4,4-(DISUBSTITUTED)CYCLOHEXAN-1-ONE MONOMERS AND RELATED COMPOUNDS

Abstract: This invention relates to derivatives of 4,4-(disubstituted)cyclohexan-1-ones and related compounds which are useful for treating allergic and inflammatory diseases.

Description: 4,4-(Disubstituted)cyclohexan-l-one Monomers and Related Compounds Field of Invention The present invention relates to novel 4,4-(disubstituted)cyclohexan-l-ones and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF). Background of the Invention Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease. One such way is by elevating levels of cAMP (adenosine cyclic 3',5'- monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg + 2-ATP to cAMP at an accelerated rate. Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of c AMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'- phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs). It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward die pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on die aiket The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resσrption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), ADDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis. AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, Le., HIV-1, HTV-2 and HTV-3. As a consequence of HTV infection, T-cell- mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HTV entry into the T lymphocyte requires T lymphocyte activation. Viruses such as HTV-1 or HTV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HTV gene expression and/or HTV replication. Cytokines, specifically TNF, are implicated in activated T-cell-mediated HTV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HTV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing die progression of HTV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HTV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HTV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon die activation state of the cells. [See Rosenberg etal., The Immunopathogenesis of HTV Infection, Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, have been shown to activate HTV replication in monocytes and or macrophages [See Poli et al., Proc. NatL Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells. TNF has also been implicated in various roles with other viral infections, such as the cytomegalσvirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted. TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al.. Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990]. The ability to control the adverse effects of TNF is furthered by the use of die compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by die excessive and/or unregulated production of TNF. Summary of the Invention The novel compounds of this invention are represented by Formula (I) : wherein: Rj is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, (CR4R5) n O(CR4R5)mR6, or -(CR4R5)r 6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independently hydrogen or Ci-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aιyloxyCι_3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrodiienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety may be unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group or an hydroxyl group; provided diat: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrotiιienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrodιienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R>s is other than H in -(CR4R5)nO(CR4R5)mR6; X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S(O)m*; m' is O, l, o 2; X2 is O or NR8; X3 is hydrogen or X; R2 is -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4; R3 is COOR14, C(O)NR4Ri4 or R7; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is O, NR7, NCR4R5C2-6 alkenyl, NOR14, NOR15, NOCR4R5C2-6 alkenyl, NNR4R14, NNR4R15, NCN, NNRδC(O)NR8Rl4, NNR8C(S)NR8Rl4, or =Z is 2-(l,3-didύane), 2-(l,3-didιiolane), dimethylthio ketal, diethylthio ketal, 2-(l,3- dioxolane), 2(1 ,3-dioxane), 2-( 1,3-oxadιiolane), dimediyl ketal or diediyl ketal; R7 is -(CR4R5)qRl2 or Cι_6 alkyl wherein the R12 or C\. alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NRIQRH, -C(O)R8, -CO2R -O(CH2)2-4θR 8 , -O(CH 2 ) q R8, -CN, -C(O)NRlθRll, -O(CH 2 )qC(O)NRiθRn, - O(CH2) q C(O)R9, -NRlθC(O)NRiθRl 1, -NRιoC(O)Rl l, -NRioC(O)OR9, -NRiθC(O)Ri3, -C(NRiθ)NRιoRl l, -C(NCN)NRiθRn, -C(NCN)SR9, -NRiθC(NCN)SR9 , -NRlθC(NCN)NRiθRll, -NRK)S(O)2R9, -S(O) m 'R9, -NRlOC(O)C(O)NRioRll, -NRlθC(O)C(O)Rιo, or R13; q is O, l, or 2; Rl2 s Ri3, C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), qiήnolinyl, naphthyl, or phenyl; Rg is hydrogen or R9; R9 is C 1 -4 alkyl unsubstituted or substituted by one to three fluorines; RlO is ORβ or Rπ; Rl 1 is hydrogen, or Cι_4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rl 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; Rl3 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, i idazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R13 is substituted on Rι 2 or R ]3 die rings are connected through a carbon atom and each second Rι_ ring may be unsubstituted or substituted by one or two C}_2 alkyl groups unsubstituted or substituted on die methyl with 1 to 3 fluoro atoms; Rj4 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; provided that: (0 R7 is not Cι_4 alkyl unsubstituted or substituted by one to tiiree fluorines; or or the pharmaceutically acceptable salts thereof. Another set of compounds of tiiis invention are represented by Formula (H) wherein: R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4 5)nC(O)NR4(CR4 5)m 6, - (CR4R5) n O(CR4R5)_nR6, or -(CR4R5)ι*R»5 wherein die alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independendy selected hydrogen or Ci-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aτyloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydrσpyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties is unsubstituted or substituted by 1 to 3 methyl groups, an ethyl group, or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydτofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)nO(CR4R5)mR6; X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S(O) m '; m' is 0, 1, or 2; X2 is O or NR8; X3 is hydrogen or X; R2 is independendy selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4; R3 is COOR14, C(O)NR4Ri4 or R7; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z" is C(Y * )Rl4, C(O)ORi4, C(Y')NRlθRl4, C(NRιo)NRιoRi4, CN, C(NOR8)Rl4, C(0)NR8NR8C(0)R8, C(O)NRgNRiθRl4, C(NORl4)R8. C(NR8)NRlθRl4, C(NRl4)NRδR8 C(NCN)NRιoRi4, C(NCN)SR9, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[l,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; Y' is O or S; R7 is -(CR4R5) q Rl2 or Cι_6 alkyl wherein the R12 or Cι_6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NRIQRI 1, -C(O)R8, -CO2R8, -O(CH2)2^0Rg, -O(CH 2 ) q R8, -CN, -C(O)NRιoRn, -O(CH 2 ) q C(O)NRιoRll, - 0(CH2) q C(O)R9, -NRιoC(O)NRiθRιι, -NRιoC(O)Rn, -NRιoC(O)OR9, -NRioC(O)Ri3, -C(NRιo)NRiθRn, -C(NCN)NRiθRn, -C(NCN)SR9, -NRlθC(NCN)SR9 , -NRιoC(NCN)NRιoRn, -NRιoS(O)2R9. -S(0)ιrfR9, -NRlθC(O)C(O)NRlθRn, -NRi()C(O)C(O)RlO, or R J3 ; q is 0, 1, or 2; Rl2 is R13, C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl; Rg is independendy selected from hydrogen or R9; R9 is C]_4 alkyl unsubstituted or substituted by one to three fluorines; RlO is ORδ or Rn; R is hydrogen, or Cj_4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rl 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; Rl3 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R13 is substituted on R- 2 or R-,3 the rings are connected through a carbon atom and each second Rι 3 ring may be unsubstituted or substituted by one or two Cj_2 alkyl groups unsubstituted or substituted on d e methyl with 1 to 3 fluoro atoms; R 4 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatoms selected from O, N, or S; provided that: (f) R7 is not C .4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I) and (II) and a pharmaceutically acceptable carrier or diluent The invention also relates to a method of mediation or inhibition of d e enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) and (II) as shown below. The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) and (II). The invention also provides a metiiod for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) and CO). This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a -mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I) and (II). This metiiod may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto. This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I) and (II). Compounds of Formula (I) and (II) are also useful in die treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo. In addition, compounds of Formula (I) and (H) are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. Detailed Description of the Invention This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting die production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) and (II). Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia. The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, direcdy or indirecdy, by the TNF inhibitors of Formula (I) and (U). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and die Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex. This invention more specifically relates to a method of treating a mammal, afflicted widi a human immunodeficiency vims (HTV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) and (ϋ). The compounds of this invention may also be used in association with the veterinary treatment of animals, other than in humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to feline immunodeficiency virus (FTV) or other retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses. The compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis. Additionally, the compounds of Formula (I) and (II) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections. Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B. The compounds of Formula (I) and (II) may also be used for inhibiting and/or reducing d e toxicity of an anti-fungal, anti-bacterial or anti- viral agent by administering an effective amount of a compound of Formula (I) and (II) to a mammal in need of such treatment Preferably, a compound of Formula (I) and (II) is administered for inhibiting or reducing die toxicity of the Amphotericin class of compounds, in particular Amphotericin B. The term "Cι_3 alkyl", "Cι_4 alkyl", "Cι_6 alkyl" or "alkyl" groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-prσpyl, isopropyl, n-butyl, sec-butyl, isobutyl, rerr-butyl, and die like. "Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1- propenyl, 2-propenyl, or 3-methyl-2-propenyl. The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbon atoms, such as cyclopropyl, cyclσpropylmethyl, cyclopentyl, or cyclohexyl. "Aryl" or "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl. The alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" means an aromatic ring system containing one or more heteroatoms. "Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo. "Inhibiting the production of IL- 1 " or "inhibiting the production of TNF' means: a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of die in vivo release of IL-1 by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcriptional level, of excessive in vivo E -l or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event The phrase "TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-β (also known as lymphotoxin) has close structural homology with TNF-α (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-α and TNF-β are inhibited by die compounds of die present invention and thus are herein referred to collectively as "TNF' unless specifically delineated otherwise. Preferably TNF-α is inhibited "Cytokine" means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce diem. The cytokine inhibited by die present invention for use in the treatment of a HTV-infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HTV gene expression and/or replication, and or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably, his cytokine is TNF-α. All of the compounds of Formula (I) and (II) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formula (I) and (II) are useful in the method of inhibiting or mediating die enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby. Preferred compounds are as follows: When Rl for the compounds of Formula (I) and (II) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, - CHF2, -CF2CHF2, -CH2CF3, and -CH2CHF2. Preferred Rl substitutents for the compounds of Formula (I) and (II) are CH2-cycloprσpyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with OH, C7-11 polycycloalkyl, (3- or 4- cyclσpentenyl), phenyl, tetrahydroruran-3-yl, benzyl or Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4θH. When the Rl term is (CR4R5), the R4 and R5 terms are independendy hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5) n or (CR4R5)m; each repeating methylene unit is independent of die other, e.g., (CR4R5) n wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of die repeating methylene unit or the branching hydrocarbon can be unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Rl substitutions, as noted above. When Rl is a C7-11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2. l]octyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety. Preferred Z terms are O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4R15, 2-(l,3-didιiane), dimethyldiio ketal, 2-(l,3-dioxolane), or dimediyl ketal. More preferred are O, NR7, NOR14, NOR15, and 2-(l,3-dioxolane). Preferred X groups for Formula (I) and (II) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) and (II) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) and (II) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a C 1-2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, - CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties. Preferred R7 moieties include R13, unsubstituted or substituted -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4- piperazinyl), (CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2)0-2phenyl. Preferred rings when Rio and Rl 1 in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-l-triazolyl, 5-(R8)-2-tria2θlyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)- 1 -piperazinyl, or pyrrolyl ring. Preferred rings when R8 and Rl4 in the moiety -NR8R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 1 -pyrazolyl, 1-triazolyl, 2-triazolyl, 1- tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I) and (II). Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l-irrridazolyl, 4-(R7)-l-imidazolyl, 5-(R7)-l-imidazolyl, 3-(R7)-l-pyrazolyl, 4-(Rrj)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l-triazolyl, 5-(R7)-l-triazolyl, 5-(R7)-l -tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l -tetrazolyl, -(Rrj)-l -piperazinyl. Where applicable, the ring may be substituted one or more times by R7. Preferred groups for NR8R14 which contain a heterocyclic ring are 5-(Ri4)-l- tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l-piperazinyl, or 4-(R 15)- 1-piperazinyl. Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[l,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl). When the R7 group is unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, pyrimidinyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by R8 either on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R8)*-4-imidazolyl, l-(R8)-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-pyrazolyl, l-(R8)-4-triazolyl, or l-(R8)-5-triazolyl. Where applicable, the ring may be substituted one or more times by R8- W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present It is most preferred tiiat W is ethynyl or 1,3-butadiynyL Preferred are tiiose compounds of Formula (I) and (II) wherein Ri is -CH2- cyclσpropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with OH, tetrahydroruran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl unsubstimted or substimted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro- substituted alkyl, R 3 is R 7 where R 7 is an unsubstimted or substituted aryl or heteroaryl ring, X is YR2, and Z is O, NR7. Z' is preferably COOR14. Most preferred are those compounds wherein Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl, W is ediynyl or 1,3-butadiynyl, R3 is a substimted or unsubstimted pyrimidinyl ring, and Z is O, NR7. Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by titis invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and die salt will not have untoward or deleterious effects in its application and use in treating diseases. Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound, dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base where the molecule contains a COOH for example. Pharmaceutical compositions of die present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of d e Formula (I) and (II). The compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended. These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at die time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol. The nature of the composition and die pharmaceutical carrier or diluent will, of course, depend upon die intended route of administration, for example parenterally, topically, orally or by inhalation. For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment lotion, pastes, aerosols, and drops suitable for administration to the skin, eye, ear, or nose. For parenteral administration die pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension. For oral administration die pharmaceutical composition will be in die form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion. When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water, for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlαrotrifluαroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, die instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of d e instant compositions. The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product. In these compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient When the diluent is a solid it may be present in lesser, equal or greater amounts than die solid active ingredient Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, die dosage of die composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg. It will be recognized tiiat some of the compounds of Formula (I) and (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention. Compounds of Formula (I) where Z is O or (II) may exist in a tautomeric form, such as the enol form. This may be represented by die =O being exocyclic to die cyclohexane ring (or as contrasted to die endocyclic or -C(-OH)=C(- now unsaturated in die 1-2 position, Z in Formula (U . It is also recognized tiiat d e 2-position of die ring in the exocyclic form can be substimted (R) such as in the compounds of Formula (I) or (II). The following examples are given to further illustrate the described invention. These examples are intented solely for illustrating the invention and should not be read to limit the invention in any manner. Reference is made to die claims fen * what is reserved to die inventors hereunder. No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention. Methods Of Preparation Synthetic Scheme(s) With Textual Description Compounds of Formula (I) may be prepared by die processes disclosed herein which comprise reacting a terminal acetylene as, e.g., compound 1 -Scheme 1. with an aryl halide, such as phenyl iodide, in the presence of a suitable catalyst, such as a copper D halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in the procedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), followed by hydrolysis of the ketal protecting group under standard conditions, provides a compound of die Formula 2_ Scheme 1. Compounds of die Formula 1 -Scheme 1 may be prepared by procedures analogous to those described in prior filed co-pending U.S. applications 07/862,083, 07/968,753 and PCT/US93/01990 designating the United States and filed 05 March 1993 (WIPO publication No. WO 93/19748) or PCT application PCT/US93 02325 published as WO 93/19750. Schema 1 a) Pd(PPh 3 ) . PPh 3, Cut, C 6 H 5 I, piperidtnβ; b) pyridinium p-tofcienesuHonate, (H 3 C) 2 CO/H 2 0 Alternatively, compounds of Formula (I) may be prepared by reacting a terminal acetylene as, e.g., compound 1 -Scheme 2. with an appropriate halide, R3X, wherein R3 represents R3 as defined in relation to Formula (I) or a group convertible to R3, in the presence of a suitable catalyst, such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in the procedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), to provide a compound of me Formula 2-Scheme 2: such compounds of d e Formula (I) may then be converted to other compounds of the Formula (I) by standard manipulation of the functional groups on the R3 moiety. Compounds of die Formula 1-Scheme 2 may be prepared by procedures analogous to diose described in prior filed co-pending U.S. applications 07/862,083, 07/968,753 and PCT/US93/01990 designating the United States and filed 05 March 1993 (WIPO publication No. WO 93/19748) or PCT application PCT/US93/02325 published as WO 93/19750.. a) Pd(PPh 3 ) 4 , PPh 3 , Cul, R 3 X, pipβridinβ Alternatively, oxidative carbonylation of a terminal acetylene as, e.g., compound 1-Scheme 3. using an appropriate metal salt, such as a copper salt with a catalytic amount of a palladium salt, in d e presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, as in the method of Tsuji et al. (Tet Lett., 1980, 21, 849), followed by hydrolysis of the mediyl ester under standard conditions, tiien provides die compound of die Formula (I) (2-Scheme 2); such compounds of d e Formula (I) may then be converted to other compounds of die Formula (I) by standard manipulation of the carboxylic ester moiety. Schema 3 Q D Q COOCH 3 a) PdCI 2 . CuCI 2 , NaO 2 CCH 3 . CO, CH 3 OH Compounds of Formula (II) may be prepared by processes analogous to those in Schemes 1, 2 and3 above, as illustrated in Scheme 4 wherein. Depending upon d e exact nature of the Z' groups of the compounds of die Formula (II), the =O group may require protection during die coupling steps described herein as, e.g., a compound of die Formula (H) wherein =O is a dimethyl ketal or 2-(l,3-dioxolane), followed by deprotection and tiien reaction by the synthetic procedures described in prior filed co- pending U.S. applications 07/862,083, 07 968,753 and PCT/US93 01990 designating die United States and filed 05 March 1993 (WIPO publication No. WO 93/19748) or PCT appUcation PCT/US93 02325 published as WO 93/19750, to provide the Formula (U compound; likewise, the Z group may require protection during the coupling steps, followed by deprotection to provide d e Formula (II) compound and such protective groups are well known to those skilled in the art (See: Greene, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, 1991.) Schema A a) Pd(PPh 3 ) 4 , PPh 3 . Cul, R 3 X, piperidinβ Preparation of the remaining compounds of d e Formulas (I) and (II) may be accomplished by procedures analogous to those described above and in the Examples, infra. It will be recognized that compounds of d e Formulas (I) and (II) may exist in distinct diastereomeric forms possessing distinct physical and biological properties; such isomers may be separated by standard chromatographic methods. The following examples are given to further illustrate the described invention. These examples are intented solely for illustrating the invention and should not be read to limit the invention in any manner. Reference is made to the claims for what is reserved to the inventors hereunder. Synthetic examples Example 1 Preparation of 4-(3-cvclopentvloxv-4-methox vphenvlV 1.1 -(ethvlenedioxv)-4-(2- pyridylethynyllcyclohexane la) 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)cyclohexane A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (1.0 g, 3.19 mmol, prepared by die procedures described in PCT applications PCT/US3 01990 (WIPO publication No. WO 93/19748) and PCT appUcation PCT/US93 02325 published as WIPO number WO 93/19750) in benzene (25 mL) was treated with p-toluenesulfonic acid (5 mg) and ethylene glycol (0.18 mL, 3.19 mmol) and was heated to reflux under an argon atmosphere; water was removed from the mixture via a Dean-Stark trap. After 1.5 h, ether (200 mL) was added, die solution was washed widi aqueous 5% sodium bicarbonate and brine, was dried (potassium carbonate) and was evaporated to provide a clear colorless oil. H NMR(250 MHz, 0X33) δ 7.0 (m, 2H), 6.85 (d, J=7 Hz, 1H), 4.8 (m, 1H), 4.0 (m, 4H), 3.85 (s, 3H), 1.58-2.20 (m, 16H). 1 b) 4-(3-cyclopentyloxy-4-medιoxyphenyl)- 1 , l-(ethylenedioxy)-4-formylcyclohexane Dϋsobutylaluminum hydride (1.0 M in toluene, 8.13 mL, 8.13 mmol) was added dropwise to a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l- (ethylenedioxy)cyclohexane (1.16 g, 3.19 mmol) dissolved in toluene (20 mL) under an argon atmosphere. After 18 h at room temperature, saturated aqueous sodium bisulfite (100 mL) was added and die mixture was extracted three times with dichloromethane. The combined organic extract was washed widi brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting wid 4: 1 hexanes ediyl acetate, provided a clear colorless oil. -*H NMR(400 MHz, CDCI3) δ 9.35 (s, 1H), 6.88 (br s, 2H), 6.80 (s, 1H), 4.73 (m, 1H), 3.95 (m, 4H), 3.85 (s, 3H), 2.33 (m, 2H), 2.10 (m, 2H), 1.57-1.99 (m, 12H). lc) 4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(ethylenedioxy)-4-ethynylcyclohexane A solution of dimediyl (diazomethyl)phosphonate (0.516 g, 3.44 mmole, prepared as in Seyferth, D.; Mar or, R. S.; Hubert, P. J. Org. Chem. 1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (10 mL) was added via cannulation to a solution of potassium t-butoxide (0.386 g, 3.4 mmol) dissolved in dry tetrahydrofuran (10 mL) at -78°C under an argon atmosphere. To this was added rapidly a solution of 4-(3-cyclc >entyloxy-4-meΛoxyphenyl)-l,l-(ethylenedioxy)-4-formylcyclohexane (0.62 g, 1.72 mmol) in dry tetrahydrofuran (10 mL). After 2 h, die reaction was warmed to room temperature, water was added and die mixture was extracted three times with ethyl acetate. The combined organic extract was washed widi brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes ethyl acetate provided a white soUd. mp 53.5-55°C. Id) 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(2-pyridylethynyl)- cyclohexane To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4- etiiynylcyclohexane (0.15 g, 0.42 mmol) and 2-bromopyridine (0.040 mL, 0.42 mmol) in piperidine (2 mL) under an argon atmosphere were added tetra_ris(triphenylphosphine)-palladium(0) (0.02 g, 4%), copper (I) iodide (0.005 g, 6%) and a smaU crystal of triphenylphosphine, and d e mixture was heated at 80°C for 0.5 h. Water was added and die mixture was extracted three times with dichlσromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, jm>vided 4-(3-cy opentyloxy-^med-θxyphenyl)--l,l-(edιylenedioxy)-4-(2- pyridyletiιynyl)cyclohexane as a white foam mp 41-42°C. -1H-NMR (400 MHz, CDCI3) δ 8.58 (d, J=4.6 Hz, IH), 7.65 (t, J=7.7 Hz, IH), 7.43 (d, J=8.0Hz, IH), 7.21 (m, 2H), 7.17 (d, J=8.5 Hz, IH), 6.84 (d, J=8.5 Hz, IH), 4.81 (m, IH), 3.99 (s, 4H), 3.84 (s, 3H), 2.25 (m, 2H), 2.15 (m, 4H), 1.8-2.0 (m, 8H), 1.59 (m, 2H). Example 2 Preparation of 4-(3-cvclopentvloxv-4-memoxyphenyl l.l-(ethylenedioxyV4- φhen vlethynvltevclohexan- 1 -one A sample of l,l-(ethylenedioxy)-4-(3-cyclopentyloxy-4-methoxyphenyl)-4- ethynylcyclohexane (0.15 g, 0.42 mmol) was treated with trace amounts of triphenylphosphine, tetrakis(triphenylphosphine)palladium (0) and copper (I) iodide. Iodobenzene (0.47 mL, 4.2 mmol) and piperidine (2 mL) were then added and d e mixture was heated under an argon atmosphere. After 3 h, the mixture was diluted wid ethyl acetate (50 mL), was washed once with dilute aqueous HC1, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography (4: 1 hexanes ediyl acetate) provided a clear colorless oil. H NMR(400 MHz, CDCI3) δ 7.44 (m, 2H), 7.3 (m, 3H), 7.23 (d, J=2 Hz, IH), 7.12 (dd, J=2 and 8 Hz, IH), 6.81 (d, J=8 Hz, IH), 4.8 (m, IH), 4.0 (s, 4H), 3.85 (s, 3H), 2.25 (m, 2H), 2.10 (m, 2H), 1.78-2.03 (m, 10H), 1.6 (m, 2H). Example 3 Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(phenylethynyl)cyclohexan- 1- one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4- (phenylethynyl)cyclohexan-l-one (0.18 g, 0.42 mmol) dissolved in 4:1 acetone/water (5 mL) was added pyridinium p-toluenesulfonate (5 mg). The mixture was heated to reflux under an argon atmosphere. After 6 h, water (15 mL) was added and die mixture extracted three times with ethyl acetate. The combined organic extract was dried (magnesium sulfate) and was evaporated. Purification by trituration from ether/hexanes provided a white soUd. mp 99-100°C. Example 4 Preparation of 4-f -cvclopentyloxy-4-methoxyphenylV4-f -pvridvlethvnvl)cvclohexan- -one A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(2- pyridyled ynyl)cyclohexane (0.17 g, 0.39 mmol) and pyridinium p-toluenesulfonate (0.10 g, 0.39 mmol) in acetone (4 mL) and water (1 mL) was refluxed for three days, d en was evaporated. Water was added, d e mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate±exanes, provided 4-(3-cyclopentyloxy^medιoxyphenyl)-4-(2-pyridyledιynyl)cyclohexan-l- one as a wax. *H-NMR (400 MHz, CDCI3) δ 8.61 (d, J=4.8 Hz, IH), 7.68 (dt, J=7.8, 1.8 Hz, IH), 7.47 (d, J=7.8 Hz, IH), 7.27 (m, IH), 7.20 (d, J=2.3 Hz, IH), 7.15 (dd, J=8.5, 2.4 Hz, IH), 6.87 (d, J=8.5 Hz, IH), 4.81 (m, IH), 3.85 (s, 3H), 3.07 (dt, J=14.4, 5.8 Hz, 2H), 2.49 (d, J=14.8 Hz, 2H), 2.41 (m, 2H), 2.27 (dt, J=13.4, 3.9 Hz, 2H), 1.8-2.0 (m, 6H), 1.61 (m, 2H). Anal. (C25H27NO3 O.65 H2O) calcd: C, 74.84; H, 7.11; N, 3.49; found: C, 75.00; H, 6.83; N, 3.52. Example -? Preparation of 4-(3-cvclopentvloxv-4-methoxyphen yl 1.1 -feth ylenedioxy)-4-(4- nitrophenylethynyPcyclohexane To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(ethylenedioxyH- ethynylcyclohexane (0.15 g, 0.42 mmol) and 4-iodonitrophenol (0.11 g, 0.42 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)- palla ιum(O) (0.02 g, 4%), copper (I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 80°C for 0.5 h, water and IE hydrochloric acid were added. The mixture was extracted three times widi dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 etiiyl acetate:hexanes, provided 4-(3-cyclopentyloxy- 4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(4-nitrophenylethynyl)cyclohexane as a red- orange wax. mp 58-59°C. -NMR (400 MHz, CDCI3) δ 8.18 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.16 (d, J=2.5 Hz, IH), 7.12 (dd, J=8.4, 2.5 Hz, IH), 6.86 (d, J=8.4Hz, IH), 4.80 (m, IH), 4.01 (s, 4H), 3.85 (s, 3H), 1.8-2.3 (m, 14H), 1.6 (m, 2H). Example 6 Preparation of 4-G-cyclopentyloxy**4-meΦoxyphenyl -4-(4-aminophenylethynyl cyclohexan-1-one To 4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(ethylenedioxy)-4-(4- nitrophenylethynyl)cyclohexane (0.19 g, 0.40 mmol) in med anol (1 mL), acetic acid (1.2 mL), and water (1.2 mL) under an argon atmosphere was added titanium trichloride (0.3 g, 2 mmol). After stirring for 1.5 h at room temperature, water (1.2 mL) and ammonium hydroxide (2.5 mL) were added. After stirring an additional 1 h, medianol (17.5 mL), 5% sodium carbonate (17.5 mL) and dichloromethane (35 mL) were added, and stirring was continued for 3 days. The suspension was filtered through Celite®, was washed weU widi dichloromethane, and was evaporated. Water was added, die mixture was extracted tiiree times with dichloromethane, die extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate exanes, provided 4-(3-cyclσpentyloxy- 4-medιoxyphenyl)-4-(4-aminophenylethynyl)cyclohexan- 1 -one as a colorless oil. *H- NMR <400 MHz, CDα3) δ 7.28 (d, J=8.4 Hz, 2H), 7.24 (d, J=2.1 Hz, IH), 7.12 (d, J=8.5 Hz, IH), 6.85 (d, J=8.5 Hz, IH), 6.64 (d, J=8.1 Hz, 2H), 4.80 (m, IH), 3.85 (s, 3H), 3.05 (dt, J=14.3, 4.1 Hz, 2H), 2.45 (br d, J=14.6 Hz, 2H), 2.29 (m, 4H), 1.8-2.0 (m, 6H), 1.61 (m, 2H). Example 7 Preparation of 4-f3- * cycl Q pen oxv-4-medιoxvpheny|>-4-f4-arffT?^^ hftn y 1p Tliyny1V cyctohexan-l-gne To 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- aminophenylethynyl)cyclohexan-l-one (0.12 g, 0.29 mmol) in dichloromethane (3 mL) under an argon atmosphere were added pyridine (five drops) and acetic anhydride (0.081 L, 0.86 mmol) and d e reaction was stirred at room temperature for 2 h. Hydrochloric acid (1£D was added, die mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, provided 4-(3-<^clopentyloxy-4-nMthoxyphenyl)-4-(4-acetamidophenylethynyl)cycltjhexan- 1 - one as a white soUd. mp 79-80°C; Anal. (C28H31NO4 O.5 H2O) calcd: C, 73.98; H, 7.10; N, 3.08; found: C, 74.11 ; H, 7.24; N, 3.03. Example 8 Preparation of 4-(3-cyclopentyloxy-4-methoxyphenvlVl.l-fethvlenedioxv -4-f3- mtrophenvlethvnvncvclohexane To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl l,l-(ethylenedioxy)-4- ediynylcyclohexane (0.14 g, 0.38 mmol) and 3-iodonitrophenol (0.10 g, 0.38 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)- palladium(0) (0.02 g, 4%), copper (I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 70°C for 0.33 h, the mixture was diluted widi dichloromethane, was washed widi IN hydrochloric acid, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting wid 2:8 etiiyl acetate:hexanes, provided l,l-(ethylenedioxy)-4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(3-nitrophenyledιynyl)cyclohexane as an orange wax. -Η-NMR (400MHz, CDCI3) δ 8.29 (s, IH), 8.16 (d, J=9.0 Hz, IH), 7.75 (d, J=7.9 Hz, IH), 7.50 (t, J=8.0 Hz, IH), 7.26 (d, J=2 Hz, IH), 7.14 (dd, J=8.3, 2 Hz, IH), 6.86 (d, J=8.3 Hz, IH), 4.82 (m, IH), 4.01 (s, 4H), 3.85 (s, 3H), 2.18 (m, 4H), 2.07 (m, 2H), 1.93 (m, 4H), 1.85 (m, 4H), 1.6 (m, 2H). Example 9 Preparation of 4-f 3-cvclQpentyloxy-4-πrethoxyphenvlV4-( 3-aminophenvlethynyl cyclohexan-1-one To 4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(ethylenedioxy)-4-(3- nitrøphenylethynyl)cyclohexane (0.17 g, 0.35 mmol) in medianol (1 mL), acetic acid (1.2 mL) and water (1.2 mL) under an argon atmosphere was added titanium trichloride (0.3 g, 2 mmol). After stirring for 1.5 h at room temperature, titanium trichloride (0.3g, 2 mmol) and water (1.2 mL) were added, and die mixture was stirred for 0.5 h at room temperature and for 0.5 h at 45-50°C, then was cooled to room temperature. Water (1.2 mL) and ammonium hydroxide (2.5 mL) were added. After stirring an additional lh, medianol (17.5 mL), 5 % sodium carbonate (17.5 mL) and dichloromethane (35 mL) were added, and stirring was continued for 2 h. The suspension was filtered through Celite®, was washed weU widi dichloromethane and d e extract was evaporated. The residue was diluted widi dichloromethane, d e organic layer was washed widi 5:95 ammonium hydroxide:water, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting widi 3:7 ediyl acetate±exanes, provided a mixture of 4-(3-cyclσpentyloxy-4- methoxyphenyl)-4-(3-aminophenyledιynyl)-cyclohexan-l-one and 4-(3-cyclopentyloxy- 4-me oxyphenyl)-l,l-(ethylenedioxy>4-(3-aminophenylethynyl)cyclohexane (0.07 g). This mixture and a spatula-tip of pyridinium p-toluenesulfonate in acetone (4 mL) and water (1 mL) was refluxed for 3 days, then was evaporated. Water was added, die mixture was extracted three times with dichloromethane, die extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes provided 4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(3-aminophenylethynyl)cyclohexan-l-one as a colorless oil. -Η- NMR (400 MHz, CDCI3) δ 7.22 (d, J=2.2 Hz, IH), 7.14 (m, 2H), 6.87 (m, 2H), 6.82 (d, J=2.8 Hz, IH), 6.66 (dd, J=9.0, 2.4 Hz, IH), 4.81 m, IH), 3.85 (s, 3H), 3.7 (br, 2H), 3.04 (dt, J-=14.3, 6.0 Hz, 2H), 2.47 (br d, J=14.6 Hz, 2H), 2.2-2.3 (m, 4H), 1.8- 2.0 (m, 6H), 1.61 (m, 2H). Example 10 Preparation of 4-r3-cvclopentyloxy-4-methoxyphenylV4-f3-acetamidoρhenvlethvnvlV cyςlohexan-1-pne To 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- aminophenylethynyl)cyclohexan-l-one (0.07 g, 0.18 mmol) in dichloromethane (2 mL) under an argon atmosphere were added pyridine (three drops) and acetic anhydride (0.05 mL, 0.53 mmol) and die reaction was stirred at room temperature for 2 h. Hydrochloric acid (IN) was added, d e mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3- acetamidophenyled ynyl)cyclohexanone as a white soUd. mp 63 -64 0 Anal. (C28H31NO4 1.75 H2O) calcd: C, 70.49; H, 7.29; N, 2.94; found: C, 70.09; H, 6.94; N, 2.83. Example 11 Preparation of 4-f3-cvclopentvloxv-4-medιoxvphenylVl.l-fethylenedioxy -4-(3- carfaomethoxyphenylethvnvDcvclohexane A mixture of 4-(3-cyclopenty loxy-4- methoxyphenyl)-l,l-(ethylenedioxy)-4-ethynylcyclohexane (0.150 g, 0.421 mmol) and mediyl 3-iodobenzoate (0.110 g, 0.421 mmol) in piperidine (2.1 mL, dry) under an argon atmosphere was treated wid a mixture of tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol), cuprous iodide (0.010 g, 0.053 mmol) and triphenylphosphine (crystal) and die mixture was heated at 80°C for 40 min. The reaction mixture was chilled to 0°C was poured into ice- water, was acidified wid 3N hydrochloric acid and was extracted five times widi methylene chloride. The organic phase was washed wid dilute hydrochloric acid, water, saturated brine, was dried over magnesium sulfate, was filtered and concentrated in vacua. The residue was preadsorbed and chromatographed on silica gel, eluting the with 15 to 20% ethyl acetate in hexanes, to afford a Ught yeUow oil. *H-NMR (250 MHz, CDCI3) δ 8.11 (t, J=1.4 Hz, IH), 7.97 (d-d, J=1.3 Hz;J=7.9 Hz, IH), 7.63 (d-d, J=7.8 Hz;J=1.3 Hz, IH), 7.39 (t, J-=7.8 Hz, IH), 7.23 (d, J=2.2, IH), 7.15 (d-d, J=8.4 Hz;J=2.3 Hz, IH), 6.89 (d, J=8.4 Hz,lH), 4.80 (m, IH), 4.00 (s, br, 4 H), 3.92 (s, 3H), 3.84 (s, 3H), 2.4 to 1.75 (m, 18H). Example 12 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvn-4-f3-carbomedιoxvphenvl- ethvnvltavclohexan- 1 -one A solution of 4-(3-cyclcpentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(3- carbomethoxyphenylethynyl)cyclohexane (0.060 g, 0.12 mmol) in tetrahydrofuran (5 mL) containing 3N hydrochloric acid (0.60 mL) under an argon atmosphere was heated at 55-60 °C for 2 h. The cooled reaction mixture was partitioned between ice cold dilute aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed wid water, saturated brine, was dried over sodium sulfate,and was concentrated in vacua. The residue was chromatographed (silica gel), eluting widi 15% etiiyl acetate/hexanes, to afford a resin. Anal. (C28H30θ5*l/4 H2O) calcd: C 74.56, H 6.82, found: C 74.43, H 6.80. tø-NMR (400 MHz, CDCI3) δ 8.15 (s , IH), 8.00 (d-d, J=1.5 Hz;J=6.6 Hz, IH), 7.65 (d-d, J=1.3 Hz, J=7.7 Hz, IH), 7.43 (t, J=7.7 Hz, IH), 12\ (d, J=2.1, IH), 7.12 (d-d, J=2.0 Hz, J=8.5 Hz, IH), 6.87 (d, J=8.5 Hz,lH), 4.81 (m, IH), 3.94 (s, 3 H), 3.86 (s, 3H), 3.04 (d-t, J=6.0 Hz, J=14.2, 2H), 2.50 (d,br, J=14.8, 2H), 2.4-2.2 (m, 4 H), 2.0-1.5 (m). Example 13 Preparation of 4-(3-cvclopentyloxy-4-methoxvphenvlVl.l-(ethylenedioxy'>-4-G- carboxyphenylethynyDcyclohexane A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(3- carbomethoxyphenylethynyl)cyclohexane (0.12 g, 0.245 mmol) in medianol (5 mL) was treated with 10% aqueous sodium hydroxide (0.3 mL, 0.734 mmol) under an argon atmosphere and was heated at 55-60 °C for 2.5 h. The cooled reaction mixture was concentrated in an argon stream and d e residue was partitioned between cold water acidified widi dilute hydrochloric acid and methylene chloride. The aqueous phase was extracted another two times with methylene chloride and die combined organic phase was dried over magnesium sulfate to afford die tided compound as an oil. -Η-NMR (400 MHz, CDCI3) δ 8.18 (s, IH), 8.02 (d, J=7.9 Hz, IH), 7.68 (d, J=7.8 Hz, IH), 7.42 (t, J=7.8 Hz, IH), 7-23 (d, J=2.2, IH), 7.14 (d-d, J=8.4 Hz * J=2.3 Hz, IH), 6.85 (d, J=8.4 Hz,lH), 4.82 (p, IH), 4.01 (t, 4.2 H), 3.85 (s, 3 2H), 2.4 to 1.5 (m, 17H). Example 14 Preparation of 4-(3-cvclQpentyloxy-4-methoxvphenvlV4-r3-carboxvphenvl- eth vnyltevclohexane- 1 -one A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(3- carboxyphenylethynyl)cyclohexane (0.11 g, 0.23 mmol) in tetrahydrofuran (6 mL) containing 3N hydrochloric acid (0.7 mL) was heated under an argon atmosphere at 55-70 °C for 2 h. The cooled reaction mixture was concentrated in vacua and d e residue was partitioned between cold water and methylene chloride. The organic phase was washed wid saturated brine solution, was dried over magnesium sulfate and was evaporated. The residue was chromatographed (silica), eluting widi methylene chloride/metiianol/water (90/5/0.25 to 90/10 0.5) and was concentrated in vacua. The residue was dissolved in medianol and was foamed in vacua to afford a white fractured glass. AnaL (C27H28 5.1/4 H2O* 1/4 CH3OH) calcd: C 73.55, H 6.68, found: C 73.51, H 6.66. -Η-NMR (400 MHz, CDCI3) δ 8.22 (t, J=1.5 Hz, IH), 8.09 (d-d, J=1.3 Hz;J=7.9 Hz, IH), 7.72 (d-d, J=1.3 Hz, J=7.8 Hz, IH), 7.47 (t, J=7.8 Hz, IH), 7.22 (d, J=2.2, IH), 7.13 (d-d, J=2.3 Hz, J=8.4 Hz, IH), 6.88 (d, J=8.5 Hz,lH), 4.82 (p, IH), 3.86 (s, 3H), 3.25 (d, J=20 Hz, CH3OH, 0.55H), 3.04 (d-t, J=5.8 Hz, J=14.5, 1.7H), 2.50 (d,br, J=14.8, 1.8H), 2.4-2.2 (m, 4 H), 2.0-1.5 (m). Example 15 4-f3-Cvclopentyloxy-4-methoxvphenvlV4-f4-ρvridvlethvnvl)cvclohexan-l-one 15a) 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(4-pyridylethynyl)-l,l- (edιylenedioxy)cyclohexane To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl- 1,1- (edιylenedioxy)cyclohexane (0.10 g, 0.28 mmol) and 4-bromopyridine (0.54 g, 2.8 mmol) in piperidine (1.5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)p__Qadium(0) (0.013 g, 4%), copper(I) iodide (0.004 g, 6%) and a small crystal of triphenylphosphine, and die mixture was heated at 80-85°C for 0.5 h. Water was added, d e mixture was extracted three times with dichloromethane, was dried (magnesium sulfate)-and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3- cyclcpentyloxy-4-methoxyphenyl)-4-(4-i yridylethynyl)-l,l- (ethylenedioxy)cyclohexane as a pale yeUow oil (0.11 g, 93%). iH-NMR (400 MHz, 0X33) δ 8.56 (d, J=5.3 Hz, 2H), 7.33 (d, J=5.3 Hz, 2H), 7.16 (d, J=2.2 Hz, IH), 7.09 (dd, J=8.5, 22 Hz, IH), 6.85 (d, J=8.5 Hz, IH), 4.80 (m, IH), 4.00 (m, 4H), 3.85 (s, 3H), 2.0 - 2.2 (m, 6 H), 1.8 - 2.0 (m, 8H), 1.59 (m, 2H). 15b) 4-(3--cyclopentylαxy--4-mcdroxyphen^ A mixture of 4-(3 yclopentyloxy- -memoxyphαιyl)-4-(4-pyridyledιynyl)-l,l- (edιylenedioxy)cyclohexane (0.10 g, 0.24 mmol) and pyridinium p-toluenesulfonate (0.06g, 0.24 mmol) in acetone (4mL) and water (1 mL) was refluxed for 20 h., then was evaporated. Water was added, d e mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3- (^clcφentyloxy^memoxyphenylH-(4-pyridyletiιynyl)cyclohexan-l-< e (0.08 g, 91%) as a white soUd, mp 148-149°C. Anal. (C25H27NO3 O.5 H2O) calcd: C, 75.29; H, 7.08; N, 3.51; found: C, 75.51; H, 6.95; N, 3.42. Example 16 4-(3-Cvclopentvloxv-4-methoxvphenyl')-4-f3-pyridylethvnyl yclohexan-l-one To a solution of 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-ethynylcyclohexan- 1-one (0.22 g, 0.70 mmol) and 3-bromopyridine (0.70 mL, 7.0 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)pa11adium(0) (0.034 g, 4%), copper(I) iodide (0.009 g, 6%) and a small crystal of triphenylphosphine, and die mixture was heated at 80-85°C for 0.5 h. Ammonium chloride was added, d e mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ediyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-l-one as an off-white soUd (0.22 g, 80%). The product was further triturated from edier-hexanes, mp 88-89°C. Anal. (C25H27NO3-0.375 H2O) calcd: C, 75.78; H, 7.03; N, 3.53; found: C, 75.77; H, 6.89; N, 3.40. Example 17 4-(2-Carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4- πrethoxyphenvltevclohexan- 1 -one 17a) 2-bromo-5-carboxymethyldιiophene 2-Bromo-5-carboxymethylthiophene was prepared by standard chemistry weU known to those versed in the art and was a white solid, mp 59-60°C. 17b) 4-(2-caιbomethoxydιien-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one To a solution of 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-ethynylcyclohexan- 1-one (0.21 g, 0.7 mmol) and 2-bromo-5-carboxymethylthiophene (0.18 g, 1.2 mmol) in triethylamine (2 mL) under an argon atmosphere were added tetra_άs(triphenyl- phosphine)palladium(O) (0.031 g, 4%), and coppeπT iodide (0.008 g, 6%), and the mixture was heated at 80-85°C for 4.5 h. Ammonium chloride was added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate)-and was evaporated. Purification by flash chromatography, eluting with 2:8 etiiyl acetate:hexanes, provided 4-(2-carbomethoxydιien-5-ylethynyl)-4-(3- cyclσpentyloxy-4-meώoxyphenyl)cyclohexan-l-one as a yeUow oU (0.25 g, 82%). *H-NMR (400 MHz, CDθ3) δ 7.67 (d, J=4.0 Hz, 1 H), 7.16 (d, J=4.0 Hz, 1 H), 7.15 (d, J=2.2 Hz, 1 H), 7.07 ( dd, J=8.4, 2.2 Hz, IH), 6.87 (d, J=8.4 Hz, 1 H), 4.80 (m, 1 H), 3.89 (s, 3 H), 3.85 (s, 3 H), 2.95 (dt J=14.5, 5.9 Hz, 2 H), 2.49 (br d, J=14.5 Hz, 2 H), 2.36 (m, 2 H), 2.26 ( dt, J=13.4, 4.0 Hz, 2 H), 1.8 - 2.0 (m, 6 H), 1.6 (m, 2H) ppm. Anal. (C26-H28O5S-0.25 H2O) calcd: C, 68.32; H, 6.28; found: C, 68.25 H, 6.12. Example 18 4-(2-Caτboxvthien-5- vlethvnvtt- (3-cvclopen oxv-4-methox vphenvncvclohexan- 1 - one, sodium salt A solution of 4-(2-carbomethoxydιien-5-yledιynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one (0.13 g, 0.30 mmol) and coarsely ground potassium hydroxide (0.025 g, 0.45 mmol) in tetrahydrofuran (5mL), methanol (5mL), and water (2mL) was stirred at room temperature under an argon atmosphere for 24 h. The reaction was acidified (10% HO), was extracted three times with 5:95 methano dichloromethane, was dried (magnesium sulfate) and was evaporated. The crude product was treated widi 10% sodium hydroxide to form die salt. Reverse phase chromatography, eluting with 1:1 methanol: water, provided 4-(2-carboxythien- 5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one, sodium salt as a white soUd (0.070 g, 55%), mp 194-195°C. Anal. (C25H25θ5SNa*1.25 H2O) calcd: C, 62.16; H, 5.74; found: C, 61.90; H, 5.49. Example 19 4-(2-Cyanodιien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -one 19a) 2-bromo-5-cyanothiophene 2-Bromo-5-cyanodιiophene was prepared by standard chemistry weU known to those versed in the art and was a colorless oil, -Η-NMR (400 MHz, CDθ3): δ 7.40 (d, J=4 Hz, 1 H), 7.10 (d, J=4 Hz, IH) ppm. 19b) 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-medιoxyphenyl)cyclohexan- 1-one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cdιynyl-cyclohexan- 1-one (0.22 g, 0.7 mmol) and 2-bromo-5-cyanodιiophene (0.13 g, 0.7 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl- phosphine)palladium(0) (0.034 g, 4%) and copper(I) iodide (0.007 g, 6%), and the mixture was heated at 85-90°C for 2 h. Ammonium chloride was added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate÷hexanes, provided 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclσpentyloxy-4- methoxyphenyl)cyclohexan-l-one (0.06 g, 18%). This was combined with product (0.017g) obtained in a second, similar reaction and was triturated from dichloromethane-hexanes to provide a white solid, mp 106-107°C. AnaL (C25H25NO3S 0.5 H2O) calcd: C, 70.07; H, 6.11; N, 3.27; found: C, 70.15; H, 5.84; N, 3.32. Example 20 4-(3-C\clcφentvloxv-4-meΦoxvphenviy4-r5-(5^ vlethvnvllcvclohexan- 1 -one 20a) 2-bromo-5-{5-methyl-[ 1 ,2,4]oxadiazol-2-yl)thiophene 2-Bromo-5-{5-methyl-[ 1 ,2,4]oxadiazol-2-yl)thiophene was prepared by standard chemistry weU known to those versed in d e an and was a white soUd, mp 48- 49°C. 20b) 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4- [5-(5-methyl-[ 1 ,2,4]oxadiazol-2- yl)thien-2-ylethynyl]cyclohexan- 1 -one To a solution of 4-(3-cyclopαιtyloxy-4-methoxyphenyl)-4-cdιynyl-cyclohexan- 1-one (0.17 g, 0.88 mmol) and 2-bromo-5-{5-metiιyl-[l-2,4]oxadiazol-2-yl)dιiophene (0.18 g, 12 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetra is(triphenylphosphine)palladium(0) (0.037 g, 4%) and copper(I) iodide (0.010 g, 6%), and d e mixture was heated at 85-90°C for 2 h. Ammonium chloride was added and die mixture was extracted three times wid dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4- memoxyph«ιylH-[5-(5-methyl-[l^,4]ox_ ia_»l-2-yl)thien-2-yle_hynyl]cyclohexan-l- one as a white wax (0.17 g, 45%), mp 94-95°C. Anal. (C27H28N2O4S) calcd: C, 68.04; H, 5.92; N, 5.88; found: C, 67.83; H, 5.89; N, 5.92. Example 21 4-(2-C^τtx>medιoxythien-4-yledιynvn-4-G-cvclopentvloxv-4-me oxvphenvlV:vclo- hexan-1-one 21a) 4-bromo-2-carboxymethyldιiophene 4-Bromo-2-carboxymethyldιiophene was prepared by standard chemistry well known to tiiose versed in the an and was a brown oU. *H-NMR (400 MHz, CDθ3) δ 7.69 (d, J=1.5 Hz, 1 H), 7.45 (d, J=1.5 Hz, 1 H), 3.90 (s, 3 H) ppm. 21b) 4-(2-< * arbomemoxythien- -yledιynyl)-4-(3-<^l φentyloxy--4- methoxyphenyl)cyclo-hexan-l-one. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-edιynylcyclohexan- 1-one (0.25 g, 0.8 mmol) and 4-bromo-2-carboxymethyldιiophene (027 g, 1.2 mmol) in triethylamine (3.5 mL) under an argon atmosphere were added tetra]ds(triphenylphosphine)palladium(0) (0.038 g, 4%) and copper(I) iodide (0.010 g, 6%), and die mixture was heated at 80-85°C for 0.5 h. Ammonium chloride was added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(2-carbomethoxythien-4-ylethynyl)- 4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one as a yeUow glass (0.15 g, 42%). J H-NMR (400 MHz, CDθ3) δ 7.81 (d, J=1.3 Hz, 1 H), 7.60 (d, J=1.3 Hz, 1 H), 7.16 (d, J=2.2 Hz, IH), 7.10 (dd, J=8.5, 2.2 Hz, 1 H), 6.86 (d, J=8.5 Hz, 1 H), 4.80 (m, 1 H), 3.90 (s, 3 H), 3.84 (s, 3 H), 2.98 (dt, J=14.8, 5.7 Hz, 2 H), 2.48 (br d, J=14.8 Hz, 2 H), 3.33 (m, 2 H), 2.26 (dt, J=13.6, 4 Hz, 2 H), 1.9 - 2.0 (m, 6 H), 1.6 (m, 2 H) ppm. Anal. (C26H28O5S) calcd: C, 69.00; H, 6.24; found: C, 68.82; H, 6.04. Example 22 4-f 2-Carboxvthien-4- vlethvnvn-4-f 3-cvclopentvloxv-4-methoxvphenvncvclohexan- 1 - one A solution of 4-(2-caιbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one (0.19 g, 0.43 mmol) and coarsely ground potassium hydroxide (0.036 g, 0.64 mmol) in tetrahydrofuran (2mL), methanol (2mL), and water (0.4mL) was stirred at room temperature under an argon atmosphere for 24 h. The reaction was acidified (10% HO), was extracted three times with 5:95 methanohdichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.1: 3:97 acetic acid:medιanol:dichloromethane, provided 4-(2-carboxythien-4-ylediynyl)-4-(3- cycloperityloxy-4-methoxyphenyl)cyclohexan-l-one as an off-white soUd (0.18 g, 95%), mp 80-82OC. Anal. (C25H26O5S O.25 H2O) calcd: C, 67.78; H, 6.03; found: C, 67.72; H, 6.02. Example 23 4-Q-Cvanothien-4-yletfιvnylV4-( 3-cvclopentyloxy* -methoxvphenvttcvclohexan- 1 -one 23a) 4-bromo-2-cyanothiophene 4-Bromo-2-cyanothiophene was prepared by standard chemistry weU known to those versed in the an and was a pinkish soUd, mp 43-44°C. 23b) 4-(2*«^anotMen-4-yleώynyl)-4-(3-cyclc^^ 1-one. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-€thynylcyclohexan- 1-one (0.25 g, 0.8 mmol) and 4-bromo-2-cyanothiophene (0.15 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl- phosphine)palladium(O) (0.038 g, 4%) and coppertj) iodide (0.008 g, 6%), and the mixture was heated at 85-90°C for 24 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 etiiyl acetate:hexanes, provided 4-(2-cyanodιien-4-yledιynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one, which was further triturated from dichloromethane- hexanes as a white solid (0.08 g, 24%), mp 112-113 0 C. AnaL (C25H25NO3S-0.375 H2O) calcd: C, 70.44; H, 6.09; N, 3.29; found: C, 70.38; H, 5.94; N, 320. Example 24 4-(3-( clopen oxv-4-n^thoxvphenvlV4-r2-f5-methv1-ri .2.41oxar * 1ia7θ1-2-v thien-4- vlethvnyll cyclohexan-1-one 24a) 4-bromo-2-f 5-methyl-[ 1 ,2,4]oxadiazol-2-yl)thiσphene 4-Bromo-2-{5-methyl-[12,4]oxadiazol-2-yl)thiophene was prepared by standard chemistry weU known to those versed in d e an and is a white soUd, mp 66- 67 θ C. 24b) ci5-[4-(3-cycl<φentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[ l,2,4]oxadiazol-2- yl)thien-4-ylethynyl]cyclohexan- l-ol] To a solution of trfl/u-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-edιynyl- cyclohexan-1-ol] (0.25 g, 0.8 mmol, prepared as described in a co-pending appUcation identified as P50287 and filed on even day herewith) and 4-bromo-2-{5-medιyl- [l,2,4]oxadiazol-2-yl)tiιiophene (020 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)paUadium(0) (0.038 g, 4%), copper(I) iodide (0.009 g, 6%), and a small crystal of triphenylphosphine, and die mixture was heated at 70-75°C for 0.5 h. Hydrochloric acid (5%) was added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, provided ci$-[4-(3-cyclopentyloxy-4-meΛoxyphenyl)-4-[2-(5- medιyl-[12,4]oxadiazol-2-yl)thien-4-yledιynyl] cyclohexan-1-ol] (0.20 g, 53%), which was further triturated from dichloromethane-hexanes to give a white solid, mp 142- 143°C. Anal. (C27H30N2O4S) calcd: C, 67.76; H, 6.32; N, 5.85; found: C, 67.85; H, 6.42; N, 5.54. 24c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[ 1 ,2,4]oxadiazol-2- yl)dιien-4-yledιynyl]cyclohexan- 1 -one To a suspension of pyridinium chlσrochromate (0.04 g, 0.20 mmol) in dichloromethane (1 mL) at room temperature under an argon atmosphere was rapidly added a solution of cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl- [12,4]oxadiazol-2-yl)dτden-4-yledιynyl]cyclohexan-l-ol] (0.06 g, 0.13 mmol) in dichloromethane (2 mL) and die mixture was stirred for 1 h. Ether (20 mL) was added and stirring was continued for 0.25 h. The mixture was filtered through CeUte® and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-medrøxyphenyl)-4-[2-(5-medιyl- [l-2,4]oxadiazol-2-yl)thien-4-ylethynyl] cyclohexan-1-one as a colorless oil. Recrystallization from dichlorometiiane-hexanes provided a white soUd (0.033 g, 53%), mp 94-95°C. Anal. (C27H28N2O4S I.O H2O) calcd: C, 65.57; H, 6.11; N, 5.66; found: C, 65.46; H, 5.74; N, 5.60. Example 25 4-f4-Carbomethoxvthien-2ylethynyn-4-f3-cvclopentyloxy-4- methoxyphenvltevclohexan- 1 -one 25a) 2-bromo- -carboxymethylthiσphene 2-Bromo-4-carboxymethylthiophene was prepared by standard chemistry weU known to those versed in the an and is a brown oil. -Η-NMR (400 MHz, CDCI3) δ 7.99 (s, IH), 7.47 (s, 1 H), 3.86 (s, 3H) ppm.. 25b) 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan- 1-one (0.35 g, 1.12 mmol) and 2-bromo-4-carboxymethyltiιiophene (0.25 g, 1.13 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)paUadium(0) (0.044 g, 4%), copper(I) iodide (0.011 g, 6%), and a small crystal of triphenylphosphine, and die mixture was heated at 80-85°C for 0.5 h. Water and hydrochloric acid (10%) were added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated- Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(4-carbomethoxydιien-2-ylethynyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)cyclohexan-l-one as a yeUow gum (0.29 g, 58%). *H-NMR (400 MHz, CDθ3) δ 8.00 (d, J=l.l Hz, 1 H), 7.61 (d, J=l.l Hz, 1 H), 7.16 (d, J=2.2 Hz, 1 H), 7.07 (dd, J=8.4, 2.2 Hz, 1 H), 6.87 (d, J=8.4 Hz, 1 H), 4.81 (m, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 2.97 (dt, J=14.4, 5.7 Hz, 2 H), 2.49 (br d, J=13.5 Hz, 2 H), 2.35 (m, 2 H), 2.29 (m, 2 H), 1.9 - 2.0 (m, 6 H), 1.6 (m, 2 H) ppm. Anal. (C26H28O5S) calcd: C, 69.00; H, 6.24; found: C, 68.76; H, 6.46. Example 26 4-(4-Cartx)xytMen-2-ylethynyl -(3-cyclopentyloxy- -me oxypheny 1 - one A solution of 4-(4-ca_boniethoxythien-2-ylediynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one (0.12 g, 0.427 mmol) and coarsely ground potassium hydroxide (0.045 g, 0.81 mmol) in tetrahydrofuran (2.5mL), methanol (2.5mL), and water (0.5mL) was stirred at room temperature under an argon atmosphere for three days. The reaction was acidified (10% HO), was extracted three times with 5:95 metiianokdichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 025:2.5:97.5 acetic acid * methanol:dichloromethane, provided 4-(4-carboxythien-2-ylethynyl)-4-(3- cyclcpentyloxy-4-methoxyphenyl)cyclohexan-l-one as an off- white foam (0.11 g, 94%), mp 75-76°C. AnaL (C25H26O5S-0.2 H2O) calcd: C 67.78; H, 6.03; found: C, 67.73; H, 5.80. Example 27 4>(3-cvclopentvloxv-4-medιoxvphenvn-4-r4-f5-me vl-ri .2.41oxadia7θl-2-vnthien-2- yletfιyηyllcyclQhexa ι-1-pne 27a) 2-bromo-4-£5-methyl-[12,4]oxadiazol-2-yl)dιiophene 2-Bromo-4-{5-methyl-[12 t 4]oxadiazol-2-yl)thiophene was prepared by standard chemistry well known to those versed in die an and was a white soUd, mp 72- 73°C. 27b) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[12 » 4]oxadiazol-2- yl)thien-2-ylethynyl] cyclohexan-1-ol] To a solution of wu-[4-(3-cyclopentyloxy-4-medioxyphenyl)-4-ediynyl- cyclohexan-1-ol (0.25 g, 0.8 mmol; prepared as described in a co-pending appUcation filed by die same inventors, identified as P50287 and filed on even day herewith) and 2-bromo-4-{5-medιyl-[12,4]oxadiazol-2-yl)dιiophene (0.20 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetτakis(triphenylphosphine)palladium(0) (0.038 g, 4%), copper(I) iodide (0.009 g, 6%), and a small crystal of triphenylphosphine, and the mixture was heated at 70-75°C for 0.5 h. Hydrochloric acid (5%) was added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting widi 1:1 etiiyl acetate:hexanes provided cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[12,4]oxadiazol-2- yl)thien-2-yledιynyl] cyclohexan-1-ol], which was further triturated from dichloromethane-hexanes to give a white soUd (0.20 g, 53%), mp 142-143°C. Anal. (C27H30N2O4S • 0.75 H2O) calcd: C, 65.90; H, 6.45; N, 5.69; found: C, 66.06; H, 6.42; N, 5.50. 27c) 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-[4-(5-medιyl-[ 12,4]oxadiazol-2- yl)thien-2-ylethynyl]cyclohexan-l-one. To a suspension of pyridinium chlσrochromate (0.07 g, 0.31 mmol) in dichloromethane (1 mL) at room temperature under an argon atmosphere was rapidly added a solution of ci-f-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-medιyl- [12,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-l-ol] (0.10 g, 021 mmol) in dichloromediane (2 mL) and stirred 0.5 h. Ether (20 mL) was added and stirring continued for 0.5 h. The mixture was filtered through CeUte® and was evaporated- Purification by flash chromatography, eluting with 25:75 ethyl acetatcdiexanes, provided 4-(3-<τclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[12,4]oxadiazol-2- yl)thien-2-ylethynyl]cyclohexan-l-one as a white solid, mp 90-91°C. Anal. (C27H28 2O4S 025 H2O) calcd: C, 67.41; H, 5.97; N, 5.82; found: C, 67.43; H, 5.87; N, 5.80. Example 28 4-G-( clopen oxy-4-meΦoxyphenviy4-f2-me^ cyclohexan- 1 -one 28a) 4-iodo-2-thiomethylpyrimidine 4-Iodo-2-dιiomedιylpyrimidine was prepared following a literature procedure (AJ. Majeed, 0. Antonsen, T. Benneche, K. Undheim. Tetrahedron 1989, 45, 993- 1006). 28b) 4-(3-cyclopentyloxy-4-me oxyphenyl)-4-(2-memylthiopyrimidin-4-ylethynyl) cyclohexan- 1 -one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan- 1-one (0.35 g, 1.12 mmol) and and 4-iodo-2-thiomethylpyrimidine(0.56 g, 2.4 mmol, as a mixture of 4-iodo-2-diiomediylpyrimidine and 4-chloro-2-thiomethylpyrimidine) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl- phosphine)palladium(0) (0.051 g, 4%) and copper(I) iodide (0.014 g, 6%), and die mixture was heated at 85-90°C for 0.5 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- me ylthiopyrimidin-4-ylethynyl) cyclohexan- 1 -one as a yeUow resin (0.35 g, 72%). - • H-NMR (400 MHz, CDCI3) δ 8.50 (d, J=5.3 Hz, 1 H), 7.17 (d, J=2.3 Hz, 1 H), 7.08 (dd, J=8.5, 2.3 Hz, 1 H), 7.03 (d, J=5.3 Hz, 1 H), 6.87 (d, J=8.5 Hz, 1 H), 4.81 (m, 1 H), 3.86 (s, 3 H), 2.99 (dt, J=14.7, 8.7 Hz, 2 H), 2.58 (s, 3 H), 2.46 (br d, J= 18.7 Hz, 2 H), 2.40 (m, 2 H), 229 (m, 2 H), 1.8 - 2.0 (m, 6 H), 1.6 (m, 2 H) ppm. 28c) 4-(3-^clcφOTtyloxy- -memoxyphenyl)-4-(2-medιylsulfonylpyrimidin-4- ylethynyl)cyclohexan- 1 -one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- me ylthiopyrimidin-4-ylethynyl)cyclohexan-l-one (0.35 g, 0.81 mmol) in chloroform (5mL) at -10°C under an argon atmosphere was dropwise added over 20 min a solution of 3-chloroperoxybenzoic acid (0.31 g, 1.78 mmol) in chloroform. The reaction was stirred for lh at -10°C, tiien for 1 h at room temperature, then was treated widi 5% sodium carbonate, was extracted three times with dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 1:99 methanoLdichlαromethane, provided 4-(3- (^clopentyloxy-4-methoxyphenyl)-4-(2-nxthylsuUonylpyrimidin-4- ylethynyl)cyclohexan-l-one as a white foam (0.27 g, 72%), mp 60-64°C. A second batch was provided by oxidation of die sulfoxide as a white foam, mp 71 -73°C. Anal. (C25H28N2O5S 0.25 H2O) calcd: C, 63.47; H, 6.07; N, 5.92; found: C, 63.43; H, 6.07; N, 5.58. Example 29 1-one Into a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- methylsulfonylpyriπύdin-4-ylethynyl)cyclohexan-l-ore (0.26 g, 0.56 mmol) in medianol (4mL) at -78°C was condensed Uquid ammonia (4 mL), die pressure tube was sealed and die reaction was stirred at room temperature for 2.5 h. After cooling, die solvents were evaporated. Purification required two flash chromatographies, eluting first with 2:98 methanokdichloromethane and secondly widi 4:6 ethyl acetate±exanes, to provide 4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one as a white soUd (0.18 g, 73%), mp 68-70°C. AnaL (C24H27N3O3 O.2 H2O) calcd: C, 70.46; H, 6.75; N, 10.27; found: C, 70.73; H, 6.79; N, 9.87. Example 30 4-f 3-cvclopentyloxy- -methoxvphenvlV4-f 1 -methvlimidazol-2- vleth vnvDcvclohexan- 1 - one 30a) l-medιyl-2-iodoimidazole l-Methyl-2-iodoimidazole was prepared by standard chemistry weU known to those versed in the an and was a white soUd, mp 58-59°C. 30b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-( 1 -methylimidazol-2-ylethynyl) cyclohexan- 1-one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan- 1-one (0.50 g, 1.6 mmol) and l-medιyl-2-iodoimidazole (0.35 g, 1.6 mmol) in triethylamine (50 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)paUadium(0) (0.074 g, 4%), copper(I) iodide (0.018 g, 6%), and a small crystal of triphenylphosphine, and the mixture was heated at 80-85°C for 1 h. Water was added and the mixture was extracted three times widi dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 ediyl acetate:hexanes, provided impure 4-(4- ca*rbomethoxythien-2-yleώynyl)-4-(3-*cyclopentylo^ one (0.16 g, 26%), which was combined with product from a second reaction (0.16 g, 43%) and purified by flash chromatography, eluting with 1:99 methanoLdichloromethane, foUowed by recrystallization from dichloromethane- hexanes, to provide pure 4-(3*^clopentyloxy-4-meώoxyphenyl)-4-(l-medιylimidazol- 2-ylethynyl)cyclohexan-l-one (0.12 g) as an off-white solid, mp 137-138°C. AnaL (C24H28N2O3-0.2 H2O) calcd: C, 72.77; H, 7.23; N, 7.07; found: C, 72.82; H, 7.99; N, 6.97. Example 31 4- ( 3-cvclopentvloxv-4-medιoxyphenylV*4-rimiHa y n1-2-ylethvnyl\rw:lohexan- 1 -one. hydrochloride salt 31a) l-t -butylcarbonyl-2-iodoimidazole l-tert-Butylcarbonyl-2-iodoimidazole was prepared by standard chemistry weU known to those versed in the an and was a white solid, mp 77-78°C. 31b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(l -r -butylcarboxyimidazol-2- ylethynyl) cyclohexan- 1 -one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan- 1-one (028g, 0.9 mmol) and l-tert.-butylcarbonyl-2-iodoimidazole (0.29 g, 0.97 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)paUadium(0) (0.042 g, 4%), copper(I)iodide (0.005g, 6%), and a small crystal of triphenylphosphine, and d e mixture was heated at 80-85°C for 1 h. Water was added and d e mixture was extracted three times with dichloromed ane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes provided 4-(3- cyclopentyloxy-4-methoxyphenyl)-4-( 1 -t -butylcarbonylimidazol-2- ylethynyl)cyclohexan-l-one (0.18 g, 4%), as a colorless oil. *H-NMR (400 MHz, CDCI3) δ 7.36 (s, 1 H), 7.20 (d, J=2.1 Hz, 1 H), 7.17 (dd, J=8.5, 2.1 Hz, 1 H), 7.01 (s, 1 H), 6.85 (d, J=8.5 Hz, 1 H), 4.85 (m, 1 H), 3.84 (s, 3 H), 3.18 (m, 2 H), 2.44 (m, 4 H), 2.22 (m, 2 H), 1.8 - 2.0 (m, 6 H), 1.6 (m, 11 H) ppm. 31c) 4-(3-cyclop«ιtyloxy-4-memoxyphenyl)-4-(imidazol-2-ylethynyl)cyclohexan- 1- one, hydrochloride salt A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(l -terr- butylcarbonyUmidazol-2-ylethynyl)cyclohexan-l-one (0.18 g, 0.37 mmol) and hydrogen chloride-saturated etiiyl acetate (40 drops) in etiiyl acetate (10 mL) was stirred under an argon atmosphere at room temperature for 24 h. The suspension was cooled to 0°C and filtered to provide 4-(3-cyclopentyloxy-4-methoxyphenyl)-4- (imidazol-2-ylethynyl)-cyclohexan- 1 -one, hydrochloride salt (0.12 g, 76%) as a white soUd, mp 183-184°C. Anal. (C23H26 2O3ΗOO.25 H2O) calcd: C, 65.70; H, 6.83; N, 6.66; found: C, 65.46; H, 6.65; N, 6.44. Example 32 Preparation of 4-f3-cvclopentvloxv-4-methoxvphenylV4-f2-r4-f2-hvdroxyethan-l- pχ y ) phenylletfιyny.)cyctohexan-l-<?ne 32a) 4-(2-hydroxyethoxy)phenyl iodide A melt of ethylene carbonate (6.5 g, 74 mmol) in a smaU flask under Argon was treated with 4-iodophenol (0.400 g, 1.82 mmol) and powdered potassium carbonate (1.26 g, 9.1mmol) and was stirred at 90°C for 3 hr. The mixture was treated widi cold dilute hydrochloric acid to decompose die excess potassium carbonate and excess aqueous sodium hydroxide solution was slowly added and d e mixture was stirred over night The suspension was extracted widi methylene chloride, was washed with water and brine, was dried over sodium sulfate and was stripped to afford a white soUd, which was purified by flash chromatography on siUca gel (20 mL) with methylene chloride to afford (0.128 g, 27%) of die titled intermediate as a white solid, mp 76-77.5°C. 32b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyedιan- 1 - oxy)phenyl]ethynyl)- 1 , 1 -(ethylenedioxy)cyclohexane A solution of 4-(2-hydroxyethoxy)phenyl iodide (0.059 g, 0.22 mmol), and 4- (3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(ethylenedioxy )-4-ethynylcyclohexane (0.080 g, 0.22 mmol) in dry piperidine (1 mL) was treated widi a mixture of tetrakis(_riphenylphosphine)palladium (0.013 g, 0.011 mmol), cuprous iodide (0.0025 g, 0.013 mmol), and triphenylphosphine (crystal), as described above in Example 11. Purification of d e crude product by chromatography (sUica gel, 1 to 2% methanol in methylene chloride) foUowed by pumping in vacua afforded d e tided intermediate as a viscous oU. -NMR (400 MHz, CD03) δ 7.39 (d, J=9.0 Hz, 2H), 724 (d, J=2.1 Hz, IH), 7.13 (d-d, J=8.3 Hz, J=2.1 Hz, IH), 6.85 (d, J=8.7, 2H), 6.84 (d, J=8.3 Hz, IH), 4.81 (p, J=2.0 Hz, IH), 4.09 (t, J=4.4 Hz, 2 H), 4.00 (s, 4H), 3.97 (t, J=4.4Hz, 2H), 3.84 (s, 3H), 2.3 to 1.5 (m, 21H with H2O). 32c) 4-(3-cycl >entyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyedιan- 1 - oxy)phenyl]ethynyl)cyclohexan-l-one A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyedιan- l-oxy)phenyl]ethynyl)-l,l-(ethylenedioxy)cyclohexane (0.090 g, 0.18 mmol) in tetrahydrofuran (8 mL) was treated widi 3N hydrochloric acid (0.9 mL) as in Example 12. Purification by chromatography (siUca gel, 40 to 50% ethyl acetate in hexanes) foUowed by drying in vacua at 60° C afforded die tided compound as a glass. Anal. (C28H3205-1/4 H2O) calcd: C 74.23, H 7.23, found: C 74.31, H 7.24. -NMR (400 MHz, CD03) δ 7.41 (d, J=8.9 Hz, 2H), 723 (d, J=2.3 Hz, IH), 7.13 (d-d, J=8.5 Hz, J=2.3 Hz, IH), 6.89 (d, J=8.7, 2H), 6.86 (d, J=8.3 Hz, IH), 4.80 (p, IH), 4.11 (t, J=4.5 Hz, 2 H), 3.98 (t J=4.4Hz, 2H), 3.85 (s, 3H), 3.04 (d-t, J=14.1 Hz, J=6.1Hz, 2H), 2.47 (d,br, J=13.0, 2H), 2.4 to 1.5 (m, 19H with H2O). Example 33 Preparation of 4-f4-caτbomethoxvphenylethvnylV4-f 3-cyclopentyloxy-4- methoxvphenvl)cvclohexan-l-one 33a) 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)- 1,1- (ethylenedioxy)cyclohexane A stirred mixture of 4-(4-cyclc*pentyloxy-4-methoxyphenyl l,l- (etiιylenedioxy -ethynylcyclohexane (0.200 g, 0.56 mmol) and methyl 4- iodobenzoate (0.147 g, 0.56 mmol) in triethylamine (2.5 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.032 g, 0.028 mmol), cuprous iodide (0.0064 g, 0.034 mmol), and triphenylphosphine (crystal) by the procedure of Example Id. The reaction mixture was extracted and chromatographed as described in Example Id and stripped in vacua to afford a light yeUow oil (0.25 g, 91%). -tø-NMR (400 MHaZ, CDθ3) δ 7.98 (d, 9.4 Hz, 2H), 7.50 (d, J=9.4 Hz, 2H), 720 (d, J=1.9 Hz, IH), 7.12 (d-d, J=1.9 Hz, J=8.6 Hz, IH), 6.84 (d, J=8.6, IH), 4.80 (p, J=3.8 Hz, IH), 4.00 (s, br, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (m, 17H with H2O). 33b) 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane A stirred solution of 4-(4-carbomeώoxyphenylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-l,l-(ethylenedioxy)cyclohexane (0.150 g, 0.12 mmol) in tetrahydrofuran (7 mL) was treated widi 3N hydrochloric acid (0.70 mL) as described in Example 14 above. The crude product was purified by chromatography (silica, 20% ethyl acetate/hexanes) and die solvent removed in vacua to afford d e tided compound as a resin (0.063 g, 46%). Anal. (C28H30O5 I/IO H2O) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87. -NMR (400 MHz, CDCI3) δ 8.01 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.20 (d, J=2.4 Hz, IH), 7.11 (d-d, J=8.5 Hz, J=2.4 Hz, IH), 6.87 (d, J=8.5, IH), 4.80 (p, IH), 3.93 (s, 3 H), 3.86 (s, 3H), 3.04 (d-t, J=62 Hz, J=14.4, 2H), 2.50 (d,br, J=14.9, 2H), 2.42-2.32 (m, 2H), 2.26 (d-t J=2.8 Hz, J=14.4 Hz, 2H), 2.00-1.5 (m, 1 IH with H2O). Example 34 Preparation of 4-(4-carboxvphenvlethvnvlV -(3-cvclopentvloxv-4- methoxvphen vltevclohexan- 1 -one A stirred solution of 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane (0.146 g, 0.326 mmol) in dry methanol (5 mL) was treated widi 10% aqueous sodium hydroxide solution (0.46 mL, 1.15 mmol) under an argon atmosphere as described in Example 13. The crude acid was purified by chromatography (silica, ethyl acetate/methylene chloride/formic acid; 10:90: 1), the product fractions washed widi water three times, was stripped in vacua , was crystaUzed with ether and was dried in vacua to afford the tided compound as a white soUd (0.077 g, 55%), mp 170-171 O C. Anal. (C27H28O5) calcd: C 74.98, H 6.53 found: C 74.78, H 6.54. Example 35 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvlM-f 2-r4-O - riiperidinocaτbonvlmethoxv)phenvl1ethvnvl^cvclohexan- 1 -one 35a) 4-iodophenoxyacetic acid mediyl ester A stirred mixture of 4-iodophenol (0.50 g, 227 mmol), methyl 2-bromoacetate (0.382 g, 2.50 mmol), and powdered potassium carbonate (0.314 g, 227 mmol) in dry acetone under argon was sealed and heated at 70°C for 4 hr. The cooled mixture was filtered, and die filtrate was evaporated in vacua. The residue was purified by chromatography (siUca, 40 to 50% methylene chloride in cyclohexane) and d e solvent was removed in vacua to afford the tided intermediate as a white solid (0.41 g, 62%), mp 69-70°C 35b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(2-[4-(l- piperidinocarbonylmethoxy)phenyl]ethynyl)cyclohexane A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l- (edιylenedioxy)-4-ethynylcyclohexane (0.150 g, 0.42 mmol) and 4-iodophenoxy acetic acid methyl ester (0.123 g, 0.42 mmol) in dry piperidine (2 mL) was treated at 80°C for 1.5 hr by the procedure of Example 11 with a mixture of tetrakis(triphenylphosphine)palladium (0.027 g, 0.023 mmol), cuprous iodide (0.0048 g, 0.025 mmol), and triphenylphosphine (crystal). The erode product was chromatographed (siUca 50 to 75% ethyl acetate in petroleum ether) and was stripped in vacua to afford die tided intermediate as a viscous yeUow oU (0232 g, 96%). *H- NMR (400 MHz, CDθ3) δ 7.38 (d, J=8.7 Hz, 2H), 724 (d, J=2.3 Hz, IH), 7.13 (d- d, J=8.4 Hz, J=2.3 Hz, IH), 6.89 (d, J=8.9, IH), 6.84 (d, J=8.4, 1H),4.81 (p, IH), 4.69 (s, 2H), 4.00 (s, 4H), 3.84 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.49 (t, J=5.5 Hz, 2H), 2.3 to 1.5 (m, 32H with H2O). 35c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-( 1 - piperidinocaιbonylmethoxy)phenyl]ethynyl)cyclohexan-l-one A stirred solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l- (ethylenedioxy -(2-[4-(l-piperidinocarbonylmethoxy)phenyl]edιynyl)cyclohexane (0232 g, 0.40 mmol) in tetrahydrofuran (9 mL) was treated widi 3N hydrochloric acid (0.90 mL) as described in Example 12 above. The crude product was purified by chromatography (siUca, 50% ethyl acetate/hexanes) and die solvent removed in vacua to afford the tided compound as a resin (0.127 g, 59%). Anal. (C28H30 5 I/IO H2O) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87. - H-NMR (400 MHz, CDθ3) δ 7.41 (d, J=9.1 Hz, 2H), 7.22 (d, J=2.3 Hz, IH), 7.11 (d-d, J=8.4 Hz, J=2.3 Hz, IH), 6.92 (d, J=8.6, IH), 6.86 (d, J=8.5, 1H),4.80 (p, IH), 4.70 (s, 2H), 4.00 (s, 4H), 3.85 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.03 (d-t J=6.1 Hz, J=14.3, 2H), 2.47 (d,br, J=14.9, 2H), 2.4-2.2 (m, 4H), 2.0 to 1.5 (m, 25H with H2O). Example 36 Preparation of 4- ( 2-r4-carboxvmethvloxyphenvlledιvnylV4-f3-cvclopentyloxy-4- memoxvphenyl tavclohexan- 1 -one 19a) 4-(2-[4-Carbomethoxymethyloxyphenyl]edιynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-l,l-(edιylenedioxy)cyclohexane A stirred mixture of 4-(3-cyclopentyloxy-4-medιoxyphenyl)-l,l- (ethylenedioxyM-ediynylcyclohexane (0.075 g, 021 mmol) and 4-iodophenoxyacetic acid methyl ester (0.060 g, 021 mmol, prepared as described in Example 35a) in dry triethylamine (2 mL) was treated at 80°C for 1.5 hr by the procedure of Example 11 with a mixture of tetrakis(triphcnylphosphine)pal1adium (0.018 g, 0.016 mmol), cuprous iodide (0.004 g, 0.021 mmol), and triphenylphosphine (crystal). The crude product was chromatographed (siUca 40 to 50% etiiyl acetate in hexanes) and stripped in vacua to afford the tided intermediate as a dark red oU (0.080 g, 73%). -H-NMR (400 MHz, CDθ3) δ 7.98 (d, 9.4 Hz, 2H), 7.50 (d, J=9.4 Hz, 2H), 7.20 (d, J=1.9 Hz, IH), 7.12 (d-d, J=1.9 Hz, J=8.6 Hz, IH), 6.84 (d, J=8.6, IH), 4.80 (p, J=3.8 Hz, IH), 4.00 (s, br, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (m, 17H with H2O). 36b) 4-(2-[4-carboxymethyloxyphenyl]edιynyl)-4-(3-cyclcpentyloxy-4- methoxyphenyl)cyclohexan- 1 -one A stirred solution of 4-(2-[4-carbomethoxymethyloxyphcnyl]ethynyl)-4-(3- cyclσpentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)cyclohexane (0.232 g, 0.40 mmol) in tetrahydrofuran (9 mL) was treated with 3N hydrochloric acid (0.90 mL) as described in Example 12 above. The crude product was purified by chromatography (siUca, 50% ethyl acetate hexanes) and die solvent removed in vacua to afford d e tided compound as a resin (0.127 g, 59%). Anal. (C28H30O5 I/IO H2O) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87. - -NMR (400 MHz, CDCI3) δ 8.01 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.20 (d, J=2.4 Hz, IH), 7.11 (d-d, J=8.5 Hz, J=2.4 Hz, IH), 6.87 (d, J=8.5, IH), 4.80 (p, IH), 3.93 (s, 3 H), 3.86 (s, 3H), 3.04 (d-t, J=6.2 Hz, J=14.4, 2H), 2.50 (d,br, J=14.9, 2H), 2.42-2.32 (m, 2H), 2.26 (d-t, J=2.8 Hz, J=14.4 Hz, 2H), 2.00-1.5 (m, 1 IH with H2O). Example 37 Preparation of 4-f 2-r4-carbomethoxymemyloxyphenvnethvnvn-4-(3-cvclopentvloxv-4- methoxyphen ylteyclohexan- 1 -one A stirred mixture of 4-(3-cyclopentyloxy-4- methoxyphenyl)-4-ethynylcyclohexan-l-one (0.075 g, 0.24 mmol) and 4- iodophenoxyacetic acid methyl ester (0.070 g, 0.24 mmol, prepared as described in Example 35a) in dry triethylamine (1.2 mL) was treated at 75°C for 1 hr widi a mixture of tetrakis(triphenylphosphine)-paUadium (0.012 g, 0.010 mmol), cuprous iodide (0.0024 g, 0.013 mmol), and triphenylphosphine (a small crystal) under argon. The reaction mixture was concentrated in vacua and d e residue treated widi cold dilute hydrochloric acid, was extracted twice with ediyl acetate and die organic phase was washed with water, brine and was dried over anhydrous sodium sulfate. The crude product was chromatographed (siUca, 25 to 30% ethyl acetate in hexanes) and was stripped in vacua to afford die tided intermediate as an amber resin (0.097 g, 85%). Anal. (C29H32O6) calcd: C 73.09, H 6.77, found: C 72.91, H 6.78. -NMR (400 MHz, CDθ3) δ 7.41 (d, J=8.9 Hz, 2H), 721 (d, J=22 Hz, IH), 7.11 (d-d, J=1.9 Hz, J=8.4 Hz, IH), 6.87 (d, J=8.9, 2H), 6.85 (d, J=8.4, IH), 4.80 (p, J=4.4 Hz, IH), 4.65 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.02 (d-t, J=62 Hz, J=142, 2H), 2.46 (d,br, J=14.8, 2H), 2.4-1.5 (m, 16H with H2O). Example 38 Preparation of 4-f 2-caτbomethoxvphenyledιynvl V4-(3-cvclσpentvloxv-4- methoxyphenyPcyctohe an-l-one A mixture of (4-cyclopentyloxy-4-methoxyphenyl)-4-cthynylcyclc*hexan-l- one (0.150 g, 0.48 mmol) and methyl 2-iodobenzoate (0.126 g, 0.48 mmol) in triethylamine (2.4 mL, dry) was treated widi a mixture of tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol), cuprous iodide (0.0048 g, 0.026 mmol), and triphenylphosphine (crystal) under an argon atmosphere and stirred at 80°C for 7 h. The reaction mixture was concentrated in vacua, and die residue treated as described in example 20, chromatographed twice (silica, 20% ethyl acetate in hexanes; and 2% ethyl acetate in methylene chloride) crystallized from etheπhexanes and dried at 60°C in vacua to afford a whjte powder (0.051 g, 24%), mp 88.5-90°C. Anal. (C28-H30O5) calcd: C 75.31, H 6.77, found: C 75.11, H 6.78. Example 39 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvn-4-f2-r3 - dicaibomethoxvphenvnethvnvlkryclohexan- 1 -one A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-l- one (0.075 g, 0.24 mmol) and dimethyl 5-iodoisophthalate (Trans World Chemicals, 0.107 g, 0.33 mmol) in triethylamine (1.9 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.012 g, 0.010 mmol), cuprous iodide (0.0025 g, 0.013 mmol), and triphenylphosphine ( a small crystal) under an argon atmosphere and was stirred at 80°C for 1 h. The reaction mixture was concentrated in vacua, and the residue was chromatogπφhed (siUca, 1 to 2% ethyl acetate in methylene chloride) and was dried at 50°C in vacua to afford a tan powder (0.100 g, 83%), mp 133.5- 135°C. Anal. (C30H33O7) calcd: C 71.41, H 6.39, found: C 71.19, H 6.41. Example 40 Preparation of 4-f2-r4-chlorophenyllethynyπ-4-(3-cyclopentyloxy-4- methoxvphenvl tevclohexan- 1 -one A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-edιynylcyclohexan-l- one (0.075 g, 0.24 mmol) and 4-chlαro-l-iodobenzene (0.057 g, 0.24 mmol) in triethylamine (1.7 mL, dry) was treated widi a mixture of tetrakis(triphenylphosphine)paUadium (0.012 g, 0.010 mmol), cuprous iodide (0.0025 g, 0.013 mmol), and triphenylphosphine ( a small crystal) under an argon atmosphere and swas tirred at 80°C for 2 h. The reaction mixture was concentrated in vacua, and die residue treated with dilute hydrochloric acid, was extracted three times with ethyl acetate and the organic phase was dried over sodium sulfate and was concentrated in vacua. The residue was chromatographed (siUca, 0.05 to 1% ethyl acetate in methylene chlαride hexanes 3:1) and die tided compound was dried at 25°C in vacua to afford a white powder (0.051 g, 50%), mp 104-105°C. Anal. (C26H27O03) calcd: C 73.83, H 6.43, found: C 73.69, H 6.41. Example 41 Preparation of 4-f 3-cvclopentvloxv-4-methoxyphenyl V4-f2-r3-f5-methyl- π 2.41oxadia7nl-3-yl^phenvllethynvl *clohexan- 1-onc 41a) 3-(3-iodophenyl)-5-medιyl-[l,2,4]oxadiazole 3-(3-Iodophenyl)-5-medιyl-[12 » 4]oxadiazole was prepared by standard chemistry weU known to those versed in the an and is a white solid, mp 90-91.5°C. 41b) 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(2-[3-(5-methyl-[12,4]oxadiazol-3- yl)phenyl]ethynyl)cyclohexan- 1 -one A stirred mixture of 4-(3-cyclσpentyloxy-4-methoxyphenyl)-4- ethynylcyclohexan-1-one (0.200 g, 0.64 mmol) and 3-(3-iodophenyl)-5-medιyl- [12,4]oxadiazole (0.201 g, 0.70 mmol) in dry triethylamine (4.6 mL) was treated widi a mixture of tetrakis(triphenylphosphine)paUadium (0.032 g, 0.028 mmol), cuprous iodide (0.0067 g, 0.035 mmol), and triphenylphosphine (a small crystal) at 75°C for 1 h 20 min under argon. The reaction mixture was concentrated in vacua and d e residue was treated widi cold dilute hydrochloric acid, was extracted twice widi methylene chloride and die organic phase was washed widi water, brine and was dried over anhydrous sodium sulfate. The crude product was chromatographed (siUca, 3 to 6% ethyl acetate in methylene chlαride/hexanes 4:1) and die pure fractions were combined, concentrated in vacua , was crystallized from ethyl ether and was dried at 60°C in vacuo to afford die tided compound as a white soUd (0.235 g, 78%), mp 122.5- 123.5°C. Anal. (C29H30N2O4) calcd: C 74.02, H 6.43, N 5.95, found: C 73.94, H 6.37, N 5.96. Example 42 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvlV4-f2-r3-f3-medιvl- π .Z.^l^a- ^^ole^- l^phenvllethvnvl^cvclohexan-l-one 42a) 5-(3-iodophenyl)-3-methyl-[ 1 ,2,4]oxadiazole 5-(3-Iodophenyl)-3-methyl-[12,4]oxadiazole was prepared by standard chemistry weU known to those versed in die an and was a white soUd, mp 102-103°C. 42b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-medιyl-[12,4]oxadiazole-5- yl)phenyl]ethy nyl)cyclohexan- 1 -one A stirred mixture of 4-(3-cyclσpentyloxy-4-methoxyphenyl)-4- ethynylcyclohexan-1-one (0200 g, 0.64 mmol) and 5-(3-iodophenyl)-3-methyl- [12,4]oxadiazole (0.201 g, 0.70 mmol) in dry triethylamine (4.6 mL) was treated under argon with a mixture of tetr__ds(triphenylphosphine)paUadium (0.032 g, 0.028 mmol), cuprous iodide (0.0067 g, 0.035 mmol), and triphenylphosphine (a small crystal) at 70°C for 1 h and at 25°C for 15 h . The reaction mixture was concentrated in vacua and a solution of d e residue was dissolved in methylene chloride, was treated wid cold dilute hydrochloric acid and was dried over anhydrous sodium sulfate. The crude product was chromatographed (silica, 5 to 10% ethyl acetate in methylene chloride hexanes 1:1) and die pure fractions were combined, concentrated in vacua , crystallized from ethyl ether and dried at 60°C in vacua to afford die tided compound as an off-white powder (0235 g, 78%), mp 88-91°C. Anal. (C29H30N2O4) calcd: C 74.02, H 6.43, N 5.95, found: C 73.77, H 6.53, N 5.78. Example 43 Preparation of 4-f 2-r3-cyanophcnylletiιynyiy4-f3-cyclopentyloxy-4- metiιoxvphenvncvclohexan-1-one A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-l- one (0.100 g, 0.32 mmol) and 3-iodobenzonitrile (0.088 g, 0.38 mmol) in triediylamine (2-5 mL, dry) was treated widi a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenylphosphine ( a small crystal) under an argon atmosphere and was stirred at 75°C for 1 h 15 min, foUowed by ambient temperature for 15 h.. The reaction mixture was concentrated in vacua, and a solution of the residue was dissolved in methylene chloride, was washed widi dilute hydrochloric acid, water, brine and was dried over sodium sulfate. The crude product was chromatographed (silica, 3% ethyl acetate in methylene chloride hexanes 4:1) and die tided compound was dried at 60°C in vacua to afford a white soUd (0.075 g, 47%), mp 123.5-125.5°C. Anal. (C27H27NO3) calcd: C 78.42, H 6.58, N 3.39, found: C 78.13, H 6.67, N 3.40. Example 44 Preparation of 4-f 3-cvclopentvloxv-4-medιoxvphenvn-4-f 2-f3.5- dicvanophen vllethvnvl clohexan- 1 -one 44a) 3,5-dicyanophenyl iodide 3,5-Dicyanophenyl iodide was prepared by standard chemistry weU known to those versed in the an and was a white soUd, mp 145.5- 146.5°C. 44b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-5-dicyanphenyl]ethynyl cyclohexan- 1-one A mixture of 4-(4-cyclopentyloxy-4-meuιoxyphenyl)-4-ethynylcyclchexan-l- one (0.150 g, 0.48 mmol) and 3,5-dicyanophenyl iodide (0.171 g, 0.67 mmol) in triethylamine (7.5 mL, dry) was treated widi a mixture of tetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol), cuprous iodide (0.005 g, 0.026 mmol), and triphenylphosphine ( a small crystal) under an argon atmosphere and was stirred at 80°C for 0.5 h and at 25°C for l5 h. The reaction mixture was concentrated in vacua, and a solution of the residue dissolved in methylene chloride was washed widi dilute hydrochloric acid, water, brine and was dried over sodium sulfate. The residue was chromatographed (siUca, 2 to 3% ethyl acetate in methylene chloride/hexanes 9:1) and was dried in vacua to afford a white powder (0.177 g, 84%), mp 147.5-148.5°C. AnaL (C28H26N2O3) calcd: C 76.69, H 5.98, N 6.39, found: C 76.41, H 5.92, N 6.39. Example 45 Preparation of 4-f3-cyclopentyloxv-4-mcthoxvphenyl 4-f2-r4- hvdroxvphenvllethynvncyclohexan- 1 -one A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-l- one (0.090 g, 0.29 mmol) and 4-iodophenol (0.076 g, 0.35 mmol) in triethylamine (3 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.013 g, 0.012 mmol), cuprous iodide (0.003 g, 0.016 mmol), and triphenylphosphine ( a small crystal) under an argon atmosphere and stirred at 75°C for 40 min. The reaction mixture was concentrated in vacua, and a solution of die residue dissolved in methylene chloride was washed wid dilute hydrochloric acid, water, brine, was dried over sodium sulfate and was concentrated in vacua. The residue was chromatographed (siUca, 4 to 7% ethyl acetate in methylene chloride hexanes 4: 1) and d e tided compound was recrystallized from medianol to afford a white powder (0.035 g, 30%), mp 144-146°C. Anal. (C26H28θ4*l/5 H2O) calcd: C 76.52, H 7.01, found: C 76.57, H 6.97. -NMR (400 MHz, CDθ3) δ 7.36 (d, 8.5 Hz, 2H), 7.23 (d, J=2.2 Hz, IH), 7.12 (d-d, J=22 Hz, J=8.5 Hz, IH), 6.86 (d, J=8.5, IH), 6.80 (d, J=8.5, 2H), 5.22 (s, IH), 4.80 (p, J=3.8 Hz, IH), 3.85 (s, 3H), 3.04 (d-t, J=6.0 Hz, J=142, 2H), 2.47 (d,br, J=14.8, 2H), 2.4-2.1 (m, 4 H), 2.0 to 1.5 (m, 12H with H2O). Example 46 Preparation of 4- -cvclopentyloxv-4-medιoxvphenvlV4-f2-r3-f5-methvl- fl .^i^lTh^^ff^-^-y^φhenyllethynyDcyclohexan-l-one 46a) 2-(3-iodophenyl)-5-medιyl-[ 1 ,3,4]dιiadiazole 2-(3-Iodophenyl)-5-metiιyl-[l,3,4]dιiadiazole was prepared by standard chemistry weU known to those versed in the an . 46b) 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(2-[3-(5-methyl-[ 1 ,3 ,4]tiιiadiazol-2- yl)phenyl]cdιynyl)cyclohexan-l-one A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4- edιynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 2-(3-iodophenyl)-5-methyl- [l,3,4]dιiadiazole (0.097 g, 0.32 mmol) in dry triethylamine (2.5 mL) was treated under argon widi a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenylphosphine (a small crystal) at 70°C for 1 h and at 25 °C for 15 h . The reaction mixture was concentrated in vacua and d e residue was partitioned between methylene chloride and cold dilute hydrochloric acid. The organic phase was chromatographed (siUca, 10 to 20% ethyl acetate in methylene chloride) and die pure fractions were combined, concentrated in vacua and dried at 50 °C in vacua and d e britde resin ground to afford die tided compound as a yeUow powder (0.128 g, 79%). Anal. (C29H30N2O3SΗ2O) calcd: C 69.02, H 6.39, N 5.55, found: C 68.91, H 6.21, N 5.35. -NMR (400 MHz, CDθ3) δ 8.06 (t, J=1.6 Hz, IH), 7.88 (d-t, J=1.4 Hz, J«=8.1 Hz, IH), 7.58 (d-d, J=12 Hz, J=9.0 Hz, IH), 7.45 (t, J=7.8 Hz), 721 (d, J=22, IH), 7.14 (d-d, J=8.4 Hz, J=2.1 Hz, IH), 6.88 (d, J=8.5, IH), 4.82 (p, J=4.1 Hz, IH), 3.86 (s, 3H), 3.04 (d-t, J=6.1 Hz, J=142, 2H), 2.84 (s, 3 H), 2.50 (d,br, J=14.9, 2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8 Hz, J=142 Hz, 2H), 2.00-1.5 (m, 12H with H2O). Example 47 Preparation of 4-(3--cyςlppentyl9 χ y-4**meth9xyphenyl)-4-(2-r3-(5-medιyi- π .3.41oxadiazol-2-vnphenvnethvnvl1cvclohexan- 1-one 47a) 2-(3-iodophenyl)-5-methyl-[ 1 ,3,4]oxadiazole 2-(3-Iodophenyl)-5-methyl-[l,3,4]oxadiazole was prepared by standard chemistry weU known to those versed in d e an and was a white soUd, mp 112.5- 113.5°C. 47b) 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(2-[3-(5-methyl-[ l,3,4]oxadiazol-2- yl)phenyl]ethynyl)cyclohexan- 1-one A stirred mixture of 4-(3-cyclσpentyloxy-4-methoxyphenyl)-4- ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 5-(3-iodophenyl)-2-medιyl- [ 1 ,3,4]oxadiazole (0.0915 g, 0.32 mmol) in dry triediylamine (3.5 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenylphosphine (a smaU crystal) at 75°C for 1 h. The reaction mixture was concentrated in vacua, die residue was extracted into methylene chloride and the organic phase was washed widi cold dilute hydrochloric add, water, brine and was dried (sodium sulfate). Purification by chromatography (siUca, 10 to 20% ethyl acetate in methylene chloride) foUowed by drying at 50 °C in vacua afforded the tided compound as a white -powder (0.068 g, 45%), mp 139-141°C. AnaL (C29H30 2O4 I/3H2O) calcd: C 73.09, H 6.49, N 5.88, found: C 73.07, H 6.35, N 5.79. -Η-NMR (400 MHz, CDθ3) 8.15 (t, J=1.6 Hz, IH), 8.01 (d-t, J=1.4 Hz, J=7.9 Hz, IH), 7.62 (d-d, J=1.5 Hz, J=7.8 Hz, IH), 7.49 (t, J=7.9 Hz), 7.21 (d, J=2.3, IH), 7.14 (d-d, J=8.5 Hz, J=2.4 Hz, IH), 6.88 (d, J=8.5, IH), 4.82 (p, J=42 Hz, IH), 3.86 (s, 3H), 3.04 (d-t, J=6.1 Hz, J=142, 2H), 2.64 (s, 3 H), 2.51 (d,br, J=15.0, 2H), 2.42-2.32 (m, 2H), 227 (d-t, J=2.8 Hz, J=14.2 Hz, 2H), 2.00-1.5 (m, 9H with H2O). Example 48 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvn-4-f 2IΕ1-f 3- cyanophenyl)ethenyl)cyctohexan-l-<?πe 48a) 3-cyanobenzylphosphonic acid diediyl ester A stirred mixture of triethyl phosphite (0-500 g, 2.95 mmol) and 3-cyanobenzyl bromide (0.609 g, 2.95 mmol) was refluxed at 140°C under argon for 2 h and die resulting volatiles were removed at room temperature in vacua to afford die tided intermediate as a colorless oil (0.62 g, 84%). -NMR (400 MHz, CDθ3) δ 7.7-7.5 (m, 3H), 7.44 (t, J=7.8 Hz, IH), 4.06 (p, J=7.6 Hz, 4H), 3.17 (d J=21.8 Hz, 2H), 127 (t, J=7.1 Hz, 6H). 48b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)- 1,1- (ethylenedioxy)cyclohexane A solution of 3-cyanobenzylphosphonic acid diediyl ester (0.54 g, 2.13 mmol) dissolved in dry tetrahydrofuran (7 mL) was added via cannulation to a solution of potassium r-butoxide (0.237 g, 2.11 mmol) dissolved in dry tetrahydrofuran (15 mL), both solutions under argon and was chiUed to 0°C. After stirring for 45 min, a solution of 4-4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(ethylenedioxy)-4- formylcyclohexane (0.38 g, 1.06 mmol) in dry tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was aUowed to warm to room temperature. After 15 h, the mixture was quenched wid aqueous ammonium chloride solution, was concentrated in vacua , was partitioned between methylene chloride/aqueous ammonium chloride solution, and the organic extract was washed wid water, brine, was dried (sodium sulfate), and was concentrated in vacua to afford a mixture containing the desired tided product and die excess phosphonate ester as a crude resin. -Ή-NMR (400 MHz, CDCI3) δ 7.62-7.4 (m, 4H), 7.36 (t J=7.8 Hz, IH), 6.90 (s and d, 2H), 6.83 (d, J=8.7 Hz, IH), 6.30 (d, J=16.4 Hz, IH), 6.16 (d, J=16.3 Hz, IH), 4.75 (p, J=4.4 Hz, IH), 4.06 (p, J=7.6 Hz, IH), 3.96 (q, J=3.3 Hz, 4H), 3.84 (s, 3 H), 3.17 (d J=21.8 Hz, 0.3H), 2.35-1.5 (m, 20H with H2O), 1.27 (t, J=7.1 Hz, 1.3H). 48c) 4-(3-cyclσpentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)- cyclohexan- 1 -one A solution of crude 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3- cyanophenyl)edιenyl)-l,l-(edιylenedioxy)cyclohexane (0.58 g, 1.06 mmol) in tetrahydrofuran (20 mL) was treated widi 3N aqueous hydrochloric acid (2.3 mL) under argon and heated at 75-80°C for 1 h. Additional hydrochloric acid (13 mL) was then added and die mixture heated at 75°C for anodier 15 min. The reaction mixture was concentrated in vacua, was extracted into methylene chloride, and d e organic extract was washed wid water, dUute sodium bicarbonate solution, brine, and was dried (sodium sulfate). Purification by chromatography (siUca, 1 to 2% ethyl acetate in mediylene chloride) and crystallization from etiiyl edier gave the tided compound as a white soUd (0.329 g, 74%). mp 116-117 0 Q AnaL (C27H29NO3 I/6H2O) calcd: C 77.48, H 7.06, N 3.35, found: C 77.63, H 6.94, N 3.33. J H-NMR (400 MHz, CIX-I3) δ 7.60 (s, IH), 7.55-7.45 (m, 2H), 7.39 (t, J=7.7 Hz, IH), 6.97 (d-d, J=2.4 Hz, J=8.5 Hz, IH), 6.89 (d, J=8.4 Hz, IH), 6.37 (d, J-16.1 Ηz, IH), 622 (d, J=16.2 Hz, IH), 4.77 (p, J=4.5 Hz, IH), 3.86 (s, 3H), 2.6-1.5 (m, 18 H with H2O). RmmplftAO Preparation of 4-f2-af^amiriopyri * n *ή t 5-yledι * ι ylV4-f3-cyclopentyloxy- - methpχyphenyl)cyctoheΛan-l-qne. SB 240712 To a stirred suspention of pyridinium chlorochromate (0.288 g, 1.34 mmol) in dry methylene chloride (4 mL) under argon was added via cannula, a solution of cis- [4-(2-acetamidcφyrimid -5-ylethynyl)-4-(3-cyclc^ntyloxy-4-metto cyclohexan- l-ol] (0.20 g, 0.445 mmol, prepared as described in a co-pending U.S. appUcation identified as P50287 (filed on even day herewith) in methylene chloride (5 mL total). After 2 h at 25 °C, ethyl acetate (ca. 10 mL) was added, die reaction filtered, and d e precipitate washed wid anodier 10 mL of ethyl acetate. The filtrate was concentrated and die residue purified by flash chromatography on siUca gel with 1:9 etiiyl acetate:dichloromethane, eluting the product widi 20:80 to 30:70 ethyl acetate:dichloromethane to provide 4-(2-acet_u_c_dopyrimidin-5-yl-ethynyl)-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one as a white solid (0.033 g, 5.5%), mp 170-171°C. *H-NMR (400 MHz, CDθ3) δ 8.65 (s, 2 H), 8.47 (s, 1 H), 7.14 (d, J=2.1 Hz, 1 H), 7.09 (dd, J=8.4, 2.3 Hz, 1 H), 6.87 (d, J=8.5 Hz, 1 H), 4.80 (p, J=4.7, 1 H), 3.86 (s, 3 H), 2.94 (dt, J=23, 8.8 Hz, 2 H), 2.50 (s superimposed upon 2.6-2.2 m, 9 H), 2.0-1.5 (m, superimposed upon water) ppm. Example 50 Proceeding in a manner set forth in any one or more of the proceeding examples, die foUowing compounds may be prepared: 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- tιifluorc«nethyl[12,4]oxadiazol-3-yl)phenyl]edιynyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3- trifluoromethyl[12,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- trifluoπ M nedιyl[l,3,4]oxadiazol-2-yl)ph«ιyl]ethynyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- trifluoromedιyl[l,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclclιexan-l-one, and 4-(3-cyclopentyloxy-4-memoxyphenyl)-4-(2-[2-acetamidopyrimidin-5- yl]ethynyl)cyclohexan-l-one. UTILITY EXAMPLES EXAMPLE A Inhibitorv effect of compounds of Formula fD and flD on in vitro TNF production bv human Tη yvytfts The inhibitory effect of compounds of Formula (I) and (II) on in vitro TNF production by human monocytes may be determined by die protocol as described in Badger et al., EPO published AppUcation 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990. EXAMPLE B Two models of endotoxic shock have been utilized to determine in vivo TNF activity for the compounds of Formula (I) and (II). The protocol used in these models is described in Badger et al., EPO published AppUcation 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990. The compound of Example 1 herein demonstrated a positive in vivo response in reducing serum levels of TNF induced by die injection of endotoxin. EXAMPLE C Isolation of PDE Isozymes The phosphodiesterase inhibitory activity and selectivity of die compounds of Formula (I) and (II) can be determined using a battery of five distinct PDE isozymes. The tissues used as sources of the different isozymes are as follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE m, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "Ia"), canine tracheaUs. PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques [Torphy and OesUnski, MoL Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992]. Phosphodiesterase activity is assayed as described in die protocol of Torphy and OesUnski, MoL Pharmacol., 37:206-214, 1990. Positive ICso's in the nanomolar to μM range for compounds of die workings examples described herein for Formula (I) and (II) have been demonstrated.

Claims: What is claimed is: 1. A compound of Formula I wherein: Ri is -(O R5)nC(0)0(CR^5)mR6, -(CR4R5)nC(O)NR4(α R5)mR6, - (CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may be unsubstimted or substimted wid one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independendy hydrogen or C 1-2 alkyl; R6 is hydrogen, mediyl, hydroxyl, aryl, halo substimted aryl, aryloxyCi-3 alkyl, halo substimted aryloxyC l -3 alkyl, indanyl, indenyl, C7- 11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydrσpyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrodiiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocycUc moiety may be unsubstimted or substimted by 1 to 3 mediyl groups, one ethyl group or an hydroxyl group; provided that: a) when R6 is hydroxyl, tiien m is 2; or b) when R6 is hydroxyl, tiien r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrotiιiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiσpyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, men R6 is other than H in -(CR4R5)nO(CR4R5)mR6; X is YR2, fluorine, NR4R5, or formyl amine; m' is O, l, or 2; X2 is O or NR8; X3 is hydrogen or X; R2 is -CH3 or -CH2CH3 unsubstimted or substimted by 1 or more fluorines; s is 0 to 4; R3 is COOR14, C(0)NR4Rl4 or R7; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is O, NR7, NCR4R5C2-6 alkenyL NOR14, NOR15, NOCR4R5C2-6 alkenyl, NNR4R14, NNR_tRi5, NCN, NNR8C(O)NR8Rl4, NNR8C(S)NR8Rl4, or =Z is 2-(l,3-dithiane), 2-(1 -ditiιiolane), dimethyltiiio ketal, diethylthio ketal, 2-(l,3- dioxolane), 2(l,3-dioxane), 2-(l,3-oxadιiolane), dimethyl ketal or diediyl ketal; R7 is -(C R5)qRi2 or Cι_6 alkyl wherein die R12 or Cj-g alkyl group is unsubstimted or substimted one or more times by methyl or ediyl unsubstimted or substimted by 1-3 fluorines, -F, -Br, -O, -NO2, -NRi Rn, -C(O)R8, -CO2R8. -O(CH2) 2 ^OR 8 , -O(CH2) q R8, -CN, -C(O)NRiθRn, -O(CH2) q C(O)NRiθRn, - O(CH2) q C(O)R9, -NRιoC(O)NRιoRll, -NRioC(O)Rn, -NRιoC(O)OR9, -NRlθC(O)Ri3, -C(NRiθ)NRlθRlL -C(NCN)NRiθRn, -C(NCN)SR9, -NRιoC(NCN)SR9 , -NRlθC(NCN)NRιoRl 1, -NRιoS(O)2R9, -S(O) m 'R9, -NRioC(O)C(O)NRioRll, -NRιoC(O)C(O)Rlθ, or R ; q is 0, 1, or 2; Rl2 is Ri3 t (CH2>q* C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl; Rg is hydrogen or R9; R9 is Cj_4 alkyl unsubstimted or substimted by one to three fluorines; RlO is ORδ or Rπ; Rl 1 is hydrogen, or Cι_4 alkyl unsubstimted or substimted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together widi the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; Rχ3 is oxazoUdinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazoUdinyl, thiazoUdinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocycUc rings is connected through a carbon atom and each may be unsubstimted or substimted by one or two Cι_2 alkyl groups unsubstimted or wherein the methyl group is substimted with 1 to 3 fluoro atoms; Rj4 is hydrogen or R7; or when R8 and R 14 are as NR8R14 diey may together with die nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; χ>rovided that: (f) R7 is not Cι_4 alkyl unsubstimted or substimted by one to tiiree fluorines; or or the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1 wherein Ri is -CH2-cyclopropyL -cyclopentyl, -3-hydroxycyclσpentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or metiiyL W is ethynyl or 1,3-butadiynyl, R3 is a substimted or unsubstimted pyrimidinyl ring, X is YR2, and Z is O, NR7. 3. A compound according to claim 2 which is 4-(3-cyclopentyloxy- -methoxyphenyl)-4-(2-methylsulfonylpyri_--id^ yletiiynyl) cyclohexan- 1 -one, 4-(2-ammopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one, or 4-(2-acetamid<φyrimidin-5-ylethynyl)-4-(3-cyclσpentyloxy-4- methoxyphenyl)cyclohexan-l-one. 4. A compound according to claims 1 wherein Ri is -CH2-cyclopropyl, -cyclopentyl, -3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyL W is ethynyl or 1,3-butadiynyL R3 R 3 is R where R 7 is an unsubstimted or substimted aryl or heteroaryl ring, X is YR2, and Z is O. 5. A compound according to claim 5 which is 4-(3-cyclopentyloxy- -memoxyphenyl)-4-(4-aminophenylethynyl)cyclc-iexan- 1-one, 4-(3-cyclcpentyloxy-4-methoxyphenyl)-4-(4-acetamidophenylethynyl)- cyclohexan- 1 -one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetamidophenylethynyl)- cyclohexan- 1 -one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carbomedιoxyphenyl- ethynyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carboxyphenyl- ethynyl)cyclohexane- 1 -one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)cyclohexan- 1-one 4-(3-cyclσpentyloxy-4-methoxyphenyl)-4-(4-pyridyledιynyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4- { [4-(2-hydroxyethan- 1 - oxy )phenyl]ethynyl } cyclohexan- 1 -one, 4-(3-cyclσpentyloxy-4-methoxyphenyl)-4-(3-pyridyledιynyl)cyclohexan-l-c«ιe, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyedιan- 1 - oxy)phenyl]ethynyl)cyclohexan-l-one, 4-(4-carbomedιoxyphenyledιynyl)-4-(3-cycl<φentyloxy-4- methoxyphenyl)cyclohexan-l-one, 4-(4-carboxyphenylethynyl)-4-(3-cyclopentyloxy-4-medιoxyphenyl)cyclohexan- 1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)4-(2-[4-(l- piperidinocarbonylmethoxy)phenyl]ethynyl)cyclohexan- 1-one, 4-(2-[4- caιboxymemyloxyphenyl]ed ynyl)-4-(3-cyclcφentyloxy-4-methoxyphenyl)cyclohexan- 1 -one, 4-(2-[4-carbomethoxymethyloxyphenyl]edιynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one, 4-(2-carbomethoxyphenylethynyl)-4-(3- cyclopentyloxy-4-medιoxyphenyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4- medιoxyphenyl)-4-(2-[3-5-dicarbomedιoxyphenyl]ethynyl)cyclohexan- 1 -one, 4- (2-[4-cMcrophenyl]ethynyl 4-(3-cyclopentyloxy-4-medιoxyphenyl)cyclohexan- 1 -one, 4-(2-carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one, 4-(2-[3-cyanophenyl]ethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1-one, 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(2-[4- hydroxyphenyl]ethynyl)cyclohexan- 1 -one, 4-(3-cyclσpentyloxy-4-methoxyphenyl)- 4-(2[E]-(3-cyanophenyl)ethenyl)cyclohexan- 1-one, 4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(2-[3-5-dicyanophenyl]ethynyl)cyclohexan- 1-one, 4-(2- carboxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -one, sodium salt 4-(2-cyanodιien-5-ylethynyl)-4-(3-cyclopentyloxy-4- metiιoxyphenyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-medιyl-[l,2,4]oxadiazol-2- yl)thien-2-ylethynyl]cyclohexan-l-<Mie, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- [3-(5-methyl-[ 1 ,2,4]oxadiazol-3- yl)phenyl]ethynyl)cyclohexan- 1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3- (3-methyl-[ 1 ,4]oxadiazol-5-yl)phenyl]edιynyl)cyclohexan- 1 -one, 4-(3- cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[ 1 ,4]oxadiazol-2-yl)dιien-2- ylethynyl]cyclohexan-l-one, 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[l,3,4]oxadiazol-2- yl)phenyl]ethynyl)cy clohexan- 1 -one, 4-(2-Carbomethoxythien-4-ylethynyl)-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -one, SB 4-(2-Carboxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one, S 4-(2-cyanothien-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one -(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-medιyl[ 12,4]oxadiazol-5- yl)phenyl]ethynyl)cyclohexan-l-one, SB 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[l,2,4]oxadiazol-2- yl)thien-4-ylethynyl]cyclohexan- 1 -one, 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4- methoxypheny l)cyclohexan- 1 -one, 4-(4-carboxythien-2-ylethynyl)-4-(3-cyclopαιtyloxy-4- methoxyphenyl)cyclohexan- 1 -one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[l,3,4]thiadiazol-2- yl)phenyl]edιynyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(l- methyUmidazol-2-ylethynyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(imidazol-2-ylethynyl)cyclohexan-l- one, hydrochloride salt, 4-(2-acetamidcφyrimid-n-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1 ,4]oxadiazol-2- yl)phenyl]ethynyl)cyclohexan-l-one, or 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-medιyl[ 1 ,3,4]tiιiadiazol-2- yl)phenyl]ethynyl)cyclohexan-l-one. 6. A compound of Formula II wherein: Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, - (CR4R5)nO(CR4R5)πιR6, or -(CR4R5)rR6 wherein the alkyl moieties may be unsubstimted or substimted widi one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independendy selected hydrogen or C 1-2 alkyl; R is hydrogen, mediyl, hydroxyL aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substimted aryloxyCi-3 alkyl, indanyl, indenyl, C7- 11 χx>lycycloalkyL tetrahydrofuranyl, furanyl, tetrahydropyranyL pyranyl, tetrahydrothienyl, thienyL tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocycUc moieties is unsubstimted or substimted by 1 to 3 methyl groups, an ethyl group, or an hydroxyl group; provided tiiat: a) when Rβ is hydroxyl, tiien m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrodιiopyranyL 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyL 2-tetrahydrofuranyLor 2-tetrahydrothienyL then r is 1 to 6; e) when n is 1 and m is 0, then Rό is odier than H in -(CR4R5)nO(CR4R5)mR6; X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S(O)m'; m' is O, l, or 2; X2 is O or NR8; X3 is hydrogen or X; R2 is independendy selected from -CH3 or -CH2CH3 unsubstimted or substimted by 1 or more fluorines; s is 0 to 4; R3 is COOR14, C(O)NR4Ri4 or R7; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is C(Y-)Ri4, C(O)ORi4, C(Y')NRιoRl4, C(NRιo)NRιoRl4, CN, C(NOR8)Rl4, C(O)NR8NR8C(O)R8, C(O)NRsNRlθRl4, C(NORi4)R8, C(NR8)NRlθRl4, C(NRi4)NR8R8 C(NCN)NRioRl4, C(NCN)SR9, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[12,3]), (3- or 5-triazolyl[1 ,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazoUdinyl), (2-, 4-, or 5-thiazoUdinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocyUc ring systems may be optionally substimted one or more times by R14; Y' is O or S; R7 is -(CR4R5)qRi2 or Cι_6 alkyl wherein die R12 or C _6 alkyl group is unsubstimted or substimted one or more times by methyl or ethyl unsubstimted or substimted by 1-3 fluorines, -F, -Br, -O, -NO2, -NRIQRI 1, -C(O)R8, -CO2R8, -O(CH2)2-4θR 8 , -O(CH 2 ) q R8, -CN, -C(O)NRlθRll, -O(CH 2 ) q C(O)NRiθRll, - O(CH2) q C(O)R9, -NRiθC(O)NRiθRll, -NRiθC(O)Rn, -NRιoC(O)OR9, -NRlθC(O)Ri3, -C(NRlO)NRiθRll, -C(NCN)NRioRn, -C(NCN)SR9, -NRlθC(NCN)SR9 , -NRlθC(NCN)NRiθRn, -NRiθS(O)2R9. -S(O) m 'R9, -NRlθC(O)C(O)NRiθRll, -NRιoC(O)C(O)RlO, or R13; q is O, l, or 2; R12 is Ri3, (CH2)q, C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyL piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl; R8 is independendy selected from hydrogen or R9; R9 is Cι_4 alkyl unsubstimted or substimted by one to three fluorines; RlO is ORδ or Rn; Rl i is hydrogen, or Cχ.4 alkyl unsubstimted or substimted by one to three fluorines; or when Rio and Rl l are as NRifjRi 1 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; Rl3 is a substimted or unsubstimted heteroaryl group selected from the group consisting of oxazoUdinyl, oxazolyL thiazolyL pyrazolyl, triazolyl, tetrazolyL imidazolyL imidazoUdinyL thiazoUdinyL isoxazolyl, oxadiazolyL and thiadiazolyL and where R13 is substimted on R12 or R* 3 the rings are connected through a carbon atom and each seccxid Rι 3 ring may be unsubstimted or substimted by one or two Ci-2 alkyl groups unsubstimted or substimted on die mediyl widi 1 to 3 fluoro atoms; Rl4 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatoms selected from O, N, or S; provided tiiat: (f) R7 is not Cj_4 alkyl unsubstimted or substimted by one to three fluorines; or the pharmaceutically acceptable salts thereof. 7. A compound according to claim 6 Ri is -CH2-cyclσpropy -cyclopentyl, -3-hydroxycyclσpentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, R3 R 3 is R where R is an unsubstimted or substimted aryl or heteroaryl ring, X is YR2, Z is O, and Z' is COOR14. 8. A compound according to claim 7 wherein W is 1 ,3-butadiynyl and R 3 is unsubstimted or substimted pyrimidin-5-yl. 9. A pharmaceuticaUy composition comprising a compound according to claim any one of claims 1 to 5 and a pharmaceuticaUy acceptable excipient 10. A method for treating asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound according to any one of claims 1 to 5.

Inventors: BENDER PAUL E, CHRISTENSEN SIEGFRIED B IV, KARPINSKI JOSEPH M, RYAN M DOMINIC, BENDER, PAUL, E., CHRISTENSEN, SIEGFRIED, B., IV, KARPINSKI, JOSEPH, M., RYAN, M., DOMINIC
Applicants: BENDER PAUL E, CHRISTENSEN SIEGFRIED B IV, KARPINSKI JOSEPH M, RYAN M DOMINIC, SMITHKLINE BEECHAM CORP, BENDER, PAUL, E., CHRISTENSEN, SIEGFRIED, B., IV, KARPINSKI, JOSEPH, M., RYAN, M., DOMINIC, SMITHKLINE BEECHAM CORPORATION
Application year: 1995
Main classification: A61K31
IPC codes: C07C45, C07C49, C07C59, C07C65, C07C69, C07C225, C07C233, C07C255, C07D213, C07D233, C07D239, C07D271, C07D285, C07D295, C07D317, C07D333, C07D405, C07D413