Arylindenopyridines and related therapeutic and prophylactic methods

Abstract

This invention provides novel arylindenopyridines of the formula: 1

Description

FIELD OF THE INVENTION

[0002] This invention relates to novel arylindenopyridines and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include inflammatory and AIDS-related disorders.

BACKGROUND OF THE INVENTION

[0003] 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.

[0004] Among known phosphodiesterases today, PDE1 family are activated by calcium-calmodulin; its members include PDE1A and PDE1B, which preferentially hydrolyze cGMP, and PDE1C 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.

[0005] 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 cAMP and thus controls the activation of distinct kinase signalling 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/AIDS, inflammatory bowel disease, asthma, allergies and psoriasis.

[0006] Few potent inhibitors of PDE7 have been reported. Most inhibitors of other phosphodiesterases have IC50's for PDE7 in the 100 μM 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 μM. However, these compounds were only 2-3 times selective for PDE7 over PDE4 and PDE3.

[0007] 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): 2

SUMMARY OF THE INVENTION

[0008] This invention provides a compound having the structure of Formula I 3

[0009] or a pharmaceutically acceptable salt thereof, wherein

[0010] (a) R1 is selected from the group consisting of:

[0011] (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;

[0012]  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 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, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;

[0013] (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;

[0014]  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 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, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;

[0015] (iii) cyano;

[0016] (iv) a lactone or lactam formed with R4;

[0017] (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;

[0018] 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,

[0019]  or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;

[0020] (b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl;

[0021] (c) R3 is from one to four groups independently selected from the group consisting of:

[0022] (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;

[0023] (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 R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;

[0024] (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, 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,

[0025]  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;

[0026] (c) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;

[0027]  wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and

[0028] (e) X is selected from S and O;

[0029] with the proviso that when R4 is isopropyl, then R3 is not halogen.

[0030] 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, R1 is not —COOR6 where R6 is ethyl.

[0031] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0032] This invention further provides a method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

[0033] Finally, this invention provides a method of preventing a disorder ameliorated 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 reducing PDE activity in appropriate cells in the subject.

DETAILED DESCRIPTION OF THE INVENTION

[0034] Compounds of Formula I are 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.

[0035] Preferred embodiments for R1 are COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably R6 is H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

[0036] Preferred embodiments for R2 are 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, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro. Preferably, R2 is optionally substituted phenyl or napthyl or R2 is 4

[0037] optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro. In another embodiment of the instant compound, R2 is —NR15R16.

[0038] Preferred substituents for R3 include:

[0039] (i) hydrogen, halo, C1-8 straight or branched chain alkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, and hydroxy;

[0040] (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC1-8alkyl, C3-7 cycloalkyl, carboxyC1-8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;

[0041] (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyC1-8alkyl, aryl, arylalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, 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.

[0042] Particularly, R3 is selected from the group consisting of 5

[0043] Preferred embodiments for R4 include hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.

[0044] In a further embodiment of the instant compound, R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R2 is NR15R16.

[0045] More particularly, R1 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: 6

[0046] , alkyl(CO)NH—, and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.

[0047] In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.

[0048] More preferably, the compound is selected from the following compounds: 7

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

[0049] 8

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

[0050] 9

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

[0051] 10

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

[0052] 11

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

[0053] 12

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

[0054] 13

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester

[0055] 14

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

[0056] 15

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

[0057] 16

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester

[0058] 17

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

[0059] 18

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

[0060] 19

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

[0061] 20

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

[0062] 21

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

[0063] 22

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

[0064] 23

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

[0065] 24

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

[0066] 25

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

[0067] 26

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

[0068] 27

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

[0069] The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically 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.

[0070] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0071] 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 pharmaceutically 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, chelating 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.

[0072] This invention further provides a method of treating a subject having a condition ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

[0073] In one embodiment, the disorder is an inflammatory disorder. In another embodiment, the disorder is an AIDS-related disorder. Examples of disorders treatable by the instant pharmaceutical composition include, without limitation, 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 the preferred embodiment, the disorder is rheumatoid arthritis.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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 therapeutically 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 μg/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.

[0079] 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.

[0080] Definitions and Nomenclature

[0081] 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.

[0082] 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;.

[0083] “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, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(c1-c8)alkyl, heterocyclyl, and heteroaryl.

[0084] “Alkoxy” shall mean —O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.

[0085] “Halogen” shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.

[0086] 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.

[0087] “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, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)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.

[0088] 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, 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, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.

[0089] 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.

[0090] Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 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.

[0091] 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.

[0092] Designated numbers of carbon atoms (e.g., C1-8) 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] Experimental Details

[0098] I. General Synthetic Schemes

[0099] 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. 28

[0100] Procedures described in Scheme 1, wherein R3a, R3b, R3c, and R3d are independently any R3 group, and R1, R2, R3, and R4 are as described above, can be used to prepare compounds of the invention wherein X is O.

[0101] 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 al., 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.

[0102] 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 MnO2 instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511). 29

[0103] 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. 30

[0104] 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. 31

[0105] 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. 32

[0106] 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. 33

[0107] 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 β-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). 34

[0108] The amines 11 can also be treated with glycolic acid to afford alcohols 15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Comm. 1993, 23, 2761) as shown in Scheme 8. 35

[0109] 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.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459). Where R6 is a hydroxyethyl group, the compounds can be further converted to piperazinones 17. 36

[0110] The 4-aminoindenopyridines 18 can be synthesized from the 4-chloroindenopyridines 19 using a known procedure (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504) or via palladium catalyzed coupling (Scheme 10). 37

[0111] II. Specific Compound Syntheses

[0112] 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.

[0113] 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 Dihydropyridine 4 (R1=COOMe; R2=3,5-dimethylphenyl; R3b,c=Cl; R3a,b=H; R4=Me)

[0114] 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 Dihydropyridine 4 (R1=CO2Me; R2=2,4-dimethylphenyl; R3=H; R4=Et)

[0115] To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol) in acetic acid (12 Ml) 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 Dihydropyridine 4 to Pyridine 1 (R1=COOMe, R2=3,5-dimethylphenyl; R3b,c=Cl; R3a,d=H; R4=Me)

[0116] 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 Dihydropyridine 4 to Pyridine 1 (R1=COOMe; R2=(4-methyl)-1-naphthyl; R3b,c=H, NO2/NO2, H; R=Me)

[0117] 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 1.303 g (37%) of pyridine 1 (R3b=NO2; R3c=H) and 0.765 g (21%) of its regioisomer (R3b=H: R3c=NO2). MS m/z 461 (M++23), 439 (M++1).

EXAMPLE 5

Alternate Three Component Hantzsch Reaction to Form Dihydropyridine 4 (R1=CO2Me; R2=cyclohexyl; R3=H; R4=Me)

[0118] 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=cyclohexyl; R3=H; R4=Me)

[0119] 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 (R1=CO2Me; R2=4-(dimethylamino)phenyl; R3=H; R4=Me)

[0120] 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 0.43 g (88%) of orange solid 1. MS m/z 395 (M++23), 373 (M++1).

EXAMPLE 8

Cleavage of Carboxylic Ester 5 (R2=2,4-dimethylphenyl; R3=H; R4=Me)

[0121] 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 (2×100 mL). The aqueous layer was cooled to 0° C. and acidified with concentrated HCl. 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 (R2=2,4-dimethylphenyl; R3=H; R4=Me; R5=H; R6=Me)

[0122] 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 CCl4 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 0.263 g (75%) of tan solid. MS m/z 357 (M++1).

EXAMPLE 10

Preparation of Pyridine 1 (R1=CO2Et; R2=4-nitrophenyl; R3=H; R4=NH2)

[0123] 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 0.527 g (35%) of a yellow solid. MS m/z 412 (M++23), 390 (M++1).

EXAMPLE 11

Hantzsch Condensation of Benzylidene 8 (R2=3-methoxyphenyl) and 1,3-indandione)

[0124] The benzylidene 8 (2.00 g, 9.2 mmol), 1,3-indandione (1.34 g, 0.2 mmol) 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=CO2Me; R2=4-methylnaphthyl; R4=Me)

[0125] 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 HCl. 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

Acetylation of Amine 11 (R1=CO2Et; R2=3,4-methylenedioxyphenyl; R4=Me)

[0126] 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 (3×35 mL). The combined organics were washed with brine, dried over MgSO4, 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 Carboxylic Acid 13 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; Y=O; n=2)

[0127] 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 Carboxylic Acid 13 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; Y=H2; n=1)

[0128] To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in 5 mL of acetonitrile was added β-propiolactone (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 HCl and extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO4, 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 Hydroxamic Acid 14 (R1=CO2Me; R2=(4-methyl)-1-naphthyl; Y=O; n=2; R4=Me)

[0129] 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 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me)

[0130] 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% HCl, 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 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; NR6R7=morpholino)

[0131] 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 (3×25 mL), the combined organics were washed with brine, dried over MgSO4 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 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; R7=H)

[0132] To a 0° C. solution of amide 16 (R6=CH2CH2OH) (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 HCl 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 CH2Cl2 yielded 0.011 (12%) of a white solid. MS m/z 478 (M++23), 456 (M++1).

EXAMPLE 20

Preparation of 4-Aminoindenopyridine 19 (R1=CO2Me; R4=Me; R6=Me; R7=phenyl)

[0133] 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-Aminoindenopyridine 19 (R1=CO2Me; R4=Me; R6=H; R7=cyclopentyl) by Palladium Catalyzed Coupling

[0134] 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 (0.010 g, 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 (3×35 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 HCl 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).

[0135] Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared.

TABLE 1
	Ia
38
								MS
No.	R1	R2	R3a	R3b	R3c	R3d	R4	(M + 1)
1	CN	39	H	H	H	H	Me	341
2	CO2Et	40	H	H	H	H	Me	388
3	CO2t-Bu	41	H	H	H	H	Me	416
4	CO2t-Bu	42	H	H	H	H	Me	432
5	CO2Et	43	H	H	H	H	Me	389
6	CO2H	44	H	H	H	H	Me	360
7	CO2Et	45	H	H	H	H	Me	480
8	CO2Et	46	H	H	H	H	Me	482
9	CO2Et	47	H	H	H	H	Me	424
10	CO2H	48	H	H	H	H	Me	376
11	CO2Et	Ph	H	H	H	H	Me	344
12	CO2Et	49	H	H	H	H	Me	374
13	CO2Et	50	H	H	H	H	Me	434
14	CO2Et	51	H	H	H	H	Me	454
15	CO2Bn	52	H	H	H	H	Me	450
16	53	54	H	H	H	H	Me	507
17	CO2Me	55	H	H	H	H	Me	390
18	CO2Me	56	H	H	H	H	Me	374
19	CO2Et	57	H	H	H	H	Me	404
20	CO2Et	58	H	H	H	H	Me	404
21	CO2Et	59	H	H	H	H	Me	454
22	CO2Et	60	H	H	H	H	NH2	411 (M + 23)
23	CO2Et	61	H	H	H	H	Me	388
25	CO2Et	62	H	H	H	H	NH2	405
26	CO2Et	63	H	H	H	H	NH2	390
27	CO2Et	Ph	H	H	H	H	NH2	345
28	CO2Et	64	H	H	H	H	Me	402
29	CO2Et	65	H	H	H	H	Me	483
30	CO2Me	Ph	H	H	H	H	Me	330
31	CO2Et	66	H	H	H	H	Me	402
32	CO2Et	67	H	NO2	H	H	Me	433
33	68	69	H	H	H	H	Me	413
34	CO2Et	70	H	H	H	H	Me	433
35	CO2Et	71	H	H	NO2	H	Me	433
36	CO2Me	72	H	H	H	H	Me	398
37	CO2Et	73	H	H	NH2	H	Me	403
38	CONH2	74	H	H	H	H	Me	359
39	CO2Et	75	H	H	H	H	Me	372
40	CO2Et	76	H	NH2	H	H	Me	403
41	CO2Et	77	H	H	H	H	Me	334
42	CO2Et	2-Thienyl	H	H	H	H	Me	350
43	CO2Me	78	H	H	H	H	Me	358
44	CO2Me	79	H	H	H	H	Me	388
45	CO2Me	80	H	H	H	H	Me	419
46	CO2Me	81	H	H	H	H	Me	388
47	CO2Me	4-Pyridyl	H	H	H	H	Me	331
48	CO2Me	82	H	H	H	H	Me	374
49	CO2Me	83	H	H	H	H	Me	454
50	CO2Me	84	H	H	H	H	Me	439
51	CO2Me	85	H	H	H	H	Me	358
52	CO2Et	86	H	H	H	H	Me	372
53	CO2Me	87	H	H	H	H	Me	410
54	CO2Me	88	H	H	H	H	Me	375
55	CO2Et	89	H	NHAc	H	H	Me	445
56	CO2Et	90	H	H	NHAc	H	Me	445
57	CO2Et	91	H	H	H	H	Me	358
58	CO2Et	92	H	H	H	H	Me	358
59	CO2Et	93	H	H	H	H	Me	358
60	CO2Et	94	H	NO2	H	H	Me	457
61	CO2Et	95	H	H	NO2	H	Me	457
62	CO2Me	96	H	H	H	H	Me	344
63	CO2Et	97	H	NH2	H	H	Me	427
64	CO2Et	98	H	H	NH2	H	Me	427
65	CO2Me	99	H	H	H	H	Me	466
66	CO2Me	100	H	H	H	H	Me	344
67	CO2Me	101	H	H	H	H	Me	344
68	CO2Me	102	H	NO2	H	H	Me	443
69	CO2Me	103	H	H	NO2	H	Me	443
70	CO2Et	104	H	H	H	H	i-Pr	400
71	CO2Me	105	H	NH2	H	H	Me	413
72	CO2Me	106	H	H	H	H	Me	399
73	CO2Me	107	H	H	H	H	Et	372
74	CO2Me	108	H	H	H	H	Me	398
75	CO2Me	109	H	H	H	H	Me	394
76	CO2Me	110	H	H	H	H	Me	372
77	CO2Me	111	H	NO2	H	H	Me	403
78	CO2Me	112	H	H	NO2	H	Me	403
79	CO2Me	113	H	H	H	H	Me	394
80	CO2Me	114	H	NHAc	H	H	Me	455
81	CO2Me	115	H	H	H	H	Me	488
82	CO2Me	116	H	NH2	H	H	Me	373
83	CO2Me	117	H	H	NH2	H	Me	373
84	CO2Me	118	H	H	H	H	Me	362
85	CO2Me	119	H	H	H	H	Me	431 (M + 23)
86	CO2Me	120	H	H	H	H	Me	380 (M + 23)
87	CO2Me	121	H	NO2	H	H	Me	439
88	CO2Me	122	H	H	NO2	H	Me	439
89	CO2Me	123	H	H	H	H	Me	430
90	CO2Me	124	H	NH2	H	H	Me	409
91	CO2Me	125	H	H	NH2	H	Me	409
92	126	127	H	H	H	H	Me	397
93	CN	128	H	H	H	H	Me	325
94	CO2Me	129	H	H	H	H	NH2	359
95	CO2Me	130	H	H	H	H	NH2	395
96	CO2H	131	H	H	H	H	Me	344
97	132	133	H	H	H	H	Me	433
98	CN	134	H	H	H	H	Me	361
99	135	136	H	H	H	H	C2H2O2	358
100	137	138	H	H	H	H	C2H2O2	357
101	139	Ph	H	H	H	H	C2H2O2	314
102	140	141	H	H	H	H	C2H2O2	361
103	142	143	H	H	H	H	C2H2O2	364
104	144	145	H	H	H	H	C2H2O2	342
105	CO2H	146	H	H	H	H	Me	380
106	CONH2	147	H	H	H	H	Me	343
107	CONHMe	148	H	H	H	H	Me	357
108	CONMe2	149	H	H	H	H	Me	371
109	150	151	H	H	H	H	C2H2O2	378
110	152	153	H	H	H	H	C2H2O2	328
111	154	155	H	H	H	H	C2H2O2	356
112	156	157	H	H	H	H	C2H2O2	328
113	CO2Me	158	H	H	H	H	Me	375
114	159	160	H	H	H	H	C2H2O2	328
115	CO2Me	161	H	H	H	H	Me	373
116	CONH2	162	H	H	H	H	Me	379
117	163	164	H	H	H	H	C2H2O2	365
118	CO2Me	165	H	H	H	H	Me	375
119	CONHMe	166	H	H	H	H	Me	393
120	CONMe2	167	H	H	H	H	Me	407
121	CO2Me	168	H	H	H	H	Me	381
122	CO2Me	169	H	Cl	Cl	H	Me	463
123	CO2Me	170	H	Cl	Cl	H	Me	427
124	CO2Me	171	H	H	H	H	Me	381
125	CO2Et	172	H	H	H	H	Me	408
126	CO2Me	173	H	Cl	Cl	H	Me	555
127	CO2Me	174	Cl	H	H	Cl	Me	427
128	CO2Me	175	H	H	H	H	Me	421
129	CO2Me	176	Cl	H	H	Cl	Me	558
130	CO2Me	177	H	H	H	H	Me	345
131	CO2Et	178	H	Cl	Cl	H	Me	477
132	CO2Me	179	H	H	H	H	Me	503
133	Ac	180	H	H	H	H	Me	472
134	Ac	181	H	H	H	H	Me	342
135	CO2Me	182	H	H	H	H	Me	331
136	183	184	H	H	H	H	Me	527
137	185	186	H	H	H	H	Me	397
138	CO2Me	187	H	H	H	H	Me	362
139	CO2H	188	H	H	H	H	Me	474
140	CO2H	189	H	H	H	H	Me	344
141	CO2Me	190	H	H	H	H	Me	346
142	CO2Me	191	H	H	H	H	Me	380
143	CO2Me	192	H	H	H	H	Me	486
144	CO2Me	193	H	H	H	H	Me	436
145	CO2Me	194	H	H	H	H	Me	518
146	195	196	H	H	H	H	Me	557
147	197	198	H	Cl	Cl	H	Me	466
148	CO2Et	—NHPh	H	H	H	H	Me	359
149	CO2Me	199	H	H	H	H	Me	360
150	CO2Me	200	H	H	H	H	Me	504
151	201	202	H	H	H	H	Me	420
152	C3H5O3	203	H	H	H	H	Me	534
153	204	205	H	H	H	H	Me	385
154	206	207	H	H	H	H	Me	373
155	208	209	H	H	NO2	H	Me	574
156	CO2Me	210	H	Br	H	H	Me	473
157	CO2Me	211	H	H	Br	H	Me	473
158	212	213	H	Cl	Cl	H	Me	489
159	214	215	H	H	NO2	H	Me	590
160	216	217	H	H	H	H	Me	411
161	CO2Me	218	H	Br	H	H	Me	436
162	CO2Me	219	H	H	Br	H	Me	438
163	CO2Me	220	H	Br	Br	H	Me	516
164	221	222	H	Cl	Cl	H	Me	597
165	223	224	H	Cl	Cl	H	Me	480
166	CO2Me	225	H	Br	Br	H	Me	552
167	CO2Et	226	H	Br	Br	H	Me	530
168	CO2Me	227	F	H	H	F	Me	540
169	CO2Me	228	H	H	NO2	H	Me	551
170	CO2Me	229	H	Cl	Cl	H	Me	573
171	230	231	H	H	NO2	H	Me	444
172	232	233	H	NO2	H	H	Me	444
173	CO2Me	234	F	H	H	F	Me	394
174	235	236	F	H	H	F	Me	433
175	CO2Me	237	H	Br	Br	H	Me	548
176	CO2Me	238	H	H	H	H	Me	355
177	CO2Me	239	H	NO2	H	H	Me	421
178	CO2Me	240	H	H	NO2	H	Me	453 (M + 23)
179	CO2Me	241	H	Cl	Cl	H	Me	443
180	CN	242	H	H	H	H	Me	341
181	CO2Me	243	H	H	H	H	Me	598
182	CO2Me	244	H	Cl	Cl	H	Me	435
183	CO2Et	245	H	H	H	H	Me	387
184	CO2Et	246	H	H	H	H	Me	373
185	CO2Me	247	H	H	H	H	Me	612
186	CO2Et	248	H	H	H	H	Me	410
187	CO2Me	249	H	H	NO2	H	Me	345
188	CO2Me	250	H	Cl	Cl	H	Me	668
189	CO2Me	251	H	H	NO2	H	Me	413
190	CO2H	252	H	Cl	Cl	H	Me	544
191	CN	253	H	H	H	H	Me	565
192	CO2Me	254	H	Br	H	H	Me	606 (M + 23)
193	CO2Me	255	H	H	Br	H	Me	584
194	CO2Et	256	H	H	H	H	Me	373
195	CO2Et	257	H	H	H	H	Me	427
196	CO2Et	258	H	Cl	Cl	H	Me	587
197	CO2Et	259	H	H	H	H	Me	437
198	CO2Et	260	H	H	H	H	Me	389
199	CO2Et	261	H	H	H	H	Me	612
200	CO2Et	262	H	Cl	Cl	H	Me	449
201	CO2Me	263	H	Cl	Cl	H	Me	450
202	CO2Me	264	H	Cl	Cl	H	Me	465
203	CO2Me	265	H	H	H	H	Me	396
204	CO2Me	266	H	267	H	H	Me	473
205	CO2Me	268	H	H	H	H	Me	345
206	CO2Me	269	H	H	H	H	Me	359
207	CO2Me	270	H	Cl	Cl	H	Me	444
208	CO2Me	271	H	H	H	H	Me	355
209	CO2H	272	H	H	H	H	Me	366
210	CO2Me	273	H	Cl	Cl	H	Me	444
211	CO2Me	274	H	Cl	Cl	H	Me	430
212	CO2Me	275	H	H	H	H	Me	416
213	CO2Me	276	H	Cl	Cl	H	Me	430
214	CO2Me	277	H	H	H	H	Me	413
215	CO2Me	278	H	OMe	OMe	H	Me	418
216	CO2Me	279	H	OMe	OMe	H	Me	454
217	CO2Me	280	H	H	H	H	Me	362
218	CO2Me	281	H	282	H	H	Me	445
219	CO2Me	283	H	H	H	H	Me	359
220	CO2Me	—NHPh	H	H	H	H	Me	345
221	CO2Me	284	H	H	H	H	Me	423
222	CO2Me	2-Pyridyl	H	H	H	H	Me	353 (M + 23)
223	CO2Me	285	H	OMe	OMe	H	Me	459
224	CO2Me	286	H	Cl	Cl	H	Me	485
225	CO2Me	287	H	H	H	H	Me	345
226	CO2Me	288	H	H	NO2	H	Me	420
227	CO2Me	289	H	H	NO2	H	Me	420
228	CO2Me	290	H	H	H	H	Me	359
229	CO2Me	291	H	H	H	H	Me	396
230	CO2Me	292	H	OH	OH	H	Me	426
231	CO2Me	293	H	H	F	H	Me	376
232	CO2Me	294	H	H	NO2	H	Me	461
233	CO2Me	295	H	Cl	Cl	H	Me	468
234	CO2Me	296	H	H	H	H	Me	373
235	CO2Me	297	H	H	H	H	Me	375
236	CO2Me	298	H	NO2	H	H	Me	443
237	CO2Me	299	H	H	NO2	H	Me	443
238	CO2Me	300	H	H	H	H	Me	398
239	CO2Me	301	H	Cl	Cl	H	Me	491
240	CO2Me	302	H	303	H	H	Me	509
241	CO2Me	304	H	H	305	H	Me	473
242	CO2Me	306	H	H	307	H	Me	509
243	CO2Me	308	H	H	H	H	Me	310
244	CO2Me	309	H	310	H	H	Me	524
245	CO2Me	311	H	H	312	H	Me	488
246	CO2Me	313	H	H	H	H	Me	308
247	CO2Me	i-Pr	H	H	H	H	Me	296
248	CO2Me	314	H	H	H	H	Me	336
249	CO2Me	Me	H	H	H	H	Me	268
250	CO2Me	315	H	H	316	H	Me	474
251	CO2Me	317	H	H	318	H	Me	487
252	CO2Me	N-Morpholino	H	H	H	H	Me	339
253	CO2Me	319	H	H	H	H	Me	337
254	CO2Me	320	H	H	321	H	Me	488
255	CO2Me	322	H	323	H	H	Me	474
256	CO2Me	324	H	325	H	H	Me	456
257	CO2Me	326	H	327	H	H	Me	431
258	CO2Me	328	H	329	H	H	Me	500
259	CO2Me	330	H	331	H	H	Me	499
260	CO2Me	332	H	333	H	H	Me	481
261	CO2Me	334	H	H	335	H	Me	500
262	CO2Me	336	H	H	337	H	Me	499
263	CO2Me	338	H	H	339	H	Me	431

[0136] III. Biological Assays and Activity

[0137] 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.

[0138] 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.

[0139] Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3 mM MgCl2, 1.7 mM 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 μl (or 1 μCi/ml). For each test well, 48 μl of enzyme was mixed with 47 μl substrate and 5 μl test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50 μl 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.

[0140] Test compounds were diluted in 100% DMSO to a concentration 20× 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 1 $$ % ⁢   ⁢ Inhibition ⁢   ⁢ listed ⁢   ⁢ in ⁢   ⁢ Table ⁢   ⁢ 1 = ( 1 - ( Sample ⁢   ⁢ CPM - NSB TB ⁢ - ⁢ NSB ) ) × 100

[0141] 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
	Ia
340
								MS	IC50 (μM)/% inh. @ μM
No.	R1	R2	R3a	R3b	R3c	R3d	R4	(M + 1)	PDE7A	PDE4	PDE5
6	CO2H	341	H	H	H	H	Me	360	45% @20	49% @5
51	CO2Me	342	H	H	H	H	Me	358	0.055	0.353	2.7
56	CO2Et	343	H	H	NHAc	H	Me	445	0.074	0.333	2.5
70	CO2Et	344	H	H	H	H	i-Pr	400	2.11
73	CO2Me	345	H	H	H	H	Et	372	1.54		0.998
82	CO2Me	346	H	NH2	H	H	Me	373	0.021	0.204	1.11, 0.864
90	CO2Me	347	H	NH2	H	H	Me	409	0.005	0.237, 0.172	2.33
98	CN	348	H	H	H	H	Me	361	1.13
119	CONHMe	349	H	H	H	H	Me	393	0.658		41% @20
133	Ac	350	H	H	H	H	Me	472	1.54
134	Ac	351	H	H	H	H	Me	342	1.14
169	CO2Me	352	H	H	NO2	H	Me	551	0.0053		0.184
170	CO2Me	353	H	Cl	Cl	H	Me	573	0.0087		0.557
190	CO2H	354	H	Cl	Cl	H	Me	544	5.9
191	CN	355	H	H	H	H	Me	565	0.593
197	CO2Et	356	H	H	H	H	Me	437	0.728	69% @5	0.362
219	CO2Me	357	H	H	H	H	Me	359	0.964	61% @5	1.1
220	CO2Me	—NHPh	H	H	H	H	Me	345	0.084	1.8	0.637
241	CO2Me	358	H	H	359	H	Me	473	0.0035	0.954	0.183
242	CO2Me	360	H	H	361	H	Me	509	0.0038	0.782	0.141
243	CO2Me	362	H	H	H	H	Me	310	2.6
245	CO2Me	363	H	H	364	H	Me	488	0.0053	0.875	0.185
248	CO2Me	365	H	H	H	H	Me	336	0.783	0.171	0.649
250	CO2Me	366	H	H	367	H	Me	474	0.0074	0.684	2.4
251	CO2Me	368	H	H	369	H	Me	487	0.0054	0.754	0.26
253	CO2Me	370	H	H	H	H	Me	337	0.905	0.85	0.303
254	CO2Me	371	H	H	372	H	Me	488	0.0067	0.664	0.765
261	CO2Me	373	H	H	374	H	Me	500	0.0063	0.477	0.63
262	CO2Me	375	H	H	376	H	Me	499	0.008	0.702	3.7

Claims

1. A compound having the structure

2. The compound of claim 1, wherein R1 is COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl.

3. The compound of claim 2, wherein R6 is selected from H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

4. The compound of claim 1, wherein R2 is selected from optionally substituted aryl and optionally substituted heteroaryl.

5. The compound of claim 4 wherein the aryl or heteroaryl groups are substituted with one to five members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.

6. The compound of claim 4 wherein, R2 is optionally substituted phenyl or napthyl or R2 is

7. The compound of claim 1 wherein R3 is selected from: (i) hydrogen, halo, C1-8 straight or branched chain alkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, and hydroxy; (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC1-8alkyl, C3-7 cycloalkyl, carboxyC1-8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 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, C1-3alkoxyl, carboxyC1-8alkyl, aryl, arylalkyl, R30R31N(CH2)p—, R30R31NCO(CH2)p—, 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.

8. The compound of claim 7, wherein R3 is selected from the group consisting of:

9. The compound of claim 1 wherein R4 is selected from hydrogen, and C1-3 straight or branched chain alkyl.

10. The compound of claim 9, wherein R4 is selected from methyl and amino.

11. The compound of claim 1 wherein R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl.

12. The compound of claim 1 wherein R1 is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:

13. A compound having the structure:

14. The compound of claim 13, wherein R1 is COOR6 wherein R6 is alkyl, R2 is NR6R7, and R3 is selected from the group consisting of

15. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.

16. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.

17. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.

18. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester.

19. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester.

20. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.

21. The compound of claim 1, which is 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.

22. The compound of claim 1, which is 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.

23. The compound of claim 1, which is 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.

24. The compound of claim 1, which is 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.

25. The compound of claim 1, which is 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.

26. The compound of claim 1, which is 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.

27. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester.

28. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, methyl ester.

29. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester.

30. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.

31. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.

32. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester.

33. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester.

34. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.

35. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.

36. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

37. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.

38. A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the compound of claim 1 or 13.

39. A method of preventing a disorder ameliorated 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 or 13 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.

40. The method of claim 38 or 39 comprising administering to the subject a therapeutically or prophylactically effective dose of pharmaceutical composition of claim 36 or 37.

41. A method of inhibiting PDE activity in a subject, which comprises contacting one or more T-cells with a therapeutically effective dose of the compound of claim 1 or 13.

42 The method of claim 38, 39 or 41, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.

43. The method of claim 38, wherein the disorder is selected from the group consisting of 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.

44. A method of artificially modifying an animal, comprising administering to the animal's T-cells a compound of claim 1 or 13.

45. A method of claim 44 wherein the animal is a mammal.

46. A method of claim 45 wherein the animal is selected from the group consisting of mouse, rat, rabbit, and guinea pig.

47. A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure of Formula I wherein R4 is C1-8 straight or branched chain alkyl and X is O.