Field of the Invention This invention relates to novel arylindenopyridines and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include neurodegenerative and movement disorders ameliorated by antagonizing Adenosine A2a receptors and inflammatory and AIDS-related disorders ameliorated by inhibiting phosphodiesterace activity.

Background of the Invention Adenosine A2a Receptors Adenosine is a purine nucleotide produced by all metabolically active cells within the body. Adenosine exerts its effects via four subtypes of cell- surface receptors (A1, A2a, A2b and A3), which belong to the G protein coupled receptor superfamily (Stiles, G. L. Journal of Biological Chemistry, 1992,267, 6451). A1 and A3 couple to inhibitory G protein, while A2a and A2b couple to stimulatory G protein. A2a receptors are mainly found in the brain, both in neurons and glial cells (highest level in the striatum and nucleus accumbens, moderate to high level in olfactory tubercle, hypothalamus, and hippocampus etc. regions) (Rosin, D. L. ; Robeva, A.; Woodard, R. L. ; Guyenet, P. G.; Linden, J. Journal of Comparative Neurology, 1998, 401, 163).

In peripheral tissues, A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S.; Varani, K.; Merighi, S.; Ongini, E.; Borea, P. A. British Journal of Pharmacology, 2000,129, 2). The

striatum is the main brain region for the regulation of motor activity, particularly through its innervation from dopaminergic neurons originating in the substantia nigra. The striatum is the major target of the dopaminergic neuron degeneration in patients with Parkinson's Disease (PD). Within the striatum, A2a receptors are co-localized with dopamine D2 receptors, suggesting an important site of for the integration of adenosine and dopamine signaling in the brain (Fink, J. S.; Weaver, D. R.; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Brain Research Molecular Brain Research, 1992,14, 186).

Neurochemical studies have shown that activation of A2a receptors reduces the binding affinity of D2 agonist to their receptors. This D2R and A2aR receptor-receptor interaction has been demonstrated in striatal membrane preparations of rats (Ferre, S.; von Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proceedings of the National Academy of Sciences of the United States of America, 1991,88, 7238) as well as in fibroblast cell lines after transfected with A2aR and D2R cDNAs (Salim, H.; Ferre, S.; Dalal, A.; Peterfreund, R. A.; Fuxe, K. ; Vincent, J. D.; Lledo, P. M. Journal of Neurochemistry, 2000,74, 432). In vivo, pharmacological blockade of A2a receptors using A2a antagonist leads to beneficial effects in dopaminergic neurotoxin MPTP (1-methyl-4-pheny-1, 2,3, 6-tetrahydropyridine) -induced PD in various species, including mice, rats, and monkeys (Ikeda, K.; Kurokawa, M.; Aoyama, S.; Kuwana, Y. Journal of Neurochemistry, 2002, 80, 262).

Furthermore, A2a knockout mice with genetic blockade of A2a function have been found to be less sensitive to motor impairment and neurochemical changes when they were exposed to neurotoxin MPTP (Chen, J. F.; Xu, K.; Petzer, J. P.; Staal, R.; Xu, Y. H.; Beilstein, M.; Sonsalla, P. K.; Castagnoli, K.; Castagnoli, N. , Jr.; Schwarzschild, M. A. Journal of Neuroscience, 2001, 21, RC143).

In humans, the adenosine receptor antagonist theophylline has been found to produce beneficial effects in PD patients (Mally, J.; Stone, T. W.

Journal of the Neurological Sciences, 1995,132, 129). Consistently, recent epidemiological study has shown that high caffeine consumption makes people less likely to develop PD (Ascherio, A.; Zhang, S. M.; Hernan, M. A.; Kawachi, I. ; Colditz, G. A.; Speizer, F. E.; Willett, W. C. Annals of Neurology,

2001,50, 56). In summary, adenosine A2a receptor blockers may provide a new class of antiparkinsonian agents (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopol, A. Emerging Therapeutic Targets, 2000,4, 635).

Phosphodiesterase Inhibitors There are eleven known families of phosphodiesterases (PDE) widely distributed in many cell types and tissues. In their nomenclature, the number indicating the family is followed by a capital letter that indicates a distinct gene. A PDE inhibitor increases the concentration of cAMP in tissue cells, and hence, is useful in the prophylaxis or treatment of various diseases caused by the decrease in cAMP level which is induced by the abnormal metabolism of cAMP. These diseases include conditions such as hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.

Among known phosphodiesterases today, PDE1 family are activated by calcium-calmodulin ; its members include PDE1A and PDE1B, which preferentially hydrolyze cGMP, and PDE1 C which exhibits a high affinity for both cAMP and cGMP. PDE2 family is characterized as being specifically stimulated by cGMP.

PDE2A is specifically inhibited by erythro-9- (2-hydroxy-3-nonyl) adenine (EHNA).

Enzymes in the PDE3 family (e. g. PDE3A, PDE3B) are specifically inhibited by cGMP. PDE4 (e. g. PDE4A, PDE4B, PDE4C, PDE4D) is a cAMP specific PDE present in T-cells, which is involved in inflammatory responses. A PDE3 and/or PDE4 inhibitor would be predicted to have utility in the following disorders: autoimmune disorders (e. g. arthritis), inflammatory bowel disease, bronchial disorders (e. g. asthma), HIV/AIDS, and psoriasis. A PDE5 (e. g. PDE5A) inhibitor would be useful for the treatment of the following disorders: cardiovascular disease and erectile dysfunction. The photoreceptor PDE6 (e. g. PDE6A, PDE6B, PDE6C) enzymes specifically hydrolyze cGMP. PDE8 family exhibits high affinity for hydrolysis of both cAMP and cGMP but relatively low sensitivity to enzyme inhibitors specific for other PDE families.

Phosphodiesterase 7 (PDE7A, PDE7B) is a cyclic nucleotide phosphodiesterase that is specific for cyclic adenosine monophosphate (cAMP).

PDE7 catalyzes the conversion of cAMP to adenosine monophosphate (AMP) by hydrolyzing the 3'-phosphodiester bond of cAMP. By regulating this conversion, PDE7 allows for non-uniform intracellular distribution of cAM P and thus controls the activation of distinct kinase signaling pathways. PDE7A is primarily expressed in T- cells, and it has been shown that induction of PDE7A is required for T-cell activation (Li, L. ; Yee, C.; Beavo, J. A. Science 1999,283, 848). Since PDE7A activation is necessary for T-cell activation, small molecule inhibitors of PDE7 would be useful as immunosuppressants. An inhibitor of PDE7A would be predicted to have immunosuppressive effects with utility in therapeutic areas such as organ transplantation, autoimmune disorders (e. g. arthritis), HIV/AI DS, inflammatory bowel disease, asthma, allergies and psoriasis.

Few potent inhibitors of PDE7 have been reported. Most inhibitors of other phosphodiesterases have IC50's for PDE7 in the 100 pM range. Recently, Martinez, et al. (J. Med. Chem. 2000,43, 683) reported a series of PDE7 inhibitors, among which the two best compounds have PDE7 IC50's of 8 and 13 3 pM. However, these compounds were only 2-3 times selective for PDE7 over PDE4 and PDE3.

Finally, the following compounds have been disclosed, and some of them are reported to show antimicrobial activity against strains such as Plasmodium falciparum, Candida albicans and Staphylococcus aureus (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997,504) :

Summary of the Invention This invention provides a compound having the structure of Formula I Formula I or a pharmaceutically acceptable salt thereof, wherein (a) Ri is selected from the group consisting of: (i)-COR5, wherein R5 is selected from H, optionally substituted Ci-s straight or branched chain alkyl,

optionally substituted aryl and optionally substituted arylalkyl ; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from Ci-s alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R2o and R21 are independently selected from the group consisting of hydrogen, C18 straight or branched chain alkyl, C37 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl ; (ii) COOR6, wherein R6 is selected from H, optionally substituted Ci. straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl ; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from Ci-s alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C18 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl ; (iii) cyano; (iv) a lactone or lactam formed with R4; (v)-CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl ; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted

heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups (b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C37 cycloalkyl ; (c) R3 is from one to four groups independently selected from the group consisting of: (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, Ci. alkoxy, cyano, C, « carboalkoxy, trifluoromethyl, Ci. alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, Ci-s carboxylate, aryl, heteroaryl, and heterocyclyl ; (ii) -NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3- 7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or Rio and Rn taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii)-NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C13alkoxyl, carboxyalkyl, R30R31N (CH2) p-, R30R31NCO (CH2) p-, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,

wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl ; (d) R4 is selected from the group consisting of (i) hydrogen, (ii) Cl-3 straight or branched chain alkyl, (iii) benzyl and (iv)-NR13R14, wherein R13 and R14 are independently selected from hydrogen and Cri-6 alkyl ; wherein the C13alkyl and benzyl groups are optionally substituted with one or more groups selected from 63-7 cycloalkyl, C1-8 alkoxy, cyano, C1 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, Cul-a carboxylate, amino, NR13R14, aryl and heteroaryl ; and (e) X is selected from S and O ; with the proviso that when R4 is isopropyl, then R3 is not halogen.

In an alternative embodiment, the invention is directed to compounds of Formula I wherein R1, R3 and R4 are as described above and R2 is- NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3 7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R15 and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR16, Ri is not-COOR6 where R6 is ethyl.

This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutical acceptable carrier.

This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

This invention further provides a method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors or reducing PDE activity in appropriate cells in the subject.

Detailed Description of the Invention Compounds of Formula 1 are potent small molecule antagonists of the Adenosine A2a receptors that have demonstrated potency for the antagonism of Adenosine A2a, A1, and A3 receptors.

Compounds of Formula I are also potent small molecule phosphodiesterase inhibitors that have demonstrated potency for inhibition of PDE7, PDE5, and PDE4.

Some of the compounds of this invention are potent small molecule PDE7 inhibitors which have also demonstrated good selectivity against PDE5 and PDE4.

Preferred embodiments for Ri are COOR6, wherein R6 is selected from H, optionally substituted CI-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably R6 is H, or C18 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

Preferred embodiments for R2 are optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl. Preferred substituents are from one to three members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluor or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.

Preferably, R2 is optionally substituted furan, phenyl or napthyl or R2 is optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and n itro. In another embodiment of the instant compound, R2 is-NRn5R, 6.

Preferred substituents for R3 include :

(i) hydrogen, halo, Cl-8 straight or branched chain alkyl, Ci. s alkoxy, cyano, C, carboalkoxy, trifluoromethyl, Ci. s alkylsulfonyl, halogen, nitro, and hydroxy; (ii) -NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC18alkyl, C3-7 cycloalkyl, carboxyC, 8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii)-NRn2CORr3 wherein Ri2 is selected from hydrogen or alkyl and Ris is selected from hydrogen, alkyl, substituted alkyl, CI-3alkoxyl, carboxyC,-8alkyl, aryl, arylalkyl, R3oR3, N (CH2) p-, R3oR31NCO (CH2) p-, heteroaryl and heterocyclyl or Ri2 and Ris taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R3r are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.

Particularly, R3 is selected from the group consisting of 0 H HON\ IH X , alkyl (CO) NH-, NH2, and N02.

Preferred embodiments for R4 include hydrogen, C13 straight or branched chain alkyl, particularly methyl, amine and amino.

In a further embodiment of the instant compound, Ri is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R2 is NR15R16.

More particularly, Ri is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl or R2 is NR15R16, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae : , alkyl (CO) NH-, and R4 is selected from hydrogen, Ci-s straight or branched chain alkyl, particularly methyl, and amino.

In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.

More preferably, the compound is selected from the following compounds: Compound 22 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 2-amino-4- (1, 3- benzodioxol-5-yl)-5-oxo-, ethyl ester

Compound 24 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (6-bromo-1, 3- benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

Compound 40 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7-amino-4- (1, 3- benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

Compound 49 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (6-bromo-1, 3- benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester Compound 51 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3, 5-dimethylphenyl)-2-methyl- 5-oxo-, methyl ester

Compound 56 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8- (acetylamino)-4- (1, 3- benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

Compound 67 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 2-methyl4-(3- methylphenyl)-5-oxo-, methyl ester

Compound 82 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7-amino-4- (3, 5- dimethylphenyl)-2-methyl-5-oxo-, methyl ester

Compound 90 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4- methyl-1-naphthalenyl)-5-oxo-, methyl ester Compound 169 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3, 5-dibromo-4- hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester Compound 170 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 7, 8-dichloro-4- (3, 5- dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester Compound 192

5H-indeno [1, 2-b] pyridine-3-carboxylic acid, 7-bromo-4- (3, 5-dibromo-4- hydroxyphenyl)-2-methyl-5-oxo-, methyl ester Compound 193 5H-indeno [1, 2-b] pyridine-3-carboxylic acid, 8-bromo-4- (3, 5-dibromo-4- hydroxyphenyl)-2-methyl-5-oxo-, methyl ester Compound 241 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8- [ (3-carboxy-1- oxopropyl) amino]-4- (3, 5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester Compound 242 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8- [ (3-carboxy-1- oxopropyl) amino]-2-methyl-4- (4-methyl-1-naphthalenyl)-5-oxo-, methyl ester

Compound 245 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3, 5-dimethylphenyl)-8- [ [4- (hydroxyamino)-1, 4-dioxobutyl] amino]-2-methyl-5-oxo-, methyl ester

Compound 250 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3, 5-dimethylphenyl)-8- [[[(2-hydroxyethyl) amino] acetyl] amino]-2-methyl-5-oxo-, methyl ester

Compound 251 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 8- [ (4-carboxy-1- oxobutyl) amino]-4- (3, 5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester Compound 254 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3, 5-dimethylphenyl)-8- [[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo- , methyl ester

Compound 261 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3, 5-dimethylphenyl)-2- methyl-8- [ (4-morpholinylacetyl) amino] -5-oxo-, methyl ester Compound 262 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2- methyl-5-oxo-8- [ (1-piperazinylacetyl) amino] -, methyl ester Compound 27 5H-indeno [1, 2-b] pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, ethyl ester Compound 66

5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (4-methylphenyl)-2- methyl-5-oxo-, methyl ester Compound 85 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3-bromophenyl)-2- methyl-5-oxo-, methyl ester Compound 221 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3-bromophenylamino)-2- methyl-5-oxo-, methyl ester Compound 265 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, methyl ester Compound 272 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (2-furyl)-2-amino-5-oxo-, methyl ester

Compound 268 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (3-furyl)-2-amino-5-oxo-, methyl ester Compound 267 5H-indeno [1,2-b] pyridine-3-carboxylic acid, 4- (2-furyl)-2-amino-5-oxo-, ethyl ester The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutical acceptable salts.

Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2- naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.

This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutical acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol,

polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like.

Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, cheating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.

This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

In one embodiment, the disorder is a neurodegenerative or movement disorder. In another embodiment, the disorder is an inflammatory disorder.

In still another embodiment, the disorder is an AIDS-related disorder.

Examples of disorders tratable by the instant pharmaceutical composition include, without limitation, Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, Senile Dementia, organ transplantation, autoimmune disorders (e. g. arthritis), immune challenge such as a bee sting, inflammatory bowel disease, bronchial disorders (e. g. asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction, allergies, and psoriasis.

In one preferred embodiment, the disorder is rheumatoid arthritis.

In another preferred embodiment, the disorder is Parkinson's disease.

As used herein, the term"subject"includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing

PDE activity in appropriate cells. In a preferred embodiment, the subject is a human. In a more preferred embodiment, the subject is a human.

As used herein,"appropriate cells"include, by way of example, cells . which display PDE activity. Specific examples of appropriate cells include, without limitation, T-lymphocytes, muscle cells, neuro cells, adipose tissue cells, monocytes, macrophages, fibroblasts.

Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. The instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.

As used herein, a "therapeutically effective dose" of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A"prophylactically effective dose"of a pharmaceutical composition is an amount sufficient to prevent a disorder, i. e. , eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.

In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition.

In another embodiment, the therapeutical and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0 pg/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical

carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.

This invention still further provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject. In the preferred embodiment, the event is an insect sting or an animal bite.

Definitions and Nomenclature Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

As used herein, the following chemical terms shall have the meanings as set forth in the following paragraphs :"independently", when in reference to chemical substituents, shall, mean that when more than one substituent exists, the substituents may be the same or different;.

"Alkyl"shall mean straight, cyclic and branched-chain alkyl. Unless otherwise stated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise stated, the alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di (C1-C8-alkyl) amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, Cl-C8- alkyl-CO-O-, C-C8-alkyl-CO-NH-, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl (c1-c8) alkyl, heterocyclyl, and heteroaryl.

"Alkoxy"shall mean-O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.

The term"bioisostere"is defined as"groups or molecules which have chemical and physical properties producing broadly similar biological properties. " (Burger's Medicinal Chemistry and Drug Discovery, M. E. Wolff, ed. Fifth Edition, Vol. 1,1995, Pg. 785).

"Halogen"shall mean fluorine, chlorine, bromine or iodine;"PH"or"Ph" shall mean phenyl ;"Ac"shall mean acyl ;"Bn"shall mean benzyl.

The term"acyl"as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term"Ac"as used herein, whether used alone or as part of a substituent group, means acetyl.

"Aryl"or"Ar,"whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1-or 2- naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with

halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, Cl-C8- alkylthio, C1-C8-alkyl-amino, di (C1-C8-alkyi) amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO-O-, C1-C8-alkyl- CO-NH-, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like."Ph"or"PH"denotes phenyl.

Whether used alone or as part of a substituent group,"heteroaryl" refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2- oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, indazolyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl, or furo [2,3-b] pyridinyl), imidazopyridinyl (such as imidazo [4,5-b] pyridinyl or imidazo [4,5-c] pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, and furyl. The heteroaryl group may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, Cl-C8- alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di (C1-C8-alkyl) amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C-C8-alkyl-CO-O-, C-C8-alkyl-CO-NH-, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1 H-quinoline.

The terms"heterocycle,""heterocyclic,"and"heterocyclo"refer to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4-to 7-membered monocyclic, 7-to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1,2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl ; oxetanyl ; pyrazolinyl ; imidazolinyl ; imidazolidinyl ; oxazolyl ; oxazolidinyl ; isoxazolinyl ; thiazolidinyl ; isothiazolidinyl ; tetrahydrofuryl ; piperidinyl ; piperazinyl ; 2-oxopiperazinyl ; 2-oxopiperidinyt ; 2-oxopyrrolidinyl ; 4-piperidonyl ; tetrahydropyranyl ; tetrahydrothiopyranyl ; tetrahydrothiopyranyl sulfone ; morpholinyl ; thiomorpholinyl ; thiomorpholinyl sulfoxide ; thiomorpholinyl sulfone ; 1, 3-dioxolane ; dioxanyl ; thietanyl ; thiiranyl ; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl ; tetrahydroisoquinolinyl ; dihydroisoindolyl ; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo- quinazolinyl) ; dihydrobenzofuryl ; dihydrobenzothienyl ; dihydrobenzothiopyranyl ; dihydrobenzothiopyranyl sulfone ; dihydrobenzopyranyl ; indolinyl ; isochromanyl ; isoindolinyl ; piperonyl ; tetrahydroquinolinyl ; and the like.

Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted- heteroaryl, or a second substituted-heterocycle to give, for example, a 4- pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.

Designated numbers of carbon atoms (e. g., Ci-s) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents

and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as . well as those methods set forth herein.

Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i. e. , hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers.

The non-racemic forms may be obtained by either synthesis or resolution.

The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

Experimental Details I. General Synthetic Schemes Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the following general schemes. The products of some schemes can be used as intermediates to produce more than one of the instant compounds. The choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.

Scheme 1 Procedures described in Scheme 1, wherein Rsa, R3b, Rsc, and R3d are independently any R3 group, and Ri, R2, R3, and R4 are as described above, can be used to prepare compounds of the invention wherein X is O.

Benzylidenes 2 may be obtained by known methods (Bullington, J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.; Pellegrino- Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998,8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949,2134).

Hantzsch reaction of the benzylidene compounds with enamines 3 can be performed in refluxing acetic acid (Petrow et al., supra). When the desired enamines are not available, alternate Hantzsch conditions may be utilized which involve adding ammonium acetate to the reaction. The resulting

dihydropyridines 4 are oxidized with chromium trioxide to obtain the desired pyridines 1 (Petrow et a/., supra). In cases where the substitution pattern on the fused aromatic ring (R3) leads to a mixture of regioisomers, the products can be separated by column chromatography.

In some cases, especially where R2 is an alkyl group, another modification of the Hantzsch may be performed which uses three components (Bocker, R. H.; Buengerich, P. J. Med. Chem. 1986,29, 1596).

Where R2 is an alkyl group it is also necessary to perform the oxidation with DDQ or Mn02 instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995,51, 6511).

Scheme 2 In order to obtain the corresponding carboxylic acids and amides, the cyanoethyl esters 5 are prepared as described above. The esters are converted to the carboxylic acids by treatment with sodium hydroxide in acetone and water (Ogawa, T.; Matsumoto, K.; Yokoo, C.; Hatayama, K.; Kitamura, K. J. Chem. Soc., Perkin Trans. 1 1993,525). The corresponding amides can then be obtained from the acids using standard means.

Scheme 3 R3a o R3a O R R3a O b) R2, R c (R _\R2 ( 3c R4 CN acetone/H20 R R N=OH nu Razz R3a O 1) o 2) HNR5R6 R3c Rsd N N RsRs 7

The procedure for making compounds where R4 is NH2 may be slightly modified. These compounds are prepared in one step from the benzylidenes 2 and alkyl amidinoacetate (Kobayashi, T.; Inoue, T.; Kita, Z.; Yoshiya, H.; Nishino, S.; Oizumi, K. ; Kimura, T. Chem. Pharm. Bull. 1995,43, 788) as depicted in Scheme 4 wherein R is R5 or R6 as described above.

Scheme 4

The dihydropyridine lactones 9 can be synthesized from benzylidenes 8 (Zimmer, H.; Hillstrom, W. W.; Schmidt, J. C.; Seemuth, P. D. ; Vogeli, R. J.

Org. Chem. 1978,43, 1541) and 1,3-indanedione, as shown in Scheme 5, and the corresponding pyridine is then obtained by oxidation with manganese dioxide.

Scheme 5

Representative schemes to modify substituents on the fused aromatic ring are shown below. The amines 11 are obtained from the corresponding nitro compounds 10 by reduction with tin (II) chloride (Scheme 6). Reaction of the amines with acetyl chloride provide the amides 12.

Scheme 6

In accordance with Scheme 7 wherein Y is O, and n is an integer from 1-3, an alkyl chain with a carboxylic acid at the terminal end can also be added to the amines 11. For example, reaction with either succinic anhydride (Omuaru, V. O. T. ; Indian J. Chem., Sect B. 1998, 37,814) or p-propiolactone (Bradley, G.; Clark, J.; Kernick, W. J. Chem. Soc., Perkin Trans. 1 1972, 2019) can provide the corresponding carboxylic acids 13. These carboxylic acids are then converted to the hydroxamic acids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy, A. S.; Kumar, M. S.; Reddy, G. R.

Tetrahedron Lett. 2000,41, 6285).

Scheme 7

The amines 11 can also be treated with glycolic acid to afford alcohols 15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Com m. 1993, 23, 2761) as shown in Scheme 8.

Scheme 8

As shown in Scheme 9, the aminoindenopyridines 11 may also be treated with chloroacetylchloride followed by amines to provide the more elaborate amines 16 (Weissman, S. A.; Lewis, S.; Askin, D.; N/olante, R. P.; Reider, P. J. Tetrahedron Lett. 1998,39, 7459). Where R6 is a hydroxyethyl group, the compounds can be further converted to piperazin ones 17.

Scheme 9

The 4-aminoindenopyridines 19 can be synthesized from the 4- chloroindenopyridines 18 using a known procedure (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997,504) or via palladium catalyzed coupling (Scheme 10).

Scheme 10

Cyanoesters 20 can be prepared by known methods (Lee, J.; Gauthier, D.; Rivero, R. A. J. Org. Chem. 1999,64, 3060). Reaction of 20 with enaminone 21 (lida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1979,44, 1074) in refluxing 1-propanol and triethylamine gave dihydropyridine 22, wherein R is R5 or R6 as described above, (Youssif, S.; El-Bahaie, S.; Nabih, E. J. Chem. Res. (S) 1999,112 and Bhuyan, P.; Borush, R. C.; Sandhu, J. S.

J. Org. Chem. 1990,55, 568), which can then be oxidized and subsequently deprotected to give pyridine 23. 0 1-propanol R TEA O i 0 20 21 0 R2 0 O XNXNH R O 2 22 chlorobenzene NH2 0* N-NH2 22 o 23

! L Specific Compound Syntheses Specific compounds which are representative of this invention can be prepared as per the following examples. No attempt has been made to optimize the yields obtained in these reactions. Based on the following, however, one skilled in the art would know how to increase yields through routine variations in reaction times, temperatures, solvents and/or reagents.

The products of certain syntheses can be used as intermediates to produce more than one of the instant compounds. In those cases, the choice of intermediates to be used to produce compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.

EXAMPLE 1 Hantzsch Condensation to Form Dihvdropyridine 4 (Rl = COOMe : R2 = 3. 5-dimethylphenyl; R3b,c = Cl; R3a,b = H; R4 = Me) To a refluxing solution of benzylidene 2 (0.500 g, 1.5 mmol) in acetic acid (10 mL) was added methyl-3-aminocrotonate (0.695 g, 6.0 mmol). The reaction was heated to reflux for 20 minutes, then water was added until a precipitate started to form. The reaction was cooled to room temperature.

The mixture was filtered and washed with water to obtain 0.354 g (55%) of a red solid. MS m/z 450 (M++23), 428 (M++1).

EXAMPLE 2 Alternate Hantzsch Conditions to Form Dihvdropyridine 4 R = COzMe ; R2 = 2. 4-dimethvlphenVl : R, = H : R4 = Et) To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol) in acetic acid (12 MI) was added methyl propionylacetate (1.98 g, 15.2 mmol) and ammonium acetate (1.17 g, 15.2 mmol). The reaction was heated for 20 min and then cooled to room temperature. No product precipitated from the solution, so the reaction was heated to reflux and then water was added until a solid began to precipitate. After cooling to room temperature, the mixture was filtered and the red solid washed with water to yield 1.29 g (90%) of product. MS m/z 396 (M++23), 374 (M++1).

EXAMPLE 3 Oxidation of Dihvdropyridine 4 to Pvridine 1 (Ri = COOMe ; R9 = 3,5-dimethylphenyl; R3b,c = Cl : Rx3ad = H : R4 = Me) To a refluxing solution of dihydropyridine 4 (0.250 g, 0.58 mmol) in acetic acid (10 mL) was added a solution of chromium (VI) oxide (0.584 g, 0.58 mmol) in 1 mL water. After 30 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to give 0.199 g (81 %) of a yellow solid. MS m/z 448 (M++23), 426 (M++1).

EXAMPLE 4 Oxidation of Dihvdropvridine 4 to Pvridine 1 (R1=COOMe; R2=(4-methyl)-1-naphthyl; R3b,c =H, NO2/NO2, H; R = Me) To a refluxing suspension of regioisomeric dihydropyridines 4 (3.59 g, 8.16 mmol) in acetic acid (40 mL) was added a solution of chromium (VI) oxide (0.816 g, 8.16 mmol) in 3 mL water. After 20 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to yield the mixture of regioisomers as a yellow solid. The products were purified by column chromatography eluting with hexanes: ethyl acetate to yield 1.303g (37%) of pyridine 1 (R3b = N02 ; Rsc = H) and 0.765 g (21 %) of its regioisomer (R3b = H: Rsc = N02). MS m/z 461 (M++23), 439 (M++1).

EXAMPLE 5 Alternate Three Component Hantzsch Reaction to Form Dihydropyridine 4 (Ri = CORME ; R2 = cyclohexyl; R3 = H; R4 = Me)

Cyclohexane carboxaldehyde (2.0 g, 17.8 mmol), 1,3-indandione (2.6 g, 17. 8 mmol), methylacetoacetate (2.0 g, 17.8 mmol), and ammonium hydroxide (1 mL) were refluxed in 8 mL of methanol for 1.5 hours. The temperature was lowered to approximately 50°C and the reaction was stirred overnight. The reaction was cooled to room temperature, filtered and the solid washed with water. The residue was then dissolved in hot ethanol and filtered while hot. The filtrate was concentrated to yield 4.1 g (68%) of the product which was used without purification. MS m/z 336 (M--1).

EXAMPLE 6 DDQ Oxidation of Dihydropyridine 4 (R1 = CO2Me ; R2-cvclohexvl : Ra = H : R4 = Me) To a solution of dihydropyridine 4 (2.50 g, 7.40 mmol) in 15 mL of dichloromethane was added 2, 3-dichloro-3, 6-dicyano-1,4-benzoquinone (1.70 g, 7.40 mmol). The reaction was stirred at room temperature for four hours.

The mixture was filtered and the residue was washed with dichloromethane.

After the filtrate was concentrated, the residue was purified by column chromatography eluting with ethyl acetate: hexanes to yield 0.565 g (23%) of a yellow solid. MS m/z 358 (M++23), 336 (M++1).

EXAMPLE 7 MnO2 Oxidation of Dihydropyridine 4 R = CO2Me : Rv = 4-(dimethvlamino) shenvl ; Ra = H ; R4 = Me) To a solution of dihydropyridine 4 (0.50 g, 1.3 mmol) in 10 mL of dichloromethane was added manganese dioxide (2.5 g, 28.7 mmol). The reaction was stirred at room temperature overnight before filtering and washing with dichloromethane. The filtrate was concentrated to yield 0.43g (88%) of orange solid 1. MS m/z 395 (M++23), 373 (M++1).

EXAMPLE 8 Cleavage of Carboxviic Ester 5 (R = 2. 4-dimethvlphenvl : R3 = H : R4 = Me)

To a suspension of ester 5 (2.75 g, 6.94 mmol) in acetone (50 mL) was added aqueous 1 M NaOH (100 mL). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 100 mL of water and washed with dichloromethane (2 x 100 mL). The aqueous layer was cooled to 0°C and acidified with concentrated HCI. The mixture was filtered and washed with water to yield 1.84 g (77%) yellow solid 6. MS m/z 366 (M++23), 343 (M++1).

EXAMPLE 9 Preparation of Amide 7 (R = 2z4-dimethvlphenvl ; R ; = H : R4 = Me : R = H ; R6 = Me) A solution of carboxylic acid 6 (0.337 g, 0.98 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. The solution was cooled and concentrated in vacuo. The residue was diluted with CCI4 and concentrated to remove the residual thionyl chloride. The residue was then dissolved in THF (3.5 mL) and added to a 0°C solution of methylamine (1.47 mL of 2.0 M solution in THF, 2.94 mmol) in 6.5 mL THF. The reaction was warmed to room temperature and stirred overnight. The mixture was poured into water, filtered, washed with water and dried to yield 0.263g (75%) of tan solid. MS m/z 357 (M++1).

EXAMPLE 10 Preparation of Pvridine 1 (R1 = CO2Et; R2 = 4-nitrophenyl; R3 = H ; R4-NHa) To a refluxing solution of benzylidene 2 (1.05 g, 3.76 mmol) in 10 mL of acetic acid was added ethyl amidinoacetate acetic acid salt (0.720 g, 3.76 mmol). The resulting solution was heated at reflux overnight. After cooling to room temperature, the resulting precipitate was removed by filtration and washed with water. This impure residue was heated in a minimal amount of ethanol and then filtered to yield 0.527g (35%) of a yellow solid. MS m/z 412 (M++23), 390 (M++1).

EXAMPLE 11 Hantzsch Condensation of Benzviidene 8 (R2 = 3-methoxvPhenvl) and 1. 3-indandione) The benzylidene 8 (2. 00g, 9.2 mmol), 1,3-indandione (1.34 g, 0.2 mmmol) and ammonium acetate (2.83 g, 36.7 mmol) were added to 30 mL of ethanol and heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethanol. A yellow precipitate was collected by filtration, washed with ethanol, and dried under vacuum to yield 1.98 g (63%) of the dihydropyridine 9. MS m/z 346 (M++1).

EXAMPLE 12 Reduction to Prepare Amine 11 (R1 = CO2M e R2 = 4-methvinaphthvl ; R4 = Me) To a refluxing suspension of pyridine 10 (0.862 g, 1.97 mmol) in 35 mL of ethanol was added a solution of tin (II) chloride dihydrate (1.33 g, 5.90 mmol) in 6 mL of 1: 1 ethanol : concentrated HCI. The resulting solution was heated at reflux overnight. Water was added until a precipitate started to form and the reaction was cooled to room temperature. The mixture was then filtered and washed with water. After drying, the residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.551 g (69%) of an orange solid. MS m/z 431 (M++23), 409 (M++1).

EXAMPLE 13 Acetvlation of Amine 11 (Ri = COEt : R ? = 324-methylenedioxvphenvl : R4 = Me) To a solution of amine 11 (0.070 g, 0.174 mmol) in 15 mL of dichloromethane was added triethylamine (0.026 g, 0.261 mmol) and acetyl chloride (0.015 g, 0.192 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water and then extracted with dichloromethane (3 x 35 mL). The combined organics were washed with

brine, dried over MgS04, and concentrated. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate to yield 0.054 g (70%) of amide 12. MS m/z 467 (M++23), 445 (M++1).

EXAMPLE 14 Preparation of Carboxviic Acid 13 Ri = COMe : R = 3,5-dimethylphenyl; R4 = Me : Y = O ; n = 2).

To a suspension of amine 11 (0.079 g, 0.212 mmol) in 5 mL of benzene was added succinic anhydride (0.021 g, 0.212 mmol). After heating at reflux for 24 hours, the reaction mixture was filtered and washed with benzene. The residue was dried under high vacuum and then washed with ether to remove the excess succinic anhydride. This yielded 0.063 g (63%) of carboxylic acid 13. MS m/z 473 (M++1).

EXAMPLE 15 Preparation of Carboxvlic Acid 13 (Ri = CO2Me : R2 = 3, 5-dimethylphenvl ; R4 = Me ; Y = H ; n = 1 ! To a refluxing solution of amine 11 (0. 078 g, 0.210 mmol) in 5 mL of acetonitrile was added p-propioiactone (0.015 g, 0.210 mmol). The reaction was heated to reflux for 72 hours before cooling to room temperature. The reaction mixture was concentrated. The residue was mixed with 10% aqueous sodium hydroxide and washed sequentially with ether and ethyl acetate. The aqueous layer was acidified with concentrated HCI and extracted with dichloromethane (2 x 25 mL). The combined organics were dried over MgS04, filtered, and concentrated. The residue was purified by column chromatography eluting with 5% MeOH in dichloromethane to yield 0.020 g (21 %) of an orange solid. MS m/z 467 (M++23), 445 (M++1).

EXAMPLE 16

Preparation of Hvdroxamic Acid 14 (R = CO2Me ; R2=(4-methyl)-1-naphthyl; Y = O : n = 2 : R4 = Me) To a 0°C suspension of carboxylic acid 13 (0.054 g, 0.106 mmol) in 10 mL of diethyl ether was added triethylamine (0. 014 g, 0.138 mmol) and then ethyl chloroformate (0. 014 g, 0.127 mmol). The mixture was stirred at 0°C for 30 minutes and them warmed to room temperature. A solution of hydroxylamine (0.159 mmol) in methanol was added and the reaction was stirred overnight at room temperature. The mixture was filtered and the residue was washed with ether and dried under vacuum to yield 0.030 g (54%) of a yellow solid. MS m/z 524 (M++1).

EXAMPLE 17 Preparation of Amide 15 DXMe : Rv = 3, 5-dimethelphenvl : R4-Me) A mixture of amine 11 (0.201 g, 0.54 mmol) and glycolic acid (0.049 g, 0.65 mmol) was heated at 120-160°C for 30 minutes. During heating, more glycolic acid was added to ensure that excess reagent was present. Once the starting material was consumed, the reaction was cooled to room temperature, and diluted with dichloromethane. The resulting mixture was extracted with 20% NaOH, followed by 10% HCI, and finally water. The combined organics were concentrated and triturated with ether. Purification by column chromatography eluting with ethyl acetate: hexanes yielded 0.012 g (5%) of a yellow solid. MS m/z 453 (M++23), 431 (M++1).

EXAMPLE 18 Preparation of Amide 16 (Ri = CO ? Me : Ru = 3, 5-dimethylphenyl; R4 = Me: NR6R7 = morpholino) To a 0°C mixture of amine 11 (0.123 g, 0.331 mmol) in 2 mL of 20% aqueous NaHCO3 and 3 mL of ethyl acetate was added chloroacetyl chloride (0.047 g, 0.413 mmol). The reaction was warmed to room temperature and

stirred for 45 minutes. The mixture was poured into a separatory funnel and the aqueous layer was removed. The organic layer containing the crude chloroamide was used without purification. To the ethyl acetate solution was added morpholine (0.086 g, 0.992 mmol) and the reaction was heated to approx. 65°C overnight. The reaction was diluted with water and cooled to room temperature. After extraction with ethyl acetate (3 x 25 mL), the combined organics were washed with brine, dried over MgS04 and concentrated to yield 0.130 g (79%) of a yellow solid. MS m/z 522 (M++23), 500 (M++1).

EXAMPLE 19 Preparation of piperazinone 17 (Ri = CO ? Me : R ? = 3, 5-dimethvlphenvl : R4. = Me: R7 = H) To a 0°C solution of amide 16 (R6 = CH2CH20H) (0.093 g, 0.20 mmol), tri n-butylphosphine (0.055 g, 0.27 mmol) in 0.35 mL ethyl acetate was slowly added di-tert-butyl azodicarboxylate (0.062 g, 0.27 mmol) in 0.20 mL ethyl acetate. The reaction was allowed to stand for 15 minutes and then heated to 40°C overnight. 4.2 M ethanolic HCI was added dropwise. The mixture was cooled to 0°C and allowed to stand for 2 hours. The mixture was filtered and washed with cold ethyl acetate. Purification by column chromatography with 1-5% MeOH in CH2CI2 yielded 0.011 (12%) of a white solid. MS m/z 478 (M++23), 456 (M++1).

EXAMPLE 20 Preparation of 4-Aminoindenopyridine 19 (roi = C02Me-, R4 = Me; R6 = Me ; R7 = phenyl) To a solution of 4-chloroindenopyridine 18 (0.069 g, 0.240 mmol) in 10 mL of 2-ethoxyethanol was added N-methylaniline (0.026 g, 0.240 mmol).

The reaction was heated at reflux for 96 hours. After cooling to room temperature, the solution was concentrated. The residue was purified by

column chromatography eluting with hexanes: ethyl acetate to yield 0.029 g (34%) of an orange solid. MS m/z 359 (M+1).

EXAMPLE 21 Preparation of 4-Aminoindenonvridine 19 (R1 = CO2Me; R4 = Me ; R6 = H ;R7 = cyclopent r) by Palladium Catalyzed Coupling A mixture of 4-chloroindenopyridine 18 (0.100 g, 0.347 mmol), cyclopentylamine (0.035 g, 0.416 mmol), palladium (II) acetate (0.004 g, 0.0017 mmol), 2- (di-t-butylphosphino) biphenyl (0. 010g, 0.0035 mmol), and cesium carbonate (0.124 g, 0.382 mmol) in 10 mL of dioxane was heated at reflux overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 x 35 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate: hexanes.

The purified oil was dissolved in ether and cooled to 0°C. To this solution was slowly added 1.0 M HCI in ether. The resulting precipitate was isolated by filtration, washed with ether, and dried under vacuum to yield 0.032 g (25%) of a yellow solid. MS m/z 359 (M++23), 337 (M++1).

EXAMPLE 22 Preparation of Dihvdropyridine 21 (R=CO ? Me : R2=2-furyl; R3=H; R4=NH2) Unsaturated cyanoester 20 (0.20g, 1.10 mmol), enamine 21 (0.20g, 0.75 mmol) and 5 drops of triethylamine were refluxed in 1-propanol (4mL).

After 3 hours, the reaction was concentrated to half the volume and cooled.

The resulting precipitate was filtered and washed with 1-propanol. The precipitate was a mixture of products and therefore was combined with the filtrate and concentrated. Purification by column chromatography, eluting with ethyl acetate: hexane yielded 0. 11 g (34%) of the red product 22. MS m/z 465 (M+ +23).

EXAMPLE 23

DDQ Oxidation/Dearotection of Dihvdronvridine 22 (R1=CO2Me; R2=3-furyl; R3=H; R4=NH2) To a solution of dihydropyridine 22 (0.05g, 0. 11 mmol) in chlorobenzene (4mL) was added 2, 3-dichloro-3, 6-dicyano-1, 4-benzoquinone (0.05g, 0.22 mmol). The reaction was refluxed overnight before cooling to room temperature and diluting with diethyl ether. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by column chromatography, eluting with ethyl acetate: hexane yielded 0.018g (52%) of yellow product 23. MS m/z 343 (M+ +23), 321 (M+ +1).

Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared.

Rsa R3b I R2 R 1 :" P3d N= Table 1 R4 Mus (M+l) 0 1 CN v l H H H H Me 341 C7H502 0 2 C02Et H H H H Me 388 0 C7H507 I 3 COZt-Bu/ 1 H H H H Me 416 C7H502 CO 4 C02t-Bu H H H H Me 432 0 \ /CgHg2 0 5 CO2Et XN'O H H H H Me 389 C6H4NO2 _ 0 6 C02H PO H H H H Me 360 C7H502 7 C02Et H H H H Me 480 o Fut. Ct4Hi302-. --. No. Rl R2 Rsa R3b R30 R3d R MS (M+l) 8 C02Et ß o\ H H H H Me 482 0 Pi \ C8H8BrO2 o_ 9 CO2Et/ H H H H Me 424 V CIIH90 o- 10 C02H H H H H Me 376 0 \ 1 CgH902 11 COzEt Ph H H H H Me 344 0- 12 C02Et 0 H H H H Me 374 _ 13 cet H H H H Me 434 Zozo Br Qu & 14 C02Et H H H H Me 454 OH I O 15 C02Bn 1 H H H H Me 450 C7HsOz No. R, R3 Rz R3b Rsc R3d (M+1) (M+1) 0 0 16 H H H H Me 507 Po N C7H502 ClIH14NO2 o- 17 C02Me H H H H Me 390 0 CaHsOz 0 18 C03Me 2 H H H H Me 374 C7H, 02 / 19 C02Et 0 H H H H Me 404 Xb-O CsH902 O- 20 C03Et ßo_ H H H H Me 404 P-0/ 0 I C8H902 & 21 C02Et H H H H Me 454 Po- C7H6BrO I 22 C02Et H H H H NH3 411 (M+23) CHsOz 23 C02Et ao ° H H H H Me 388 0-i C Soc MS No. Rl Rz R3a R36 R3c R3d Ry (M+l) 0- 25 C02Et H H H H NH2 405 0 \ C8H9O2 0 26 CO2Et XN.-o H H H H NHa 390 C6H4NO2 27 C02Et Ph H H H H NH2 345 o- 28 CO, Et AX H H H H Me 402 CgHllO / 29 C02Et H H H H Me 483 0 \ s CsHsBrOz 30 C02Me Ph H H H H Me 330 0 3 1 CO3Et C8H7O, H H H H Me 402 CsH702 , o 0 32 C02Et ß) 0 H NO2 H H Me 433 C7Hs02 0 33-r'-/ 1 H H H H Me 413 0 i /CyH, 02 N C4H4NO2

MS No. R, Ri R3, R3b Rsc R3d R4 ms (M+l) 34 CO2Et 0--\o H H H H Me 433 , neo 07 C7H4NO4 0 35 C02Et PO H H NO2 H Me 433 C Hsz F 36 COZMe H H H H Me 398 F F C7H4F3 O 37 COVET $ H H NH : 2 H Me 403 Zu C7Hs02 38 CONHz. T H H H H Me 359 \ -° CyHOz 39 COzEt CaH9 H H H H Me 372 CgH9 0 40 C02Et pO H NH, H H Me 403 \/-° #702 41 CO3Et CH30 H H H H Me 334 ° CJO 42 CO2Et 2-Thienyl H H H H Me 350 43 C02Me H H H H Me 358 Zu MS No. Ri Rz R3a R3b Rsc Rsd R4 (M+l) 0 44 CO2Me H H H H Me 388 CaH702 1 C8H02 45 CO2Me °t_y° H H H H Me 419 Nt--O 0' C7H4N04 0- 46 C03Me C HllO H H H Me 388 CgHllO 47 C02Me 4-Pyridyl H H H H Me 331 48 COzMe o H H H H Me 374 Zu c, Hsoz 49 C02Me /° H H H H Me 454 ber C, H4BrO2 _ 50 C02Me ß o-H H H H Me 439 C7H6BrO 51 C02Me CsH9 H H H H Me 358 CaH CgHg | 52 C02Et ß H H H H Me 372 Zu CgHg 53 C02Me t H H H H Me 410 CI, EGO V C"H90 MS No. RI Rz R3 R3b Rsc R3d R4 _ (M+l) 0 54 > ßN-o H H H H Me 375 C6H4N02 55 C02Et PO H NHAc H H Me 445 C7H502 0 56 CO2Et) 0 H H NHAc H Me 445 CHsQz C7H502 y 57 C02Et H H H H Me 358 CyH ? 58 COzEt/ H H H H Me 358 C7H7 CyH ? 59 CO2Et C7H7 H H H H Me 358 _ F 60 CO2Et/ F H NO2 H H Me 457 C7H4F3 71'3 F 61 C02Et F H H NO2 H Me 457 F -/ 62 C02Me H H H H Me 344 C7H7 F 63 CO2Et/ F H NH2 H H Me 427 F F F 64 CO3Et C7H F3 H H NH2 H Me 427 ZU C7H4F3 MS No. R3a R2 R3a R3b Rsc Rsd Rs (M+l) F F 65 COzMe F H H H H Me 466 CsH3F6 CsHaFg F C$H3F6 66 C02Me C H7 H H H Me 344 C7H7 67 CO2Me e} H H N Me 3 C7H7 F 68 C02Me HH F F H N02 H H Me 443 F C7H4F3 F 69 C02Me C7HZF3 H H N02 H Me 443 F CHaFs 70 COZEt H H H H i-Pr 400 CaH9 F 71 C03Me C7HF3 H NH2 H H Me 413 F a a 72 C02Me H H H H Me 399 i a C6H3CIz 73 C H H H H Et 372 C8H9 F 74 COzMe F F H H H H Me 398 S C7HqF'3 Mus No. Rt RZ R3a R3b Rsc R3a Ra (M+l) 75 C02Me H H H H Me 394 / CnH9 76 C02Me H H H H Me 372 CgH 77 CO2Me t H N03 H H Me 403 CgHg 78 CO3Me X H H NO2 H Me 403 CgHg 79 3 r H H H Me 394 Cash9 F 80 COzMe D'H NHAc H H Me 455 F C7H4F3 ber 81 C02Me H H H H Me 488 zu C6H3Br2 82 C03Me L H N 2 H H Me 373 /CsH9 83 COzMe, -. H H N H2 H Me 373 CgH9 Rsa R4 MS No. Rl RZ R3a R3b R3c (M+l) 84 CO, ME F H H H H Me 362 C7H6F 85 Cl) 2mye H H H H Me 431 - (M+23) C6H4Br 86 C02Me H H H H Me 380 (M+23) Cor7 87 C02Me > H N02 H H Me 439 CnHg 88 C02Me H H N02 H Me 439 CI, HG 89 C02Me t H H H H Me 430 C 14H9 90 C02Me > H NH2 H H Me 409 CnHs 91 C03Me 9 H H NH2 H Me 409 Cils9 92 H H H H Me 397 0 o CgH9 N CNOz MS No. Ri RZ R3a R3b R3c R3d t (M+l) 93 CN H H H H Me 325 C8H9 I- 94 CO, Me ~ H H H H NH2 359 s C8H9 95 CO. Me 3 H H H H N 2 395 CI, HO 96 CO2H LX H H H H Me 344 C8H9 97 L=N 9 H H H H Me 433 o N C4H4N02 CIlH9 98 CN C,, H9 H H H Me 361 CI, HG P'"\ 99 0 zozo H H H H C2H202 358 zozo CzH2O2 C7HsOz N 100 o N H H H H C2H202 357 AO o, C2H202 C8HIoN Ph 101 o H H H H C2H202 314 AO li I C2H202 MS No. Ri R2 Rsa R2G Rsc Pad Ra (M+l) 102 XK P-C6H4NO2 H H H H C2H202 361 0 - I C2H20 103 o \Y-\ H H H H CJ02 364 ho Au CaH202 C2H202 CzHOz 104 0 H H H H C2H202 342 ho CH Caha z L-xtiUz 105 CO2H C, IH9 H H H H Me 380 CI, HG 106 CONH2 C8H2 H H H H Me 343 C8H9 107 CONHMe C2H9 H H H H Me 357 i C8H9 108 CONMe2-0 H H H H Me 371 CaH9 109 0 H H H H C2H202 378 AO -P XCS CzHzOz CtiHs 110 0 H H H H C2H202 328 AO p CaH C2H202 CO Mus (milz (M+1) 111 o H H H H C, H202 356 au -+-i C2H202 CgHIl 112 0 r H H H C, H202 328 AO CH CzHzOz 113 COzMe r Uon H H H H Me 375 info 0' C6H4N02 114 114 o fJ H H H C, H202 328 AO y C7H7 CzHaOz \ 115 CO2Me N-H H H H Me 373 C8H, oN 116 CONH2 H H H H Me 379 C, ho CaH9 117 0 H H H H C2H202 365 Au -+-i C9H6N C6N C, H202 0 118 CO3Me CjE4NOz H H H H Me 375 0' C6H4NO2 Mus (milz 119 CONHME H H H H Me 393 CI, HG 120 CONMe2 H H H H Me 407 Cash9 121 COMe \y-N H H H H Me 381 v i C9H6N 122 CO3Me CH9 H Cl Cl L Me 463 CaH CI1H9 123 CO2Me CSH9 H Cl C1 H Me 427 i CsH$ 124 CORME fj H H H H Me 381 N 11 125 COEt (H H H H Me 408 CnHg ber 126 COMe \-H Cl Cl H Me 555 , b-Br 127 CO2Me CgH9 Cl H H Cl Me 427 CsH$ MS No. R, Rz R3a R3b Rsc R3d R4 (M+l) 2-NO2-4, 5- 128 CO2Me OCHZO-H H H H Me 421 C6H2 129 CO2Me ß Cl H H Cl Me 558 C6H3Br2 130 CO2Me CH6N H H H H Me 345 QU, N C6H6N 131 CO2Et ß H ci ci H Me 477 CaH Br 132 CO2Me XR H H H H Me 503 - Br C6H4Br2N 133 Ac H H H H Me 472 ex C6H3Br2 134 Ac H H H H Me 342 CgH 135 CO2Me NW H H H H Me 331 o CsH4N. 0 Br 136- V-H H H H Me 527 0 b-Br N C6H3Br2 C4H4NO2 MS No. R, R2 R3. R3b R3. R3d R4 ms (M+1) 137 uN H H H H Me 397 zon C4H4NO2 C6H9 OH 138 C02Me wu H H H Me 362 1" Ber er 139 COzH \-H H H H Me 474 , b-Br 140 C02H )-H H H H Me 344 Caha ou 141 COzMe OH H H H H Me 346 C6H50 C6H50 142 COxMe/\ H H H H Me 380 Cor7 QfCHjjCHa 143 C02Me H H H H Me 486 T GsHzs 144 CO2Me b H H H H Me 436 C3HW 145 COMe \ H H H H Me 518 0 X C7H5Br2O MS No. R, R3 R3. R3b Rsc R3d R4 ms (M+l) err 146 <-N ß H H H H Me 557 o 0 N C4HSBrzO 147 o H Cl Cl H Me 466 o N C4H4NO2 CaH9 148 COzEt-NHPh H H H H Me 359 149 CO2Me CoH70 H H H H Me 360 CyH B (oh CHO 150 CO2Me hOH H H H H Me 504 ex C6H3Br2O 151 o-N 3 H H H H Me 420 - N C4H4NO, C9H6N B (OH 152 C3HsO3 ß H H H H Me 534 ex C6H3BT2O 153 o OH H H H H Me 385 <N C6HsO CaHaNO2 154 zozo H H H H Me 373 zozo \ C2H4NO2 C6H9 er 155 \ H H N02 H Me 574 " - N CNO, cB Mus No. Rl RZ R3a R36 Rsc Rsd Rt (M+1) 156 COMe/ (H Br H H Me 473 C, Hg 157 CO2Me ß H H Br H Me 473 Cl Hg 158 oN t H Cl Cl H Me 489 N C4114N02 C, H6N o 159 0 Br OH H H N02 H Me 590 gaz p Br C6H3Br20 1 SO \ H H H H Me 411 ZON C9HgN 161 COzMe/" H Br H H Me 436 /CsH9 162 C02Me), b- H H Br H Me 438 Zu CgH ? 163 COzMe -. H Br Br H Me 516 C8H9 0 Br 164 Br H Cl ci H Me 597 C4H4N02 C6H3BT2 C6H3Br2 zon C9H N C3H503 C9H6N R3a R4 MS No. Rl R R3a R3b R3c (M+1) 166 C02Me H Br Br H Me 552 Ci, ho C11H9 167 CO2Et C Hs H Br Br H Me 530 CgHg er 168 C02Me \-/F H H F Me 540 C6H3Br20 Z 169 CO2Me SH H H NO2 H Me 551 C6H3Br20 S'OH 170 C02Me \-/H Cl CI H Me 573 C6H3BI2 171 H H NO2 H Me 444 N _4 NO 2 C8H9 172 oN ß H NO2 H H Me 444 --N C4H4N02 C8Ho _ _ 173 C02Me )-F H H F Me 394 CaH$ 174 o F H H F Me 433 N L I C4H4NO2 C8H9 C4H4N02 CsHa MS No. R, R2 Rsa R3b R3. R3d R4 s (M+1) / 175 CO2Me 0 H Br Br H Me 548 xi-o CaH902 N 176 C02Me H H H H Me 355 CyH4N ou 177 CO2Me CgUJO H NOZ H H Me 421 C8H9O ou 178 CO3Me u H H N02 H Me 453 (M+23) C8H9O ou 179 COxMe -/H Cl Cl H Me 443 CgH90 ou 180 C rgND H H H H Me 341 CgHsO OH 181 CO2Me Cx H H H H Me 598 i C6H3120 F 182 CO2Me/\ H Cl Cl H Me 435 Xi-F C6H3F2 183 C02Et H H H H Me 387 NH IL C8H, oN MS No. Rl Rz R3a R36 Rsc Rsa Ra (M+l) 184 CO2Et H H H H Me 373 nu NH - K. C7H6N i 185 C02Me 0-H H H H Me 612 I C7H5120 186 CO2Et wHX H H H H Me 410 H xN (/ C9H7N2 I OU 187 CO2Me ß H H NO2 H Me 345 Pi I C6H3I20 OH 188 COZMe \ H Cl Cl H Me 668 Pi I C63I2 F 189 COZMe/\ H H NOZ H Me 413 Xi-F CsH3Fz ber 190 COZH/\ H ci ci H Me 544 Ob-w 'oh 191 CN ß H H H H Me 565 Pi I C6H3I20 OH 192 COMe)-/H Br H H Me 606 (M+23) C6H3Br2O Rsa R4 MS No. R, R2 R3a R3b R3c (M+l) OH 193 CO2Me Fb H H Br H Me 584 C6H3Br20 194 C02Et 9 H H H H Me 373 N- x C, HAN a 195 CO2Et aX H H H H Me 427 nu NH C6H, CI3N OH 196 C02Et \--/H Cl Cl H Me 587 ex C6H3Br20. 197 CO2Et 0 H H H H Me 437 NH C6HsBrN 0- 198 CO2Et <$ H H H H Me 389 NH C7HX8NN° OU 199 CO2Et \ H H H H Me 612 Pi I C6H3I20 200 C02Et F H Cl Cl H Me 449 P-F C6H3F2 MS No. R, R2 R3, R3b Rsc R3d ms (M+l) 201 C02Me H ci Cl H Me 450 C9H6N F 202 COzMe X fF H Cl Cl H Me 465 9 F \ F F 203 C02Me r i ; H H H H Me 396 X6 F \ C, HSFZO 204 CO2Me H "H H Me 473 N, xi-0 CsHg NH- NH2 205 C02Me NH2 H H H Me 345 C6H6N H 206 CO2Me C7HbN H H H Me 359 CyHsN 207 CO2Me XN02 H Cl Cl H Me 444 C6H4NO2 208 CO2Me HNNO N H H H H Me 355 CyHN 209 CO3H CloH7 H H H H Me 366 Cor7 Rsa R4 MS No. Ri R2 R3. R3b R3. R3d R4 ms (M+l) 210 CO3Me Ab H Cl Cl H Me 444 C6H4NO2 211 CO2Me KF H ci ci H Me 430 F C7H6F F 212 C02Me F H H H H Me 416 P-FF F F CH3Fa F 213 COMe/-/H Cl Cl H Me 430 C7H6F 214 CO2Me VH H H H H Me 413 NH NU C6H4C12N 215 CO2Me C6Ho H OMe OMe H Me 418 CsH9 216 CO2Me C,, H9 H OMe OMe H Me 454 CI, HG 217 CO2Me ßbF F H H H H Me 362 F _ _ 218 COZMe/ H,., o o H H Me 445 CgH ho C3H6NO2 C3H6N02 Mus No. R, R R3a R3b R3c Rsd Rt (M+l) 219 COMe C") H H H H Me 359 N- X CyHsN 220 CO2Me-NHPh H H H H Me 345 221 CO2Me sNH H H H Me 423 NH 14 _ C6H5BrN _ 222 CO3Me 2-Pyridyl H H H H Me 353 (M+23) a. 223 COMe/ H OMe OMe H Me 459 a CbH3 CIZ F 224 C02Me F H Cl ci H Me 485 C7H3F4 C7H3F4 225 Co2Me H H H H Me 345 C6H6N C6H6N 226 COMe -EH H NO2 H Me 420 C6H4N02 N32 227 C02Me H H NO2 H Me 420 C6H4NO2 228 COZMe H H H H Me 359 NH NU CyHgN MS No. R, R2 Rsa R3b B4 R3d R4 ms (M+l) 229 CO3Me r N H H H H Me 396 ZU NH X CsHyNz 230 C02Me H OH OH H Me 426 aHe 231 CO2Me r 7 H H F H Me 376 C8H9 F 232 C02Me P-7 F H H N02 H Me 461 F F C7H3F4 F 233 CO2Me/ H Cl Cl H Me 468 C, oH6F 234 COZMe H H H H Me 373 NH X C8HoN 0- 235 CO2Me 0 H H H H Me 375 NH NH C7H8NO _ F 236 C02Me XCS H N02 H H Me 443 \ CoHsF MS No. R, R2 R3 R3b Rsc Rsd Rt (M+1) F 237 CO2Me H H NO2 H Me 443 I _ CioHsF F 238 CO2Me 3 H H H H Me 398 C) oHgF \ 239 C02Me N-H ci ci H Me 491 C. 2H. 2N 240 CO2Me C,, H9 H on H H Me 509 o CUL$ 0 CaH9 CANOs 241 CO2Me ß H H o H Me 473 xi-0 C46N3 CNOs 242 COxMe \)-/H H o H Me 509 HO NA H 0 C46N03 C1 H9 243 CO2Me ß CoHg H H H H Me 310 Cl 244 COzMe H 0 H H H Me 524 H nia a C4H7N203 CHs 245 CO3Me CaH9 H H H"-^ XII H Me 488 nu IN C4i17N23 C8H9 No. Ri R2 R3a R3b R3c R3d R, ms (M+l) 246 CO2Me C H7 H H H H Me 308 C4H7 247 CO2Me i-Pr H H H H Me 296 248 CO2Me ;) H H H H Me 336 Cyclohexyl 249 CO2Me Me H H H H Me 268 250 COzMe)-\ H H HO~HosH H Me 474 ZON H CaH9N202 89 251 CO2Me ß H H 0 0 H Me 487 H CSHgN03 C8H9 252 CO2Me N-H H H H Me 339 Morpholino 253 COzMe Q H H H H Me 337 NH YL C5H, oN 254 CO2Me > H H H Me 488 Ho-1- H CsHaN2O2 C8H9 I I 255 CO2Me > H s H H Me 474 H O C4H9N2002 C8H9 I I 256 C02Me H HN H H Me 456 . nez il O t/VNs C4H7N20 No. Rl R R3a R3b R3. R3d R4 MS (M+l) 257 C02Me H o,., H H Me 431 OH nu zu o CgHg C2HaN02 258 CORME ME H H H Me 500 r-.--rN, II CsaNaz CgH9 259 CO2Me 4 H (NtNs H H Me 499 0 C6Hl2N30 CaH CgH 260 CO2Me > H H H H Me 481 N o CgH 261 C02Me H H o o H Me 500 "NX %-" X6-H CgH 262 CO2Me ß H H FN) o H Me 499 H C8H9 C6Hl2N30 819 CsH9 263 C02Me H H o H Me 431 HO A v H C8H9 C2H4N02 0 264 C02Me H H H H NH2 397 (M+23) C7H502 Ph 265 COZMe H H H H NH2 353 M+23 0- 266 CO2Me < H H H H NH2 413 (M+23) CsHgOz 2-Furyl 267 CO. MeH H H H NH2 321 3-Furyl 268 COMeH H H H NH3 321 2-Furyl 269 CO2Me H H H H Me 320 2-Fury ! 270 CO2Me 2-Furyl H H H NH2 Me 335 2-Furyl 271 CO,, ME NHOH H H H Me 351 2-Furyl 272 CO2Et H H H H NH2 335 2-Fury ! 273 CO2Et 2-Furyl H Br H H NH2 413 2-fury 274 CO, ET 2-F uryl H H Br H NH2 413 n 275 CO2Et ° H H H H Me 467 Br C7H4BrO2 276 CO2Me ß H H H H Me 481 N"x J o CJ16N30 C8H9 CgHg xi-lu lof CsHs ° C 4H7N20 278 CO2Me C8H9 H 0 H H Me 473 HA Y--,-H 0 C46N03 H 0 279 C02Me C8Ho H H H Me 513 280 C02Me H H H Me 516 Ou H / CgH9 281 COZMe/ H ,. H H Me 501 CgHg xi-0 CgHg b 282 C02Me H H H Me 566 I H / H 0 CsHs H M9 H H < H Me 488 H O r C$H9 I I 284 COZMe/ H H , o H Me 541 H LU Cash9

III. Biological Assays and Activi Liqand Binding Assay for Adenosine A2a Receptor Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (PerkinElmer, RB-HA2a) and radioligand [3H] CGS21680 (PerkinElmer, NET1021). Assay was set up in 96-well polypropylene plate in total volume of 200 mL by sequentially adding 20 mL1 : 20 diluted membrane, 130 mLassay buffer (50 mM Tris-HCI, pH7.4 10 mM MgCl2, 1 mM EDTA) containing [3H] CGS21680,50 diluted compound (4X) or vehicle control in assay buffer. Nonspecific binding was determined by 80 mM NECA. Reaction was carried out at room temperature for 2 hours beofre filtering through 96- well GF/C filter plate pre-soaked in 50 mM Tris-HCI, pH7.4 containing 0.3% polyethylenimine. Plates were then washed 5 times with cold 50 mM Tris-HCI, pH7.4., dried and sealed at the bottom. Microscintillation fluid 30 ml was added to each well and the top sealed. Plates were counted on Packard Topcount for [3H]. Data was analyzed in Microsoft Excel and GraphPad Prism

programs. (Varani, K.; Gessi, S.; Dalpiaz, A.; Borea, P. A. British Journal of Pharmacology, 1996,117, 1693) Adenosine A2a Receptor Functional Assay CHO-K1 cells overexpressing human adenosine A2a receptors and containing cAMP-inducible beta-galactosidase reporter gene were seeded at 40-50K/well into 96-well tissue culture plates and cultured for two days. On assay day, cells were washed once with 200mL assay medium (F-12 nutrient mixture/0. 1% BSA). For agonist assay, adenosine A2a receptor agonist NECA was subsequently added and cell incubated at 37 C, 5% CO2 for 5 hrs before stopping reaction. In the case of antagonist assay, cells were incubated with antagonists for 5 minutes at R. T. followed by additon of 50 nM NECA. Cells were then incubated at 37C, 5% CO2 for 5 hrs before stopping experiments by washing cells with PBS twice. 50 mL 1X lysis buffer (Promega, 5X stock solution, needs to be diluted to 1X before use) was added to each well and plates frozen at-20C. For b-galactosidase enzyme colormetric assay, plates were thawed out at room temperature and 50 mL 2X assay buffer (Promega) added to each well. Color was allowed to develop at 37C for 1 hr. or until reasonable signal appeared. Reaction was then stopped with 150 mL 1 M sodium carbonate. Plates were counted at 405 nm on Vmax Machine (Molecular Devices). Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Chen, W. B.; Shields, T. S.; Cone, R. D.

Analytical Biochemistry, 1995,226, 349; Stiles, G. Journal of Biological Chemistry, 1992,267, 6451) Assay of Phosphodiesterase Activity The assay of phosphodiesterase activity follows the homogeneous SPA (scintillation proximity assay) format under the principle that linear nucleotides preferentially bind yttrium silicate beads in the presence of zinc sulfate.

In this assay, the enzyme converts radioactively tagged cyclic nucleotides (reaction substrate) to linear nucleotides (reaction product) which are selectively captured via ion chelation on a scintillant-containing bead.

Radiolabeled product bound to the bead surface results in energy transfer to the bead scintillant and generation of a quantifiable signal. Unbound radiolabel fails to achieve close proximity to the scintillant and therefore does not generate any signal.

Specifically, enzyme was diluted in PDE buffer (50mM pH 7.4 Tris, 8.3mM MgCl2, 1.7mM EGTA) with 0. 1 % ovalbumin such that the final signal : noise (enzyme: no enzyme) ratio is 5-10. Substrate (2, 8-3H-cAMP or 8- 3H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4,5, 7A) buffer to 1 nCi per pLI (or 1 llCi/ml). For each test well, 481l1 of enzyme was mixed with 47, u1 substrate and 5. 1 test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50, u1 aliquot of evenly suspended yttrium silicate SPA beads in zinc sulfate was added to each well to terminate the reaction and capture the product. The plate was sealed using Topseal-S (Packard) sheets, and the beads were allowed to settle by gravity for 15-20 minutes prior to counting on a Packard TopCount scintillation counter using a 3H glass program with color quench correction. Output was in color quench-corrected dpm.

Test compounds were diluted in 100% DMSO to a concentration 20x final assay concentration. DMSO vehicle alone was added to uninhibited control wells. Inhibition (%) was calculated as follows : Nonspecific binding (NSB) = the mean of CPM of the substrate + buffer + DMSO wells Total Binding (TB) = the mean of the enzyme + substrate + DMSO wells % Inhibition listed in Table 1 = (1- (Sample CPM-NSB) ) X 100 TB-NSB

The IC50 values were calculated using the Deltagraph 4-parameter curve-fitting program. The IC50 and % Inhibition data on PDE 4,5, and 7A are listed for the indicated compounds in Table 2 below.

Table 2 ICso () M)/% inh. @ No. Rl RZ R3a R36 R3 R3d R4 (M+1) PDE7A PDE4 PDE5 6 COZH H H H H Me 360 45% @20 49% @5 z CyHsOz MS ic ; o (M)/% inh. @M No. RI R2 R3a R3b R3c R3d R4 (M+l) PDE7A PDE4 PDE5 51 Cyme H H H H Me 358 0. 055 0. 353 2. 7 CaH9 56 C02Et 2_ H H NHAc H Me 445 0. 074 0. 333 2. 5 C7H502 I CpHsOz 70 COzEt--/ H H H H i-Pr 400 2. 11 CgHg 73 Cyme H H H H Et 372 1. 54 0. 998 C8H9 82 CO2Et C H9 H H Me 373 0. 021 0. 204 1. 11, 0. 864 CgH 90 C02Me H NH2 H H Me 409 0. 005 0. 237, 2. 33 0. 172 CnHs 98 C N CI, H9 H H H Me 361 1. 13 Ci, ho 119 CON H Me 9 H H H H Me 393 0. 658 41% @20 CnHg 133 Au/\ H H H H Me 472 1. 54 C6H3Br2 No. R, Ra R3a R3b R3 R3a R MS'ICSO « % inh. @, M No. Rt R2 R3a R3b R3c R3d R4 ) PDE7A PDE4 PDE5 (M+l) pDE7A PDE4 PDE5 134 Ac H H H H Me 342 1. 14 CgH C8H9 OH 169 CO2Me RROH H H NO2 H Me 551 0. 0053 0. 184 wR C6H3Br2O OH 170 CO2Me HOH H C1 C1 H Me 573 0. 0087 0. 557 er / C6H3Br20. 190 COH \-H a Cl H Me 544 5. 9 C6H3Br2 * OH 191 CN ß H H H H Me 565 0. 593 i C6H3Iz0 197 CO2Et H H H H Me 437 0. 728 69% @5 0. 362 i NH x C6H5BrN 219 CO2Me QN-H H H H Me 359 0. 964 61% @5 1. 1 N- X CyHsN 220 COZMe-NHPh H H H H Me 345 0. 084 1. 8 0. 637 241 CO2Me < H H O H Me 473 0. 0035 0. 954 0. 183 N H O C H C4H6N03 C8H9 242 CO2Me 9 H H O H Me 509 0. 0038 0. 782 0. 141 NA Y--,-H 0 C4H6N03 G H9 MS ICso (pM)/% inh. (01lM No. R, R2 Rsa R3b R3c R3d Ru (M+l) PDE7A PDE4 PDE5 243 CO2Me < H H H H Me 310 2. 6 Cs 245 CO2Me/ H H H o H Me 488 0. 0053 0. 875 0. 185 N-N H O 0 C8H9 248 C02Me X H H H H Me 336 0. 783 0. 171 0. 649 Cyclohexyl 250 COzMe)-}, H H o H Me 474 0. 0074 0. 684 2. 4 H BD H C8H9 C4H9N202 251 C02Me H H 0 0 H Me 487 0. 0054 0. 754 0. 26 H C8Hg CsH8NO3 CaH CgH ? 253 CO2Me Q H H H H Me 337 0. 905 0. 85 0. 303 NH x Oh 254 COZMe/ H H H HO~1S2N H Me 488 0. 0067 0. 664 0. 765 H CsHaNzoa CgHg 261 CO2Me ß H H H Me 500 0. 0063 0. 477 0. 63 N N H CsHuN202 C$H9 262 CO2Me A H H HN) O H Me 499 0. 008 0. 702 3. 7 ON,, KNA H CsHlzN30 C8H9 Table 3 ME No. R, R2 Rsa R3b R3c R3d R4 (M+l) A2a A2a Al binding antagonist binding function OH 14 CO2Et FOH H H H H Me 454 451 7 OH OH 22 C02Et H H H H NH2 411 70 253 (M+23) C7H502 0 18 CO2Me 1 H H H H Me 374 159 >1000 584 C7H502 COz Ph 27 CO2Et H H H H NH2 345 42 36 554 23 CO2Et aoJ H H H H Me 388 251 0-i C7H502 n 275 C02Et ßs, H H H H Me 467 263 CyHBrO 41 COzEt PO H H H H Me 334 271 C4H30 57 r\- C02Et H H H H Me 358 400 C7H7 C7H7 67 C02Me H H H H Me 344 39 128 1853 C7H7 66 CO. 2Me 0 H H H H Me 344 46 151 1591 C7H7 85 C02Me er H H H H Me 431 35 >1000 5570 (M+23) C6H4Br 82 CO2Me ß H NH2 H H Me 373 294 C8H9 95 CO2Me 9 H H H H NH2 395 286 CnHs 135 CO2Me Ng H H H H Me 331 123 CN 130 CO2Me < H H H H Me 345 222 -N" C6H6N ou 141 C02Me H H H H Me 346 172 i C6H50 183 C02Et H H H H Me 387 191 NH x C8HloN 208 CO2Me N H H H H Me 355 171 CyHLtN 197 CO X < 1 K S S nu x C6H5BrN 217 CO. Me ß H H H H Me 362 119 F C7H6F er 221 CO2Me H H H H Me 423 76 258 2180 NH X NU 2-Pyridyl 222 CO2Me H H H H Me 353 237 (M+23) 0- 198 CO2Et X H H H H Me 389 185 NH x C7H8NO OU 199 CO2Et \ H H H H Me 612 301 pi I C6H3120 H 1"179 xb-0 279 C02Me C8H9 H H H Me 513 261 C02Me H H 9 o H Me 500 472 NV \N H C6HI1N22 CaH9 280 CO2Me I H as, H H Me 516 237 H 0 0 C8Hg 276 CO2Me H H H NH H Me 481 304 N, ON,,,, yN 0 /CSH6N3 C8H9 258 C02Me H H H H Me 500 211 N"x oh o CeHnN2O2 CsH9 281 C02Me H H H Me 501 201 H I o C8Hg _ 262 CO2Me H H H HN) O H Me 499 332 LD 4 J4N H C8Hg C6H, 2N30 184 CO2Et/4 H H H H Me 373 140 NH NH zu C7H8N _ a 195 CO2Et a a H H H H Me 427 171 ago NH X C6H4C12N _ 260 C02Me H 14 H H Me 481 163 . ON'-yN 0 CsH9 C8H9 263 CO2Me < H H o H Me 431 480 HO") ( H H C8H9 C2H4NO2 245 CO2Me > H H Ho HH H Me 488 276 N I I H C4H7N203 S CaHNz3 CgH9 0 264 CO2Me, 1 H H H H NH2 397 342 (M+23) C7Hs02 Ph 265 CO2Me H H H H NH2 353 50 (M+23) 2-Furyl 267 C02Me H H H H NH2 321 <15 3-Furyl 268 C02Me H H H H NH2 321 21 2-Furyl 269 COzMe H H H H Me 320 192 2-Furyl 270 CO2Me H H H NH Me 335 303 2 2-Furyl 271 CO2Me NH H H H Me 351 276 OH 2-Fury) 272 CO2Et 2-Fuwl H H H H NH2 335 <5 2-Fury ! 273 COzEtH Br H H NH2 4l3 279 2-Fury ! 274 CO2Et H H Br H NH2 413 143