydroquinoline, isoquinoline, benzimidazole,
quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine,
pyrido[3,2-c]pyridazine, purido[3,4-b]-pyridine, 1H-
pyrazole [3,4-d]pyrimidine, pteridine, 2 (IH)-quinolbne, 1 (2H)-isoquinolone, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaiine-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine, or cinnoline.
wherein R6 is H, alkyl, substituted alkyl, or cycloalkyl;
wherein R5 H, alkyl, substituted alkyl, aryl, or substituted, aryl.
In one embodiment, of the : compound, the compound has the structure:
(Structure Removed)
In another embodimentsof the, compound, R3 is phenyl.
In another embodiment of the compound, R6 is hydrogen or methyl.
In another embodiment of the compound, R5 is. hydrogen, methyl,
phenyl, 3-chiorophenyloxy mechyl, or trans-2- phenylamino methyl pyrrolidino methyl.
This invention further provides a compound having the structure:
(Structure Removed)

wherein m is 0, 1, or 2;
wherein R1 is cyclopropyl methyl, methyl, methylamino, or aminoroethyl.;
wherein R3 is aryl, substituted aryl, or heteroaryl;
wherein R6 is H, alkyl, substituted alkyl, or cycloalkyl;
wherein R5 is H, alkyl, substituted alkyl, aryl, arylalkyl, amino, substituted aryl, wherein said
substituted alkyl is -C (R5) (R8) NR9R10 wherein R7 and R8are each H or alkyl, wherein R9 and R10 are each alkyl or cycloalkyl, or R9,R10and the nitrogen together form a ring system of between 4 and 7 members.
In one embodiment of compound V, m is 0 and Ra- is phenyl.
In another embodiment of compound V, m is 1 and R3 is phenyl.
In another embodiment of compound V, m is 2 and R3 is phenyl.
In another embodiment of compound V, R5 and R6 are methyl.
In another embodiment of compound V, R5 and R6 are methyl.
In another embodiment of compound V, R5 and R6 are methyl.
In another embodiment of compound V, the compound has the
structure:
(Structure Removed)
(Compound 1316)
In another embodiment of compound V, the compound has the structure:
(Structure Removed)
(Compound 1311)

In; another embodiment of compound V, the compound has the structure:
(Structure Removed)
(Compound 1202)
In another embodiment of compound V, the compound has the structure:
(Structure Removed)
(Compound 1310)

In another embodiment of compound V, the compound has the structure:
(Structure Removed)
(Compound 1312)
This invention further provides a . compound having the structure:
(Structure Removed)
(Compound 609)

This invention also provides a 'compound having the structure:
(Structure Removed)
wherein R3 is unsubstitutec aryl.
wherein R6 is H, alkyl, substituted alkyl, or cycloaikyl;
wherein R5 is H, alkyl, substituted alkyl, aryl, arylalkyl,
amino, substituted aryl, wherein sr.id substituted alkyl is
-C(R7) (R8)NR9,R10 wherein R7 andR8 are each H or alkyl,
wherein R9 and R10 are each alkyl or cycloaikyl, or R9, R10
and the nitrogen together form a ring system of between 4
and 7 members.
In one embodiment of compound VI, the compound has- the structure:
(Structure Removed)
(Compound 1309)

In one embodiment of compound 1309, the compound has the structure:
(Structure Removed)

In another embodiment of compound 1309, the compound has the
structure:
(Structure Removed)
This invention also provides a compound having the structure:
(Structure Removed)
wherein R1 is 3-hydroxy cyclopentyi ethylamino
carbonylamino propyl, N,N-diethylamino carbonylamino
ethyl, thioacetamido ethyl, 3-amino acetyloxy cyclopentyi,
3-hydroxy cyclopentyi, 2-pyrrolyl carbonyl aminoethyl, 2-
imidazolidinone ethyl, l-aminoca,rbonyl-2-methyl propyl, 1-
aminocarbonyl-2-phenyl ethyl, 3-hydroxy azetidino, 2-
imidazolyl ethyl, acetamido ethyl, 1-(R)-phenyl-2-
hydroxyethyl, or N-methylaminocarbonyl pyridyl-2- methyl;
wherein R5 and R6 are independently H, substituted or unsubstituted alkyl, or aryl.
In one embodiment of the compound, the compound has the
structure:
(Structure Removed)
(Compound 1700)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1701)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1702)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 17 04)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1705)

In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1706)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 17 07)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 17 08}
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1709)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1710)
In another embodiment of the compound, the compound has the
structure:
(Structure Removed)
{Compound 1712)
In another embodiment of the compound, the compound has the structure:'
(Structure Removed)
(Compound 1713)
In another embodiment of the compound:, the compound has the
structure:
(Structure Removed)

In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1714)
In another embodiment of the compound, the compound has the
structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1715)
In another embodiment of the compound, the compound has the
structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)

This invention also provides a compound having the structure:
(Structure Removed)
wherein R1, R2 and the nitrogen together are 3-hydroxy pyrrolidino, 3-methyloxy carbonylmethyl pyrrolidino, 3-aminocarbonylmethyl pyrrolidino, or 3-hydroxymethyl piperadino;
wherein R5 and R6 are independently H, substituted or unsubstituted alkyl, or aryl.
In one embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1711)

In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1703)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1716)


In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
(Compound 1717)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the
structure:
(Structure Removed)
(Compound 1718)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
In another embodiment of the compound, the compound has the structure:
(Structure Removed)
This invention also provides a method for treating a disease associated with A3 adenosine receptor in a subject, comprising administering toithe subject a therapeutically effective amount of any of the compounds IV, V, VI, VI, or VIII.

In one embodiment of the method, the subject is a mammal.
In another embodiment of the method, the mammal is a human.
In another embodiment of the method, said A3 adenosine receptor
is associated with a central nervous system disorder, a
cardiovascular disorder, asthma, hypersensitivity, rhinitis,
hay fever, ; serum sickness, allergic vasculitis, atopic
dermatitis, \ dermatitis, psoriasis, eczema, idiopathic
pulmonary fibrosis, eosinophilic chiorecystitis, chronic
airway inf lamrat ion, hypereosinophilic syndromes, eosinophilic
gastroenteritis, edema, urticaria, eosinophilic myocardial
disease, episodic angioedema with eosinophilia, inflammatory
bowel disease, ulcerative colitis, allergic granulomatosis,
carcinomatosis, eosinophilic granuloma, familial histiocytosis,
hypertension,: mast cell degranulation, tumor, cardiac hypoxia,
cerebral ischemia, diuresis, renal failure, neurological
disorder, mental disorder, cognitive disorder, myocardial
ischemia, bronchoconstriction, arthritis, autoimmune disease,
Crohn's disease, Grave's disease, diabetes, multiple sclerosis,
anaemia, psoriasis, fertility disorders, lupus erthyematosus,
reperfusion ihjury, brain arteriole diameter, the release of
allergic mediators, scleroderma, stroke, global ischemia,
central nervous system disorder, cardiovascular disorder,
renal disorder, inflammatory disorder, gastrointestinal
disorder, eye disorder, allergic disorder, respiratory
disorder, or immunological disorder.
Diseases associated with adenosine Al, A2a, A2b and A3 receptors are disclosed In WO 99/06C53 and WO-09822465, WO-0S705138, W0-09511681, WO-09733379, JP-09291089, PCT/US98/l6053 and U.S. Patent No. 5,516,894, the entire content of which are fully
incorporate herein by reference.
This invention also provides a water-soluble prodrug of any of the compounds 'IV, V, VI, VII, or VIII; wherein said water-soluble prodrug that is metabolized in vivo to an active drug which selectively inhibit A3 adenosine receptor.
In one embodiment of the prodrug, said prodrug is metabolized in vivo by esterase catalyzed hydrolysis.
This invention: also provides a pharmaceutical composition comprising the prodrug and a pharmaceutically acceptable carrier.
This invention; also provides a method for inhibiting the
activity of an A3 adenosine receptor in a cell, which comprises
contacting said cell with any of the compounds IV, V, VI, VII,
or VIII.
In one embodiment of the method, the compound is an antagonist of said A3 adenosine receptor.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is an ophthalmic formulation.
In another embodiment of the pharmaceutical composition', said pharmaceutical composition is an periocular, retrobulbar or intraocular injection formulation.
In another embodiment of the pharmaceutical composition, sajid pharmaceutical composition is a systemic formulation.
This invention also provides a method for treating a
gastrointestinal disorder in an subject, comprising
administering to the an effective amount of any of the
compounds IV, V, VI, VII, or VIII.
In one embodiment of the method, said disorder is diarrhea.
In another embodiment of the method, the subject is a human.
In another embodiment of the method, the compound is an antagonist of A3 adenosine receptors.
This invention, further provides a method for treating respiratory disorder in a subject, comprising administering to the subject an effective amount of any of the compounds IV, V,
VI, VII, or VIII.
In one embodiment of the method, said disorder is asthma, chronic obstructive pulmonary disease, allergic rhinitis, or an upper respiratory disorder.
In another embodiment of the method, the subject is a human.
In another embodiment of the method,, said compound is an antagonist of A3 adenosine receptors.
This invention also provides a method for treating damage to the eye of a subject which comprises administering to said subject an effective amount of any of the compounds IV, V, VI,
VII, or VIII.
In one embodiment of the method, said damage comprises retinal

or optic nerve head damage.
In another embodiment of the method, said damage is acute 01 chronic.
In another embodiment of the method, said damage is the result of glaucoma, edema, ischemia, hypoxia or trauma.
In another embodiment of the method, the subject is a human.
In another embodiment of the method, the compound is an antagonist of A3 adenosine receptors.
This invention also provide a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds IV, | V, VI, VII, or VIII and a pharmaceutically acceptable carrier.
In one embodiment of the pharmaceutical composition, said therapeutically effective amount is effective to treat a respiratory disorder or a gastrointestinal disorder.
In another embodiment of the pharmaceutical composition, said gastrointestinal disorder is diarrhea..
In another embodiment of the pharmaceutical composition, said
respiratory disorder is asthma, allergic rhinitis, or chronic
obstructive pulmonary disease.
In another embodiment of the pharmaceutical composition, said pharmaceutical ;composition is an ophthalmic formulation.

in another embodiment of the pharmaceutical composition, said pharmaceutical composition is an periocular, retrobulbar or intraocular injection formulation.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is a systemic formulation.
In another embodiment of the pharmaceutical composition, said pharmaceutical composition is a surgical irrigating solution.
This inventio also provides a packaged pharmaceutical composition for treating a disease associated with A3 adenosine receptor in a subject, comprising: (a) a container holding a therapeutically effective amount of any of the compounds IV, V, VI, VII, or VIII; and (b) instructions for using said compound for treating said disease in a subject.
Compounds represented by the formula IV, V, VI, VII, and VIII can be synthesized by the Schemes I-IX.
As used herein, "A compound is A3 selective." means that a compound has a binding constant to adenosine A3 receptor of at least ten time higher then that to adenosine A,, A2a, or A2b-
The invention is further illustrated by the following examples which in no way should be construed as being further limiting. The contents of all references, pending patent applications and published patent applications, ciTed throughout this application, including those referenced in the background section, are hereby incorporated by reference. It should be understood that the models used throughout the examples ar,e accepted models and that the demonstration of efficacy in these

models is predictive of efficacy in humans.
A skilled artisan will know that metabolism of the compounds disclosed herein in a subject produces certain biologically active metabolites which can serve as drugs.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Example 24: Adenosine A3 Antagonist Experimentals Compound 1700 (Table 17 below): MS (ES) : 366.1 (M++l).
Compound 1710 (Table 17 below): MS (ES): 381.1 (M++l).
Compound 1316 (Table 17 below): MS (ES): 353.2 (M++l). Compound 1703 (Table 17 below): MS (ES): 357.1 (M++l). Compound 1719 (Table 17 below): 1H-NMR (200MHz, d6-DMSO) ( 1.7.5 (m, 2H), 3.11 (m, 2H) , 3.35 (s, 3H) , 3.59 (m, 2H) , 5.72 (m, 1H), 5.96 (m, 1H), 6.55 (s, 1H) , 7.15 (s, 1H), 7.49 (m, 2H), 8.32 (m, 2H).
Compound 1704 (Table 17 below): MS (ES): 367.0 (M++l).
Compound 1706 (Table 17 below): !H-NMR (200MHz, CDC13) d 1.22 (m, 2H), 1.60-2.40 (m, 4H), 4.53 (m, 1H), 4.94 (m, 1H), 5.70 (d, 1H, J - 8.2 Hz), 6.35 (d, 1H, J = 2.8 Hz), 6.97 (d, 1H, J
= 2.0 Hz), 7.50 (m, 3H), 8.40 (m, 2H), 10.83 (brs, 1H).
Compound 1707 (Table 17 below) : MS(ES) : 34 7.0 (M++l) .
Compound 170.8 (Table 17 below): MS (ES) 399.0 (M+ + l).
Compound 170|9 (Table 17 below) : MS (ES) 385.9 (M+ + l).
Compound 1710 (Table 17 below): MS (ES) 434.0 (M+-I).
Compound 1711 (Table 17 below) : 1H-NMR (200MHz, CD,OD) d 3.95 (d, 2H, J =; 5.8Hz), 4.23 - 4.31 (m, 2H) , 4.53 (t, 2H, J = 8.8Hz), 6.30 (d, 1H, J = 3.0Hz), 6.98 (d, 1H, J = 3.0Hz), 7.45 - 7.48 .(m, 3H) , 7.83 - 8.42 (m, 2H) , 9.70 (brs, 1H) . MS (ES): 2 81.1 (M++l) J , , , ,-j l.L.,\-
→Compound 1712(Table below):
1H-NMR (200MHz, CD3OD) d 3.02 (m, 2H) , 3.92 (m, 2H), 5.09 (2,|2H), 6.53 is, 1H), 6.90-7.04 (brs, 1H), 6.92 (m, 2H), 7.02 (m, 1H), 7.21 (dd, 1H, J = 8.2Hz), 7.40 (m, 3H), 7.50-7.80 [br s, 1H), 8.33 (m, 2H) . MS (ES): 445.1 (M"+l).
Compound 17l| (Table 17 below): 'H-NMR (200MHz, CDC13) d 1.65--1.80(m, |7H), 1.88-2.00(m, 1H) , 2.10 - 2.40 (m, 1H) , 2.70-3.05 (m,3H), 3.09-3.14 (m, 2H), 3.16-3.38 (m, 1H), 3.45 (d, 1H, J = l;4Hz), 3.53-3.60 (m, 2H) , 3.84-3.92 (m, 2H) , 3.97 (d, 1H, J = 14Hz), 5.55 (t, 1H, J = 5.8Hz), 6.17 (s, 1H) , 6.55-6.59 (m,; 2H) , 6.64-6.71 (m, 1H) , 7.11-7.19 (m, 2H) , 7.43-7.46 (m,3H), 8.38-8.42 (m, 2H), MS (ES) : 484.0 (M*+l).
Compound 1714 (Table 17 below): MS (ES): 471.0 (M*+l). Compound 1715(Table 17 below): MS (ES): 505.0 (M* + l).
Compound 1716 | (Table 17 below): 'H-NMR (200MHz, CD3OD) d 1.65 (m, 1H), 2.18 i (m, ' 1H) , 2.49 (br d, 2H, J = 6.2Hz), 2.64 (m, 1H), 3.38 (m, ilH), 3.69 (s, 3H), 3.72 (m, 1H), 3.93 (m, 1H) , 4.10 (m, 1H),!5'.06 (2, 2H), 6.58 (s, 1H) , 6.92 (m, 2H) , 7.02 (m, 1H) , 7.23 t(dd, 1H, J = 8.1Hz), 7.39 (m, 3H) , 8.32 (m, 2H).

MS (ES) : 477.1 (M~+l) .
Compound 1717 i (Table 17 below) : H-NMR (£0.0MHz, CD,OD) d 1.69 (m, 1H), 2.26 (m, 1H), 2.42 (d, 2H, J=7.4Hz), 2.72. (m, 1H) ,
3.53 (m, 1H), 13.83 (m, 1H) , 4.02 (m, 1H), 4.14 (ddr 1H, J =
1.0.6, 7.0Hz), J5.14 (2, 2H), 6.69 (s, 1H) , 6.96 (m, 2H) , 7.06 (m, 1H), 7.25 (dd, 1H, J -8.0Hz), 7.39 (m, 3H), 8.35 (m, 2H) .
MS (ES) : 462.2 (M'+l) .
Compound 1718 (Table 17 below) : XH-NMR (200MHz, CD300) d 1.40 -2.00 (m, 5H) 3R52 (d, 2H, ,7.6Hz), 3.30-4.00 (m, 1H) , 4.00 - 4.20 (m, 3H), 4.50 (m, 2H) , 6.36 - 6.50 (m, 2H) , 6.54 (s, 1H), 6.84 - 6.9^2 (m, 1H) , 7.05 (t, 1H, J= 8.2Hz), 7.30 - 7.45 (m, 3H) , 8.24 |(d, 2H, J = 9.8Hz). MS (ES) : 449.0 (M'+l).

TABLE 17. Adenosine A3 Receptor Selective Compounds
* at least 10 times more selective than other three subtypes.
(Table Removed)
This invention provides a compound having the structure:
1505 This invention; also provides a compound having the structure:
(Structure Removed)
This invention further provides a compound having the structure:
(Structure Removed)
This invention also provides a compound having the structure:
(Structure Removed)
This invention further provides a compound having the structure:
(Structure Removed)
This invention also provides a compound having the structure:
(Structure Removed)
This invention;also provides a compound having the structure:
(Structure Removed)
This invention further provides a compound having the structure:
(Structure Removed)
This invention also provides a compound having the structure:
(Structure Removed)
This invention further provides a compound having the
structure:

(Structure Removed)
This invention further provides a compound having the
structure:
(Structure Removed)
This invention also provides a compound having the structure:
(Structure Removed)
(Structure Removed)
This invention further provides a compound having the structure:
(Structure Removed)
This invention also provides a compound having the structure:
(Structure Removed)
This invention further provides a compound having the structure:
(Structure Removed)
In a further embodiment the invention provides a method for treating a disease associated with A1 adenosine receptor in a subject, comprising administering to the subject a therapeutically effective amount of compounds 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, or 1520.
In a further embodiment the invention provides the above method, whereih the subject is a mammal.
In a further embodiment the invention provides the above method, wherein: the mammal is a human.
In a further embodiment the invention provides the above method, wherein said Ai adenosine receptor is associated with cognitive disease, renal failure, cardiac arrhythmias, respiratory epithelia, transmitter release, sedation, vasoconstriction, bradycardia, negative cardiac inotropy and dromotropy, branchoconstriction, neutropil chemotaxis, reflux condition, or ulcerative condition.

in a further embodiment the invention provides a water-soluble prodrug of compound 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, or 1520, wherein the water-soluble prodrug is metabolized in vivo to produce an active drug which selectively inhibits A1 adenosine receptor.
In a further embodiment the invention provides, wherein said prodrug is metabolized in vivo by esterase catalyzed hydrolysis.
In a further embodiment the invention provides a pharmaceutical composition comprising the above prodrug and a pharmaceutically acceptable carrier.
In a further embodiment the invention provides a method for inhibiting the activity of an A1 adenosine receptor in a cell, which comprises contacting the cell with compounds 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, or 1520.
In a further embodiment the invention provides the above method for inhibiting the activity of an A1 adenosine receptor in a cell, wherein the compound is an antagonist of the A1 adenosine receptor.
In a further embodiment the invention provides the above method for inhibiting the activity of an A1 adenosine receptor in a cell, wherein the cell is human cell.
In a further embodiment the invention provides the above method for inhibiting the activity of an A1 adenosine receptor in a human cell, jwherein the compound is an antagonist pf A1 adenosine receptors.

In a further embodiment the invention provides a method for treating a disease associated with A1 adenosine receptor in a subject, wherein said disease is asthma, chronic obstructive pulmonary disease, allergic rhinitis, or an upper respiratory disorder.
In a further embodiment the invention provides a method for treating a disease associated with A1 adenosine receptor in a subject, wherein said disease is asthma, chronic obstructive pulmonary disease, allergic rhinitis, or an upper respiratory disorder and wherein the subject is a human.
In a further embodiment the invention provides a method for treating the above disease, wherein said compound is an antagonist of A1 adenosine receptors.
In a further embodiment the invention provides a combination therapy for asthma, comprising the compound 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, or 1520, and a steroid, 02 agonist, glucocorticoid, lucotriene antagonist, or anticolinergic agonist.
In a further embodiment the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, or 1520, and a pharmaceutical ly acceptable carrier.
In a further embodiment the invention provides a method for treating a respiratory disorder with the compound 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, or 1520, wherein said respiratory disorder is asthma, allergic: rhinitis, or chronic obstructive pulmonary-disease .

In a further embodiment the invention provides the above; pharmaceutical composition(s) , wherein said pharmaceutical composition is an periocular, retrobulbar or intraocular injection formulation.
In a further embodiment the invention provides the above pharmaceutical composition(s), wherein said pharmaceutical composition is a systemic formulation.
In a further embodiment the invention provides the above pharmaceutical composition(s) , wherein said pharmaceutical composition is a surgical irrigating solution.
In a further embodiment the invention provides a packaged pharmaceutical composition for treating a disease associated with A1 adenosine receptor in a subject, comprising:
a container holding a therapeutically effective amount of the compounds 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, or 1520; and
instructions for using said compound for treating said disease in a subject.
In a further embodiment the invention provides a
pharmaceutically acceptable salt of the compound 1505, 1506,
1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517,
1518, 1519, or 1520.
In a further embodiment the invention provides the, above pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt of the compound 1509, 1511, 1515, 1518, or 1519 contains a cation selected from the group, consisting of sodium,

calcium and ammonium.
In yet a further embodiment the invention provides a method for treating a disease associated with Ai adenosine receptor in a subject, wherein the Ai adenosine receptor is associated with congestive heart failure.
Exemplification
Example 21: Synthesis of 1- [6-(4-Hydroxy-4-phenyl-piperidin-l-yl-methyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidine-2-carboxylic acid amide (1505).
Compound 1505 was synthesized in a manner similar to that of Example 17 using synthesis scheme IX with L-prolineamide and 4-phenyl-piperidin-4-ol to obtain:
(Structure Removed)
1H-NMR (d6-DMSO) d 1.53 (s, 1H) , 1.60 (s, 1H), 1.84-2.30 (m, 6H), 2.66 (m, 2H), 3.60 (s, 2H), 3.88 (m, 1H), 4.02 (m, 1H) , 4.66 (d, 1H, J = 6.8Hz), 4.73 (s, 1H), 6.44 (s, 1H), 6.94 (s, 1H), 7.12 - 7.50 (m, 10H) , 8.35 (m, 2H) , 11.6. (brs, 1H); MS (ES) : 305.1 (M* + l); mp = 234-235°C.
Example 22: Synthesis of [N-(2-Phenyl-7H~pyrrolo [2, 3-d]pyrimidin-4-yl) (L)-prolinamide (1506)
Compound 1506 was synthesized using synthesis scheme VII with L-proiineamide to obtain:
(Structure Removed)
1H-NMR (DMS0-d6) d 2.05 (m, 4H) , 3.85 (m, 1H) , 4.05 (m, 1H) , 4.70 (d, 1H, J=8.0Hz), 6.58 (brs, 1H) , 6.95 (brs, 1H), 7.15 (d, 1H, J=3.4Hz), 7.40 (m, 3H) , 7.50 (brs, 1H) , 8.40 (m, 2H) , 11.6 (brs, 1H) ; MS (ES): 308.3 (M*+l). rnp= 236-238°C.
Example 23: Synthesis of [N- (2~phenyI~6-methoxymethyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)- (L)-prolinamide (1507)
Compound 1507 was synthesized using precursor compound 23 of synthesis scheme IX to obtain:
(Structure Removed)
Bromide 23 (4.23g, lOmmol) is dissolved in anhydrous methanol (60mL) and DCM (120mL) and treated with AgO2CCF3, under N: at rt for lh. The solid is removed by filtration and washed with DCM (2x20mL) . The filtrate is concentrated in vacuo. The residue is redissolved in DCM (80mL). The resulted solution is then washed with saturated NaHC03 solution and brine, dried over MgSO„, filtered and concentrated to give 3.71g (4, 99%) off white solid. aH-NMR (CDC13) d 1.75 (s, 9H), 3.51 (s, '3H), 4.83 (s, 2H), 6.70 (s, 1H) , 7.47 (m, 3H) , 8.52 (m, 2H) .
(Structure Removed)
Aryl chloride 4 (2.448g, 6.55mmol), DMSO
The tert-butoxycarbonyl protected aryl bromide 23 (4.0g, 9.5mmol), dry DMSO (25ml), NaH,PO4 (454mg, 3.79mmol) and Na,HPO,
(1.62g, 11.4nunol) were combined and heated to 50°C under argon for approximately 3.5h. The mixture was then poured into water
(200ml) and extracted with three 100ml portions of EtOAc. The combined organic layers were thoroughly washed with water, brine, dried over MgS04, filtered and concentrated to give a yellow solid which was purified by triturating with ethanol. to give 1.55g of a pale yellow solid (7). The mother liquor was purified by flash chromatography (10% EtOAc in hexane) to give an additional 454mg (60%).1H-NMR (CDC1,) d 1.77 (s, 9H) , 7.25 (s, 1H), 7.48 (m, 3H), 8.52 (m, 2H) 10.39 (s, 1H); m.p.* 156°C (dec) .
(Structure Removed)
Aldehyde 7 (600rng, 1.7mmol) was dissolved in dry THF (20ml) and
cooled to 0°C under argon. To this was added a 0°C solution of
(tert-butoxycarbonylmethylene) -triphenylphosphorane (694mg,
1.8mmol) in 10ml of dry THF dropwise through a cannula. After 3h the mixture was concentrated and purified by triturating with ethanol to give 565mg (73%) of a white solid (8). 'HNMR (CDC13) d 1.58 (s, 9H), 1.79 (s, 9H), 6.46 (d, 1H), 6.95 (s, 1H), 7.48 (m, 3H), 8.09 (d, 1H), 8.56 im, 2H).
(Structure Removed)
A solution of compound 8 (565mg 1.2mmol) in 5ml THF was diluted to 100ml with EtOAc. After adding 600mg of catalyst (5% wt Pd, 50% H20) and purging with argon, the mixture was hydrogenated under atmospheric pressure. After 8h the mixture was filtered, concentrated and purified with flash chromatography (10% EtOAc in hexane) to isolate 200mg (35%) of 9 as a clear oil that crystallized upon standing. 1HNMR (CDC1,) d 1.42 (s, 9H), 1.75 (s, 9H) , 2.65 (t, 2H), 3.32 (t, 2H) , 6.41 (s, 1H) 7.45 (m, 3H) , 8.51 (m, 2H).
(Structure Removed)
Aryl chloride 9 (200mg, 0.44mmol), DMSO (10ml) and L-prolinamide (440mg, 4.4mmol) were combined and heated to 85°C under argon. After 14 hours the mixture is cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the agueous layer washed with EtOAc (3x) . The combined organic layers were thoroughly washed with water (3x), brine, dried over MgSO„, | filtered and concentrated to give 10 as a yelldw film which was purified by flash chromatography (2.5% MeOH in CH,C12) . 185mg (97%). MS (ES) : 435.8 (M+ + l) .
(Structure Removed)
Ester 10 (30mg, mmol) in 5ml dioxane was hydrolyzed by adding 0.5ml concentrated HCI. After 3 hours the mixture was concentrated in vacuo and recrystalized in EtOH/ EtOAc to obtain 1509 as a white solid (20mg, 61%). MS (ES): 380 (M++l).
Example 26: Synthesis of [N- (2-phenyl-6-aminocarbonyl methoxymethyl-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) - (L) -prolinamide (1510)
Compound 1510 was obtained using precursor compound 23 of synthesis scheme IX to obtain:
(Structure Removed)
Bromide 23 (1.27g, 3mmol) and molecular sieve (5g) are stirred in anhydrous methyl glycolate (5.8g, 60mmol) and DCM (40mL). The solution is treated with AgOTf under N, and allowed to stir for 3h. The solid is removed by filtration and washed with DCM (2x20mL). The filtrate is concentrated :n vacuo. The residue is
reciissolved in DCM (80mL) . The resulted) solution is then washed with water, saturated NaHC03 solution and brine, dried over MgSO4, filtered and concentrated to give 1.35g (99%) off white solid (12). ty-NMR (CDC13) d 1.75 [s, 9H) , 3.80 (s, 3H), 5.0 (s, 2H), 6.78 (s, 1H), 7.47 (m, 3H), 8.52 (m, 2H).
(Structure Removed)
Aryl chloride 12 (177mg, 0.41mmol), DMSO (lOmL), L-prolinamide (4 66mg, 4mmol) and NaHC03 (500mg) are combined and heated to 120°C under nitrogen. After 4h, the reaction is cooled to room temperature and diluted with water (60ml). The resulted slurry is extracted with DCM (5x30mL). The combined organic layers are washed with saturated NaHC03 solution and brine, dried over MgS04, filtered and concentrated to give brown solid. Pure product (154mg„ 92%) is obtained after flash column as white solid (13). !H-NMR (CDC13) d 2.15 (m, 3H), 2.52 (m, 1H), 3.55 (s, 3H), 4.58 (s, 2H), 5.08 (s, 1H, ), 5.85 (brs, 1H), 6.48 (s, 1H), 7.08 (brs, 1H), 7.42 (m, 3H), 8.40 (m, 2H) , 10.58 (brs, 1H) ; MS (ES) : 410.1 (M' + l) .

(Structure Removed)
Methyl ester 13 (124mg, 0.3mmol) is dissolved in H0CH3 (15mL). Ammonia is bubbled through the solution for 0.5h. The reaction mixture is then stirred for another 3h at rt. After removal of solvent lllmg of a white solid (1510, 93%) is obtained. 'H-NMR (CDC13) d 1.82 (m, 3H), 2.20 (m, 1H) , 2.80 (m, IK), 3.10 (m, 1H) , 3.63 (dd, 2H, j1=13.8Hz, J,=19.4Hz), 3.87 (m, 1H) , 4.07 (m, 1H), 4.97 (m, 1H), 5.96 (m, 2H), 6.35 (s, 1H), 6.86 (brs, 1H), 7.11 (brs, 1H), 7.37 (m, 3H) , 8.28 (m, 2H), 11.46 (brs, 1H); MS (ES) : 394.8 (N+1) .
Example 27: Synthesis of [4-(2-Carbamoylpyrrolidin-l-yl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine~6-carboxylic acid] (1511)
Compound 1511 was synthesized using precursor compound 15 of synthesis scheme VII to obtain:
(Structure Removed)
To a suspension of sodium hydride (780mg of a 60% oil
suspension, 19.5ramol) in dry DMF (20mL), cooled by an ice/water
bath, under nitrogen, is added a solution of the
pyrrolopyrimidine 15 (2.00g, 7.52mmol) in DMF (lOmL) over 5
min. After 15 min, benzenesulfonyl chloride (1.2mL, 9.40mmol)
is added, then the cooling bath is removed. After 4h, the
reaction mixture is poured into a mixture of ice and sat. NaHC03
sol., the precipitated solid is filtered off and triturated
with acetone (3 ) and methanol (2 ), yielding 2.37g of a beige
solid. This solid (16) contains approx. 10mol-% DMF (based on
that 83% yield) and can be used in the next step; a pure sample
can be obtained by chromatography on silica gel using acetone
as eluent. lH-NMR (CDC13) : d 6.70 (d, J = 4.2Hz, 1H) ,
7.47-7.63 (m, 6H), 7.76 (d, J= 4.2Hz, 1H), 8.24-8.32 (m, 2H), 8.48-8.56 (m, 2H) ; IR (solid): n = 3146 cm"1, 1585, 1539, 1506, 1450, 1417, 1386, 1370, 1186, 1176, 1154, 1111, 1015, 919, 726, 683, 616, 607; MS (ES): 372/370 (MH+); mp =226-227 °C.
(Structure Removed)
o a solution of the A7-sulfonyl compound 16 (337mg, 0.911mmol) in dry THF (34mL), cooled by dry ice/acetone, is added LDA'THF (l.OmL, 1.5M solution in cyclohexane, 1.5mmol). After 45min, carbon dioxide is bubbled into the solution for 5min, tj:hen the cooling bath is removed. When the solution has reached:ambient temp., the solvents are evaporated, yielding 398mg of the salt 17, containing 0.5 equiv. of (iPr) 2NCO2Li, as yellow solid. The

salt is used without purification in the next step. lH-NMR (D6-DMSO): d = 6.44 (s, 1H), 7.50-7.75 (m, 6H), 8.33-8.40 (m, 2H), 8.53 (dd, J = 8.0, 1.6Hz, 2H)-
(Structure Removed)
A solution of the lithium salt 17 (5'0mg) and L-prolinamide (122mg, 1.07mmol) in DMSO (1.5raL) is heated'under nitrogen to 80 °C for 15.5h. 4% aq. acetic acid (lOmL) is added to the cooled solution, and the mixture is extracted with EtOAc (5'10mL). The combined organic layers are washed with 4% aq. acetic acid (lOmL), water (lOmL) and brine (lOmL) and are dried over MgS04. Filtration and concentration gives 40mg of 18 as a yellowish solid, which is used without purification in the next step. aH-NMR (CD3OD) : d= 1.95-2.36 (m, 4H) , 3.85-3.95 (m, 1H), 3.95-4.17 (m, 1H), 4.72 (brs, 1H) , 7.14 (s, 1H) , 7.35-7.45 (m, 3H), 7.45-7.70 (m, 3H), 8.33-8.50 (m, 4H).
(Structure Removed)
A solution of sodium hydroxide in methanol (1.5mL, 5M, 7.5mmol) is. added to a solution of the pyrroiopyrimicine 18 (40mg, 0.081mmol) in methanol (2mL). After 2h, the pH is adjusted to 5, most of the methanol is evaporated, the mixture is extracted with EtOAc (5 lOmL), the combined organic layers are washed with brine and dried over MgS04. Filtration and concentration yields 24mg of a pale yellow solid, which is triturated with toluene/EtOAc/MeOH to yield 15.6mg (55%) of the acid 1511 as slightly yellowish solid. XH-NMR (CD3OD) : d = 2.05-2.20 (m, 4H), 3.95-4.10 (m, 1H), 4.15-4.25 (m, 1H), 4.85 (brs, 1H), 7.14 (s, 1H), 7.35-7.42 (m, 3H), 8.38-8.45 (m, 2H); IR (solid): n = 31S2 cm"1, 2964, 2923, 2877, 1682, 1614, 1567, 1531, 1454, 1374, 1352, 1295, 1262, 1190, 974, 754, 700; MS (ES): 352 (M+1); m.p. = 220 °C (decomp.).
Example 28: Synthesis of 1- ( 6-methyl-2-phenyl-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-(S)-pyrrolidine-2 -carboxylic acid amide (1512)
Compound 1512 was synthesized by the following steps:
(Structure Removed)
Aryl chloride 20 (3g, 10.7 mmol), DMSO (50ml) and (S)-
prolinamide were combined and heated to 85°C under argon. After
stirring overnight (14hrs), the mixture was. cooled to room
temperature and poured into 800mi of water. This was extracted with three 200ml portions of EtOAc. The combined organic layers were thoroughly washed with water (3 x 300 ml) , brine, dried over MgSO4, filtered and concentrated to give a dark brown solid. The solid was recrystallized twice from EtOAc to yield 1.95g (57%) of a tan solid (1512). XHNMR(DMSO-d6) d 1.8-2.2 (m, 4H), 2.3 (s, 3H), 3.8 (m, 1H), 4.0 (m, Iff), 4.6 (d, 1H) 6.2 (s, 1H), 6.9 (s, 1H), 7.2 (m, 3H) , 7.3 (s, 1H), 8.4 (m, 2H) , 11.5 (s, 1H); MS (ES): 322 (M*+l)
Example 29: Synthesis of 1-[6-(2-Hydroxy-ethoxymethyl) -2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -pyrrolidine-2-carb oxylic acid amide(1513)
Compound 1513 was synthesized in a manner similar to that of Example 17 using synthesis scheme IX with L-prolineamide and ethane-1,2-diol to obtain:
(Structure Removed)
Example 30: Synthesis of 4-(6-Imidazol-l-ylmethyl-
2-phenyl-7H-pyrrolo[2, 3-d]pyrimidin-4-ylamino)-cyclohexanol
(1514) .
Compound 1514' was synthesized in a manner similar to that of Example 17 using synthesis scheme IX with N-6 amino cyclohexanol and imidazole to obtain:
(Structure Removed)
MS (ES): 389 (M' + l)
Example 31: Synthesis of 4-(4-Hydroxy-cyclohexylamino)
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (1515)
Compound 1515 was synthesized in a manner similar to that of Example 27 using synthesis scheme IX with N-6 amino cyclohexanol to obtain:
(Structure Removed)
MS (ES): 353 (M++l)
Example 32: Synthesis of 4-[6-(2-Hydroxy~ethoxymethyl) -2~phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-cyclohexanol (1516)
Compound 1516 was synthesized in a manner similar to that of Compound 1513 using synthesis scheme IX with N-6 amino cyclohexanol to obtain:
(Structure Removed)
MS. (ES) : 383 (M++l)
Example 33: Synthesis of 4-(4-Hydroxy-cyclohexylamino) -2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1517)
(Structure Removed)
A solution of the lithium salt 17 (0.13mmol) in dry DMF (4mL) is stirred with methyl iodide (O.lmL, 1.6mmol) at 20 °C under argon for 3h. DMF is evaporated, and aqueous ammonium chloride solution is added (15mL). The mixture is extracted with EtOAc (3'15mL), the combined organic layers are washed with water (2'lOmL) and brine (lOmL) and are dried over MgSO4. Filtration and concentration gives 21mg (38%) of the methyl ester 22.
(Structure Removed)
A solution of the methyl ester 22 (24.5mg, 0.057mmol) and 4-
trans-aminocyclohexanol (66mg, 0.57mmol) in DMSO (1.5mL) is
heated under nitrogen to 80 °C for 5h, then the heating is
stopped, and stirring at 20 °C is continued for 13.5h. 4% aq.
acetic acid (lOmL) is added to the cooled solution, and the
mixture is extracted with EtOAc (3'10mL). The combined organic
layers are washed with 4% aq. acetic acid (lOmL), water (lOmL)
2N NaOH (lOmL), water (lOmL), and brine (lOmL) and are dried
over MgSO4. To a solution of the crude material obtained after
filtration and concentration (1H NMR indicates about 50%
removal of the benzenesulfonyl group) in THF (2mL) is added a
solution of NaOH in MeOH (0.5mL of 5m solution, 2.5mmol)' at
ambient temperature. After 20min, water and sat. NaHC03
solution (5mL each) are added, and the mixture is extracted with EtOAc (4'15mL). The combined organic layers are washed with 2n NaOH (lOmL), water (lOmL) , and brine (lOmL) and are dried over MgSO4. Chromatography of the crude material obtained after filtration and concentration on silica gel, elating with hexanes/EtOAc 1:1 © 1:2 yields 8.6mg (41%) of 1517 as a white solid, mp. 225-227 °C. 1H-NMR (CD3OD) : d = 1.38-1.62 (m, 4H) , 1.95-2.10 (m, 2H), 2.10-2.25 (m, 2H), 3.55-3.70 (m, 1H), 3.91 (s, 3H), 4.20-4.35 (m, 1H), 7.32 (s, 1H), 7.35-7.47 (m, 3H) , 8.35-8.42 (m, 2H) ; IR (solid): n = 3352 cm"1, 3064, 2935, 2860, 1701, 1605, 1588, 1574, 1534, 1447, 1386, 1333, 1263, 1206, 1164, 1074, 938, 756, 705; MS (ES) : 367 (MH*) .
Example 34: Synthesis of [4-(2-Carbamoyl-pyrrolidin-l-yl) -2-phenyi-7H-pyrrolo[2,3-d]pyriraidin-6-ylmethoxy]-acetic acid methyl ester (1518)
Compound 1518 was synthesized in a manner similar to example 26 using precursor compound 12 to obtain:
(Structure Removed)
MS (ES): 410 (M++l)
Example 35: Synthesis of [4-(2-Carbamoyl-pyrrolidin-l-yl)
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethoxy]-acetic acid

Compound 1519 was synthesized in a manner similar to compound 1S18 wherein the methyl ester group was hydrolized with a base to obtain:
(Structure Removed)
MS (ES): 396 (M++l)
Example 40: Synthesis of 4-(4-Hydroxy-cyclohexylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid amide (Structure Removed)

Gaseous ammonia is condensed into a solution of the pyrrolopyrimidine 23 (7.8mc, 0.Q21mmol) in methanol (6mL), cooled by dry ice/acetone, until a total volume of 12mL is reached. After stirring for lOd at 20 °C, the solvents are evaporated, and the residue is purified by preparative TLC on silica gel, eluting with 5% MeOH in CH2C12. The material thus obtained is triturated with ether to yield 6.5mg (88%) of the amide 1520 as white solid, mp. 210-220 °C (decomp.).1H-NMR (CD3OD) : d = 1.40-1.60 (m, 4H) , 2.00-2.15 (m, 2H) , 2.15-2.25 (m, 2H) , 3.55-3.70 (m, 1H) , 4.20-4.35 (m, 1H) , 7.16 (s, 1H), 7.35-7.47 (m, 3H), 8.34-8.40 (m, 2H) ; IR (solid): n = 3358 cm-1, 3064, 3025, 2964, 2924, 2853, 1652, 1593, 1539, 1493, 1452, 1374, 1326, 1251, 1197, 1113, 1074, 1028, 751, 699; MS (ES): 352 (MH+) .
Activity of Compounds
Adenosine 1 (AJ receptor subtype saturation and competition radio ligand binding were carried out for compounds 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1516, 1517, 1518, 1519, and 1520 as described herein and inter alia, on pages 152-153 of this specification. All of the aboveReferenced compounds .equaled or surpassed the A1 receptor binding affinity of reference compounds 1318 or 1319 as described herein and, inter alia, in Table 13, on page 171 of the specification.
The water solubilities of the above compounds listed in Table 18 are expected to be better than reference compounds 1318 or

1319 due to their cLogP values, which were calculated using the computer program CS ChemDraw, ChemDraw Ultra ver. 6.0 ©1999 as provided by CambridgeSoft Corporation, 100 Cambridge Park Drive, Cambridge, MA 02140.
The compounds specific to the A1 receptor listed in Table 18 had lower cLogP values, between about 1.5 to about 3.4, as compared to reference compounds 1318 or 1319 with a cLogP value about 3.8. It was not predicted that the more polar A1 receptor compounds listed in Table 18 having lower cLogP values than the reference compounds 1318 or 1319 would still retain the potency and A1 receptor binding selectivity as compared to those reference compounds.
Table 18
(Table Removed)
Pages 288-293 relate to additional compounds specific to A-., receptor
This invention provides a compound having the structure:
(Structure Removed)
This invention also provides a compound having the structure:
(Structure Removed)
In a further embodiment the invention provides a method for treating a disease associated with A2a adenosine receptor in a subject, comprising administering to the subject a

therapeutically effective amount of compounds 1609 or 1610.
The invention also provides the above method .wherein the subject is a mammal.
The invention further provides the above method, wherein the mammal is a human.
The invention also provides the method for treating a disease associated with A2a adenosine receptor in a subject, wherein the A2a adenosine receptor is associated with locomotor activity, vasodilation, platelet inhibition, neutrophil superoxide generation, cognitive disorder, senile dementia, or Parkinson's disease.
The invention provides the above method, wherein the compound treats the diseases by stimulating adenylate cyclase.
The invention also provides a water-soluble prodrug of the compound 1609 or 1610, wherein the water-soluble prodrug is metabolized in vivo to an active drug to selectively inhibit an
A2a adenosine receptor.
The invention also provides a water-soluble prodrug of the compound 1609 or 1610, wherein the prodrug is metabolized in vivo by esterase catalyzed hydrolysis.
The invention also provides a pharmaceutical composition comprising the water-soluble prodrug of the compound 1609 or 1610, and a pharmaceutically acceptable carrier.

The invention also provides a method for inhibiting the activity of an A2a adenosine receptor' in a cell, which comprises contacting the cell with compound 160S or 1610.
The invention also provides a method for inhibiting the activity of an A2s adenosine receptor in a cell, which comprises contacting the cell with compound 1609 or 1610, wherein the compound is an antagonist of said A2a adenosine receptor.
The invention also provides the above method, wherein the cell is a human cell.
The invention also provides the above method, wherein the cell is a human cell and the compound is an antagonist of A2a adenosine receptors.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound 1609 or 1610 and a pharmaceutically acceptable carrier.
The invention also provides the above pharmaceutical composition, wherein the therapeutically effective amount is effective to treat Parkinson's disease and diseases associated with locomotor activity, vasodilation, platelet inhibition, neutrophil superoxide generation, cognitive disorder, or senile dementia.
The invention also provides the above pharmaceutical composition, wherein the pharmaceutical composition is an ophthalmic formulation.
The invention also provides the above pharmaceutical

composition, wherein the pharmaceutical composition is an periocular, retrobulbar or intraocular injection formulation.
The invention also provides the above pharmaceutical composition, wherein the pharmaceutical composition is a systemic formulation.
The invention also provides the above pharmaceutical composition, wherein the pharmaceutical composition is a surgical irrigating solution.
The invention also provides a combination therapy for Parkinson's disease, comprising the compounds 1609 or 1610, and any of the dopamine enhancers.
The invention also provides a combination therapy for cancer, comprising the compound 1609 or 1610, and any of the cytotoxic
agents.
The invention also provides a combination therapy for glaucoma, comprising the compound 1609 or 1610, and a prostaglandin
agonist, a muscrinic agonist, or a p-2 antagonist.
The invention also provides a packaged pharmaceutical composition for treating a disease associated with A2a adenosine receptor in a subject, comprising:
(a) a container holding a therapeutically effective amount of the compound 160 9 or 1610; and
(b) instructions for using the compound for treating said disease in a subject.
Exemplification
Example 41: Synthesis of 1- (6-Phenyl-2-pyridin-4-yl- 7H-pyrrolo[2, 3-d]pyrimidin-4-yl]-pyrrolidine-2-carboxylic acid amide (1609).
Compound 1609 was synthesized by reacting L-prolinamide with the appropriate chloride intermediate described in synthesis scheme II on page 82 to obtain:
(Structure Removed)
1H-NMR (d6-DMS0) d 1.95-2.15 (m, 4H) , 4.00 (brs, 1H) , 4.15 (brs, 1H), 4.72 (brs, 1H) , 6.90 (brs, 1H), 7.19 (brs, 1H), 7.30 (t, 1H, J = 7.0Hz), 7.44 (t, 2H, J = 7.0Hz), 7.59 (s, 1H), 7.92 (brs, 2H), 8.26 (d,2H, J = 6.2Hz), 8.65 (d, 2H, J = 6.2Hz); MS (ES) : 384.9 (M* + l); Mpt = 280-316°C (decomp.).

Example 42: Synthesis of 1- [6-(3-Methoxy-phenyl)-2-pyridin-4-yl- 7H-pyrrolo [2, 3-d] pyrimidin-4-yl] -pyrrolidine-2-carboxylic acid amide (1610).
Compound 1610 was synthesized by reacting L-prolinamide with the appropriate chloride intermediate described in synthesis scheme II on page 82 to obtain:
(Structure Removed)
1H-NMR(d6-DMSO) d 2.07(m,4H), 3.85{s,3H), 4.02(m,lH),
4.17(m,lH), 4.75(m,lH), 6.89(m,lH), 7.00(s,lH), 7.23(s,lH), 7.35(t,lH,J=8.2Hz), 7.53(s,2H), 7.60(s,lH), 8.28(d,2H,J=5.8Hz), 8.67(d,2H,J=5.8Hz) , 12.37(s,1H); MS (ES): 415.0 (MT1).
Activity of Compounds
Adenosine 2a (A2a) receptor subtype competition radio ligand binding were carried out for compounds 1609 and 1610 as described herein and inter alia, on page 153 of this specification. Compounds 1609 and 1610 were found have A2a receptor binding affinity and selectivity.
Pages 294-300 relate to additional compounds specific to A,
receptor
This invention also provides a compound having the structure:
(Structure Removed)
In a further embodiment the invention provides a method for inhibiting the activity of an A3 adenosine receptor in a cell, which comprises contacting the cell with the compound 1720.
In a further embodiment the invention provides a method for inhibiting the activity of an A3 adenosine receptor in a cell, wherein the compound is an antagonist of the A3 adenosine receptor.
In a further embodiment the invention provides the above method for inhibiting the activity of an A3 adenosine receptor in a cell, wherein the cell is human cell.
In a further embodiment the invention provides the above method for inhibiting the activity of an A3 adenosine receptor in a cell, wherein the cell is a human cell and wherein the compound is an antagonist of A3 adenosine receptors.
In a further embodiment the invention provides a method of treating damage to the eye of a subject which comprises administering to the subject a composition comprising a therapeutically effective amount of the compound 1720.
In a further embodiment the invention provides the above method, wherein the damage comprises retinal or optic nerve head damage.
In a further embodiment the invention provides a therapy for glaucoma, comprising administering to a subject a therapeutically effective amount of the compound 1720.
In a further embodiment the invention provides a therapy for glaucoma comprising one or more adenosine receptor antagonists, preferably comprising an adenosine receptor A3 antagonist (preferably an N-6 substituted 7-deazapurine, most preferably [2-(3H-Imidazol-4-yl)-ethyl]-(2-phenyl-7H-pyrrolo.[2,3-d]pyrimidin-4-yl)-amine).
In an alternative embodiment the invention provides a combination therapy for glaucoma comprising an adenosine receptor A3 antagonist (preferably . an N-6 substituted 7-deazapurine, most preferably [2-(3H-Imidazol-4-yl)-ethyl)-{2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine)) and one or more other compounds selected from the group consisting of beta adrenoceptor antagonists (i.e. beta adrenergic antagonists or
b-blockers) (e.g. timolol maleate, betaxolcl, carteolol, levobunolol, metipranolol, L-653328 (the acetate ester of L-652698), beta 1 adrenoceptor antagonists) , alpha-2 adrenoceptor agonists (e.g. aplaclonidine, brimonidine, AGN-195795, AGN-190837 (an analog of Bay-a-6781)) , carbonic anhydrase inhibitors (brinzolamide, dorzolamide, MK-927 (an inhibitor of the. human carbonic anhydrase II isoenzyme), inhibitors of carbonic anhydrase IV isoenzyme), cholinergic agonists (e.g. muscarinic cholinergic agonists, carbachol, pilocarpine HC1, pilocarpine nitrate, pilocarpine, pilocarpine prodrugs (e.g. DD-22A)), prostaglandins and prostaglandin receptor agonists (e.g. latanoprost, unoprostone isopropyi, PGF2 alpha agonists, prostanoid-selective FP receptor agonists, PG agonists such as the hypotensive prostamides) , angiotensin converting enzyme (ACE) inhibitors (e.g. Spirapril, spiraprilat), AMPA receptor antagonists, 5-HT agonists (e.g. a selective 5-HT 1A receptor agonist such as MKC-242 (5-3- [ ( (2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy-1,3-benxodioxole HC1), angiogenesis inhibitors (e.g. the steroid anecortave), NMDA antagonists (e.g. HU-211, memantine, the cannabinoid NMDAReceptor agonist dexanabinol, prodrugs and analogs of dexanabinol, NR2B-selective antagonists (e.g. eliprodil (SL-82.0715)), renin inhibitors (e.g. CGP-38560, SR-43845), cannabinoid receptor agonists (e.g. tetrahydrocannabinol (THC) and THC analogs, selective CB2 cannabinoid receptor agonists (e.g. L-768242, L-759787), compounds such as anandamide that bind to both brain-specific CB1 receptors and peripheral CB2 receptors), angiotensin receptor antagonists (e.g., angiotensin II receptor antagonists (e.g. CS-088), selective angiotensin II AT-I

receptor antagonists, such as losartan potassium),
hydrochlorothiazide (HCTZ), somatostatin agonists {e.g. the
non-peptide somatostatin agonist NNC-26-9100), glucocorticoid
antagonists, mast cell degranulation inhibitors (e.g.
nedocromil), alpha-adrenergic receptor blockers (e.g.
dapiprazole, alpha-2 adrenoceptor antagonists, alpha 1
adrenoceptor antagonists (e.g. bunazosin)), alpha-2
adrenoceptor antagonists, thromboxane A2 mimetics, protein
kinase inhibitors (e.g. H7), prostaglandin F derivatives (e.g.
S-1033), prostaglandin-2 alpha antagonists (e.g. PhXA-34),
dopamine Dl and 5-HT2 agonists (fenoldopam), nitric-oxide-
releasing agents (e.g. NCX-904 or NCX-905, nitric-oxide-
releasing derivatives of timolol), 5-HT 2 antagonists (e.g.
sarpogrelate), NMDA antagonists (e.g. prodrugs and analogs of
dexanabinol), alpha 1 adrenoceptor antagonists (e.g.
bunazosin), cyclooxygenase inhibitors (e.g. diclofenac, or the
non-steroidal compound nepafenac), inosine, dopamine D2
receptor and alpha 2 adrenoceptor agonists (e.g. talipexole),
dopamine Dl receptor antagonist and D2 receptor agonists (e.g.
SDZ-GLC-756), vasopressin receptor antagonists (e.g.
vasopressin V2 receptor antagonists (e.g. SR-121463)),
endothelin antagonists (e.g. TBC-2576), 1-(3-hydroxy-2-
phosphonylmethoxypropyl}cytosine (HPMPC) and related analogs
and prodrugs, thyroid hormone receptor ligands (e.g. KB-
130015), muscarinic Ml agonists, NMDAReceptor antagonists
(e.g. the cannabinoid NMDAReceptor antagonist dexanabinol), PG
agonists such as the hypotensive lipids, prostamides, sodium
channel blockers, NMDA antagonists, mixed-action ion channel
blockers, beta adrenoceptor antagonist and PGF2 alpha agonist

combinations (e.g. latanoprost and timolol), guanylate cyclase activators (e.g. atrial natriuretic peptide (ANP) or non-peptide mimetics, inhibitors of AN? neutral endcpeptidase, nitrovasodilators (e.g. nitroglycerin, hydralazine, sodium nitroprusside) , . endothelin receptor modulators (e.g. ET-1 or non-peptide mimetics, sarafotoxin-S6c), ethacrynic acid, other phenoxyacetic acid analogs (e.g. indacrinone, ticrynafen), actin disrupters (e.g. latrunculin), calcium channel blockers (e.g. verapamil, nifedipine, brovincamine, nivaldipine) and neuroprotective agents.
A combination therapy for glaucoma, comprising the compound of 1702, and one or more compounds selected from the group consisting of beta adrenoceptor antagonists, alpha-2 adrenoceptor agonists, carbonic anhydrase inhibitors, cholinergic agonists and prostaglandin receptor agonists.
In a further embodiment the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound 1720 and a pharmaceutically acceptable carrier.
In a further embodiment the invention provides a packaged pharmaceutical composition for treating a disease associated with A3 adenosine receptor in a subject, comprising:
a container holding a therapeutically effective amount of the compound 1720; and
instructions for using said compound for treating said disease in a subject.

In a further embodiment the invention provides a method of making a composition which comprises the compound 1720, the method comprising admixing the compound 1702 with a suitable carrier.
In a further embodiment the invention provides a pharmaceutically acceptable salt of compound 1720, wherein the pharmaceutically acceptable salt contains an anion selected from the group consisting of maleic, fumaric, tartaric, acetate, phosphate and mesylate.
Exemplification
Example 43: Synthesis of- [2-(3H-Imidazol-4-yl)-ethyl]- (2-
phenyl-7H-pyrrolo[2, 3-djpyrimidin-4-yl)-amine (1720)
Compound 1720 was synthesized using precursor compound 1 of synthesis scheme VII to obtain:

(Structure Removed)
Aryl chloride 1 (400mg, 1.50mmol), DMSO (lOmL) and histamine
(1.67g, . 15.0nvmol) are combined and heated to 120°C under
nitrogen- After 6.5h, the reaction is cooled to room
temperature and partitioned between EtOAc and water. The layers
are separated and the aqueous layer is extracted with EtOAc
(3x). The combined organic layers are washed with brine (2x),
dried over MgSO,, filtered and concentrated to yield 4 94mg of a
brown solid. The solid is washed with cold MeOH and
recrystallized from MeOH to yield lS7mg (43%) of an off white solid (1720). 'H-NMR (CD3OD) d 3.05 (t, 2H, J = 7.0Hz), 3.94 (t, 2H, J = 7.0Hz), 6.50 (d, 1H, J = 3.5Hz), 6.88 (brs, 1H), 7.04 (d, 1H, J = 3.5H2), 7.42 (m, 3H) , 7.57 (s, 1H), 8.34 (m, 2H) ; MS (ES) : 305.1 (NH1); Mpt = 234-235°C.
Activity of Compounds
Adenosine 3 (A3) receptor competition radio ligand binding was carried out for compound 1720 as described herein and inter alia, on pages 153-154 of this specification. Compound 1720 was found to have an A3 receptor binding affinity greater than 10 times that of reference compound 1308 as described herein and, inter alia, in Table 13, on page 169 of the specification.
Incorporation by Reference
All patents, published patent applications and other references disclosed herein are hereby expressly .incorporated herein by reference.
Equivalents
Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, many
equivalents to specific embodiments of the invention described
specifically herein. Such equivalents are intended to be
encompassed in the scope of the following claims.






What is- claimed is:1. A compound having the structure.:(Structure Removed)wherein .R1. is(Structure Removed)
and
R2 is H; or-
-NR1S2 together ar(Structure Removed)
wherein R3 is ;a: siibstituted or unsubstitutel phenyl or pyrielyl ring;
wherein R.5 is H- ,CH3,. substituted ox", unsubsti tilted, a-I-kyl, aryl or phenyl,(Structure Removed)
wkereim Si is o or S; and
wherein R6 is: H, CH3 ByBstitiutecl or unstibstltuted alkyl, cyoloalyl ox'(Structure Remove)or a ph-axWaeeuti-Gaily aceeptable salt thereof, whereinwhen R1 isRs is(Structure Removed)
wherein. .X is 0 or S; atielwherein wliecr JR1 isR5 is phenyl; and wherein 'when R1: is(Structure Removed)R1is 4chlorbplienyl.
2. The campou/ad of clai:m: I .having the struebure;(Structure Removed)
wherein R3 is substituted or unsubsfci't.utesl pheayl,- wherein R5 apcj R6 are indep-eMdently; H, or alkyl.
3 The eoinpousd. of claim 2, havihg the structure:
(Structure Removed)
The- compbunel of claim. 3, having the- strttic ture:
(Structure Removed)
5> The compouad of claim 3, having tdhe st-rwotrure:.
6. The compound of claim 3, having the-structure:
(Structure Removed)
7. Ihe- compound of -claim- 3, having the' structure:(Structure Removed)
P. The; fiompoud of claim. % having the structure:(Structure Removed)
wteerefin R3. ,is: a substituted or tpSsubstitti'fced phenyl; wherein E5 a :R6 are- independently H, or" a:lkyl,
9. The Gomppund of' claim 8;, having the structure:
(Structure Removed)
lb, The compowird af claim- 1 isreing the- strueture:
(Structure Removed)
wherein R3 As sialDSfci'tutecJ paeiryCl;
wherein; Rs and .R6, are d-Rdegeria'entiy .'H-:, sx alkyl..
11. The: isesmpOMnd: 0f claim10. Slaving the structure:
(Structure Removed)
Thecompound of claims1, having the structure;
14. The compound of claims12, having the structure;:
15, The compound of claims12, having the structure
(Structure Removed)wherein NR1R2 is (D)-2-amitioaatbcsriyl pyrrolidine {D)-2-hydroxymR6thyl pyrrolidine), (D)-S-hyai-axymefchyl- trans-A-hydroxy pyrrolidine), oir pipera-zino;
wherein R1 is a substituted or unsubstltuted phenyl or pyridine;
wherein R5 is H- phenyl of'
(Structure Removed)wherein Rs is M, alfcyl, substitiited alkyi;, -or cyc'loalkyl.
(Structure Removed)16. The compound of claims15, having the structure

wherein NR2R2 is subatituted or unsubstituted 3-hydroxyrae,thyl piperadino;
wherein R3 is a' substituted or unsubstituted 4-pyridyl, wherein lis is H or alkyl.;: add
wherein. Rs is :H or alkyl.
17. The compound of claims12, having the structure

(Structure Removed)IS- The compound of claims12, having the structure:

-T9 . The compound of claims15, having the structure



(Structure Removed)20 - The compound of claims12, having the structure
The compound of claims15, having the structure
:
(Structure Removed)2.S. *£he: eompouaci of- claiw15-, hsvlag1 the stiupture:
23. The compound of claims1, having the structure
(Structure Removed)24=. The. compound of: claim '3, having the structure;
25- The compound of claims24, having the structure

26. The compound of claims24, having the structure

27'. The compound of claims1, having the structure:
wherein R5 is S1., ax .methyl.
2g>. The compound of claims27, having the structure:

2R6. The compound of claims27, having the structure:36. A : method of pr.feparinicj the compdurid of. eriairfr 27, comprising the steeps of
(Structure Removed)wherein R5 phrenyl,
or R5 aad 8g are epeicieatly H, substituted or uasubstit«ted alkyl, a;ey 1.
32'. The compound of claims1, having the structure:;

13. The compound of claims1, having the structure:;


3 The compound of claims1, having the structure:;
The compound of claims1, having the structure:;
36. The compound of claims31, having the structure:;
iff, The compound of claims31, having the structure:; BO
3S. The compound of claims31, having the structure:;
3,9. The compound of claims31, having the structure:
40. The compound of claims31, having the structure:
The compound of claims37, having the structure:

4.2. The compound of claims31, having the structure:
The compound of claims1, having the structure:44. The compound of claims31, having the structure:
The compound of claims31, having the structure::
6. The compound of claims31, having the structure:
47 The compound of claims31, having the structure:
48- The compound of claims31, having the structure:
The compound of claims31, having the structure:
5D . The compound of claims31, having the structure:
The compound of claims31, having the structure:
The compound of claims51, having the structure:

The compound of claims51, having the structure:

54. The compound of claims1, having the structure:
wherein. Si, Is aacl. the aitrogen togetheir are

wherein. R5- and S6 are indfependeatly .B, substituted or

The compound of claims54, having the structure:
56. The compound of claims56, having the structure:
57. The compound of claims55, having the structure:
52,. The compound of claims54, having the structure:;

The compound of claims54, having the structure::
60. The compound of claims59, having the structure
The compound of claims59, having the structure

62. The compound of claims54, having the structure::
63. The compound of claims54, having the structure:.
The compound of claims62, having the structure:
G5 . The compound of claims54, having the structure:
The compound of claims65, having the structure:cure:;
67. The compound of claims65, having the structure:
The compound of claims1, having the structure:

SR:|R2 together are
therein R3- Is a stibstitaited ®r 'langufos-fejitsaitecl' pJienyl or pyridyl .xlxxR6i
wherein :RS is p, CH3<. substituted- or unsubstituted aikyi aryl phenyl>
wherein as and
wherein R5 is- K, CH3 substituted or- lansufostit-tited alkyl, cycloalkyl or
70. A compound substantially as herein described with reference to the foregoing examples.
71. A method for preparing the compound substantially as herein described with reference to the foregoing examples.

Documents:

in-pct-2002-00622-del-abstract.pdf

in-pct-2002-00622-del-assignment.pdf

in-pct-2002-00622-del-complete specification [granted].pdf

in-pct-2002-00622-del-correspondence-others.pdf

in-pct-2002-00622-del-correspondence-po.pdf

in-pct-2002-00622-del-description (complete).pdf

in-pct-2002-00622-del-form-1.pdf

in-pct-2002-00622-del-form-13.pdf

in-pct-2002-00622-del-form-19.pdf

in-pct-2002-00622-del-form-2.pdf

in-pct-2002-00622-del-form-3.pdf

in-pct-2002-00622-del-form-4.pdf

in-pct-2002-00622-del-form-5.pdf

in-pct-2002-00622-del-gpa.pdf

in-pct-2002-00622-del-pct-101.pdf

in-pct-2002-00622-del-pct-210.pdf

in-pct-2002-00622-del-pct-304.pdf

in-pct-2002-00622-del-pct-401.pdf

in-pct-2002-00622-del-pct-409.pdf

in-pct-2002-00622-del-pct-416.pdf

in-pct-2002-00622-del-petition-137.pdf

in-pct-2002-00622-del-petition-138.pdf


Patent Number 244741
Indian Patent Application Number IN/PCT/2002/00622/DEL
PG Journal Number 52/2010
Publication Date 24-Dec-2010
Grant Date 17-Dec-2010
Date of Filing 19-Jun-2002
Name of Patentee OSI PHARMACEUTICAL INC.
Applicant Address 106 CHARLES LINDBERGH BLVD., UNIONDALE, NEW YORK 11553-3649, U.S.A
Inventors:
# Inventor's Name Inventor's Address
1 ARLINDO L CASTELHANO 3 EAGLE COURT, NEW CITY, NEW YORK 10579, U.S.A
2 BRYAN MCKIBBEN 15 GREENRIDGE AVENUE, APT. 8, WHITE PLAINS, NY 10605, U.S.A.
3 DAVID J WITTER 12 ARBUTUS ROAD, PUTNAM VALLEY, NEW YORK 10579, U.S.A.
PCT International Classification Number A61K 31/519
PCT International Application Number PCT/US00/32702
PCT International Filing date 2000-12-01
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 09/454,254 1999-12-02 U.S.A.
2 09/454,074 1999-12-02 U.S.A.
3 09/454,075 1999-12-02 U.S.A.