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

Abstract: The present invention relates to novel 4,4-(disubstituted)cyclohexan-1-ols monomers 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).

Description: 4,4-(disubstituted)cyclohexan-l-oIs monomers and related compounds Field of Invention The present invention relates to novel 4,4-(disu____uted)cyclohexan-l-o_. monomers and related compounds, pharmaceutical compositions containing these compounds, and tbeύr use _- tre____g __le-g_c _ιιd ^ inhibiting the production of Tumor Necrosis Factor (TNF). Background of the Invention Bronchial asthma is a complex, multifac orial 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 c AMP (adenosine cyclic 3'_>'- monophosphatc). 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-A TP 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 inflarnmarory cells. The principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3 ' -pho_phodiester 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 the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on die market 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, osteoarthriύs, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cκrcbral r___da_ia, chronk pulmonary inflammatory disease, silicosis, pulmonary saicoidosis, bone resorption 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), AIDS, 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 (HTV). At least three types or strains of HIV have been identified, Le., fflV- 1, fflV-2 and HTV-3. As a consequence of HTV infection, T-ceil- mediated immunity is impaired and infected individuals manifest severe opportunistic infections and or unusual neoplasms. HIV 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 HTV, 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-ceU-mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytolrine activity such as by inhibition of cytolάne production, notably TNF, in an HTV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the 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 the activation state of the cells. [See Rosenberg et al.. The Immunopathogenesis of HIV 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 monolrine 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 cytomegalovirus (CMV), influenza virus, adenσvirus, 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 the 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 the excessive and/or unregulated production of TNF. Summary of the Invention Compounds of the Formula (I): wherein: R! is -(CR4R5)nC(O)O(CR4R5)mR-. -(CR4R5)nC(O)NR4(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independently selected hydrogen or Ci-2 alkyl; R6 is hydrogen, methyl, hydroxyL aryl, halo substituted aiyL aryloxyCl-3 alkyl, halo substituted aryloxyCi-3 alkyL indanyL indenyL C7.11 polycycloalkyL 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 or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group; provided that: a) when R is hydroxyl, then m is 2; or b) when R6 is hydroxyL then r is 2 to 6; or c) when R<> is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyτanyl, 2-tctrahydrothiopyranyL 2-tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then Rό 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, or 2; X2 is O or NR8; X3 is hydrogen or X; X4 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NRβR8, or NRβRβ * R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; R3 is COOR14, C(O)NR4Rl4 or R7i Z is OR14, OR15, SR14, S(O) m 'R7, S(O)2NRi()Rl4, NR10 14, NRi4C(O)R9, NR10COO 14, NRiθC(O)OR7, NR10COONR10R14, NRιoS(O)2NRlθRl4, NRlθC(NCN)NRιoRi4, NRlθS(O)2R7, NRioC(CR4NO2)NRlORl4. NRlθC(NCN)SR9, NRioC(CR4NO2)SR9, NRιoC(NRιo)NRιoRl4, NRlθC(O)C(O)NRlθRl4,or NRiθC(O)C(O) Ri4; Y is O or S; R7 is -(CR4R5)qRl2 or C\. 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, -N loRll. -C(O)R8, -CO2R8, -O(CH 2 )2-4θR8, -O(CH2) q R8, -CN, -C(O)NRioRll, -O(CH2) q C(O)NRiθRll, - 0(CH 2 ) q C(O)R9, -NRlθC(O)NRlθRll, -NRlθC(O)Rll, -NRi()C(O)OR9, -NRlθαθ)Ri3, -C(NRιo)NRlORll, -C(NCN)NRιoRn, -C(NCN)SR9, -NRiθC(NCN)SR9 , -NRlθC(NCN)NRiθRii, -NRιoS(O)2R9, -S(0)rfR9, -NRlθC(O)C(O)NRlθRll, -NRlθC(O)C(O)RlO, or R 13 ; q is 0, 1, or 2; Ri2 is R 3, 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), pyirolyL piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl; Rg is independently selected from hydrogen or R9; R9 is C _4 alkyl optionally substituted by one to three fluorines; Rlθ is OR8 or Rn; Rl l is hydrogen, or Cι_4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NR10R 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms 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 Rn is substituted on R12 or R !3 the rings are connected through a carbon atom and each second Rn ring may be unsubstituted or substituted by one or two C .2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; Rj4 is hydrogen or R7; or when R8 and R 14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; Ris is C(O)Ri4, C(O)NR«Ri4, S(O),NRsRi4 or S(O),R 7 where q is 0, 1 or 2; provided that: (f) R7 is not Cι_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 a pharmaceutically acceptable carrier or diluent The invention also relates to a method of mediation or inhibition of the 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) 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). The invention also provides a method 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). 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). This method 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). Compounds of Formula (I) are also useful in the 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) 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 die enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I). 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 TV 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, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HTV-1, HTV-2 and HTV-3, cytomegalovirus (CMV). influenza, adenovirus and the 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 with a human immunodeficiency virus (HTV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I). 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 (FIV) or other retro viral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, macdi 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) 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) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) to a mammal in need of such treatment Preferably, a compound of Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B. The term "C1.3 alkyl", "Cμ 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-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t -buty and the 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, cyclopropylmethyl, 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. 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, Le., chloro, fluoro, bromo, or iodo. "Inhibiting the production of _L-l" 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 the 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 DL-l or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of die 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 cytoldne to be released, such as but not limited to IL-1 or DL-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 the compounds of the present invention and thus are herein referred to collectively as 'TNF" unless specifically delineated otherwise. Preferably TNF-α is inhibited. "Cytoldne" means any secreted polypeptide mat affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytoldne includes, but is not limited to, monokines and lympho-rines regardless of which cells produce them. The cytoldne inhibited by the present invention for use in the treatment of a HTV-infected human must be a cytoldne 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) 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 con-pounds of Formula (I) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby. Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this 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 the salt will not have untoward or deleterious effects in its application and use in treating diseases. Preferred compounds are as follows: When Ri is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a Cι_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) are CH2- cyclopropy CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with OHC7-I l polycycloalkyL (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)l-3θ(CH2)0-2CH3, and -(CH2)2-4θH. When Ri term contains the moiety (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 the other, e.g., (CR4R5) n wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Rl substitutions, as noted above. When R is a C7.11 polycycloalkyL examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclolS.ll.O^Jdecyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987. 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 that W is ethynyl or 1,3 -butadiynyl. Z is preferably OR14, OR15, SR14, S(O) m 'R7, S(O)2NRlθRl4, NRlθRl4, NRi4C(O)R9, NRlθC(O)Ri4, NRlθC(O)OR7, NRiθC(O)NRlθRl4, NRιoS(O)2NRιoRl4, NRlθC(NCN)NRl()Rl4, NRiθS(O)2R7, NRlθC(CR4Nθ2)NRιoRi4, NRlθC(NCN)SR9, NRioC(CR4NO2)SR9, NRιoC(NRlθ)NRiθRi4, NRlθC(O)C(O)NRlθRl4. or NRlθC(O)C(O)ORi4. Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a Ci-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 mediyl, or the fluoro- substituted alkyls, specifically a C__2 alkyL such as a -CF3, -CHF2, or -CH2CH 2 moiety. Most preferred are die -CHF2 and -CH3 moieties. Preferred R7 moieties include unsubstituted or substituted -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)l-2(2---αid___olyl), (CH2)2(4-mcapholinyl), (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 Ri 1 in the moiety -NR10R1 together with die nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyL 2-(R8)-l-imida_olyL 1-pyrazolyL 3-(R8)-l-pyrazolyL 1- triazolyl, 2-triazolyl, 5-(Rs)-l-triazolyL 5-(R8)-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)-l- piperazinyL or pyirolyl ring. Preferred rings when Rio and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached may foπn a 5 to 7 membered ring comprised of carbon or carbon 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 pyπolyl. 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). Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l-i___d_zolyL 4-(R7)-l-imidazolyl, 5-(R7)-l-im_dazolyL 3-(R7)-l-pyrazolyl, 4-(R7)-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)- 1 -tetrazolyl, 4-(R7)-l- piperazinyL Where applicable, the ring may be substituted one or more times by R7. Preferred groups for NR10R14 which contain a heterocyclic ring are 5-(Ri4)- 1-tetrazolyl, 2-(Ri4)-l-imidazolyL 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l-piperazinyL or 4-(Ri5)-l-piperazinyl. Preferred rings for R13 include (2-, 4- or 5-ir__da_olyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ ,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[l,3,4]), (2-thiadia_olyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 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, triazolyl, tetrazolyL or thiazolyl, die heterocyclic ring itself may be unsubstituted or substituted by Rs on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R8)-4-imidazolyL l-(R8)-5-imida_c_yL 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- Preferred are those compounds of Formula (I) wherein Rj is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyL -C4-6 cycloalkyl unsubstituted or substituted by OH, tctrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluσro- substituted alkyl, W is ethynyl or 1,3-butadiynyl; R3 is R 7 where R7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z is OR 14, OR 15, NRioRl4, or NRi4C(O)R9- Most preferred are those compounds wherein Rl 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 ethynyl or 1,3-butadiynyl, and R3 is a substituted or unsubstituted pyrimidinyl ring. It will be recognized that some of die compounds of Formula (I) 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 die scope of the present invention. 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 the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of die formula (I). 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 the 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 die 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 pare nteral 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 die pharmaceutical composition is employed in die 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 wit water; for solid systems, lactose, kaolin and mannitoL and for aerosol systems, dkhlorodifluoromethane, chlc-Otrifluoroethane and compressed carbon dioxide. Also, in addition to die pharmaceutical carrier or diluent, the instant compositions may include odier ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and die like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions. The pharmaceutical preparations thus described are made following the conventional techniques of die pharmaceutical chemist as appropriate to the desired en product In these compositions, d e amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of die active ingredient When die diluent is a solid it may be present in lesser, equal or greater amounts than the 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 d e 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, me 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. No unacceptable toxicological effects are expected when these compounds are administered in accordance with die present invention. Methods Of Preparation Synthetic Scheme(s) With Textual Description Compounds of Formula (I) may be prepared by the processes disclosed herein which comprise reacting a terminal acetylene, wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, as, e.g., compound 1-Scheme 1. with an appropriate halide, R3X, wherein R3 represents R3 as defined in relation to Formula (I) or a group convertible to R3, in d e 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 pr° Cedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), provides a compound of die Formula 2-Scheme 1. Compounds of the Formula 1-Scheme 1 may be prepared by pr° Cedures analogous to those described in copending U.S. application 07/862111 , 07/968761 and PCT application number PCT/US93 02516 published under WIPO publication number WO93 19751. sri__n- i a) Pd(PPh 3 ) 4l PPh 3 , Cul, R 3 X, pipβrid.n. Alternatively, compounds of the Formula (I), wherein Z and R3 represent Z and R3 as defined in relation to Formula (I) or a group convertible to Z or R3, may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 2. by die synthetic pr° Cedures described in PCT application number PCT/US93 01990 and PCT/US93/02325 published as WIPO publication number WO93/19750 . Schema 2 Alternatively, oxidative carbonylation of a terminal acetylene as, e.g., compound 1-Scheme 3. using an appropriate metal salt such as a copper salt widi a catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, as in die method of Tsuji et al. (Tet Lett, 1980, 21, 849), then provides the compound of the Formula 2= Scheme 3: such compounds may men be converted to other compounds of d e Formula (I) by manipulation of de ketone as described above and by independent manipulation of d e carboxylic ester moiety using standard txansesterification or amidation conditions. Syntheses of such ketone starting materials are described in published PCT application PCT/US93 02O45 (WIPO publication number WO 93/19748) or published PCT application PCT/US93 02325 (WIPO publication numbe WO/93/19750). Sch ma 3 COOCH a) PdCI 2 . Cuα 2 . NaO 2 CCH , , CO, CH 3 OH; as inSchβm. 2 likewise, oxidative carbonylation of a terminal acetylene as, e.g., compound _L Scheme 4. wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, using an appropriate metal salt, such as a copper salt with a catalytic amount of a palladium salt, in die presence of a suitable base as an acid tπφ, such as sodium acetate, in a suitable alcohoL such as medianol, as in die method of Tsuji et al. (Tet Lett, 1980, 21, 849), tiien provides the compound of the Formula 2-Scheme 4: such compounds may men be converted to other compounds of the Formula (I) by manipulation of die carboxylic ester moiety using standard txansesterification or amidation conditions. _en«m_ _ q Dor «.b QT X P COOCH a) P CI 2 , CuCI 2 . NaO 2 CCH 3 , CO, CH 3 OH Compounds where Z is a group other than -OH can be prepared by methods known in the art and in particular by manipulation of die -OH. Such methods are described in co-pending U.S. application 07/968753 and PCT application serial number PCT/US93 02325 (WIPO pubUcation number WO/93/19750). Preparation of d e remaining compounds of die Formula (I) may be accomplished by procedures analogous to those described above and in the Examples, infra. It will be recognized tiiat some compounds of die Formula (I) 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 die described invention. These examples are interned solely for illustrating die invention and should not be read to limit the invention in any manner. Reference is made to the claims for what is reserved to die inventors hereunder. Experimentals Example 1 Preparation of cύ- 4-f3-cycloρentyloxy-4-methoxvphenvlV4-f4-pvridvlethvnvlV cvclohexan-l-oll la) tr ns-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-l-ol] and cύ- [4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclc-iexan-l-ol] To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-edιynylcyclohexan-l- one (0.34 g, 1.1 mmol, prepared as described in published PCT application PCT/US93/001990 (WIPO pubUcation number WO 93/19748) or PCT/US93 02325 (WIPO pubUcation number WO/93/19750) in 1,2-dimethoxyethane (5 mL) under an argon atmosphere was added sodium borohydride (0.08 g, 2.2 mmol) and die mixture was stirred at room temperature for 0.5 h. Water was added, die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes, provided ι αn_"-[4-(3-<^clopentyloxy-4-π-e_ιoxyphenyl)-4-ethynylcyclc-iexan-l-ol] (described in U. S. Patent application in PCT application number PCT/US93 02516 pubUshed under WIPO pubUcation number WO93/19751_as c«-[4-(3-cyclσpentyloxy-4- medioxyphenylH-ethynylcyclohexan- l-ol]) as a wax. *H-NMR (400 MHz, CDCI3) δ 7.14 (d, J=2.3 Hz, IH), 7.04 (dd, J«8.5, 2.3 Hz, IH), 6.82 (d, J=8.5 Hz, IH), 4.79 (m, IH), 3.83 (s, 3H), 3.68 (m, IH), 2.46 (s, IH), 1.7 - 2.1 (m, 14H), 1.6 (m, 2H). cύ-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan- l-ol] also was isolated from this pr° Cedure as a colorless oU. *H-NMR (400 MHz, CDCI3) δ 7.17 (d, J=1.9 Hz, IH), 7.10 (d, J=8.4 Hz, IH), 6.84 (d, J=8.4 Hz, IH), 4.80 (m, IH), 4.13 (br s, IH), 3.84 (s, 3H), 2.38 (s, IH), 2.15 (m, 4H), 1.7 - 2.0 (m, 10H), 1.75 (m, 2H). 1 b) cύ-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridyledιynyl)cyclohexan- 1 -ol] To a solution of rrαn_"-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4- ethynylcyclohexan-1-ol] (0.15 g, 0.48 mmol) and 4-bromopyridine (0.75g, 5 mmol) in piperidine (2 mL) under an argon atmosphere were added tetr_Jris(_riphenylpho_phine)- paUadium(0) (0.022 g, 4%), copper (I) iodide (0.005 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 and die mixture was extracted three times with dichloromethane, die extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 ethyl acetate hexanes, provided cw-[4-(3- cyclopentyloxy-4-memoxyphenyl)-4-(4-pyridyledιynyl)-cyclohexan-l-ol] as a pale yeUow soUd, which was triturated from ether-hexanes. mp 183 - 184° C. *H-NMR (400 MHz, CDCI3) δ 8.6 (br, 2H), 7.35 (m, 2H), 7.14 (d, J=2 Hz, IH), 7.06 (dd, J=8.5, 2Hz, IH), 6.85 (d, J=8.5Hz, IH), 4.79 (m, IH), 3.85 (s, 3H), 3.7 (m, IH), 1.8 - 2.1 (m, 14H), 1.6 (m, 2H). Example 2 cύ-r4-(3-cyclopentvloxy-4-memoxvphenvlV4-f pvτid-2-vlethvnvlV^clohexan- 1 -oil To a solution of franϊ-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.14 g, 0.43 mmol) and 2-bromopyridine (0.40 mL, 4.3 mmol) in piperidine (2 mL) under an argon atmosphere were added tetr__ris(triphenyl- phosphi_ne)palla_ium(0) (0.020 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h. Ammonium chloride was added and d e mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 75:25 ethyl acetate:hexanes, provided άs-[4-(3- _yclopentyloxy--l-methoxyphenylV4-(pyrid-2-yleΦvnvl)cvclohexan-l-oll as a white solid (0.14 g, 84%), mp 49-51° C. Anal. (C25H29NO3 O.5 H2O) calcd: C, 74.97; H, 7.55; N, 3.50; found: C, 74.90; H, 7.52; N, 3.33. Example 3 Resolution of f+/-)-3-(3-cyclppcntylo * .y-4-mcthoxyphcnyl)-3-cthynyl- cvclohexan-l-one The compound from Example lb was resolved in the foUowing manner to give enantiomeric oUs: HFLC Rt = 15.5 min (enantiomer 1 = El), 23.2 min (enantiomer 2 = E2) (Diacel Chiralpak AS®; 21.2 x 250 mm. hexaneasopropanol, 4:1; 10 mL min; UV detection at 295 nm). F.-a p1_ 4 Preparation of (+/-. 3-f3-cyclopentyloxv-4-methoxyphenvlV3-phenvlethvnvl- cvclohexan-1-one To a solution of he compound of Example lb (0.125 g, 0.4 mmol) and iodobenzene (0.4 mL, 2.0 mmol) in piperidine (6 mL) under an argon atmosphere was added trace tetr__ds(triphenylphosphine)palladium(0), coppeπ ) iodide and triphenylphosphine. The mixture was refluxed for 5 h, then concentrated in vacua. The residue was diluted with ethyl acetate (100 mL), was washed wid brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting widi 2:1 hexanes ed yl acetate, foUowed by trituration from ether/hexanes, provided die tide compound as white solid (0.09 g, 58%), m.p. 90-91° C. Example s Preparation of (+/-. 3-(3-cvclopcntyloxy-4-mcthoxvphcnvl 3-(3- carbomethoxyphenvl _;th vnvlcvclohexan- 1 -one 5a) methyl 3 -iodobenzoate Methyl 3-iodobenzoate was prepared by standard chemistry well known to those versed in die an and is a white soUd, cap.40-41° C 5b) (+/-) 3-(3-cyclopentyloxy-4-metlκ)xyphenyl)-3-(3-caιbomethoxyphenyl)ethynyl- cyclohexan- 1 -one To a solution of die compound from Example lb (0.30 g, 0.96 mmol) and mediyl 3-iodobenzoate (0.30 g, 1.15 mmol) in triediylamine (10 mL) under an argon atmosphere was added trace tetra__-s(triphenylphosphine)p_Uadium(0), coppeπ ) iodide and triphenylphosphine. The mixture was refluxed for 0.5 h and was then concentrated in vacua. The residue was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and was evaporated. Purification by flash chromatography, eluting with 2: 1 hexanes/ediyl acetate, provided d e tide compound as a pale yeUow oil (0.35 g, 80%). Anal (C28H30O5 I.O H2O) calcd: C, 72.39; H, 6.94; found: C, 72.47; H, 6.80. Example 6 Preparation of (+/-) 3-(3-carboxvphenvlethvnvl.-3-(3-cvclopentvloxv-4- methoxvphenvltavclohexan- 1 -one To a solution of die compound from Example 5(b) in 5:5:2 THF/methanol water (10 mL) under an argon atmosphere was added sodium hydroxide (0.60 g, 1.5 mmol). The mixture was heated at 60° C for 2 h and was then concentrated in vacua. The residue was extracted from 3M HC1 with ediyl acetate, was washed widi brine, was dried (MgSθ4) and was evaporated. Purification by flash chromatography, eluting win.98:2:0.3 chlσrofcπm methanol acetic acid, provided a white solid, m.p. 71-73° C Example 7 Preparation of 3-f3-cvclQpentyloxv-4-methoxyphenylV3r3-f5-methyl-ri.3.41dιiadiazol- 2-yl)p_cnyl-r_ιyπyll_ycl_hcxan-l- πc 7a) l-iodo-3-(_ " i__;thyl-[l,3,4]_______ol-2-yl)be__xnc l-Iodo-3-(5-me yl-[l,3,4]dιiadiazol-2-yl)benzene was prepared by standard chemistry weU known to those versed in the art and is white solid, mp. 86-89° C. 7b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-medιyl-[ 1 ,3,4] tiiiadiazoW- yl)phenyledιynyl]cyclohexan-l-one To a solution of the compound from Example 3 (El) ( 0.10 g, 0.32 mmol) and l-icdcκ3-(5-me_-yl[l,3,4]th_ax__i__-θl-2-yl)beι__ene (0.10 g, 0.32 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetra___.(triphenylphosphine)pa]ld-um(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 0.20 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes ediyl acetate provided die tide compound as a white soUd (0.135 g, 87%), m.p. 97-99° C. The enantiomer was prepared in a similar manner, starting widi die compound from Example 3 (E2), as a white solid, m.p. 97-99° C. Example 8 Preparation of 3-f 3-cyclopentvloxy-4-methoxvphenvlV3-r3-(5-methvl- ri.3.41oxadiazol-2-vl^phenvlethvnvllcvclohexan-l-one 8a) l-Iodo-3-(5-π_.thyl[l,3,4]oxadizol-2-yl)benzene l-Iodo-3-(5-methyl[l,3,4]oxadiazol-2-yl)benzene was prepared by standard chemistry weU known to those versed in the an and is a white solid, mp. 104-105° C. 8b) 3-(3-cyclσpentyloxy-4-me oxyphenyl)-3-[3-(5-medιyl[l,3,4]oxa_iazol-2- yl)phenylethynyl]cyclohexan-l-one To a solution of die compound from Example 3 (0.125 g, 0.4 mmol) and 1- kxlo-3-(5-medιyl-[l,3,4]oxadiazol-2-yl)benzene (0.09 g, 0.32 mmol) in uiethylamine (3 mL) under an argon atmosphere was added trace tctrak_s(triphenylpho_phine)- paUadium(O), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h , was cooled to room temperature and was concentrated in vacua. The residue was partmoned between ethyl acetate and water. The organic phase was washed wid brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 ethyl acetate/hexanes, followed by recrystalUzation from ethyl acetate/hexanes, provided the tide compound as a white solid (0.11 g, 61%), m.p. 117-119° C The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 117-119° C. Example ? Preparation of 3-(3-cvclopentyloxv-4-methoxvphenvlV3-r3-f3-methvl- ri.2.41oxadiazol-5-vnphenvlethvnvncvclohexan-l-one 9a) l-iodo-3-(3-medιyl-[l^,4]oxadiazol-5-yl)benzene l-Iodo-3- (3-methyl-[l^,4]oxadiazol-5-yl)benzene was prepared by standard chemistry weU known to those versed in die an and is a white soUd, p. 101.5-103° C. 9b) 3-(3-cyclopentyloxy-4-memoxyphenyl)-3-[3-(3-memyl-[l^,4]ox____zol-5- yl)phenylethynyl]cyclohexan- 1-one To a solution of d e compound from Example 3 (0.125 g, 0.4 mmol) and 1- iodo-3-(3-meώyl-[l^,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3mL) under an argon atmosphere was added trace tetr___s( phenylpho_phine)- palladium(O), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed wid brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting widi 2:1 hexanes ediyl acetate, foUowed by trituration from hexanes ethyl acetate, to provide die tide compound as a white solid, m.p. 122 123° C. The enantiomer was prepared in a similar manner, starting wid the compound from Example 3 (E2), as awhite solid, mp. 122-123° C. Example 10 Preparation of 3-f3-cyclopentyloxv-4-methoxvphenvn-3-r3-(5-methvl- ri^^loxadiazol-S-vl'ψhenylethynyncvclohexan-l-one 10a) l-icdo-3-(5-methyl-[l,2,4]oxadiazol-3-yl)benzene l-io_o-3-(5-medιyl-[l^_:,4]oxadiazol-3-yl)benzene was prepared by standard chemistry weU known to those versed in die an and is a white soUd, mp. 86-87° C. 10b) 3- (3-cyclopentyloxy-4-medιoxyphenyl)-3-[3-(5-me_ιyl-[l ,2,4]oxadiazo.-3- yl)phenylediynyl]cyclohexan-l-one To a solution of die compound from Example 3 (0.125 g, 0.4 mmol) and 1- iodo-3-(5-medιyl-[l^,4]oxadia_ol-3-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetra_ds(triphenylphosphine)- paUadium(O), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ediyl acetate and water. The organic phase was washed widi brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, foUowed by trituration from hexanes ethyl acetate, provided die tide compound as colorless crystals (0.12 g, 67%), m.p. 116-118° C. T e enantiomer was prepared in a similar manner, starting wid die compound from Example 3 (E2), as colorless crystals, m.p.l 16-118° C. Example 11 Preparation of 3-f 3-cvclopen oxy-4-methoxyphenvn-3 (3- cyanophenylethvnyl'teyclohexan- 1 -one To a solution of d e compound from Example 3 (El) (0.125 g, 0.4 mmol) and 3-iodobenzonitrile (Trans world, 0.09 g, 0.4 mmol) in triethylamine (3mL) under an argon atmosphere was added trace tet-_-άs(triphenylpho.phine)pall___tium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ediyl acetate and water. The organic phase was washed widi brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting widi 2: 1 hexanes/ethyl acetate, to provide the tide compound as a clear yeUow glass (0.12 g, 73%). MS(EI) m/e 414 [M+H]+. The enantiomer was prepared in similar manner, starting with die compound from Example 3 (E2), as a clear yeUow glass. Example 12 Preparation of H3-cyclopcntyloxy-4-mcthoxyphcnyl)-3-(3- nitrophenvlethvnvncvclohexan-1-onc To a solution of the compound from Example 3 (El) (0.2 g, 0.64 mmol) and 3- iodonitrobenzene (Aldrich, 0.16 g, 0.64 mmol) in triethylamine (4 mL) under an argon atmosphere was added trace ted-akis(triphenylpho_phine)paUadium(0), copper(_) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed wid brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting widi 3:1 hexanes ediyl acetate, provided die tide compound as yellow solid (0.25 g, 90%), p. 46-48° C The enantiomer was prepared in a similar manner, starting widi die compound from Example 3 (E2), as a yeUow solid, mp. 46-48° C. Example 13 Preparation of 3-f3-cvclopentvloxv-4-me oxvDhenvn-3-f2- hydroxyethoxvphenvlethvnvl clohcxan-1-one 13a) 2-hydroxyedιoxy-l-iodobenzene 2-hydroxyedιoxy- 1 -iodobenzene was prepared by standard chemistry weU known to those versed in he an and is a colorless oU. *H NMR( 400 MHz, CDCI3) δ 7.77 (dd, J=7.9, 1.3 Hz, IH), 7.3 (t, J=7H, IH), 6.84 (d, J=7.9 Hz, IH), 6.74 (t J=7.9 Hz, IH), 4.13 (t, J=4.3 Hz, 2H), 3.99 (t, J=4.3 Hz, 2H), 2.2 (br s, IH). 13b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-hydroxyedioxyphenylediynyl)- cyclohexan- 1-one To a solution of d e compound from Example 3 (El) (0.25 g, 0.8 mmol) and 2- hydroxyethoxy-1-iodobenzene (0.21 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetra_as(triphenylphosphine)pal_adium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 1 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting widi 1 : 1 hexanes ethyl acetate, provided die tide compound as a white soUd (0.05 g, 14%), m.p. 93-94° C. Example 14 Preparation of 3-(3-acetamidophenylethynylV3-f 3-cyclopentvloxv-4- methoxvphenvltavclohexan- 1 -one 14a) 3-acetamido-l-iodobenzene 3-acetamido-l-iodobenzene was prepared by standard chemistry weU known to those versed in die an and is a white solid, mp. 117-118° C. 14b) 3-(3-acetamidcphenylethynyl)-3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one To a solution of die compound from Example 3 (El) (0_2 g, 0.64 mmol) and 3- acetamido-1-iodobenzene (0.17 g, 0.64 mmol) in triethyl___ine (5 mL) under an argon atmosphere was added trace tetπϋ-is(_riphenylphosphine)palladium(0), coppeτ(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.3 h, was cooled to room temperature and was concentrated in vacua. The residue was purified by flash chromatography, eluting widi 1:1 hexanes/ethyl acetate, to provide die tide compound as tan solid (0.17 g, 60%), m_p. 58-60° C Example 1„ Preparation of 3- 3-cyclopentyloxy-4-methoxvphenvn-3- - meth-tnesιιlfonamidophenylethynvl .clohexan-1-one 15a) l-iodo-3-mem_-K.su_fonamidobenzene l-iodo-^rnethanesulfonamidobenzene was prepared by standard chemistry weU known to those versed in the an and is light-pink soUd, mp. 102-103° C. 15b) 3-(3-cyclσpentyloxy-4-methoxyphenyl)-3-(3- D_eth_uιesulfon___idophenylethynyl)cyclohex_n- 1 -one To a solution of d e compound from Example 3 (El) (0.2 g, 0.64 mmol) and 1- rødo-3- methanesulfonamidobenzene (0.19 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)p_lladium(0), coppeτ(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.3 h, was cooled to room temperature and was concentrated in vacua. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ediyl acetate, to provide the title compound as a tan solid (0.18 g, 58%), m.p. 59-62° C. Example 16 Preparation of 3-r3-aminoph_nvlethvnvl 3-(3-cvclopentyloxv-4- methoxvphenvlV^clohexan-1-one 16a) l-iodo-3-trifluoroace_a_-iidoben_ene l-ic)dc 3-t__fluoroacetam_dobenzene was prepared by standard chemistry weU known to those versed in the art and is a white solid, m.p. 120-121° C 16b) 3-(3-cyclcφentyloxy-4-methoxyphenyl 3-(3-trifluoroacetamidophenyleu_ynyl)- cyclohexan-1-one To a solution of the compound from Example 3 (El) (0.5 g. 1.6 mmol) and 1- iodo-3-trifluoroacetamidobenzene (0.5 g, 1.6 mmol) in triethylamine (10 mL) under an argon atmosphere was added a small amount of tetrakis(triphenylpho_phine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was purified by flash chromatography, eluting with 3:1 hexanes ethyl acetate, to give the tide compound as a pale yeUow solid (0.62 g, 78%), m.p. 63-65° C. 16c) 3-(3-__ιαnophenyle_ ynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclcjhexan- 1 - one To a solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3- trifluσroacetamidophenylethynyl)cyclohexan-l-one (0.62 g, 1.24 mmol) in 95:5 memanol/water (10 mL) under an argon atmosphere was added potassium carbonate (0.86 g, 6.2 mmol). The mixture was refluxed for 6 h and was stirred for 18 h at room temperature. The soUd precipitate was collected and purified by trituration from ethyl acetate/hexanes to provide die tide compound as a white soUd (0.39 g, 77%), m.p. 100-102° C. Example 17 ci--r4-r4-cv_nothien-2-yle_ιynvlV4-f3-cvclopen oxv-4-methoxvDhenvlV ςyclohcxan-1-0-1 17a) 2-bromo-4-cyanothiophene 2-Bromo-5-cyanothiophene was prepared by standard chemistry weU known to those versed in the an and is a colorless oU. -NMR (400 MHz, CDCI3) δ 7.85 (d, J=2.2Hz, 1 H), 7.25 (d, J=2.2 Hz, IH) ppm. 17b) cw-[4-(4-cyanodιien-2-ylethynyl)-4-(3-cyclopentyloxy-4-medιoxyphenyl)- cyclohexan-1-ol] To a solution of /r n5-[4-(3-cyclopentyloxy-4-medioxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.20 g, 0.64 mmol) and 2-bromo-4-cyanothiophene (0.12 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.030 g, 4%), copper(I) iodide (0.008 g, 6%), and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h. Hydr° Chloric acid (5 %) was added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatogπφhy, eluting widi 1 : 1 ethyl acetate:hexanes, followed by trituration from dicMoroii-e____e-hex_-.es, provided c_.-[4-(4-cyanothien-2- yledιynyl>4-(3-cyclc entyloxy^medιoxyphenyl)cyclohexan-l-ol] as a pale yeUow soUd (0.12 g, 45%), mp 70-71° C. Anal. (C25H27NO3S) calcd: C, 71.23; H, 6.46; N, 3.30; found: C, 71.24; H, 6.72; N, 3.14. Example 18 rLV-r4-f -__γdnι_i_n.y.nτy- -ιra^ yl ) thicn-2-ylethyny.l cyclohexan-1-oll 18a) 2-bromo-4-{5-meΛyl-[l,2,4]oxadiazol-2-yl)tMophene 2-Bromo-4-(5-meΛyl-[l,2,4]oxadiazol-2-yl)thiophene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp 72- 73° C 18b) ci--[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-me_hyl-[ l,2,4]oxa_iazol-2- yl)thien-2-yledιynyi] cyclohexan-1-ol] To a solution of rr<βnj-[4-(3-cycl(φentyloxy-4-medιoxyphenyl)-4-edιynyl- cyclohexan- 1 -ol] (0.25 g, 0.8 mmol) and 2-bromo-4-{5-methyl-[ 1 ,2,4]oxadiazol-2- yl)thiophene (0.20 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetra_άs(triphenylphosphine)palladium(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. Hydrchloric 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 cis [4-(3-cyclcpentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[ l,2,4]oxadia_ol-2- yl)thien-2-yledιynyl]cyclohexan-l-ol], which was further triturated from dicMcro_r_eti_ane-hex__r.es to give a white solid (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 Example 19 ci -r4-r2-aminopyrimidin-4-ylethvnvlV4-f3-cvclopentvloxv-4- cyclohexan- 1 -oil 19a) 4-iodo-2-mio_∞ ylpyrimidine 4-Iodo-2-thiomethylpyrimidine was prepared following a literature procedure (AJ. Majeed, 0. Antonsen, T. Benneche, K. Undheim. Tetrahedron 1989, 45, 993- 1006). 19b) c«-[4-(3-cyclopentyloxy-4-memoxyphenyl)-4-(2-memylthiopyrimidin-4- ylethynyl) cyclohexan- l-ol] To a solution of _r_w.-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-€thynyl- cyclohexan-1-ol] (0.30 g, 0.95 mmol) and and 4-iodo-2-dύomethylpyrimidine(0.50 g, 2.5 mmol, as a mixture of 4-iodo-2-dιiomethylpyrimidine and 4-chloro-2- diiomediylpyrimidine) in triediylamine (2 mL) under an argon atmosphere were added tetrakis(triphenylpho_phine)p_lladi_m(0) (0.044 g, 4%) and copper(I) iodide (0.010 g, 6%), and die mixture was heated at 80-85° C for 0.5 h. Ammonium cMoride was added and die mixture was extracted three times with dicMoromediane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:1 ediyl acetate:hexanes, provided _ , -[4-(3-cyclopentyloxy-4- medrøxyphenyl)-4-(2-me ylthiopyrirnidin-4-ylethynyl)cyclohex_m-l-ol] as a yeUow oti (0.36 g, 87%). 1H-NMR (400 MHz, 0X33) δ 8.45 (d, J=5.0 Hz, 1 H), 7.15 (d, J=2.3 Hz, 1 H), 7.03 (dd, J=8.5, 2.3 Hz, 1 H), 7.01 (d, J=5.0 Hz, 1 H), 6.84 (d, J=8.5 Hz, 1 H), 4.81 (m, 1 H), 3.84 (s, 3 H), 3.72 (m, 1 H), 2.57 (s, 3 H), 2.14 (br d, J=12 Hz, 2 H), 2.05 (m, 2 H), 1.8 - 2.0 (m, 10 H), 1.6 (m, 2 H) ppm. 19c) cj_--[ (3-cyclopentyloxy-4-medκ)xyphenyl)-4-(2-methylsulf myipyrimidin-4- yledιynyl)cyclohexan- 1 -ol] To a solution of c__--[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- memyldύopyrimidin-4-ylethynyl)cyclohexan-l-ol] (0.36 g, 0.82 mmol) in cMoroform (5mL) at -10° C under an argon atmosphere was dropwise added over 20 min. a solution of 3-cMoroperoxybenzoic acid (0.34 g, 1.97 mmol) in chloroform (3 mL). The reaction was stirred 3h at -10° C, then 3 h at room temperature. A second portion of 3-cMoroperoxybenzoic acid (0.11 g, 0.62 mmol) in cMoroform (1 mL) was added and stirring was continued for 1.5 h. The reaction was quenched widi sodium carbonate (5%), was extracted three times with dicMoromediane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting widi 2.5:97.5 medianoLdicMoromediane, provided αs-[4-(3-cyclσpentyloxy-4- n__tiκ>xyphenyl)-4-(2-π_e_-ylsulfθ-.y-pyrimidώ as a wMte foam (0.31 g, 81%), mp 75-77° C. *H-NMR (400 MHz, CDCI3) δ 8.84 (d, J=5.3 Hz, 1 H), 7.54 (d, J=5.3 Hz, IH), 7.10 (d, J=2.3 Hz, 1 H), 7.04 (dd, J=8.5, 2.3 Hz, 1 H), 6.85 (d, J=8.5 Hz, 1 H), 4.81 (m, 1 H), 3.85 (s, 3 H), 3.73 (m, 1 H), 3.38 (s, 3 H), 2.20 (br d, J=12 Hz, 2 H), 2.06 (m, 2 H), 1.8 - 2.0 (m, 10 H), 1.6 (m, 2 H) ppm. 19d) cis- [4-(2-ammcφyrimkiin-4-yledιynyl)-4-(3-cyclopentyloxy-4-nκΛoxyphenyl> cyclohexan- l-ol] Into a solution of cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- memylsulfonylpyrimidin-4-ylethynyl) cyclohexan- l-ol] (0.31 g, 0.66mmol) in methanol (5 mL) at -78° C was condensed liquid ammonia (5 mL). The pressure tube was sealed and die reaction was stirred at room temperature for 2 h. After cooling, the solvents were evaporated. Purification by flash chromatography, eluting wid 4:% medianohdicMoromethane, foUowed by trituration from dicMσrometiiane-ether- hexanes, provided cw-[4-(2-am opyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-ol] as a white solid (0.19 g, 74%), mp 173-174° C. AnaL (C 4H29N3O3 • 0.25 H2O) calcd: C, 69.96; H, 7.22; N, 10.20; found: C 69.66; H, 7.10; N, 10.11. Example 20 _i.-f4- ( 2-_n nnpvr.m_H.n-5-ylethvn^^ cvclohcxan-l-ol " . To a solution of ιrαns-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.20 g, 0.64 mmol) and and 2-a____o-_^bromopyrimidine (0.55 g, 3.2 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.030 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and die mixture was heated at 80-85° C for 0.5 h. Water was added and die mixture was extracted diree times widi dicMoromediane, was dried (potassium carbonate) and was evaporated. Purification by two successive flash chromatographies, eluting first with 5:95 medianohdicMoromethane, men widi 3:97 medianoLdicMoromediane, provided cis-[4- (3-cyclopentyloxy-4-memoxyphenyl)-4-(2-amm<φyrimidin-5-yledιynyl) cyclohexan-1- ol] as a tan-brown soUd (0.076 g, 29%), mp 136-137° C Anal. (C24H29N3O3 • 0.75 H2O) calcd: C, 68.47; H, 7.30; N, 9.98; found: C, 68.25; H, 7.09; N, 9.78. Example 21 cis-r4-(Φiazol-2-yledιvnylV4-(3-cvclopen To a solution of _ _ιnj-[4-(3-<7clopentyloxy-4-m__hoxyphenyl)-4-ethynyl- cyclohexan- l-ol] (0.15 g, 0.48 mmol) and and 2-bromothiazole (0.20 mL, 2.4 mmol) in triethylamine (1.5 mL) under an argon atmosphere were added tetra___s(_riphenyl phosphine)p_Jladium(0) (0.022 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and die mixture was heated at 80-85° C for 1 h. Ammonium cMoride was added and die mixture was extracted three times wi h dicMoromediane, dried (magnesium sulfate), and evaporated. Purification by two successive flash chromatograpMes, eluting first with 6:4 ediyl acetate:hexanes, tiien with 2:98 methano dichloromethane, provided ci_-[4-(3-cyclopentyloxy-4- t_eΛoxyphenyl)-4-(2-am cφyrimidin-_HyleΛynyl)cyclohexω as an off-wMte foam (0.13 g, 68%), mp 45-48° C. Anal. (C23H27NO3S • 0.5 H2O) calcd: C, 67.95; H, 6.94; N, 3.45; found: C, 67.91; H, 6.76; N, 3.39. Example 22 trfly y-r4-r3-cvclopentvloxv-4-methoxyphenvIV4-fpvrid-2-vlethvnvl)cvclohexvl-l- amine] 22a) c«-[4-(3-eyclopentyloxy-4-meώoxyphenyl)-4-ethynylcyclohexy l-amine] To a solution of tr_wu * -[4-(3-cyclopentyloxy-4-medioxyphenyl)-4-ethynyl- cyclohexan-1-ol] (1.0 g, 3.18 mmol), phthalimide (0.70 g, 4.77 mmol) and triphenylphosphine (1.25 g, 4.77 mmol) in tetrahydrofuran (32 mL) was dropwise added die hyl azodicarboxylate (0.75 mL, 4.77 mmol), and die solution was stirred under an argon atmosphere at room temperature for 2 h. Evaporation and purification by flash chromatogπφhy, eluting with 2:8 ediyl acetate hexanes, provided d e intermediate phthalimide (1.43 g) as a waxy wMte solid, mp 45-52° C. This was dissolved in 2:1 edianohtetrahydrofuran (30mL), was treated with hydrazine hydrate (1.55 mL, 32 mmol) and was stirred under an argon atmosphere at room temperature for 4 days. Water was added and die mixture was extracted tiiree times with 10:90 methano dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatogπφhy, eluting widi 0.5:5:95 ammonium hydroxide:meth__nol:dichloromethane, provided α_:-[4-(3 -cyclopentyloxy-4- methoxyphenyl)-4-ediynyl-cyclohexyl-l-amine] as a colorless oil (0.71 g, 72%). *H- NMR (400 MHz, CDCI3) δ 7.17 (d, J=2.2 Hz, IH), 7.09 (dd, J=8.5, 2.2 Hz, IH), 6.82 (d, J=8.5 Hz, IH), 4.81 (m, IH), 3.82 (s, 3 H), 3.26 (br s, IH), 2.36 (s, IH), 2.1- 2.2 (m, 4 H), 1.8 - 2.0 (m, 10 H), 1.6, (m, 2H) ppm. 22b) cύ-[l-rerf-butoxyca_i»nylammo-4-(3-cyclcφentyloxy-4-methoxyphenyl)-4- ethynylcyclohexane] A mixture of cw-[4-(3-cyclcf_»tyloxy-4-medιoxyphenyl)-4-edιynylcyclohexyl- 1-amine] (0.55 g, 1.75 mmol) and di-t -butyldicarbonate (0.42 g, 1.93mmol) in dicMoromethane (8mL) was stirred 20 h and was evaporated. Purification by flash chromatography, eluting widi 2:8 ediyl acetate:hexanes provided, cis-[\-tert- butoxycartx>nylam_Jio-4-(3-cyclopentyloxy-4-n^ as a colorless oU (0.70 g, 97%). *H-NMR (400 MHz, CDCI3) δ 7.13 (d, J=2.2 Hz, IH), 7.02(dd, J=8.5, 2.2 Hz, IH), 6.84 (d, J=8.5 Hz, IH), 4.81 (m, IH), 4.64 (m, 1 H),3.84 (s, 3 H), 2.36 (s, IH), 2.05 (m, 2 H), 1.6 - 2.0 (m, 14 H), 1.45, (s, 9 H) ppm. 22c) trans-[ l-rβn-butoxycarix>nylaπ_ino-4-(3-cycl(^ntyloxy^methoxyphenyl)-4- fpyrid-2-yledιynyl-cyclohexanel To a solution of cis -[l-rerr-butoxyc_rbonylamino-4-(3-cycl<φentyloxy-4- methoxyphenyl)-4-cώynylcyclohexane] (0.35 g, 0.85 mmol) and 2-bromopyridine (0.80 mL, 8.5 mmol) in piperidine (2.5 mL) under an argon atmosphere were added tctrakis(triphenylphospMne)p__l_dium(0) (0.039 g, 4%), copper(I) iodide (0.010 g, 6%) and a small crystal of triphenylphosphine, and d e mixture was heated at 80-85° C for 0.5 h in the dark. Water was added and the mixture was extracted tiiree times widi dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting widi 25:75 ediyl acetate:hexanes .provided trans-[\-tert butoxvcarrx.nvlarmno-4-(3-cyclopentyloxy-4-__cthoxvphenylV4- yrid-2-yledιynyU cyclohexane] as a Ught yellow solid (0.30 g, 72%), mp 69-70° C. iH-NMR (400 MHz, CDθ3) δ 8.57 (d, J=4 Hz, 1 H), 7.66 (dt, J»8, 4 Hz, 1 H), 7.42 (d, J=8 Hz, 1 H), 7.26 (br, 1 H), 7.17 (d, J-2.2 Hz, IH), 7.09 (dd, J-8.5, 2.2 Hz, IH), 6.85 (d, J=8.5 Hz, IH), 4.82 (m, IH), 4.64 (br s, 1 H), 3.85 (s, 3 H), 2.2 (m, 2H), 1.8 - 2.1 (m, 12 H), 1.6 (m, 2H),1.45, (s, 9 H) ppm. 2_ ) -rα/__^[4-(3-cyclopentylσxy-4-methoxyphOT^ aαύne] To a solution of trαnj-[l-ιerr-butoxycarbcmyl____ιo-4-(3-cyclopentyloxy-4- tnedιoxyphenyl)-4-(pyrid-2-yled ynylcyclohexane] (0.30 g, 0.61mmol) in dicMoromediane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.60 mL, 7.89 mmol). The reaction was stirred at room temperature for 6 h, was cooled to 0° C, quenched widi sodium bicarbonate, was diluted wid water, was extracted widi three times dicMoromediane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatogπφhy, eluting widi 0.7:7:93 ammonium hydroxide:med_uιol:dicMoromethane provided £r<uu-[4-(3-cyclopentyk>xy-4- methoxyphenyl)-4-φyrid-2-ylethynyl)cyclohexyl-l-amine] as a very viscous oU (0.19 g, 82%). !H-NMR (400 MHz, CDCI3) δ 8.59 (d, J=4 Hz, 1 H), 7.63 (dt, J=7.8, 4 Hz, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 7.26 (m, 1 H), 7.22 (m, 2H), 6.81 (d, J=8.5 Hz, IH), 4.84 (m, IH), 3.81 (s, 3 H), 3.4 (br s, 1 H), 2.31 (m, 4H), 1.8 - 2.0 (m, 10 H), 1.6 (m, 2 H) ppm Anal. (C25H30N2O2 • 0.5 H2O) calcd: C, 75.16; H, 7.82; N, 7.01; found: C, 75.42; H, 7.77; N, 6.91. Example 23 _rfl_tt-r4-(3-cvclopentvloxv-4-methoxyph^ aπnamidcL To a preparation of acetic formic anhydride (0.035 mL, 0.38 mmol) at 0° C under an argon atmosphere was added a solution of rrαn_?-[4-(3-cyclσpentyloxy-4- metiιoxyphenyl)-4-(pyrid-2-yledιynyl)cyclohexyl- l-amine] (0.096 g, 0.24 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirred for 3 h at room temperature, was diluted widi dichloromethane, was washed widi sodium bicarbonate and water, was dried (magnesium sulfate) and was evaporated Purification by flash chromatograhy, eluting widi 5:95 medιanol:dicMoromethane, provided trans -[4-(3-cyclopentyloxy-4- meAoxyphenyl)-4-(pyrid-2-yledιynyl)cyclohexyl-l-fαrrr-_m_ide] (which contains a trace of acetamide) as a wMte foam (0.08 g, 79%), mp 75-76° C Anal. (C26H30N2O3 0.375 H2O) calcd: C, 73.43; H, 7.26; N, 6.59; found: C, 73.46; H, 7.29; N, 6.25. Example 24 _Tflng-r4-G-cvcl-φen-γloxy-4-i--sΦ^ vl.dιien-2-vlethynynςyclplι χyl-l-a mj "e1. cy_lo _-yl * __ ____ » . salt 24a) 2-bromo-5-_(5-me_ yl-[l^,4]ox_____ol-2-yl)_ιiophene 2-Bro___o-5-_5-meΛyl-[l,2,4]oxadia__ol-2-yl)tf__ophene was prepared by standard chemistry weU known to those versed in the an and was a wMte soUd, mp 48- 49° C 24b) ιrαn$-[l-ι -butDxyc__t>onylaι__-_o-^ (_^__βdιyl-[l^,4]oxadia_ol-2-yl)_ιien-2-yle_ιynyl]cyclohex_ne] To a solution of cis -[ 1 - βrr-butoxyc_ιbonyl_αιιino-4-(3-cyclopentyloxy-4- methoxyphenyl)-4-edιynylcyclohexane] (0.30 g, 0.73 mmol) and 2-bromo-5-(5-methyl- [l,2,4]ox_dia_»l-2-yl)tiιiophene (0.18 g, 0.73 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetr__is(triphenylphosphine)palla_ium(0) (0.033 g, 4%) and copper(I) iodide (0.008 g, 6%) and a smaU crystal of triphenylphosphine, and die mixture was heated at 80-85° C for 1 h. Water was added and die mixture was extracted three times with dicMoromediane, was dried (magnesium sulfate) and was evaporated Purification by flash chromatogπφhy, eluting with 2:8 ediyl acetate:hexanes, followed by trituration from dichlσromethane-hexanes, provided trans-[ 1 -rerr-butoxyc_rbonyl__-ήno-4-(3-cyclcpentyloxy-4-medκ)xyphenyl)-4-[5-(5- memyl-[l,2,4]oxadiazol-2-yl)dιien-2-yled ynyl]cyclohexane] as a yellow foam (0.38 g), containing ~ 40 % of l,4-_»__-{[f-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l- cyclohexyl-l-a_nir_e]-4-yl}buta-l,3-diyne by ^H-NMR. 24c) »r__j-[4-(3-< clopentyloxy-4-methoxyphenyl)-4-[5-(5-metiιyl-[ l,2,4]ox_diazol- 2-yl)dιien-2-yledιynyl]cyclohexyl-l -amine], cyclohexylsulfamate salt A solution of trans-[ 1 - βrr-butDxyc_Λonyl_α__uιo-4-(3-cycl<φcntyloxy-4- methoxyphenyl)-4-[5-(5-methyl-[ 1 ,2,4]oxad___»l-2-yl)tMen-2-ylethynyl] cyclohexane] (0.38 g, containing 40 % of d e dimer) in dichloromethane (10 mL) at 0° C under an argon atmosphere was treated with trifluoroacetic acid (0.50 mL, 6.5 mmol) and die mixture was stirred far 24 h at room temperature. The solution was quenched widi sodium bicarbonate at 0° C, was diluted with water, was extracted diree times with 10:90 methanoLdicMoromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatogaphy, eluting widi 0.5:5:95 ammonium hydroxide:medianol:dicMoromediane, provided ir αn_ -[4-(3-cyclopentyloxy-4- methoxyphenyl)-4-[5-(5-methyl-[ 1 ,2,4]oxadi_zol-2-yl)tMen-2-ylethynyl]cyclohexyl- 1 - amine] as a glassy soUd (0.18 g, 59 %). TMs was dissolved in acetone (0.5 mL) and added to a solution of cyclohexylsulfamic acid (0.066 g, 0.37 mmol) in acetone (0.5 mL). The salt was isolated and die free amine was recovered. A second chromatography using the same solvent system provided free amine (0.048 g), wMch was treated with cyclohexylsulfamic acid (0.018 g, 0.10 mmol) in acetone (1 mL). After die addition of edier (20 mL), the precipitate was filtered off to provide trans-[4- (3-cyclopentyloxy-4-medκ>xyphenyl)-4-[5-(5-medιyl-[ 1 ,2,4]oxadiazol-2-yl)thien-2- ylethynyl]cyclohexyl-l-amine], cyclohexylsulfamate salt (0.043 g, 18%) as a wMte solid, mp 134-135° C AnaL (C33H44N4O S2O.5 H2O) calcd: C, 59.52; H, 6.81; N, 8.41 ; found. C, 59.37; H, 6.71; N, 8.46. Example 2f> cfr-[4-(3^topemytoxy^πιctfιoxyp._6nylW 25a) cis-[ l-j -butDxyα__onyla__i_o-4-(3-cyd^ ethynyl-cyclohexane] A solution of 4-(3-cyctopentytoxy-4-me__oxyphenyl)-4-edιynyl-cyclc-iexan-l- one (0.82g, 2.63 mmol), ammonium acetate (2.03 g, 26 mmol), sodium cyanoborohydride (0.17 g, 2.63 mmol) and several 4Λ molecular sieves in methanol (10 mL) was stirred under an argon atmosphere at room temperature for 3 days. Several crystals of methyl orange were added, then hydrogen cMoride-saturated methanol to ~ pH 3. The reaction was made basic with sodium hydroxide (10 %), was extracted widi 10:90 meth__ιol:dicMc_omethane, was dried (potassium carbonate) and was evaporated to provide crude _rαns-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4- eώynylcyclohexyl-1-amine] as a yeUow oU (0.88 g, 100 %). A solution of the intermediate in dicMoromethane (15 mL) was treated widi di-terr.-butyldicarbonate (0.63g, 2.89 mmol), was stirred 5 h and was evaporated. Purification by flash chromatography, eluting with 15: 85 ethyl acetate:hexanes, provided trans-[l-tert- t_Hitoxyc__rbonyl____u_o-4-(3-cyclopentyloxy-4-me as a wMte foam (0.57 g, 53%, -NMR shows ~ 20 % cis isomer), mp.39-43° C. 1 H- NMR (400 MHz, OX33) δ 7.11 (d, J=2.2 Hz, IH), 7.04 (dd, J=8.5, 2.2 Hz, IH), 6.82 (d, J=8.5 Hz, IH), 4.80 (m, IH), 4.6 (m, 0.2 H), 4.5 (m, 0.8 H), 4.0 (m, 0.2 H), 3.84 (s, 0.6 H), 3.83 (s, 2.4 H), 2.43 (s, 0.8 H), 2.36 (s, 0.2 H), 1.6 - 2.1 (m, 16 H), 1.46, (s, 9 H) ppm 25b) cis-[ 1 -ϊβrt-butoxyc__tonyl___ιbo^(3-cyclcφentyloxy-4-met--θxyphenyl)^ (pyrid-2-yleώynylcyclohexane To a solution of rrαn_-[ l-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4- med_oxyphenyl)-4-e_ιynylcyclohexane] (0.45 g, 1.09 mmol) and 2-bromopyridine (1.0 mL, 11 mmol) in piperidine (3 mL) under an argon atmosphere were added tetr__ris(triphenylphosphine)paUadium(0) (0.050 g, 4%), copperfl) iodide (0.012 g, 6%) and a smaU crystal of triphenylphosphine, and die mixture was heated at 80-85° C for 0.5 h in the dark. Water was added and d e mixture was extracted tiiree times with dicMoromediane, was dried (magnesium sulfate) and was evaporated Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided c«-[l-tert- butoxycarrx>nylamino-4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(pyrid-2- ylediynylcyclohexane] as a yeUow foam (0.41 g, 78%, contains ~ 35 % trans isomer by iH-NMR), mp 40-43° C. tø-NMR (400 MHz, OX33) δ 8.4 (m , 1 H), 7.65 (m, 1 H), 7.4 (d, 1 H), 7.1 (m, 3 H), 6.85 (m, 1 H), 4.8 (m, IH), 4.6 (m, 0.65 H), 3.85 (s, 1 H), 3.84 (s, 2 H), 3.55 (m. 0.65 H), 1.5 - 2.2 (m, 16 H), 1.45, (s, 9 H) ppm 25c) ct_-[4-(3-cyclopcntyloxy-4-memoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexyl-l-amine] To a solution of cύ-[l-rerr-butoxy(»rt my-amiικ>-4-(3-cyclopentyloxy-4- methoxyphenyl 4-(pyrid-2-ylethynylcyclohexane] (0.41 g, 0.84 mmol) in dicMoromethane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.65 mL, 8.4 mmol). The reaction was stirred at room temperature for 20 h, was cooled to 0° C, was quenched with sodium bicarbonate, was diluted with water, was extracted twice with 10:90 medianohdicMσromediane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 0.5:5:95 ammonium hydroxide:me anol:dicMoromedιane, foUowed by trituration from ether, provided cw-[4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(pyrid-2- yledιynyl)cyclohexyl-l-aπ_ine] as a wMte soUd (0.23 g, 69%, containing ~ 20 % of die trans isomer), mp 78-80° C. Anal. (C25H30N2O2) calcd: C, 66.06; H, 6.65; N, 6.16; found: C, 65.73; H, 6.96; N, 5.98. Example 26 ci_?-r4- -cvclopentvloxv-4-methoxyphenylV4- yrid-2-vlethvnyl^clohexyl-l- foπLamidcl To a preparation of acetic formic anhydride (0.057 mL, 0.64 mmol) at 0° C under an argon atmosphere was added a solution of cw-[4-(3-cyclopentyloxy-4- medιoxyphenyl)-4-(pyrid-2-yledιynyl)cyclohexyl-l -amine] (0.16 g, 0.40 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirred for 3 h at room temperature, was diluted widi dicMoromethane, was washed widi sodium bicarbonate and water, was dried (magnesium sulfate) and was evaporated Purification by flash chromatograhy, eluting widi 5:95 methanol.dicMoromethane, provided ci5-[4-(3-cyclopentyloxy-4- memoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-l-formamide] (wMch contains a trace of acetaα-iide) as a white foam (0.08 g, 79%), mp 80-81° C. Anal. (C26H30N2O3 0.375 H2O) calcd: C, 73.43; H, 7.26; N, 6.59; found: C, 73.46; H, 7.29; N, 6.25. Example 27 ci -r4-f3-c -cl-φentvloxy-4-methoxyphenvn-4-r5-(5-meωvl-ri_2.41oxadiazol-2- vnthien-2-vlethvnvllcvclohexvl-l-aminel. cvclohexvlsulfamate salt 27a) 2-bromo-5-{5-mediyl-[ 1 ,2,4]ox_diazol-2-yl)tiιiophene 2-Bromo-5-{5-methyl-[l^,4]oxa_ia-θl-2-yl)dιiophene was prepared by standard chemistry weU known to those versed in the an and is a white soUd, mp 48- 49° C. 27b) cw-[ l-te^butoxyca_rbonyl______no-4-(3^ (5-methyl-[ 1 ^,4]oxadiazol-2-yl) thien-2-ylcthynyl]cyclohcx_ne] To a solution of rrans-[4-(3-cyclopentyloxy-4-medioxyphenyl)-4-ediynyl- cyclohexyl-1-amine] (0.21 g, 0.52 mmol) and 2--ro___-5-{5-methyl-[l A4]oxadiazol- 2-yl)dιiophene (0.13 g, 0.52 mmol) in triethylamine (5 mL) under an argon atmosphe were added tetra_ds(triphenylphosphine)p_-ladium(0) (0.024 g, 4%), coρper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and d e mixture was heated at 80-85° C for 1 h. Ammonium cMoride was added and the mixture was extracted three times wid dicMoromethane, was dried (magnesium sulfate) and was evaporated Purification by two successive flash chromatographies, eluting first wi h 2:8 ediyl acetate:hexanes, then with 2:8 acetone:hex__es, provided cύ-[l-t_rt- butoxyca_ »nyl_ j ___-o-4-(3-cyclopentyloxy-4-memoxyphenyl)-4-[5-(5-__e [l^,4]oxadiazol-2-yl)dιien-2-ylethynyi]cyclohexane] as a wMte foam (0.20 g, 69%, contains - 20 % dimer impurity by -NMR), mp 60-68° C . 27c) ci5-[4-(3-cyclopentyloxy-4-memoxyphenyl)-4-[5-(5-memyl-[l^,4]oxa__ϋ__zol-2- yl)dιien-2-ylethynyl]cyclohexyl-l -amine], cyclohexylsulfamate salt A solution of cis -[l-t€n-__toxyc__ tonylamino-4-(3-cyclcpentyloxy-4- methoxyphenyl)-4-[5-(5-methyl-[ 1 ^,4]oxadiazol-2-yl)dιien-2-ylethynyl]cyclohexane] (0.21 g, containing 20 % of the dimer) in dicMoromethane (5 mL) at 0° C under an argon atmosphere was treated widi trifluoroacetic acid (0.28 mL, 3.6 mmol) and was stirred 24 h at room temperature. The solution was quenched widi sodium bicarbonate at 0° C, was diluted widi water, was extracted tiiree times with 10:90 methanoLdicMoromed ane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatogaphy, eluting with 0.3:3:97 ammonium hydroxide:mem__nol:dichloro___ethane, provided c«-[4-(3-cyclopentyloxy-4- memoxyphenyl)-4-[5-(5-memyl-[l,2,4]ox_di__»--2-y^ amine] as a colorless glass (0.11 g, 0.24 mmol, 69%). This intermediate was dissolved in acetone (0.5 mL) and was added to a solution of cyclohexylsulfamic acid (0.045 g, 0.24 mmol) in acetone (1 mL). After the addition of ether, die precipitate was filtered off to provide c«-[4-(3-cycl<jpentyloxy-4-___et_κ)xyphenyl)-4-[5-(5-medιyl- [l,2,4]oxadiazol-2-yl)tMen-2-yiethynyl]cyclohexyl-l-amine], cyclohexylsulfamate salt (0.14 g, 58%) as a wMte soUd, mp 152-154° C. Anal. (C33H44N4O6S2) calcd: C, 60.34; H, 6.75; N, 8.53; found: C, 60.01; H, 6.63; N, 8.32. Example 28 cis- 4-( 3-cvclopentvloxv-4-memoxvphenvn-4-f 2-f3-( 3-methvl.1 _2.41oxadiazol-5- yltøhenyllcthynylteyclohexan-l-oll. 28a) 5-(3-iodophenyl)-3-methyl[ 1 ,2,4]oxadiazøle 5-(3-Iodophenyl)-3-medιyl[l,2,4]oxadi_zole was prepared by standard chemistry weU known to tiiose versed in the an and was a wMte soUd, mp 102-103° C. 28b) cύ -[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[ 1 ^,4]oxadiazol-5- yl)phenyl]edιynyl)cyclohexan-l-ol] To a solution of rβn_-[4-(3-<yclopentyloxy-4-methoxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.11 g, 0.35 mmol) and 5-(3 -iodophenyl)-3-methyl[l,2,4]oxadiazole (0.15 g, 0.52 mmol) in triethylamine (4 mL) under an argon atmosphere were added tet___άs(__phenylphosphi__e)p______iuπ__ (0.017 g, 0.015 mmol), copper(I) iodide (0.004 g, 0.021 mmol) and a ________ crystal of triphenylphosphine. After heating the mixture at 70° C for 1.5 h„ the reaction was quenched by addition of aqueous ammonium cMoride solution, and die solvent was concentrated. The mixture was extracted three times with methylene cMoride, and the organic phase was washed with water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting widi 45:55 ediyl acetate:hexanes and crystallizing from ethyl ether, provided ciϊ-[4-(3-cyclopentyloxy-4-methoxyphenyI)-4-(2-[3-(3-me yl[l^,4]ox____azol-5- yl)phenyl]ethynyl)cyclohexan-l-ol] as a wMte solid (0.144 g, 87%), mp 71.5-73.5 ° C. Anal. (C29H32N2O4) calcd: C, 73.71; H, 6.83, N, 5.93 found: C, 73.60; H, 6.91, N, 5.76. Example 29 __f-r4-f 3-cvclopentvloxv-4-methoxvphenyn-4-f 2-r3-(5-methvir 1.3.41oxadiazol-2- ylfrhcnvHeth v-iyl _n__lohexan-l -oil. 29a) 2-(3-iodophenyl)-5-methyl[l,3,4]oxadiazole 2-(3-Iodophenyl)-5-methyl[l,3,4]oxadiazole was prepared by standard chemistry weU known to those versed in die an and is a wMte solid, mp 112- 113.5 ° C. 29b) ci_-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[ 1 ,3,4]oxadiazol- 2-yl)phenyl]edιynyl)cyclohexan-l-ol] To a solution of _r ns-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-edιynyl- cyclohexan-1-ol] (0.125 g, 0.40 mmol) and 2-(3-iodophenyl)-5- methyl[l,3,4]oxadiazole (0.171 g, 0.60 mmol) in triethylamine (7 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)paUadium (0.020 g, 0.017 mmol), cσpperfl) iodide (0.0042 g, 0.022 mmol) and a small crystal of triphenylphosphine. After heating the mixture at 75° C for 1.75 h, the reaction was quenched by addition of aqueous ammonium chloride solution, and die solvent was concentrated The mixture was extracted three times with methylene chloride, and die organic phase was washed widi water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting widi 40 to 50% ethyl acetate in methylene chloride and crystallizing from ethyl edier, provided cύ-[4-(3-cyclopentyloxy-4-medιoxyphenyl)-4- (2-[3-(5-methyl[l,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclc_ιexan-l-ol] as a wMte soUd (0.119 g, 63%), mp 117.5-119 ° C. Anal. (C29H32N2O4 I/8H2O) calcd: C, 73.36; H, 6.85, N, 5.90 found: C, 73.25; H, 6.94, N, 5.75. -NMR (400 MHz, OX33) δ 8.12 (s . IH), 7.98 (d-d. J=1.4 Hz;J=7.9 Hz, IH), 7.60 (d-d, J=1.3 Hz, J=7.8 Hz, IH), 7.46 (t, J=7.8 Hz, IH), 7.19 (d, J=2.2, IH), 7.10 (d-d, J=2.1 Hz, J=8.5 Hz, IH), 6.85 (d, J=8.5 Hz, IH), 4.81 (p, J=4.3 Hz, IH), 3.85 (s, 3H), 3.73 (m, IH), 2.63 (s, 3H), 2.2-1.8 (m, 14H), 1.7-1.5 (m, 7H with H2O). Example 30 ci--r4-(3-cyclcφen oxv-4-medιoxvphenvn-4-(2-r3-(5-memviri^.41nχaH_aτnl- _. yltøhcnvlletiιvnvncyclohcxan-1 -oil. To a solution of 4-(3-cyclopentytoxy-4-medιoxyphenyl)-4-(2-[3-(5- __cthyUl^,4]ox_u_iazol-3-yl)phenyl]edιynyl)cyclohexan-l-one (0.084 g, 0.18 mmol, prepared as described in co-pending appUcation P50283 filed on even date herewidi) in 1 ,2-dimethoxyethane (3 mL) under an argon atmosphere was added dropwise a solution of sodium borohydride (0.015 g, 0.40 mmol) in 1,2-dimethoxy ethane (5 mL). After 2 h stirring at room temperature, the reaction was quenched by addition of aqueous ammonium cMoride solution. The solvent was concentrated and die residue was extracted into methylene cMoride, was washed widi water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting wid 35% ediyl acetate in hexanes and crystallizing from ediyl edier, provided α_-[4-(3- cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[ 1 ,2,4]oxa _azol-3- yl)phenyl]ethynyl)cyclohexan-l-ol] as a white solid (0.050 g, 58%), mp 101-103 ° C. AnaL (C29H32N2O4.I/5H2O) calcd: C, 73.15; H, 6.86, N, 5.88 found: C, 73.11; H, 6.85, N, 5.85. -NMR (400 MHz, CIX33) δ 8.18 (s , IH), 8.00 (d, J=7.9 Hz, IH), 7.58 (d, J=7.8 Hz, IH), 7.43 (t, J=7.8 Hz, IH), 7.19 (d, J=2.2, IH), 7.10 (d-d, J=2.1 Hz, J=8.5 Hz, IH), 6.85 (d, J=8.5 Hz, IH), 4.82 (p, J=4.3 Hz, IH), 3.85 (s, 3H), 3.72 (m, IH), 2.67 (s, 3H), 2.2-1.8 (m, 13H), 1.7-1.5 (m, 6H with H2O). The odier compounds of d is invention may be prepared by proceeding in a similar manner, but substituting d e appropriate starting materials and intermediates for those recited in tiiis Example. Examples are: ci_-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- trifluoromedιyl[l^,4]ox_di_-_>l-3-yl)phenyl]edιynyl)cyclohexan-l-ol], ci_»-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3- trifluoromethyU 1 ^,4]oxadiazol-5-yl)phenyl]e_ιynyl)cyclohex_n- 1 -ol], ci_f-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- tr__-_roπ_e_ιyl[l,3,4]ox__iazol-2-yl)phenyl]e_ιynyl)cyclohex_n- l-ol], and c_f-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- trifluoromethyU 1 ,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan- 1 -ol]. Example 31 Preparation of cij-4-f3- _^lopentvloxy-4-methoxyphenvn-4-r3-f5-trifluoromethvl- Il^ l xa-lia^l-g-yDphcnylehynyDcyclohcxan-l-ol 31a) 3-(3-iodophenyl)-5-trifluoromethyl-[ 1 ,2,4]oxadiazole 3-(3-Iodophenyl)-5-trifluoro__«thyl-[l,2,4]ox-_di___ole was prepared by standard chemistry weU known to those versed in the an and was a wMte solid, mp 36- 37° C. 31b) cw-4-(3-Cyclcpentyloxy-4-n_e_5oxyphenyl)-4-[3-(5- fluoromediyl- [l,2,4]oxadiazol-3-yl)pheny-ethynyl)cyclohexan-l-ol A stirred mixture of _rαnj-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.22 g, 0.7 mmol) and 3-(3-iodophenyl)-5-trifluoron__ethyl- [l,2,4]oxadiazole (0.24 g, 0.7 mmol) in dry triethylamine (5 mL) was treated under an argon atmosphere trace tett_Jris(triphenylpho_phine)palladium and copper(I) iodide. The mixture was refluxed for 0.2 h, was coo d to RT and was evaporate The residue was adsorbed onto silica gel and was purified by flash chromatography eluting with 1 : 1 hexanes/ethyl acetate and trituration from hexanes/ ethyl acetate provided d e tide compound as a white soUd (0.26g, 71%), mp 85-86° C Example 32 Preparation of cty-4-f3-cvclopentvloxv-4-methoxvphenvlV4-r3-(S-methyl- n .3.41thiariiazol-2-vl)phenvlethvnvncvclo-_exan-l-ol 32a) l-iodo-3-(5-memyl-[l,3,4]thi__diazol-2-yl)benzene l-lodo-3-(5-methyl-[l,3,4]dιiadiazol-2-yl)benzene was prepared by standard chemistry weU known to those versed in the a and was wMte soUd, mp. 86-89° C. 32b) 4-(3-cyclc entyloxy-4-rrιethoxyphenyl)-4-[3-(5-memyl-[l,3,4]tMam___-l-2- yl)phenyledιynyl]cyclohexan-l-ol To a solution of _r n_ , -[4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.15 g, 0.48 mmol) and 1 -iodo-3-(5-methyl-[l,3,4]thiadiazol-2- yl)benzene (0.15 g, 0.48 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace te_raJάs(triphenylphosphine)pa__dium(0) and copper(I) iodide. The mixture was refluxed for 0.20 h, was cooled to room temperature and was concentrated in vacua. Purification by flash chromatography, eluting with 1:1 hexanes ethyl acetate and trituration from hexanes/ethyl acetate provided die tide compound as a wMte soUd (0.17g, 74%), m.p. 129-130° C. Example 33 Preparation of _ra/_;-r4-f2-ace___ido vrimidin-5-vlethvnvlV4-(3-cvclot)entvlov-4- methoxvphen vl tavclohexan- l-oll To a suspension of cw-[4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.50 g, 1.59 mmol) and 2-acet____-do-5-_romopyrimidine (0.35 g, 1.59 mmol) in triethylamine (7 mL) under an argon atmosphere was added tetra_is(triphenylphosphine)palla_ium(0) (0.073 g, 4%) and copper(I) iodide (0.019 g, 6%) and the mixture was heated at 80-85° C for 0.75 h. Water was added and the mixture was extracted tiiree times widi dicMoromethane, was dried (magnesium sulfate) and was evaporated. The residue was pre-adsorbed onto silica and purified by chromatoraphy on silica gel, eluting the nonpolar impurities with 30:70 to 50:50 ediyl acetrø:dichloromethane, and eluting die desired product in 60:40:1 ethyl acetate:dicMoromethane:methanol. TMs was crystallized from ethyl acetate:hexanes to provide trαw-[4(χ2-acetamid<φyrimid_n-5-yl-ethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-ol] as a wMte solid (0.47g, 66%), πφ 163-164° C. Anal. (C26H31N3040.25 H20) calcd: VC, 69.47; H, 6.95; n, 9.35; found: C, 69.27; H, 6.98; N, 8.97. Example 34 Preparation of tra w 4-(2-amin pyrimidin-^yl-_thynylH-(3-cyclopcntyloxy- - metfioxyphmyl Vcyclohexan- l-ol To a solution of sodium medioxide (0.137 g, 2.5 mmol) in dry methanol (3.8 mL) was added via cannula a solution of trα_5-[4-(2-acetamidopyrimidin-5-ylethynyl 4-(3-cyclopentyIoxy-4-methoxyphenyl)cyclohexan-l-ol] (0.32 g, 0.71 mmol) in dry methanol (7.6 mL including rinses). After stirring for 3 h at 25°C, the reaction was quenched into cold water, extracted widi methylene cMoride, filtered, dried (magnesium sulfate) and concentrated in vacua. The resulting sotid was recrystallized from ethyl acetate:hexandes and dried in vacua at 80° C to afford die desired product as a wMte soUd (0.154 g, 53%), mp 170.5- 172.0°C. Anal. (C24H29N3030.1251120) calcd: C, 70.35; H, 7.20; N, 10.25; found: C, 70.34; H, 7.18; N, 10.14. Example 35 Preparation of __f-r4-Q-methvl_mιinopvrimidin-5-vlethvnvlV4-(3-cvclopentvloxv-4- mcthoxyphenvltavclohexan-1-oH 35(a) 5-bromo-2-_-_ethyl_cet__-ddopyrimidine, A mixture of 2-_x tami_to-5-bromopyrimidine (0.22g, 1 mmol,) potassium carbonate (0.21g, 1.5 mmol) and iodomediane (O.lOmL, 1.6 mmol) in tetrahydrofuran was stirred at room temperature for three days. The mixture was filtered, was evaporated and was purified by flash chromatography, eluted with 2:8 ediyl acetate:hexanes, to provide die desired product as a white soUd (0.03g, 13%) Η-NMR (dX3 3 , 400 Mhz) δ 8.58 (s, 2H), 3.39 (s, 3H), 2.39 (s, 3H) ppm 37b) cis -[4-(2-memylaceta_mdopyrirmdin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4^ medιoxyphenyl)-cyclohexan- l-ol], To a suspension of trans -[4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-€thynyl- cyclohexan-1-ol) (0.20 g, 0.64 mmol) and a mixture (-6:4) of 2-acetamido-5- bromopyrimidine and 5-b_omo-2-meΛylacet___ri_bpyri_mdine (0.14 g, -0.32 mmol of each component) in αiethylamine (5 mL) under an argon atmosphere was added tetrakis(triphenylphospMine)p__l_dium(0) (0.03 g, 4%) and copper(I) iodide (0.008 g, 6%) and the mixture was heated at 80-85° C for 0.5 h. The reaction was cooled, water was added and die mixture was extracted three times with dicMoromediane, was dried (magnesium sulfate) and was evaporated. The residue was purified by chromatography on siUca gel with 1:1 and 1:3 ediyl acetate:hexanes, to provide die desired compound as a colorless oU (wMch contains a trace amount of 2-ac____ιmdo-5-_roπx>pyτimidine). 'H- NMR (CDOs, 400 Mhz) δ 8.65 (s, 2H), 7.12 (d, J=2.0 Hz, IH), 7.07 (dd, J=8.3, 2.0 Hz, IH), 6.85, d, J=8.3Hz, IH), 4.80 (m, IH), 3.85 (s, 3H), 3.83 (m, lH), 3.49 (s, 3H), 2.48 (s, 3H), 1.8 - 2.2 (m, 14H, 1.65 (m, 2H) ppm 37c) c«-[4-(2-___;thyla____κφy__m_d_n-_^ylethynyl)-4-(3-cyc methoxyphenyl)-cyclohexan-l-ol] To a stirred mixture of sodium methoxide (0.025 g, 0.43 mmol) in dry methanol (2 mL) under an argon atmosphere was added a solution of ci_-4-(2- meΛyl_ret______ )py__ι__id_n-5-yleώ methoxyphenyl)cyclohexan-l-ol (0.07 g, 0.15 mmol). The mixture was refluxed for 0.5 h, was cooled to room temperature, wa diluted widi water, was extracted three times with dicMoromediane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting wi h 3:1 ediyl acet_te:hexanes, foUowed by trituration from ethyl acetate hexanes, provided die tide compound as a wMte solid (0.032 g, 61%), m.p. 118-119°C. Anal. (C25H31N3O30.75 H2O) calcd:C, 69.02; H, 7.52; N, 9.66; found: C, 68.84; H, 7.11; N, 9.53. Example 36 Preparation of _ _tnj-r4-(2-_ι__nop vτimi-_n-5-yle_-ynv^^ metfιoxvphenyl_ryclohexvI-l-amine1. cyclohexylsulfamate salt 34a) 5-bromo-2-propionamidopyrimidine 5-Bromo-2-propionamidopyrimidine was prepared by standard chemistry weU known to those versed in the an and was a wMte soUd, mp 161-164° C. 34b) trans -[ 1 -rerr-butoxyc__bonyl_____ncH4-(_^^clopentyloxy-4-__ethoxyphenyl)-4-(2- propior_a____dopyrimidin-5-ylediynyl-cyclohexane] To a solution of c«-[l- erf-butoxyc_rtx)ny___ι_ino-4-(3-cyclt)pentyloxy-4- π_ethoxyphenyl)-4-ethynylcyclohexane] (0.29 g, 0.69 mmol) and 5-bromo- 2- pπφionamidopyrimidine (0.16 g, 0.69 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetr_ s(triphenylphosphine)p-Jladium(0) (0.032 g, 4%), and copper(I) iodide (0.008 g, 6%) and the mixture was heated at 80-85° C for 0.5 h. Water was added and die mixture was extracted three times with dicMoromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided ιr_ιns-[l-tt/ -butoxyc__bonylamino- 4-(3-cyclcpentyloxy-4-methoxyphenyl)^(2-propionamid<φyrim_lin-5-yle_ιynyl)- cyclohexane] as a wMte soUd (0.21 g, 54%), mp 87-89° C. -NMR (400 MHz, OX33) δ 8.57 (s, 2H), 8.17 (m, IH), 7.11 (d, J=2.2 Hz, IH), 7.03 (dd, J=8.5, 2.2 Hz, IH), 6.86 (d, J=8.5 Hz, IH), 4.81 (m, IH), 4.63 (m, IH), 3.85 (s, 3H), 2.75 (q, J=7.4 Hz, 2H), 1.8 - 2.1 (m, 14H), 1.62 (m, 2H), 1.46, (s, 9H), 1.24 (t, J=7.4 Hz, 3H) ppm 34c) tr_vtf-[4-(2-_____-opyr____din-^ cyclopentyloxy-4-methoxyphenyl) cyclohexane] A mixture of xrαn.-[l- _ -butoxycarbony_a__ι_no-4-(3-cyclopentyloxy-4- n_;_ιoxyphcnyl)-4-(2-propioαamidφyrimidi_-5-yle-hyny (0.21 g, 0.37 π__κ)l) and _D Uum rredioxide (0.07g, 1.29 mmol) in n__eth__nol (5 mL) was refluxed under an argon atmosphere for 0.5 h, then cooled Water was added and the reaction was extracted three times with d-chkromethane, was dried (magnesium sulfate) and was evaporated to provide pure irαnj-[4-(2-__ι___opyrimidin-_^yledιynyl)-l-ιβrr- t_toxycarbonyla__rii_ -(3-cye_openty^ cyclohexane] (0.18 g, 97%) as a white solid p 183-185° C 1H-NMR (400 MHz, OX3 3 ) δ 8.34 (s, 2H), 7.13 (d J=2.3 Hz, IH), 7.03 (dd J-8.5, 2.3 Hz, IH), 6.86 (d J=8-5 Hz, IH), 5.27 (d J=2.2 Hz, 2H), 4.81 (m, IH), 4.64 (m, IH). 3.85 (s, 3H), 1.8 - 2.1 (m, 14H), 1.61 (m, 2H), 1.46 (s, 9H) ppm 34d) trαm-[4-(2-a__ninopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- r_-__oxyphenyl)cyclohexyl-l-am_ e], cyclohexy__ι_Tamate salt To a solution of _rαn_-[4-(2-__-__opyri___din-5- ylethynyl)-l-tβn-- b_toxyc__t<)nylamino-4-(3-cyclop-ntyloxy-4-medκ)xyphenyl) cyclohexane] (0.18 g, 0.35mmol) in dicMoromediane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.27 mL, 3.52 mmol). The reaction was stirred at room temperature for 24 h, was cooled to 0° C, was quenched with sodium bicarbonate, was diluted widi water, was extracted with three times 10/90 π_eth__κ)Vd_cMoromethane, was dried (magnesium sulfate) and was evaporated Purification by flash chromatography, eluting widi 0.5:10:90 ammonium hydroxide:__et___mol:dicMc_romethane provided _rαns-[4~(2-amiικ>pyrimidin-5- yle±ynyl)-4-(3-cyclopentyloxy-4-med»xyphenyl^ as a very viscous, colorless oil (0.13 g, 0.33 mmoL 95%). This intermediate was dissolved in acetone (0.5 mL) and treated with a solution of cyclohexylsulfamic acid (0.059 g, 0.33 mmol) in acetone (1.0 mL). Dilution with ether and filtration, foUowed by trituration from dicMoromethane/hexanes provided the tide compound as a wMte soUd mp >230° C (dec.). Example 37 c_:..f4-^-am_nnpvτ-midin- -vle_ ynylV~4-f3-cvclopentvloxy-4- methoxyphenvlVcvclohexvl-l-aminel. cyclohexylsulfamate salt αs-[4-(2- aimncpyrin__dm-5-ylediynyl)-4-(3-^ amine], cyclohexylsulfamate salt is prepared in the same manner as rr_u__-[4-(2- a___røpyr____ -5-yle_ιynyl)-4-(3-cyc^^ amine], except starting from cis -[l-rβrr-butoxyc__tonyl_mino-4-(3-cyclopentyloxy-4- methoxyphenylH-ethynyl-cyclohexane]. UTILITY EXAMPLES EXAMPLE A Inhibitory effect of compounds of Formula (I) on in vitro TNF production by human monocytes The inhibitory effect of compounds of Formula (I) on in vitro _ * NF production by human monocytes may be determined by the protocol as described in Badger et al., EPO published Application 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 die compounds of Formula (I). The prototocol used in these models is described in Badger et al., EPO published Application 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 the injection of endotoxin. EXAMPLE C Isolation of PDE Isozymes The phosphodiesterase inhibitory activity and selectivity of the compounds of Formula (I) can be determined using a battery of five distinct PDE isozymes. The tissues used as sources of the different isozymes are as foUows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE HI, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "la"), canine tracheaUs. PDEs la, lb, Ic and m 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 foUowed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992]. Phosphodiesterase activity is assayed as described in the protocol of Torphy and Cieslinski, 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) have been demonstrated.

Claims: What is claimed is: 1. A compound of Formula I wherein: Rl is -(CR4R5) n C(0)0(CR4R5)mR-. -(CR_0-5) n C(O)NR4(α_4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4Rs)τR6 wherein die alkyl moieties unsubstituted or substituted widi one or more halogens; 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 aryloxyCi-3 alky halo substituted aryloxyC 1.3 alkyL indanyL indenyL C7- 11 polycycloalkyL tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyL tetrahydrodiienyl, diienyl, tetrahydrodiiopyranyl, diiopyranyl, C3.6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one 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-tetrahydrodιiopyranyL 2-tetrahydrofuranyl, or 2-tetrahydrodιienyl, then m is 1 or 2; or d) when R5 is 2-tetrahydropyranyl, 2-tetrahydrod iσpyranyL 2-tetF_hydrofuranyl, or 2-tetrahydroduenyl, then r is 1 to 6; e) when n is 1 and m is 0, men R6 is other than H in -(CR_α_5)nO(CR_α-5)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; X4 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NRβR β ; R2 is independendy selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; R3 is COOR14, C(0)NR4Rl4 or R7; Zis OR14, OR15, SR14, S(O R7, S(0)2NRiθRi4, NR10R14, NRl4C(O)R9, NR10C0 R14. NRiθC(O)OR7, NRlθC(Y')NRiθRl4. RlθS(O)2NRιoRi4, NRιoC(NCN)NRiθRl4- NRiθS(O)2R7, NRioC(CR4Nθ2)NRiθRl4, NRlθC(NCN)SR9, NRlθC(CI Nθ2)SR9, NRloC(NRlθ)NRlθRl4. NRlθC(O)C(O)NRiθRl4.or NRιoC(O)C(O)ORi4; Y' is O or S; R7 is -(CR4R5)qRi2 or C\.(j alkyl wherein the R12 or C\. alkyl group is unsubstituted or substituted one or more times by methyl or ediyl unsubstimted or substituted by 1-3 fluorines, -F, -Br, -O, -NO2, -NRIQRI 1 , -C(O)R8, -CO2R8. -0(CH2)2_4θI_8. -O(CH 2 ) q R8, -CN, -C(O)NRιoRl l, -O(CH2)qC(O)NRιoRιι, - O(CH 2 ) q C(O)R9, -NRιoC(O)NRiθRn, -NRiθC(O)Rn, -NRιoC(O)OR9, -NRιoC(O)Ri3, -C(NRiθ)NRlθRll. -C(NCN)NRlθRl l. -C(NCN)SR9, -NRlθC(NCN)SR9 , -NRιoC(NCN)NRιoRll, -NRlθS(O)2R9, -S(O) m 'R9, -NRιoC(O)C(O)NRιoRl 1, -NRl()C(O)C(O)Riθ, or R13; 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-dιienyl), quinolinyl, naphthyl, and phenyl; Rg is independendy selected from hydrogen or R9; R9 is C1.4 alkyl optionally substituted by one to three fluorines; RlO is ORβ or Rn; Rl is hydrogen, or Cι_4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with die nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; Rl3 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazoUdinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazoUdinyL diiazoUdinyl, isoxazolyl, oxadiazolyL and diiadiazolyl, and where Ri. is substituted on R 12 or Rn die rings are connected through a carbon atom and each second R ]3 ring may be unsubstituted or substituted by one or two Cι_2 alkyl groups unsubstituted or substituted on die methyl with 1 to 3 fluoro atoms; Rl4 is hydrogen or R7; or when R8 and R14 are as NR8R14 diey may togeth with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and on or more additional heteroatoms selected from O, N, or S; R15 is C(O)R u , C(O)NRsRu, S(O),NRtRι 4 or S(O) < ^_ 7 where q is 0, 1 or 2; provided that: (f) R7 is not C _ alkyl unsubstimted or substituted by one to three fluorines; or die pharmaceutically acceptable salts d ereof . 2. A compound according to claim 1 wherein Ri is -CH2-cyclopropyl, -CH2-C5-6 cycloalkyL -C4-6 cycloalkyl unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl unsubstituted co- substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro- substituted alkyl, W is ethynyl or 1,3-butadiynyL R3 is R7 where R 7 is an unsubstimted or substituted aryl or heteroaryl heteroaryl ring, X is YR2, and Z is OR 14, OR is, NR10R14. or NRi4C(O)R9. 3. A compound according to claim 2 wherein R 7 is unsubstituted or substimted -(CH2)0-2(2-, 3- or 4-ρyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4- morpholinyl), (CH2)2(4-piperazinyl), (CH2)l-2(2-dιienyl), (CH2)l-2(4-thiazolyl), substituted or unsubstituted pyrimidinyl, or unsubstimted or substimted (CH2)0-2phenyL 4. A compound according to claim 3 wherein R 7 is substimted or unsubstimted pyτimidin-5-yL 5. A compound according to claim 4 wherein Z is OH and wMch is cύ-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- medιoxyphenyl)cyclohexan-l-ol], ci5-[4-(2-aιι__-opyrimidin-4-yle_hynyl)-4-(3-cyclopentyloxy- cyclohexan-1-ol], tran$-[4-(2-acet_____dkϊpyri_mdm-_Hy^ methoxyphenyl)cyclohexan- l-ol], trαnj-[4-(2-__m__opyriπι__-n-5-yl-eώynyl 4-(3-cyclc)^ methoxyphenyl)-cyclohex_ιn-l-ol, or c_f-[4-(2-memylaminopyrimidm-5-yledιynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-ol]. 6. A compound according to claim 1, 2 or 3 wherein Z is OH and wMch is cw-[4-(3-cyclopentyloxy-4-memoxyphenyl)-4-(pyrid-4-yledιynyl)cyclohexan- 1 - ol], ci5-[4-(3-cyclopentyloxy-4-me oxyphenyl)-4-φyrid-2-yledιynyl)cyclohexan- 1 - ol], c«-[4-(4-cyanodιien-2-ylethynyl)-4-(3-cyclopentyloxy-4-medιoxyphenyl)- cyclohexan-1-ol], cύ-[4-(dιiazol-2-ylethynyl)-4-(3-cydcpentyloxy-4-memoxyphenyl)cyclohexan- l-ol], cw-[4-(3-cyclopentyloxy-4-π_et_κ_»xyphenyl)-4-[4-(5-π_5thyl-[l^,4]ox_-d_Azol-2- yl)tiιien-2-ylethynyl] cyclohexan- l-ol], cύ-[4-(3-cyclopentyloxy-4-medκ>xyphenyl)-4-(2-[3-(3-memyl[12,4]oxadiazol- 5-yl)phenyl]edιynyl)cyclohexan-l-ol], ci_ * -[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-medιyl[ 1 ,3,4]oxadiazol- 2-yl)phenyl]edιynyl)cyclohexan-l-ol], cis -[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-me_hyl[ 1 ,2,4]oxadiazol- 3-yl)phenyl]ethynyl)cyclohexan-l-ol], cis-4-(3-cyclcpentyloxy-4-methoxyphenyl)-4-[3-(5-trifluoromem [l t 2,4]oxadi___ol-3-yl)phenylethynyl)cyclohex__-_- l-ol, or cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-medιyl-[ 1 ,3,4]thiadiazol-2- yl)phenylethynyl]cyclc_exan-l -ol. 7. A compound according to claim 1, 2 or 3 wherein Z is NRιoRl4, or NRi4C(O)R9 wMch is ιr n_»-[4-(3-cyclopentyloxy-4-memoxyphenyl)-4-(pyrid-2-yledιynyl)cyclohexyl- 1 -amine], rrαn_t-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-yledιynyl)cyclohexyl- 1-formamide], rrfln_.-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl- [l^,4]oxadiazol-2-yl)dιien-2-yle_ιynyl]cyclohexyl-l -amine], cyclohexylsulfamate salt ci_-[4-(3-cyclopentyloxy-4-n_ethoxyphenyl)-4-(pyrid-2-yledιynyl)cyclohexyl-l- amine], ci5-[4-(3-cyclopentyloxy-4-n_edιoxyphenyl)-4-(pyrid-2-yledιynyl)cyclohexyl- 1 - formamide], cis -[4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-[5-(5-medιyl-[ 1 ,2,4]oxadiazol-2- yl)dιien-2-yleuiynyl]cyclohexyl-l-amine], cyclohexylsulfamate salt, r nj-[4-(2-aπ___nopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl- 1 -amine] , cyclohexylsulfamate salt, or c_t-[4-(2-am_-opyrimidin-5-yle_ιynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl-l -amine], cyclohexylsulfamate salt 8. A pharmaceutical composition comprising a compound of Formula I according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient 9. A method for treating asthma wMch comprises administering to a mammal in need thereof a compound of formula (I) according to any one of claims 1 to 7 alone or admixed with a pharmaceutically acceptable excipient

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: A61K31, A61P29, A61P43, C07C45, C07C49, C07C65, C07C69, C07C205, C07C225, C07C233, C07C255, C07C311, C07D213, C07D239, C07D271, C07D277, C07D285, C07D333, C07D413