IL116490A - Cyclohexanol derivatives and pharmaceutical compositions comprising them - Google Patents

Description

WIN D^DTlil ϋ"Π9ΠΠ O'TODm "71]ΝυρπΤ7Ρ"Ί. ΠΐΤ?1Π CYCLOHEXANOL DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM Field of Invention The present invention relates to novel 4,4-(disubstituted)cyclohexan- l-ols monomers and related compounds, pharmaceutical compositions containing these compounds, and to their use in the preparation of a medicament for treating allergic and inflammatory diseases and for inhibiting the production of TNF.

Background of the Invention Bronchial asthma is a complex, lnultifactorial 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 approach1' is to regulate the activity of die cells responsible for the pathophysiology of the disease.

One such way is by elevating levels of cAMP (adenosine cyclic 3'^'-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg+2-ATP to c AMP at an accelerated rate.

Cyclic AMP modulates die activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP 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 S) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.

WO 9319747 discloses certain PDE4 inhibitors which have a substituted 4-phenylcyclohexyl core structure and are substituted at the 3,4- position of the phenyl ring and on the 1,4 positions on the cyclohexyl ring. Those compounds differ from those disclosed herein in their substitution at the 4-position on the cyclohexyl ring.

The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone 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 (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HTV-2 and HIV-3. As a consequence of HIV infection, T-cell-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 HIV-l or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, 2a 116490/2 macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV 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 HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.

TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al, Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al, Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al. , Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991 ; and Luke et al. Journal of Infectious Diseases, 162:21 1-214, 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 The invention relates to compounds of the Formula (I): wherein: Rj is -(CR4R5)nC(0)0(CR4R5)mR6, -(CR4R5)nC(0)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR wherein the alkyl moieties are 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 C]-2 alkyl; 3 116490/3 R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7.1 1 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-6 is hydroxyl, then m is 2; or b) when R.6 is hydroxyl, then r is 2 to 6; or c) when R.6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R.6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)nO(CR4R5)m 6> X is YR-2, fluorine, NR4R5, or formyl amine; Y is O or S(0)m'; m' is 0, 1, or 2; X2 is O or NR.8; X3 is hydrogen; R2 is independently selected from -CH3 or -CH2CH3, wherein R2 is unsubstituted or substituted by 1 or more halogens; s is 0 to 4; W is ethynyl or 1,3-butadinyl; R3 is R13 or Rj6, which R13 or Ri6 is unsubstituted or substituted one or more times by Rl7; Z is OR.14, OR15, SR14, S(0)m'R7, S(O)2NRi0Rl4, NR10R14, NRI 4C(0)R9, NRioC(Y')Ri4, NRioC(0)OR7, NRioC(Y')NRioRl4, N i0S(O)2NRi0Rl4, NRioC(NCN)NRioRl4, NRioS(0)2R7, NRioC(CR4N02)NRioRl4, NRioC(NCN)SR9, NRioC(CR4N02)SR9, NRioC(NRio)NR.loRl4, NRioC(0)C(0)NRioRl4,or NRioC(0)C(0)ORi4; Y' is O or S; R7 is -(CR4R5)qRi2 or C\.$ alkyl wherein said R12 or C\.^ alkyl is unsubstituted or substituted one or more times by R17; q is 0, 1, or 2; Rl2 is R13, C3-C7 cycloalkyl, or R16; Rg is independently selected from hydrogen or R.9; 4 116490/3 RQ is Ci _4 alkyl unsubstituted or substituted by one to three fluorines; R] ] is hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and R\ \ are as NRioRl 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 an heterocyclic group selected from oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and when Ri2, RB or R]6 is substituted by Rn, the rings of the bonded R and R]2, Ri3 or R16 groups are connected through a carbon atom, and each second R ring is unsubstituted or substituted by one or two methyl or ethyl groups, wherein the methyl group(s) may be unsubstituted or substituted with 1 to 3 fluoro atoms; Rj4 is hydrogen or R7; or when R8 and Ri 4 are as NRs l4 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; Ri5 is C(0)R14, C(0)NRgRi4, S(0)qNRgRi4 or S(0)qR7 where q is 0, 1 or 2; Rl6 is an aryl or heterocyclic group selected from (2-, 3- or 4-pyridyl), pyrimidinyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl; Rl7 is -F, -Br, -CI, -N02, -NR10Ri ], -C(0)R8, -C02Rs, -0(CH2)2-40R8, -0(CH2)qR8, -CN, -C(0)NRioRl l, -O(CH2)qC(O)NRi 0Rl l, -0(CH2)qC(0)R9, -NRioC(0)NRi oRl l , -NRi oC(0)Ri 1, -NR] oC(0)OR9, -NR] oC(0)Ri 3, -C(NRio)NRioRl l, -C(NCN)NRioRl 1, -C(NCN)SR9, -NRi oC(NCN)SR9 , -NRioC(NCN)NRioRl l, -NRioS(0)2R9, -S(0)m'R9, -NRi 0C(O)C(O)NRi0Rl l, -NRlOC(0)C(0)Rio, R13, or methyl or ethyl, which methyl or ethyl is unsubstituted or substituted by 1-3 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 the use of an effective amount of a compound of Formula (1) in the preparation of a medicament for mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV.

The invention further provides a use of an effective amount of a compound of Formula (I) in the preparation of a medicament for the treatment of allergic and inflammatory disease. 5 The invention also provides a use of an effective amount of a compound of Formula (I) in the preparation of a medicament, for the treatment of asthma.

This invention also relates to a use of an effective TNF inhibiting amount of a compound of Formula (I) in the preparation of a medicament for inhibiting TNF production wherein used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.

This invention also relates to a use of an effective TNF inhibiting amount of a compound of Formula (I) in the preparation of a medicament for treating human immunodeficiency virus (HIV).

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 use of an effective amount of a compound of Formula (I) in the preparation of a medicament for mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV and to inhibiting the production of TNF.

Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-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 use of an effective TNF inhibiting amount of a compound of Formula (I) in the preparation of a medicament for treating human immunodeficiency virus (HIV). 6 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 retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.

The compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis. Additionally, the compounds of Formula (I) 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 adrninistering an effective amount of a compound of Formula (I) to a mammal in need of such treatment.

Preferably, a compound of Formula (I) is adirunistered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.

The term "C1.3 alkyl", "C1.4 alkyl", "Ci_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, terf-butyl, 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. 7 "Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.

"Inhibiting the production of IL- 1 " or "inhibiting the production of TNF' means: a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below nonnal 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 IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event The phrase 'TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-β (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-B are inhibited by the compounds of the present invention and thus are herein referred to collectively as 'TNF" unless specifically delineated otherwise. Preferably TNF-a is inhibited.

"Cytokine" means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them.

The cytokine inhibited by the present invention for use in the treatment of a HIV-infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV 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-a 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 compounds 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. 8 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 C 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 Ri substitutents for the compounds of Formula (I) are C¾-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with OHC7-11 polycycloalkyl, (3- or -cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)l-3C(O)CXCH2)0-2CH3, -(CH2)l-3O(CH2)0-2CH3, and -(Ο¾)2-40Η.

When Ri term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4Rs)n or (CR4R5)m; each repeating methylene unit is independent of the other, e.g., (CR4Rs)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 Ri substitutions, as noted above.

When Ri is a C7-11 polycycloalkyl, examples are bicyck>[2.2.1]-heptyl, bicyclo[2.2.2]octyl, additional examples of which are described in Saccamano et a/., WO 87/06576, published S 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(0)m-R7, S(0)2NRioRi4, NR10R14, NRl4C(0)R9, NRioC(0)Ri4, NRl0C(O)OR7, NRl0C(O)NRi0Rl4, NRioS(0)2NRioRl4. NRioC(NCN)NRioRl4, NRioS(0)2R7, NRl0C(CR4NO2)NfRl0Rl4, NRl0C(NCN)SR9, NRl0C(C3 NO2)SR9, NRioC(NRio)NRlORl4, NRioC(0)C(0)NRioRi4, or NRi0C(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 mat wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a Cl-2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro- 9 substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.

Preferred R7 moieties include unsubstituted or substituted -(CH2)0-2(2-, 3- or 4- pyridyl), (CH2)l-2(2-imidazolyl), (C¾)2(4-rx >roholinyl), (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 -NRioRl 1 together with the 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)- 1-imidazolyl, l-pyrazolyl, 3-(R8)- 1 -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)- 1-triazolyl, S-(R8)-2-triazolyl, 5- (R 8)- 1-tetrazolyl, 5- (R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)-l-piperazinyl, or pyrrolyl ring.

Preferred rings when Rio and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached may 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, l-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyL The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)- 1-imidazolyl, 4-(R7 - 1-imidazolyl, 5-(R7)- 1-imidazolyl, 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)- 1-triazolyl, 5- (R7)- 1-tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l-tetrazolyl, 4-(R7)-l-piperazinyl. Where applicable, the ring may be substituted one or more times by R7.

Preferred groups for NR 0R14 which contain a heterocyclic ring are 5-(Ri4>-1-tetrazolyl, 2-(Ri4)-l-irnidazolyl, 5- (R 14)- 2-tetrazolyl, 4-(Ri 4)- 1 -piperazinyl, or 4- (Ri5)-l-ppenurinyl.

Preferred rings for R 13 include (2-, 4- or S-imidazolyl), (3-, 4- or S-pyrazolyl), (4- or 5-triazolyl[l,2,3]), (3- or 5-triazolyl[ ,4]), (5-tetrazolyl), (2-, 4- or 5- oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or S-oxadiazolyl[l,2,4]>, (2-oxadiazolyl[l,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imida.»lidinyl).

When the R7 group is unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by R8 on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R8)-4-imidazolyl, l-(R8)-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-pyrazolyl, l-(R8)-4-triazolyl, or 10 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, tetrahydrofuran-3-yl, (3- or -cyclopentenyl), benzyl or -Ci-2 alkyl unsubstituted or 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 R7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z is OR 14, ORIS, NR10R14, or NRl4C(0)R9.

Most preferred are those compounds wherein Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2*. Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, and R3 is a substituted or unsubstituted pyrimidinyl ring.

It will be recognized that some of the 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 the 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 the 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 the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for administration to the skin, eye, ear, or nose.

For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension. 11 For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.

When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water, for solid systems, lactose, kaolin and mannitol and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.

The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.

In these compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient When the diluent is a solid it may be present in lesser, equal or greater amounts than 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 the symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, the dosage of the 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 the present invention.

Methods Of Preparation Synthetic Schemes) 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 the presence of a suitable catalyst, such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence 12 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 the 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 W093/19751. fifihftrnn 1 a) Pd(PPh 3)4, PPh 3, Cul, R 3X, piperidine 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 the 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 with 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 the method of 13 Tsuji et al. (Tet Lett, 1980, 21, 849), then provides the compound of the Formula 2-Scheme 3: such compounds may then be converted to other compounds of the Formula (I) by manipulation of the ketone as described above and by independent manipulation of the carboxylic ester moiety using standard transesterification or amidation conditions. Syntheses of such ketone starting materials are described in published PCT application PCT US93A>2045 (WIPO publication number WO 93/19748) or published PCT application PCT/US93/02325 (WIPO publication number WO/93/19750).

SGhflme a 2. a) PdCI 2, CuCI 2, NaO 2CCH 3 > CO, CH 3OH; as inScheme 2 Likewise, oxidative carbonylation of a terminal acetylene as, e.g., compound Xz 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 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 4: such compounds may then be converted to other compounds of the Formula (I) by manipulation of the carboxylic ester moiety using standard transesterification or amidation conditions. 14 a) PdCI 2. Cua 2, NaO 2CCH3, CO, CH ,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 the -OH. Such methods are described in co-pending U.S. application 07 968753 and PCT application serial number PCT/US93/02325 (WO publication number WO/93/19750).

Preparation of the remaining compounds of the Formula (I) may be accomplished by procedures analogous to those described above and in the Examples, It will be recognized that some compounds of the 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 the described invention.

These examples are intented solely for illustrating the invention and should not be read to limit the invention in any manner. Reference is made to the claims for what is reserved to the inventors hereunder.

Experimentals Example 1 Preparation of ciJ-r4-(3-cyclc^ntyloxy-4-ire^^ cyclohexan-l-oll la) r nj-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-l-ol] and cis-[4-(3-cyclcpentyloxy-4-rnemoxyphenyl)-4-ethynylcyclohexan-l-ol] To a solution of 4-(3-cyclopentyloxy-4-metlK)xyphenyl)-4-ethynylcyclohexan-l-one (0.34 g, 1.1 mmol, prepared as described in published PCT application PCTAJS93/001990 (WIPO publication number WO 93/19748) or PCT/US9302325 (WEPO publication 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 the mixture was stirred at room temperature for 0.5 h. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. 15 Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes, provided ira/ii-[4-(3-cyclopentyloxy-4-memoxyphenyl^^ (described in U. S. Patent application in PCT application number PCT/US93/02516 published under WIPO publication number W093/1975 l_as cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan- 1 -ol] ) as a wax. ^H-NMR (400 MHz, CDCI3) 5 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). cu-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan- 1 -ol] also was isolated from this pr° Cedure as a colorless oil. *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). lb) «H^(3-cyclopentyloxy-4-niethoxyph^ To a solution of rr Example 2 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 tetrakis(triphenyl-phosphine)palladium(O) (0.020 g, 4%), copperiT) 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 the 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 cw-[4-(3-cyclopentyloxy-4-methoxyphenyl -^yrid-2-ylethvnvl)cvclohexan-l-oll as a white solid (0.14 g, 84%), mp 49-51° C. Anal. (C25H29NO3 O.5 ¾0) calcd: C, 74.97; H, 7.55; N, 3.50; found: C, 74.90; H, 7.52; N, 3.33. 16 116490/2 E ample 3 gis-f4-f4-<^^othien-2-vlcthvnv^^ cyctohcxan-l-on 17a) 2-bromo-4-cyanothiophene 2-Bronx>-S-€yanothiophene was prepared by standard chemistry well known to those versed in the art and is a colorless oil. *H-NMR (400 MHz, CDCI3) δ 7.85 (d, J=2.2Hz, 1 H), 7.25 (d, J=2.2 Hz, 1H) ppm. 17b) ciH4-(4-cyaiK>thien-2-yleA cyclohexan-l-ol] To a solution of trans -[4-(3-cydcpentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-l-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 tetraids(triphenyl-phosphinc)palladiuni(0) (0.030 g, 4%), copper(I) iodide (0.008 g, 6%), and a small crystal of triphenylphosphine, and die mixture was heated at 80-85° C for 0.5 h. Hydr° Chloric acid (5 %) was added and the 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, followed by trituration from dichloromethane-hexanes, provided c«- [4- (4-cyanothien-2-ylemynyl)-4-(3K7ck)penryk>xy-4-meth^^ as a pale yellow solid (0.12 g, 45%), mp 70-71° C AnaL (C25H27NO3S) calcd: Q 71.23; H, 6.46; N, 3.30; found: C, 71.24; H, 6.7¾ N, 3.14. 17 P50287 116490/2 E ample 4 ynthien-2-ylethvnvn cvclohexan-1-οΙΊ 18a) 2-bromo-4-i5-wethyl-[l ,4]oxadiazol-2-y})t iophene 2-Bromo-4-{5-methyl-[ 1 ^,4]oxadiazol-2-yl)thiophcnc was prepared by standard chemistry well known to those versed in the ait and is a white solid, mp 72-73° C. 18b) c«-[4 3-cyclopentyloxy-4-methoxypte^ yl)thien-2-ylethynyl] cyclohexan-l-ol] To a solution of i7ou-[ -(3 ydc entytoxy^methoxyphenyl)-4-ethynyl-cyclohexan-l-ol] (0.25 g, 0.8 mmol) and 2-bron«>^i5-memyl-[lA4]oxadia2ol-2-yI)thiophene (020 g, 0.8 mmol) in triethylamine (5 mLj under an argon atmosphere were added tetralds(triphenylphosphme)palladium(0) (0.038 g, 4%), copperiT) iodide (0.009 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 70-75° C for 0.5 h. Hydrchloric acid (5%) was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, duting with 1:1 ethyl acetate:hexanes, provided cis [4-(3-cyclopentyloxy-4-nKmoxypheriy^^ yl)thien-2-ylethynyl]cyclohexan- l-ol], which was further triturated from dfchloromethane-hexanes to give a white solid (020 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, 6.4¾ N, 5.50 Examjlc 5 cvclohexan-1-οΠ 19a) 4-iodo-2-thiomemylpyriimdine 4 οάο-2-ύύοπΆώγ}ργήήύώι» was prepared following a literature procedure (AJ. Majeed, 0. Antonsen, T. Benneche, K. Undheim. Tetrahedron 1989.45, 993-1006). — P50287 116490/2 19b) c«-[4-(3-cyclopCTtyloxy- -nK&oxyphenyl)-4-(^ ylethynyl) cyclohexan-l-ol] To a solution of irans-[4-(3 The reaction was stirred 3h at -10° C, then 3 h at room temperature. A second portion of 3-chloroperoxybenzoic acid (0.11 g, 0.62 mmol) in chloroform (1 mL) was added and stirring was continued for 1.5 h. The reaction was quenched with sodium carbonate (5%), was extracted three times with dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 2.5:97.5 methanol:dichk»omethane, provided os-[4-(3-cyclopentyloxy-4- niethoxyphenyl)-4-(2-irjcmyls^ as a white foam (0.31 g, 81%), mp 75-77° C. iH-NMR (400 MHz, CDCI3) δ 8.84 ( Example 6 cvclnhexan-ϊ-οΠ To a solution of tnzru -[4-(3-cyck>pentyloxy-4-^^ cyclohexan-l-ol] (0.20 g, 0.64 mrnol) and and 2-ainiix>-5-bromopyrimidi-ne (0.55 g, 3.2 mmol) in piperidinc (2 mL) under an argon atmosphere were added tetrakds(triphenyl-phosphine)palladium(0) (0.030 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h. Water was added and the mixture was extracted three times with dicMoromethane, was dried (potassium carbonate) and was evaporated. Purification by two successive flash chromatograpWes, elutmg fn¾t with 5:95 inethanolrdichlorome thane, then with 3:97 nietiianol:dichloroinethane, provided cis-[ -(3-cycIopentyloxy-^methoxyphenyl)-4-(2-am^ cyclohexan-l-ol] as a tan-brown solid (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. τ-Γ4-(Φί«1»»-2-γ1^ν^^ To a solution of ira«-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-l-ol] (0.15 g, 0.48 mmol) and and 2-bronx)thiazole (0.20 mL, 2.4 mmol) in triethylarnine (1.5 mL) under an argon atmosphere were added tetralds(triphenyl pnosphine)palladium(0) (0.022 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 1 h.

Ammonium chloride was added and the mixture was extracted three times with dkMoromethane, dried (magnesium sulfate), and evaporated. Purification by two successive flash chromatographies, eluting first with 6:4 ethyl acetate:hexanes, men with 2:98 methanohdichloromethane, provided or-[4-(3-cyclopentyloxy-4-memc*yphenyl)-4-(2-annnop^ as an off-white foam (0.13 g, 68%), mp 45-48° C. Anal. (C23H27NO3S · 0.5 ¾0) calcd: C, 67.95; H, 6.94; N, 3.45; found: C, 67.91; H, 6.76; N, 3.39. 20 Example 8 amine] 22a) c«-[4-(3-cyclopentylc«y^metlroxyphenyl 1 -amine] To a solution of rrfl¾y-[4^3^clopciityloxy^methoxyphcnyl)-4-ethynyl-cyclohexan-l-ol] (1.0 g, 3.18 mmol), phthalimide (0.70 g, 4.77 mmol) and (1.25 g, 4.77 mmol) in tetrahydroruran (32 mL) was dropwise added diethyl azodicarbox late (0.75 mL, 4.77 mmol), and the solution was stirred under an argon atmosphere at room temperature Evaporation and purification by flash chromatography, elating with 2:8 ethyl acetate hexanes, provided the intermediate phthalimide (1.43 g) as a waxy white solid, mp 45-52° C. This was dissolved in 2:1 ethanolrtetrahydrofuran (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 the mixture was extracted three times with 10:90 memano c chloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 0.5:5:95 ammonium hyc¾oxide:methanol:dichlc«miethane, provided ciy-[4-(3-cyclopentyloxy-4-methoxyphenyl>4^thynyl yclohexyl-l-annne] as a colorless oil (0.71 g, 72%). *H-NMR (400 MHz, ΟΧ¾> 57.17 (d, J=2.2 Hz, lH), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.81 (m, lH), 3.82 (s, 3 H), 3.26 (br s, 1H), 2.36 (s, 1H), 2.1-2.2 (m, 4 H), 1.8 - 2.0 (m, 10 H), 1.6, (m, 2H) ppm. 22b) cu-[l-/m-buloxvcaitonylammo-4-(3-cvdopentylox ethynylcyclohexane] A mixture of cis-[4-(3-cyclc¾)entyk>xy-4-tnemc yphenyl>4-cmynyk 1 -amine] (0.55 g, 1.75 mmol) and di-½rt-butyldicarbonatc (0.42 g, 1.93mmol) in dichlcromethane (8mL) was stirred 20 h and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes provided, cis-[\-tert-butoxycarbonylamijK>-4-(3-cycto^ as a colorless oil (0.70 g, 97%). *H-NMR (400 MHz, CIX¾) δ 7.13 (d, J=2.2 Hz, 1H), 7.02(dd, J=8.5, 22 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.81 (m, lH), 4.64 (m, 1 H),3.84 (s, 3 H), 2.36 (s, lH), 2.05 (m, 2 H), 1.6 - 2.0 (m, 14 H), 1.45, (s, 9 H) ppm. 22c) jranHl-ttrt-bulDxycaibcii l i^ (pyrid-2-ylethynyl-cyclohexanel — To a solution of cis -[l-te t-bu∞xycarbonylaiiiino -(3-^^ nxthoxyphenyl> -emynylcyclohexane] (035 g, 0.85 mmol) and 2-bromopyridine (0.80 mL, 8.5 mmol) in piperidine (2.5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.039 g, 4%), copper(I) iodide (0.010 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h in the dark. Water was added and the mixture was extracted three times with 21 dichlorome thane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate rhexanes .provided trans-[\-tert- butoxycarfaonylamino^(3- ^lopentvIoxy-4-roethoxyph cyclohexane] as a light yellow solid (0.30 g, 72%). mp 69-70° C. *H-NMR (400 MHz, CDC13) 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 (or. 1 H).7.17 (d, 1=22 Hz, 1H).7Λ9 (dd, J=8.5, 2.2 Hz, 1H), 6.85 (d, J=8.5 Hz, lH), 4.82 (m, 1H), 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, 2 H),1.45, (s, 9 H) ppm. 22d) tra u-[^(3- 7ck}penityloxy-4-methox^ amine] To a solution of ans-[l-im-butoxycartonylarnmo^ meAoxyphenyl)-4-(pyrid-2-yleAynylcydc^exane] (0.30 g, 0.61 mmol) in dichJoromethane (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 with sodium bicarbonate, was diluted with water, was extracted with three times dichloromethane. was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.7:7:93 ammonium hydroxide:methand:dicMoromethane provided ir Example ? formamide].

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 OO¾y-[4-(3-cyclopcntyk)xy-4-rnemoxyphenyl)-4-(pyrki-2-ylethynyl)cyclc^ (0.096 g, 0.24 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirred for 3 h at room temperature, was diluted with dichloromethane, was washed with sodium bicarbonate and water, was dried (magnesium sulfate) and was evaporated. Purification by flash clirotnatDgrahy, eluting with 5:95 rnethanol:dichloroinethane, provided iranJ-[4-(3-cyctopentyloxy-4-methoxyphenyl)-4-(pyrkl-2-ylethynyl)cyclohexyl-l-^ (which contains a trace of acetamide) as a white foam (0.08 g, 79%), mp 75-76° C Anal.

(C26H30 2O3 O.375 H2O) calcd: C, 73.43; H, 7.26; N, 6.59; found: C 73.46; H, 7.29; N, 6.25. 22 P50287 Example 1Q ;rfl/iJ-r4 r3-cvclorentvloxv^m vnthien-2-vlethvnvlTcydohm vl-1-aiTrine1. cvclohrxvlsulfamate salt 24a) 2-bromo-5-i5-methyl-[ 1 ^,4]oxadiazol-2-yI)thiophenc 2-Brotno-5-{5-methyl-[ 1 ^,4]oxadia2ol-2-yl)thiophcnc was prepared by standard chemistry well known to those versed in the art and was a white solid, mp 48-49* C 24b) trans-[\ -fe/t-butoxycarbonylammo-4-(S (5-methyl-[ 1 A4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane] To a solution of cis-[ l-im-butoxycarbonylamino-4-(3- ^clopentyloxy^ metlx)xyphenyl)-4-«thynylcvclohexane] (0.30 g, 0.73 mmol) and 2-bromo-5-(5-methyl-[l,2,4]oxadiazol-2-yl)thiophene (0.18 g, 0.73 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakas(triphenylphospWne)palladiurQ(0) (0.033 g, 4%) and copper(I) iodide (0.008 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 1 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, followed by trituration from dichloromethane-hexanes, provided /ra/iHl-&rt-butoxycaitonylam methyl-[½4]oxadiazol-2-yl)thi^ as a yellow foam (0.38 g), containing - 40 % of l,4-Wr-{[/-4-(3 7dopentyloxy-4-metiioxyphe^ cyclohexyl-l-amine]^yl}buta-l,3-diyne by *H-NMR. 24c) rm^-[4-(3 ^clopenryloxy-4-n«thoxvphenyl>4-[5-(5-nietiiyl-[ 1 ,2,4]oxadiazol-2-yl)t-uM-2-yleAynyl]cyclohexyl-l -amine], cyclohexylsulfamate salt A solution of *ro/ti-[l-.m-butoxyciirb∞ylam methoxyphenyl)-4-[5-(5-methyl-[ 1 ^,4]oxadiazol-2-yl)thien-2-ylethynyl] cyclohexane] (0.38 g, containing 40 % of the dimer) in dichloroaxthane (10 mL) at 0° C under an argon atmosphere was treated with trifluoroacetic acid (0.50 mL, 6.5 mmol) and the mixture was stirred for 24 h at room temperature. The solution was quenched with sodium bicarbonate at 0° C, was diluted with water, was extracted three times with 10:90 niemanokdichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatogaphy, eluting with 0.5:5:95 ainmonium hydroxide:metha-K>l:dkhk^ provided n*o«-[4-(3-cydopentyloxy-4- amine] as a glassy solid (0.18 g, 59 %). This was dissolved in acetone (0.5 mL) added to a solution of cyclohexyhulfamic acid (0.066 g, 0.37 mmol) in acetone (0.5 mL). The salt was isolated and the free amine was recovered. A second chromatography using the same solvent system provided free amine (0.048 g), which was treated with cyclohexylsulfamic acid (0.018 g, 0.10 mmol) in acetone (1 mL). 23 P50287 After the addition of ether (20 mL), the precipitate was filtered off to provide /raaj-[4- (3-<^lopentyloxy-4-n>cthoxyphenyl)^[5^5-methyl-[ 1 ,2,4]oxadiazol-2-yl)thien-2- ylethynyl]cyclohexyl- 1 -amine], cyclohexylsulfamate salt (0.043 g, 18%) as a white solid, mp 134-135° C AnaL (C33H44N4O6S2O.5 H2O) calcd: C, 59.52; H, 6.81; N, 8.41; found: C 59.37; H, 6.71; N, 8.46.

Example 11 25a) cis- [ 1 -½rr-butDxycarbonylamino^(3-cyclopentyloxy-4^ ethynyl-cyclohexane] A solution of 4-(3-cyclopentyloxy-4-methoxyptenyl)-^ 1 - one (0.82g, 2.63 mmol), ammonium acetate (2.03 g, 26 mmol), sodium cyanobopohydride (0.17 g, 2.63 mmol) and several 4A molecular sieves in methanol (10 mL) was stiired under an argon atmosphere at room temperature for 3 days.

Several crystals of methyl orange were added, men hydrogen chloride-saturated methanol to ~ pH 3. The reaction was made basic with sodium hydroxide (10 %), was extracted with 10:90 methanol:dichlo*omethane, was dried (potassium carbonate) and was evaporated to provide crude rrons-[4-(3-cydopcntyloxy-4-methoxyphenyl)-4- ethynylcyclohexyl-l-amine] as a yellow oil (0.88 g, 100 %). A solution of the ~ intermediate in dichloromethane (15 mL) was treated with di-½rr.-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- butDxycarbonylanTino-4-(3-cyclopentyk)xy-4-nx as a white foam (0.57 g, 53%, 1H- MR shows - 20 % cir isomer), mp.39-43° C *H- MR (400 MHz, CDCI3) 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) cir-[l-itfrr-butDxycarbonylan3mo-4-(3-«y^ (pyrid-2-ylethynylcycIohexane To a solution of fra r-[ l-fm-butoxycarb∞ylam n»thoxyphenyl)-4-€mynylcyclohexane] (0.45 g, 1.09 mmol) and 2-bixxiiopyridine (1.0 mL, 11 mmol) in piperidine (3 mL) under an argon atmosphere were added tetrakis(t^henylphosphij-e)palladium(0) (0.050 g, 4%), copper(D iodide (0.012 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h in the dark. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided cis-[l-tert- Dutoxycartx)nyIamino-4-(3-cyclopentyloxy-4-met-^ 24 ylethynylcyclohcxanc] as a yellow foam (0.41 g, 78%, contains ~> 35 % trans isomer by iH-NMR), mp 4043° C JH-NMR (400 MHz, αΧ¾) 88.4 (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, 1H), 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) -j-[4^3-cyclopcntylaxy-4-mctboxyphcnyl)-4-(pyrid-2-ylethynyl)cyclohexyl- 1-amine] To a solution of (¾-[l-ie^buto yc itxMyl miix^ methoxyphenyl 4^yrid-2-ylcttiyiiylcy k)h (0.41 g, 0.84 mmol) in dichloromethane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.65 mL, 8.4 mmol). The reaction was tirred 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 rnetrianohdichlorcfrjethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 0.5:5:95 ammonium hydnxide:methanol:dicM^ followed by trituration from ether, provided m-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pv^ ylethynyl)cyclohexyl- 1-amine] as a white solid (0.23 g, 69%, containing ~ 20 % of the 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 12 cjj-r4-(3^clopentvloxv-4-iriethoxvphenvlV4-^vrid-2- 1 - folTnaiBdej 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 dr-[4-(3-cyclopentyk>xy-4-methoxyphenyl)-4^yrid-2-yletiiYnyl)cyclohexyl- 1-am (0.16 g, 0.40 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirred for 3 h at room temperature, was diluted with dkhlcfornethane, was washed with sodium bicarbonate and water, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatograhy, eluting with 5:95 rriethariol:dicMc4omethane, provided cis-[4-(3-cyck)pentyloxy-4-methoxvphenyl)-4-(pyrid-2-yfethynyl)cvctohexyl- 1-fOTrnamide] (which contains a trace of acetamide) as a white foam (0.08 g, 79%), mp 80-8 C Anal.

(C26H30 2O3-0.375 H2O) calcd: C.73.43; ft 7.26; N, 6.59; found: C, 73.46; ft 7,29; N, 6.25.

Example s ynmien-2-ylethynylTcydohexyl-l-aminel. cvclohexvlsulfamate salt 27a) 2-bromo-5-{5-methyl-[ 1 ^.4]oxadiazol-2-yl)thiophene 2-Bromo-5-£5-methyl-[l^,4]oxadiazol-2-yl)thiophene was prepared by standard chemistry well known to those versed in the art and is a white solid, mp 48-49° C 25 27b) cu-[l-½rr-butDxycazb∞ylamino-4^ (5-n^yl-[lA4]oxadiazol-2-yl)thien-2-yIcthynyllcycIohcx To a solution of ftcw-[4-(3-<^Iopentyk>xy-4-n^ cyclohexyl- 1 -amine] (0.21 g, 0-52 mmol) and 2-bron»-5-{5-me&yl-[l ,2,4]oxadiazol-2-yl)thiophene (0.13 g, 0.52 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetraki^triphenylplwsphinejpalladinmCO) (0.024 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 1 h. Aznmooium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by two successive flash chromatographies, eluting first with 2:8 ethyl acetate:hexanes, then with 2:8 acetone:hexanes, provided cis-[l-tert-butoxycarbonylaan 4-(3-cydopen^ [1 A4]oxadiazol-2-yl)d-ien-2-ylethynyl]cyclohexane] as a white foam (0.20 g, 69%, contains ~ 20 % dimer impurity by !H- MR), mp 60-68° C . 27c) cii-[4-(3-cyclopentyloxy-4-i^ yl)thien-2-ylethynyl]cyclohexyl- 1 -amine], cydctexylsummate salt A solution of cis-[ 1 -iert-butoxycaibonylanunc^(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-{5-methyl-[ 1 ^,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane] (0.21 g, containing 20 % of the dimer) in dichloromethane (5 mL) at 0° C under an argon atmosphere was treated with trifluoroacetic acid (0.28 mL, 3.6 mmol) and was stirred 24 h at room temperature. The solution was quenched with sodium bicarbonate at0° C was diluted with water, was extracted three times with 10:90 methanol:dichloromethane, was dried (potassium carbonate) and was evaporated Purification by flash chramatogaphy, eluting with 0.3:3.-97 ammonium hydioxidennetharioko^hlcromethane, provided cis- [4-(3-cyclopentyloxy-4-inethoKyphenyl)^[5-(5-i∞^ 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, the precipitate was filtered off to provide [ 1 A4]oxadia-K)l-2-yl)thien-2-ylethynyl]cyclohexyl- 1 -amine] , cydcflexylsulfamate salt (0.14 g, 58%) as a white solid, 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.

E ample 14 yl^henyllethynylK^vclohexan-l-oll. 28a) 5-(3-iodophenyl)-3-mcthyl[l-2,4]oxadiazole 5-(3-Icdophenyl)-3-memyl[l ,2,4]oxadiazole was prepared by standard chemistry well known to those versed in the art and was a white solid, mp 102-103° C 26 yl)phcnyl]ethynyl)cyclohcxan- 1 -ol] To a solution of ira/zH4-(3-<^lopentyloxy-4-methoxyp cyclohexan-l-ol] (0.11 g, 0.3S mmol) and 5-(3-iodc^henyl 3-methyl[l A4]oxadiazole (0. IS g, 0.S2 mmol) in triethylamine (4 mL) under an argon atmosphere were added tetra-ds(triphenylphosphinc)pal1ariinm (0.017 g, 0.015 mmol), copper(I) iodide (0.004 g, 0.021 mmol) and a small crystal of triphenylphosphine. After heating the mixture at 70° C for 1.5 h., the reaction was quenched by addition of aqueous ammonium chloride solution, and the solvent was concentrated. The mixture was extracted three times with methylene chloride, and the organic phase was washed with water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes and crystallizing from ethyl ether, provided cir-[4-(3-cyclopentyloxy-4-n^∞ypbe yl)phenyl]ethynyl)cyclohexan-l-ol] as a white 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 15 m-f4-(3-cvclopenryloxy-4-metlic yp- en yltehfflyllahynyilcyclcjiexaihl-Qll. - 29a) 2-(3-iodophcnyl 5-methyl[1 ,4]oxacliazole 2-(3-lbdophenyI)-5-methyI[l,3,4]oxadiazole was prepared by standard chemistry well known to those versed in the art and is a white solid, mp 12-113.5 0 C. 29b) ciH4-(3-<7clopentyloxy-4-met^ 2-yl)phenyl]ethynyl)cyclohexan- l-ol] To a solution of rram-[4^3-cyclopentyloxy-4-methoxyphenyl)-4-^ cyclohexan-l-ol] (0.125 g, 0.40 mmol) and 2-(3-iodophcnyl)-5- methyl[1 ,4]oxadiazole (0.171 g, 0.60 mmol) in triethylamine (7 mL) under an argon atmosphere were added tetrakis(triphenyh¾hosphine)paHadi After heating the mixture at 75° C for 1.75 h, the reaction was quenched by addition of aqueous ammonium chloride solution, and the solvent was concentrated. The mixture was extracted three times with methylene chloride, and the organic phase was washed with water, was dried (sodium sulfate) and was evaporated. Purification by flash _ chromatography, eluting with 40 to 50% ethyl acetate in methylene chloride and crystallizing from ethyl ether, provided cw-[4-(3-cydcpentyloxy^nie^xyphenyl)-4- (2-[3-(5-methyl[l,3,4]oxadiazol-2-yl)phcnyl]ethynyl)cyclohexan-l- )lJ as a white solid (0.119 g.63%), mp 117.5-119 eC. AnaL (C29H32N2O4 I/8H2O) calcd: C 73.36; H, 6.85, N, 5.90 found: C 73.25; H, 6.94, N, 5.75. !H-NMR (400 MHz, CDQ3) 5 8.12 (s , lH), 7.98 (d-d, J=1.4 Hz;J=7.9 Hz, lH), 7.60 (d-d, J=1.3 Hz, J=7.8 Hz, 1H), 27 5 287 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), Z2-1.8 (m. 14H), 1.7-1.5 (m, 7H with H2O).

Example 16 vl^phenvllethvnvltevclohexan-1 To a solution of 4-(3-<7clopentyloxy^methoxyp.ienyl)-4-(2-{3-(5-nicthyUl^,4]oxaliazol-3-yl)phenyl]cuiynyl)cyclohexan (0.084 g, 0.18 mmol, prepared as described in co-pending application P50283 filed on even date herewith) in 1,2-diinethoxyethane (3 mL) under an argon atmosphere was added dropwise a solution of sodium borohydride (0.015 g, 0.40 mmol) in 1 ^-dimethoxyethane (5 mL). After 2 h stirring at room temperature, the reaction was quenched by addition of aqueous ammonium chloride solution. The solvent was concentrated and the residue was extracted into methylene chloride, was washed with water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35% ethyl acetate in hexanes and crystallizing from ethyl ether, provided cir-[4-(3-cyclopentyloxy-4-inethoxyphenyl^^ yl)phenyl]ethynyl)cyclohexan-l-ol] as a white solid (0.050 g, 58%), mp 101-1030 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. *H-NMR (400 MHz, (3X33) 68.18 (s , IH), 8.00 (d, 7=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 (in, 6H with H2O).

The other compounds of this invention may be prepared by proceeding in a similar manner, but substituting the appropriate starting materials and intermrdiarns for those recited in this Example. Examples are: c«-[4-(3-cyclopentyloxy-4-mem∞yphenyl)-4-(2-[3-(5-trifluoioiiKAyl[l,2,4]oxadiazol^ c«-[4-(3-cyclopentyIoxy-4-methoxyphenyI)-4-(2-[3-(3-trifluoranemyI[l,2,4]oxadiazoW^ c«-[4-(3-cyclopentyk>xy-4-njemoxyphenyl)-4-(2-[3-(5-trifluoromemyl[l,3,4]oxadiazd^^ CK-[4-(3- ^clopentyk)xy-4-niethoxyphenyI)-4-(2-[3-(5-trifluoromediyll 1 ,4]tWadiazol-2-yl)phcnyl]ethynyl)cyclohexan-l-ol].

Example 17 ri ?.41oxadia7iol-3-ylVphenvlethvnvl^cvclohexan-l-ol 31a) 3-(3-iodophenyl)-5-trifluc^memyl-[l^,4]oxadiazole 28 3-(3-Iodophenyl 5-triflucromethyl-[ 1 ,2-4]oxadiazole was prepared by standard chemistry well known to those versed in the art and was a white solid, mp 36-37° C. 31b) cw-4-(3-Cyclopentyloxy-4-me±oxyphei^^ [1^4]oxadiazcd-3-yl)pbenylethvnyl)cyclohexan- l-ol A stirred mixture of fr¾i/ii-[4-(3-cydooertfyk>xy-4-n_eihoxy^^ cyclohexan-l-ol] (0.22 g, 0.7 mmol) and 3-(3-kxiophenyl 5-tr uoromethyl-[l,2,4]oxadiazole (0.24 g, 0.7 mmol) in dry triemylamine (5 mL) was treated under an argon atmosphere trace tcti¾lds(triphenylphosphine)palladiiim and copper(I) iodide. The mixture was refluxed for 0.2 h, was cooled to RT and was evaporatedThe 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 the title compound as a white solid (0.26g, 71 %), mp 85-86° C Example 18 Preparation of cu-4-f¾^clopentvloxv-4-methoxvphenvn-4-r3-f5-methvl- ri^^lThiitfliny^l-^- l^h n lcth n ltoloh x n-l-cl 32a) l-iodo-3-<5--∞thyl-[1 ,4]thiadia2ol-2-yl)ben2ene 1 -Iodo-3-(5-methyl-[ 1 ,4]thiadiazol-2-yl)benzene was prepared by standard chemistry well known to those versed in the art and was white solid, m.p. 86-89° C. 32b) 4-(3-cyclcpcntyloxy-4-mcthoxyphCT^ yl)phenylethynyl]cyclohexan-l-ol - _ To a solution of rra/iH4-(3-cyclopentyloxy-4-niethoxy^ cyclohexan-l-ol] (0.15 g, 0.48 mmol) and l-iodo-3-(5-methyl-[13,4]thiadiazol-2-yl)benzene (0.15 g, 0.48 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palla,ium(0) and copper(I) iodide. The mixture was refluxed for 020 h, was cooled to room temperature and was concentrated in vacuo. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate and trituration from hexanes/ethyl acetate provided the title compound as a white solid (0.17g, 74%), tap. 129-130° C.

Example 19 me hoxvphenvl'tevclohexan-l -oil To a suspension of cis-[4-(3-cyctopemylc>xy-4-inethoxyphenyl)-^ cyclohexan-l-ol] (0.50 g, 1.59 mmol) and 2-acetarmdo-5-rjroii¾)pvriim^e (0.35 g, 1.59 mmol) in triethylamine (7 mL) under an argon atmosphere was added tetralds(tripheny]phosphme)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 three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. The residue was pre-adsorbed onto silica and purified by 29 chromatoraphy on silica gel, eluting the nonpolar impurities with 30:70 to 50:50 ethyl acetate:dichloromethane, and eluting the desired product in 60:40:1 ethyl acetate:dichloi«)methanen∞thanc4. This was crystallized from ethyl acetate:hexanes to provide 0'anr-[4O(2-acetainidopyrimidk methoxyphenyl)cyclohexan- l-ol] as a white solid (0.47g, 66%), mp 163-164° C. Anal. (C26H31N3040.25 H20) cakdcVC, 69.47; H.6.95; n, 9.35; found; Q 69.27; H, 6.98; N, 8.97.

Example 20 inethoiKvphmvlVcydolHam-l-ol To a solution of sodium methoxide (0.137 g, 2.5 mmol) in dry methanol (3.8 mL) was added via cannula a solution of trans-[4- (2-acetamidopyrimidin-5-ylethynyl>-4-(3- ^lopentyIoxy-4-iMthoxyphenyl)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 with methylene chloride, filtered, dried (magnesium sulfate) and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate :hexandes and dried in vacuo at 80° C to afford the desired product Preparation of cu-i4-(2-iMmvl.fflrinqiv^ mcthQxyphenyDcy lohc aji-l-oll A mixture of 2-acetan.idc-5-bronx>pyrimidine (0.22g, 1 mmol,) potassium carbonate (0.2 lg, 1.5 mmol) and iodo nethane (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 ethyl acetatethexanes, to provide the desired product as a white solid (0.03g, 13%) 'H-NMR (CDCb, 400 Mhz) δ 8.58 (s, 2H), 3.39 (s, 3H), 2.39 (s, 3H) ppm. 37b) cis -[4-(2-nieuiylacetamidopyriniidm memoxyphenyl)-cyclohexan- l-ol] , To a suspension of ironi-[4-(3-cyctopentyloxy-4-methoxyphenyl)-4-^ cyclohexan-l-ol) (0.20 g, 0.64 mmol) and a mixtuie (-6:4) of 2-acetaimdo-5-bromopyriniidine and 5-bronx>-2-inediylacetaimdopvr^ (0.14 g, ~0.32 mmol of each component) in triemylamine (5 mL) under an argon atmosphere was added tetrakis(triphenylphosphiine)paUadium(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 the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. The residue was purified by chromatography 30 on silica gel with 1:1 and 1:3 ethyl acetaterhexanes, to provide the desired compound as a colorless oil (which contains a trace amount of 2-acetamido-5-bromopyrimiduie). 1H- NMR (C Cb.400 Mhz) 58.65 (s, 2H), 7.12 (d, 2.0 Hz, IH), 6.85, d, J=8.3Hz, IH), 4.80 (m, IH), 3.85 (s, 3H), 3.83 (m, IH), 3.49 (s, 3H), 2.48 (s, 3H), 1.8 - 2.2 (m, 14H, 1.65 (m, 2H) ppm. 37c) cu-[4-(2-memyIaminopyrimidin-5-yleA methoxyphen l)-cyclohexan- 1 -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 ά*4-(2- memylacetamidopyriimdi^ 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 with water, was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 ethyl acetate:hexanes, followed by trituration from ethyl acetate/hexanes, provided the title compound as a white solid (0.032 g, 61%), m.p. 118-119°G Anal (C25H31N3030.75 H20) calcd C, 69.02; H, 7.52; N, 9.66; found: C, 68.84; H, 7.11; N, 9.53.

Example 22 34a) 5- bronio-2-propionan-ttdopyriniidine 5-Brofno-2-propionamidopyrinddine was prepared by standard chemistry well known to those versed in the art and was a white solid, mp 161-164° C 34b) fr Water was added and the mixture was extracted three times with dfchlcromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided trare-[l'tm-ba!boxyca^aoay\anano^ 4~(3-cyclopentylc*y-4-methoxypl cyclohexane] as a white solid (0.21 g, 54%), mp 87-89° C. *H-NMR (400 MHz, CDCI3) 58.57 (s, 2H), 8.17 (m, IH), 7.11 (d, J=22 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. 31 P50287 cyclopentyloxy-4-methoxyphenyl) cyclohexane] A mixture of trans- [ 1 -tert-butoxycarbonylarnino-4^3-cyclopentyloxy-4-niemoxyphenyl)^2-prcf>ionam (0-21 g, 0.37 mmol) and sodium rnethoxide (0.07g, 1 9 mmol) in methanol (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 dkUoromethane, was dried (magnesium sulfate) and was evaporated to provide pure tra«-[4-(2-atninopyrin-idin-5^ 97%) as a white solid, mp 183-183° C.1H-NMR (400 MHz, CDC ) 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 - 1 (m, 14H), 1.61 (m, 2H), 1.46 (s, 9 )ppm. 34d) irflni-[4^2-an^pyriri n-5-ylediynyl)-4-(3-cyclope inetlxjxyphenyljcyclohexyl- 1 -amine], cyclctexylsulfamate salt To a butoxycarbonylarj-djic^(3^cIopenty^ cyclohexane] (0.18 g, 0.35mmol) in dkhloromethane (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 with water, was extracted with three times 10/90 methanoVdicUoromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.5:10:90 ammonium hydroxide:nKthand:dchlorome thane provided trans- [4-(2-aminopyrirnidin-5-ylethynyl)-4-(3^clopenrykjxy-4-r^ as a very viscous, colorless oil (0.13 g, 0.33 mmol, 95%). This intennediate 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, followed by trituration from dichloromethanehexanes provided die title compound as a white solid, mp >230° C (dec.).

Example 23 aminppyriniid^ amine], cyclohexylsulfarnate salt is prepared in the same manner as trans-[A-{2-aminopvrirmdin-5-ylethynyl)-4-(3-cycl 1 -amine], except starting from cis - [ 1 - rerr-butoxycaibony larnino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4^thynyl-cyclohexane]. 32 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 TNF 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 the 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 follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "la"), canine trachealis. PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy etal, 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 uM range for compounds of the workings examples described herein for Formula (I) have been demonstrated. 33

Claims (10)

P50287 116490/2 What is claimed is:

1. A compound of Formula I wherein: Rl is -(CR4R5)nC(0)0(CR4R5)mR6, -(CR4R5)nC(0)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)m 6, or -(CR4R5)r 6, wherein the alkyl moieties are 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 aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCl-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 R6 is hydroxyl, then m is 2; or b) when Re is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2 -tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6; 34 P50287 116490/3 e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)nO(CR4R5)mR6; X is Y 2, fluorine, NR4R5, or formyl amine; Y is O or S(0)m' ; m' is 0, 1, or 2; X2 is O or NRe; X3 is hydrogen; R2 is independently selected from -CH3 or -CH2CH3, wherein R2 is unsubstituted or substituted by one or more halogens; s is 0 to 4; W is ethynyl or 1,3-butadiynyl; R3 is Ri3 or R\Q, which R13 or R Q is unsubstituted or substituted one or more times by R17; Z is OR14, ORi5, SRi4, S(0)m*7, S(0)2NRioRl4, Rl0Rl4, NRi4C(0)R9, NRioC(Y')Rl4. NRioC(0)OR7, NRioC(Y')NRioRl4, NRioS(0)2NRioRl4, NRioC(NCN)NRioRl4. NRioS(0)2R7, NRioC(CR4N02)NRioRl4. NRioC(NCN)SR9, RioC(CR4N02)SR9, NRioC(NRio)NRioRl4, NRioC(0)C(0)NRioRl4,or NRioC(0)C(0)ORi4; Y" is O or S; R7 is -(CR4R5)qRi2 or Ο . alkyl, wherein said R12 or C .Q alkyl is unsubstituted or substituted one or more times by R17; q is 0, 1, or 2; Rl2 is Ri3, C3-C7 cycloalkyl, or R Q ; R3 is independently selected from hydrogen or R9; R9 is Οχ.4 alkyl unsubstituted or substituted by one to three fluorines; RlO is OR8 or Rn; Rll is hydrogen, or C .4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rn are as NRioRll 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 0, N, or S; 35 116490/4 Rl3 is an heterocyclic group selected from oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and when R.\2, Rl3 or Rig is substituted by R 17 , the rings of the bonded R13 and R12. R^3 or Rig groups are connected through a carbon atom, and each second R13 ring is unsubstituted or substituted by one or two methyl or ethyl groups, wherein the methyl group(s) may be unsubstituted or substituted with 1 to 3 fiuoro atoms; Rl4 is hydrogen or R7; or when Re and 14 are as NR¾Rl4 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; Ri5 is C(0)Ri4, C(0)NR8Rn, S(0)qNReR or S(0)qR? where q is 0, l or 2; Rig is an aryl or heterocyclic group selected from (2-, 3- or 4-pyridyl), pyrimidinyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl; R17 is -F, -Br, -CI, -N02, -N ioRn, -C(0)Re, -CO2R8. -0(CH2)2-40R8> -0

2. A compound according to claim 1 wherein R^ 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 or substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl, X is YR2, and Z is OR14, O is, 10 14, or N i4C(0)R9. 36 116490/2

3. A compound according to claim 2 wherein Rie is (2-, 3- or 4-pyridyl), pyrimidinyl, or phenyl.

4. A compound according to claim 3 wherein Rie is pyrimidin-5-yl.

5. A compound according to claim 4 wherein Z is OH and which is c/i-[4-(2-an^opyrimidm-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxy-phenyl)cyclohexan-l -ol], cii-[4-(2-ammopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxy-pheny l)-cy clohexan- 1 -ol] , ra/w-[4-(2-acetaniidopyriniidm-5-ylemynyl)-4-(3-cyclopentyloy^ methoxyphenyl)cyclohexan-l-ol], /ra«5-[4-(2-aminopyrimidin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexan-l-ol, or cw-[4-(2-memylammopyriniidm-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -ol] .

6. A compound according to claim 1, 2 or 3 wherein Z is OH and which is cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-4-ylethynyl) cyclohexan-l-ol], c/j-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl) cyclohexan-l-ol], c/i-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-l-ol], cw-[4-(thiazol-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-l-ol], cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[l,2,4] oxadiazol-2-yl)thien-2-y lethynyl] cy clohexan- 1 -ol], cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[l,2,4] oxadiazol-5-yi)phenyl]ethynyl)cyclohexan-l-ol], cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[l,3,4] oxadiazol-2-yl)phenyl]ethynyl)cyclohexan- 1 -ol], cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[l,2,4] oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-l-ol], c/i-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-trifluoromethyl-[l,2,4] oxadiazol-3-yl)phenylethynyl)cyclohexan-l -ol, or 37 116490/2 cis-4-(3^cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl-[l,3,4] thiadiazol-2-y l)phenylethynyl]cyclohexan- 1 -ol.

7. A compound according to claim 1, 2 or 3 wherein Z is NR10R14, or NRi4C(0)R9 which is ira ts-^- S-cyclopentyloxy^-methoxyphenylJ^- pyrid^-ylethynyl) cyclohexyl-1 -amine], fran-f-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl) cyclohex l-1 -formamide], rans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[l,2,4] oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl- 1 -amine], cyclohexylsulfamate salt cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl) cyclohexy 1- 1 -amine], cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl) cy clohexyl- 1 -formamide] , cij-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1^2,4] oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-l -amine], cyclohexylsulfamate salt, /rans-[4-(2-aminopyrimidm-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxy-phenyl)cyclohexyl-l -amine], cyclohexylsulfamate salt, or cw-[4-(2-am opyrirmchn-5-ylemyn^ phenyl)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. Use of a compound of formula I as defined in any one of claims 1 to 7 in the preparation of a pharmaceutical compositionfor treating asthma, substantially as described in the specification.

10. A compound of formula I as defined in any one of claims 1 to 7 for use' as a medicament for treating asthma. 38