"Compounds Useful for Treating Allergic or Inflammatory Diseases"

Field of Invention

The present invention relates to novel compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).

Background of the Invention

Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli. Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease. One such way is by elevating levels of cAMP (adenosine cyclic 3',5'- monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973], When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg ⁺ 2-ATP to cAMP at an accelerated rate.

Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of 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 5) inhibition of onocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the

case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the 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, 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, HIV- 2 and HIV-3. As a consequence of HTV 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 HTV-1 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 HTV gene expression and/or HIV replication.

C-ytoldnes, specifically TNF, are implicated in activated T-cell-mediated HTV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-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 EQV 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 etal., 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, 162:211-214,1990].

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 This invention relates to the novel compounds of Formulas (I) and (II) as shown below, useful in the mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). These compounds also have Tumor Necrosis Factor (TNF) inhibitory activity.

This invention also relates to the pharmaceutical compositions comprising a compound of Formulas (I) or (II) 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) or (II) as shown below.

The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) or (II).

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) or (II).

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) or (II). 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) or (II).

Compounds of Formula (I) or (II) 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) or (II) 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. Certain novel compounds of this invention are represented by Formula (I):

wherein:

Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5) _n O(CR4R5)mR6, ^or -(CR4Rs)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; ris 1 to 6; R4 and R5 are independently selected hydrogen or C_-2 alkyl;

Ro ^" is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-,3 alkyl, halo substituted aryloxyCι_3 alkyl, indanyl, indenyl, C7-H 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 and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when Rζ is hydroxyl, then m is 2; or b) when R 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 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 Rβ is other than H in -(CR4R5) _n O(CR4R5) _m R6; X is YR2, halogen, nitro, NR4R5, or formyl amine;

Yis O orS(O) _m -;

m ¹ is 0, 1, or 2;

X2 is O or NR8;

X3 is hydrogen or X;

R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;

R3 is hydrogen, halogen, C1-4 alkyl, halo-substituted C1-4 alkyl,

CH2NHC(O)C(O)NH2, -CH=CR8'R8', cyclopropyl optionally substituted by R8\ CN, OR8, CH2OR8, NR8R10, CH2NR8R10, C(Z')H, C(O)ORg, C(O)NRsRl0, or C≡CRg'; Z is O, NR9, NOR8, NCN, C(-CN)2, CRδCN, CR8NO2, CR8C(O)OR8,

CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgRg ;

Z is O, NR7, NCR4R5C2-6 alkenyl, NOR14, NOR15, NOCR4R5C2-6 alkenyl, NNR4R14, NNR4R15, NCN, NNRgC(O)NRgRi4, NNRgC(S)NRgRi4, or =Z is 2-(l,3-dithiane), 2-(l,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2-(l,3-dioxolane), 2(l,3-dioxane), 2-(l,3-oxathiolane), dimethyl ketal or diethyl ketal;

R7 is -(CR4R5)qRi2 or C\.^ alkyl wherein the R12 or Cj.g alkyl group is optionally substituted one or more times by C 1-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -CI, -NO2, -Si(R4)3. -NRioRll. -C(O)R8, -CO2R8, -ORδ, -CN, -C(O)NRioRll, -OC(O)NRi0Rll, -OC(O)R8, -NRιθC(O)NRiθRll, -NRi0C(O)Rn, -NRιoC(O)OR9, -NRi0C(O)Rl3, -C(NRiθ)NRiθRl 1, -C(NCN)NRioRll, -C(NCN)SR9, -NRlθC(NCN)SR9 , -NRιoC(NCN)NRιoRll, -NRιoS(O)2R9, -S(O) _m ^I R9, -NRioC(O)C(O)NRioRll, -NRιoC(O)C(O)Riθ, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2; R12 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;

R8 is independently selected from hydrogen or R9;

R8' is Rδ or fluorine; R9 is Cj_4 alkyl optionally substituted by one to three fluorines;

RlO is ORδ or Rn;

Rl is hydrogen, or C _4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;

Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cι_2 alkyl groups;

R 4 is hydrogen or R7; or when Rg and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;

Rl5 is C(O)Rl4, C(O)NR4Rl4, S(O)2R7, or S(O)2NR4Rl4; provided that:

(f) when Z is O, X is YR2, Y is oxygen, X2 is oxygen, X3 is hydrogen, s is 0, R2 is CH3, and Ri is CH3, then R3 is other than CN;

(g) when Z is O, 2 is oxygen, X3 is hydrogen, s is 0, and X is YR2, then R3 is other than hydrogen; (h) when Z is N-O-CH2CH=CH2, X is YR2, Y is oxygen, X2 is oxygen, X3 is hydrogen, s is 0, R2 is CH3, and Ri is CH3, then R3 is other than CN;

(i) when R 2 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or

0 ^" ) when Z is O or =Z is 2-(l,3-dioxolane) and R3 is CH3, CH2OH or CH2OC1-4 alkyl then RχX2 is not C1-C3 alkoxy and X is not halogen, methoxy, ethoxy, methylthio, or ethylthio; or the pharmaceutically acceptable salts thereof.

Another set of compounds of this invention are represented by Formula (II)

wherein:

R _L is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5) R6, -(CR4R5 nO(CR4R5) _m R6. or -(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; ris 1 to 6;

R4 and R5 are independendy selected hydrogen or Ci-2 alkyl; Ro ^" is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-I l 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 and heterocyclic moieties is unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or

b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-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; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)nO(CR4R5)m 6; X is YR2, halogen, nitro, NR4R5, or for yl amine;

Y is O or S(O) _m '; m' is 0, 1, or 2; X2 is O or NR8;

X3 is hydrogen or X;

R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted

C1-4 alkyl, -CH=CRg'Rg', cyclopropyl optionally substituted by Rg', CN, ORg, CH ₂ ORg, NRgRio, CH2NRgRlO, C(Z')H, C(O)ORg, C(O)NRgRιo, or C≡CRg';

Z' is O, NRQ, NORg, NNRgRg, NCN, C(-CN)2, CRgCN, CR8NO2, CR8C(O)OR9, CR8C(O)NR8Rg, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgRg; Z" is C(Y')Ri4, C(O)ORi4, C(Y')NRιoRl4, C(NRιo)NRιoRl4, CN,

C(NORg)Ri4, C(O)NRgNRgC(O)Rg, C(O)NRgNRioRl4, C(NORi4)Rg, C(NRg)NRlθRl4, C(NRi4)NRgRg C(NCN)NRioRl4. C(NCN)SR9, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[l,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[l,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or

5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; Y" is O or S; the remaining the substituents for compounds of Formula (II). including, R7, q, R12, Rg, Rg*, R9, RlO. Rl 1, Rl3, Rl4, and R15 have the same definitions given in regards to Formula (I),where applicable; provided that: f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N- piperazinyl, N-piperidinyl, or N-mo holinyl, then q is not 1; or g) when Z" is C(O)ORi4 where R14 is lower alkyl and R3 is CN, then R1X2 is not C1-C3 alkoxy and X is not halogen, methoxy, ethoxy, methylthio, or ethylthio; or the pharmaceutically acceptable salts thereof.

Detailed Description of the Invention This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting 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) or (II).

Phosphodiesterase IN 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-infaict dementia. The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, direcdy or indirectly, by the TNF inhibitors of Formula (I) or (II). Such viruses include, but are not limited to HIV-1, HIV-2 andHTV-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 (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or (II).

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 Ientiviruses.

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) or (II) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections. Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such

as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.

The compounds of Formula (I) or (U) 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) or (II) to a mammal in need of such treatment. Preferably, a compound of Formula (I) or (II) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B. Preferred compounds are as follows: When Rl for the compounds of Formula (I) or (II) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2. -CH2CF3, and -CH2CHF2- Preferred Rl substitutents for the compounds of Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7-H polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH ₂ )1-3O(CH2)0-2CH3, and -(CH2)2-4OH.

When the Ri term is (CR4R5), the R4 and R5 terms are independently 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 optionally 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 bicyclo[2.2. l]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.θ2>6]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety.

Preferred Z terms are O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4R15, dimethyl ketal or dimethylthio ketal. More preferred are O or NOH.

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 Cl-2 alkyl optionally 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 fiuoro-substituted alkyls, specifically a Cl-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.

Preferred R3 moieties are C(O)NH2. C≡CRg, CN, C(Z')H, CH2OH, CH2F, CF2H, and CF3. More preferred are C≡CH and CN. Z' is preferably O or NORg.

Preferred R7 moieties include optionally substituted -(CH2)l-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cycIohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)l'-2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4-piperazinyl), (CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), and (CH2)0-2phenyl;

Preferred rings when Rio and Rl 1 in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1- imidazolyl, 2-(Rg)-l-imidazolyl, l-pyrazolyl, 3-(R8)- l-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(Rg)-l-triazo-yl, 5-(Rg)-2-triazolyl, 5-(Rg)-l-tetrazolyl, 5-(Rg)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazIoyl, morpholinyl, piperazdnyl, 4-(Rg)-l-piperazinyl, orpyrrolyl ring.

Preferred rings when Rg and R14 in the moiety -NRgRi4 together with the nitrogen to which they are attached may form a 5 to 7 membered ring optionally containing at least one additional 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)-l-imidazolyl, 4-(R7)-l-imidazolyl, 5-(R7)-l-imidazolyl, 3-(R7)-l-pyrazolyl, 4-(R7)-l-pyrazolyl, 5-(R7)-l-pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l-triazoIyl, 5-(R7)-l-triazolyl, 5-(R7)-l-tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l-tetrazolyl, 4-(R7)-l-piperazinyl. Where applicable, the ring may be substituted one or more times by R7.

Preferred groups for NRgRi4 which contain a heterocyclic ring are 5-(Ri4)-l- tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l-pϊperazinyl, or 4-(Ri5)-l-piperazinyl.

Preferred rings for R 3 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[l,2,3]), (3- or 5-triazolyl[l,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[l,3,4]), (2-thiadiazolyl[l,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 optionally substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be optionally substituted by Rg either on an available nitrogen or carbon atom, such as l-(Rg)-2-imidazolyl, l-(Rg)-4-imidazolyl, l-(Rg)-5-imidazolyl, l-(Rg)-3-pyrazolyl, l-(Rg)-4-pyrazolyl, l-(R8)-5-pyrazolyl, l-(R8)-4-triazolyl, or l-(Rg)-5-triazolyl. Where applicable, the ring may be substituted one or more times by Rg.

Preferred are those compounds of Formula (I) wherein R is -CH2-cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Cl-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl, R3 is CN or C≡CRg; and X is YR2. Most preferred are those compounds wherein Ri is -CH2-cyclopropyl, cyclopentyl, methyl or CF2H; R3 is CN or C≡CH; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl.

A preferred subgenus of Formula (I) are the compounds of Formula (Ia)

wherein: Rj is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Cl-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)θ-2CH3, -(CH2)1-3O(CH2)0-2CH ₃ , and -(CH2)2-4OH;

X is YR2, halogen, nitro, NR4R5, or formyl amine;

Y is O or S(O) _m '; m' is 0, 1, or 2;

R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, Ci-4 alkyl, halo-substituted C1-4 alkyl CH2C(O)C(O)N,

CH2NHC(O)C(O)NH2, CN, CH2OR8, C(Z')H, C(O)OR8, C(O)NRsRlθ, or C≡CRs; Z is O or NOR8;

Z is O, NR7, NOR14, NOR15, NNR4R14, NNR4R15, NCN, or =Z is 2-(l,3- dithiane), dimethylthio ketal, 2-(l,3-dioxolane), or dimethyl ketal; R7 is -(CR4R5)qRi2 or Cι_6 alkyl wherein the R12 or Cι_6 alkyl group is optionally substituted one or more times by Cl-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -CI, -NO2, -Si(R_.)3, -NR ₁₀ Rπ, -C(O)R8, -CO2Rg, -ORg, -CN, -C(O)NRlθRn, -OC(O)NRioRll, -OC(O)R8, -NRiθC(O)NRlθRl l, -NRιoC(O)Rn, -NRiθC(O)OR9, -NRιoC(O)Ri3, -C(NRio)NR_θRl l, -C(NCN)NRιoRll, -C(NCN)SR9, -NRioC(NCN)SR9 , -NRioC(NCN)NRioRl 1, -NRιoS(O)2R9, -S(O) _m 'R9, -NRioC(O)C(O)NRιoRll, -NRiθC(O)C(O)RlO, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2;

Rl2 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), or phenyl; Rg is independently selected from hydrogen or R9;

R9 is Cι_4 alkyl optionally substituted by one to three fluorines;

RlOis ORg orRn;

Rl 1 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines; or when Rχo and Rπ are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;

Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolϊdinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cι_2 alkyl groups;

Rχ is hydrogen or R7; or when Rg and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring optionally contaimng one or more additional heteroatoms selected from O, N, or S;

Rl5 is C(O)Rl4, C(O)NR4Rl4, S(O)2R7. or S(O)2NR4Rl4; provided that: a) when Z is O, X is YR2, Y is oxygen, R2 is CH3, and Ri is CH3, then R3 is other than CN; b) when R12 is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, orN- morpholinyl, then q is not 1; or the pharmaceutically acceptable salts thereof.

Exemplified preferred compounds of Formula (I) are:

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l- one;

4-(3,4-bisdifluorome oxyphenyl)-4-cyanocyclohexan-l-one;

4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)cyclohexan- 1 -one; 4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan- 1 -one;

4-cyano-4-(3-cyclopentyloxy-4-difluoromemoxyphenyl)cycloh exan-l-one;

4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)c yclohexan-l-one;

4-cyaπo-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l -oneoxime;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-l -one; 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one dimethyl ketal;

4-(3-cyclopentyloxy-4-methoxyphenyI)-4-formylcyclohexan-l -one dimethyl ketal;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyc lohexan-l-one;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyc lohexan-l-one- dimethyl ketal; 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohe xan- 1-one;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cycl ohexan-l-one dimethyl ketal;

4-aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclo hexan-l-one;

4-aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex an- 1 -one dimethyl ketal;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan- l-one;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohex- 1 -one dimethyl ketal; 4- (3 ,4-bisdifluoromethoxyphenyl)-4-ethynylcyclohexan- 1 -one;

4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-l-one dimethyl ketal;

4-(3,4-bisdifluoromethoxyphenyl)-4-formylcyclohexan-l-one dimethyl ketal;

4-(3,4-bisdϋluoromethoxy)-4-ethynylcyclohex-l-one dimethyl ketal;

4-(3,4-bisdifluoromethoxyphenyl)-4-(oxamidomethyl)cyclohe xan-l-one; 4-aminomethyl-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan- 1-one dimetiiyl ketal;

4-(3,4-bisdifluoromethoxyphenyl)-4-(oxamidomethyl)cyclohe xan- 1 -one dimethyl ketal;

4-cyano-4- [3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]cyclohexan- 1 -one;

4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]c yclohexan- 1 -one oxime;

4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-4-ethyny lcyclohexan- 1 -one;

4-cyano-4-(3-cyclopropmethoxy-4-methoxyphenyl)cyclohexan- 1 -one oxime.

Preferred Z" groups are for compounds of the Formula (II) are C(O)Ri4, C(O)ORi4, C(O)NRιoRl4, C(NRιo)NRιoRl4, CN, C(NORg)Rι , C(O)NRgNRgC(O)Rg, C(O)NRgNRιoRl4, C(NORi4)Rg, C(NRg)NRιoRl4,

C(NRi4)NRgRg, C(NCN)NRιoRl4, C(NCN)SR9, (1-, 4- or 5-{Ri4}-2-imidazolyl), (1- , 4- or 5-{Ri4}-3-pyrazolyl), (1-, 2- or 5-{Ri4}-4-triazolyl[l,2,3]), (1-, 2-, 4- or 5-{Ri4}-3-triazolyl[l,2,4]), (1- or 2-{Ri4}-5-tetrazolyl), (4- or 5-{Ri4)-2-oxazolyl), (3- or 4-{Ri4}-5-isoxazolyl), (3-{Ri4)-5-oxadiazolyl[l,2,4]), (5-{Ri4}-3-oxadiazolyl[l,2,4]), (5-{Ri4)-2-oxadiazolyl[l,3,4]), (5-{Ri4}-2-thiadiazolyl[l,3,4]), (4- or 5-{R }-2-thiazolyl), (4- or 5-{Ri4}-2-oxazolidinyl), (4- or 5-{Ri4}-2-thiazolidinyl),(l-, 4- or 5- {Ri4}-2-imidazolidinyl). The remaining preferred substituents for compounds of die Formula (II) are the same as those listed above for compounds of the Formula (I), where applicable.

Exemplified preferred compounds of Formula (II) are:

2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxypheny l)cyclohexan-l-one;

4-(3,4-bisdifluoromethoxyphenyl)-2-carbomethoxy-4-cyanocy clohexan- 1 -one;

2-carbomethoxy-4-cyano-4-(3-difluoromethoxy-4-methoxyphen yl)cyclohexan-l- one;

2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyp henyl)cyclohexan-

1-one;

2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluorometh oxy- phenyl)cyclohexan- 1 -one;

2-cariκ)memoxy-4-cyano-4-(3-cyclor)ropylmemoxy-4-difluorome moxypte cyclohexan-1-one;

2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxy phenyl)cyclohexan- 1-one; 4-cyano-4-(3-cyclopropylmemoxy-4-difluoromemoxyphenyl)-2-[2- (trimethylsilyl)- ethoxycarbonyl)]-cyclohexan-l-one;

2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluorometho xy- phenyl)cyclohexan-l-one; (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2,4-dicyanocy clohexan- 1 -one; and

2-ammocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoro methoxy- phenyl)cyclohexan- 1-one.

It will be recognized that some of the compounds of Formula (I) and (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention.

Some compounds of Formula (I) or (H) may exist in a tautomeric form, such as the represented by the =O being exocyclic to the cyclohexane ring (or

as contrasted to the endocyclic or -C(-OH)=C(R)- moiety wherein the aturated in the 1-2 position, i.e. cyclohex- 1-ene , or

H in Formula (I) or Z" in Formula (II). It is also recognized that the 2-position of the ring in the endocyclic form can be substituted (R) such as in the compounds of Formula (II).

The term "Cι_ ₃ alkyl", "C1.4 alkyl", "Ci.g alkyl" or "alkyl" groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, unless die chain length is limited diereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, and die like.

"Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2- propenyl, 2-propynyl, 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, ornaphthyl. Preferably

the aryl is monocyclic, i.e, phenyl. The alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.

"Heteroaryl" means an aromatic ring system contaimng one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.

"Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.

"Inhibiting the production of IL-1" or "inhibiting the production of TNF" means: a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of 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 J-L-l or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event. The phrase "TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to EL-1 or IL-6. A disease state in which D -l, 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. "Cytokine" means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce diem.

The cytokine inhibited by the present invention for use in the treatment of a HTV- infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HTV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably, his cytokine is TNF-α.

All of the compounds of Formula (I) and (II) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formula (I) and (H) 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.

METHODS OF PREPARATION: Preparing compounds of Formula (I) can be carried out by one of skill in the art according to the procedures outlined in die Examples, infra. The preparation of any remaining compounds of Formula (I) not described therein may be prepared by die analogous processes disclosed herein which comprise: a) for compounds wherein X and Xi are other than Br, I, NO2, amine, formyl amine, or S(O)m' when m' is 1 or 2, reacting a compound of Formula (2)

wherein Ri represents Ri as defined in relation to Formula (I) or a group convertable to Ri and X represents X as defined in relation to Formula (I) or a group convertable to X and X3 represents X3 as defined in relation to Formula (I) or a group convertable to X3 and Xi is H, widi a lithium halide and a silyl halide in an appropriate solvent followed by reduction with an appropriate reductant, such as a siloxane, to provide a compound of Formula (3) wherein X4 is a halide. Alternatively, reduction of a compound of Formula (2) wherein X is H widi a suitable reductant, such as sodium borohydride, provides a compound of Formula (3) wherein X4 is OH. Reaction of such a compound of Formula (3) with, for example, phosphorous trichloride, thionyl chloride, phosphorous tribromide, cupric bromide, or carbon tetrabromide and triphenylphosphine, also provides a compound of Formula (3) wherein X4 is a halide;

halide displacement by cyanide provides a compound of Formula (3) wherein X4 is CN. Reaction of a compound of Formula (3) wherein X4 is CN with an excess of an acrylate, such as methyl, ethyl, phenyl, benzyl or t-butyl acrylate, in the presence of a base, such as excess metal hydride or catalytic or excess quaternary amine base, such as benzyltrimethylammonium hydroxide, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane when a metal hydride base is used or these solvents or acetonitrile when a quaternary amine base is used, then provides a compound of Formula (4) in which X4 is CN and Rl6 is an alkyl, phenyl, or benzyl group;

reaction of a compound of Formula (4) with a base, such as excess metal hydride, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at an elevated temperature then provides a compound of Formula (5) wherein X4 is CN and Ri6 is an alkyl, phenyl, or benzyl group;

alternatively, a compound of Formula (5) [a subset of me compounds of Formula (II)] may be obtained direcdy from a compound of Formula (3) wherein X4 and Ri6 are as described above by reaction with an excess of an acrylate, such as methyl, ethyl, phenyl, benzyl, or t- butyl acrylate, with excess base, such as a metal hydride, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dime oxyedιane, at an elevated temperature.

Treating a compound of Formula (5) with, e.g., sodium chloride in aqueous dimethylsulfoxide at elevated temperature, effects saponification and decarboxylation of die ester moiety to provide a compound of Formula (I) in which R3 is CN and Z is O. Alternatively, a compound of Formula (2) wherein Xi is H may be homologated to a compound of Formula (3) wherein X4 is COOR17 by any number of processes known in the art, such as reaction with methyl methylsulfinyl-methyl sulfide and a base, such as sodium hydroxide, followed by treatment with, for example, alcoholic (R17OH) acid. Reaction of such a compound of Formula (3) wherein X4 is COOR17 with an excess of an acrylate, such as methyl, ethyl, phenyl, benzyl, or t-butyl acrylate, and with excess base, such as a metal hydride, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2- dimethoxyethane, provides a compound of Formula (4) wherein X4 is COOR17 and Ri6 and R 17 are independendy an alkyl, phenyl, or benzyl group. Reaction of a compound of Formula (4) wherein X4 is COOR17 and Ri6 and R17 are independently an alkyl, phenyl, or benzyl group with a base, such as excess metal hydride, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dimemoxyethane, at an elevated temperature then provides a compound of Formula (5) wherein Xi is COOR17 and Ri6 and R17 are independendy an alkyl, phenyl or benzyl group. Treatment of a such a compound of Formula (5) widi, e.g., sodium chloride in aqueous dimethylsulfoxide at elevated temperature effects saponification and decarboxylation of the β-keto ester moiety to provide a compound of Formula (I) wherein R3 is COOR17 nd Z is O, ald ough under certain reaction conditions, some compounds of Formula (I) wherein R3 is COOH and Z is O will

also be obtained. The carboxyl group of such a compound of Formula (I) may then be converted into a number of esters, in which R3 is COORg, or amides, in which R3 is CONRgRg, using any of the very wide varieties of standard transformations known in the art. In some cases, the keto carbonyl of such a compound of Formula (I) may require protection as, e.g., a ketal, prior to ester or amide formation, with liberation of the protected ketone under appropriate mild acidic conditions as the final step. The simple amide derivative, that in which R3 is CONH2 and Z is O, may be treated, after appropriate protection of the ketone, with a dehydrating agent to provide, after ketone deprotection, the compound of Formula (I) in which R3 is CN and Z is O. Compounds of Formula (I) wherein R3 is CHO and Z is O may be prepared from the compound of Formula Q in which R3 is CN and Z is O after appropriate protection of die ketone as, e.g., a ketal, followed by reduction of the CN moiety with, e.g., di- isobutylaluminum hydride, followed by appropriate workup and ketone deprotection.

Compounds of Formula Q) wherein R3 is CH2OH and Z is O may be prepared by reduction of die compound of Formula (I) in which R3 is CHO and =Z is a ketal protecting group with, e.g., sodium borohydride, followed by appropriate workup and ketone deprotection.

Compounds of Formula (I) wherein R3 is CH2NRgRg and Z is O may be prepared by reduction of die compound of Formula (I) in which R3 is CN and =Z is a ketal protecting group widi, e.g., lithium aluminum hydride or hydrogen in d e presence of a catalyst, followed by appropriate workup, standard alkylation by Rg and tiien ketone deprotection.

Compounds of Formula (I) wherein R3 is OH and Z is O may be prepared from the compound of Formula (I) in which R3 is CHO and =Z is a ketal protecting group by, e.g., Bayer- Villiger oxidation of the aldehyde and ester saponification to provide the compound of Formula (I) in which R3 is OH and =Z is a ketal protecting group, followed by ketone deprotection.

Compounds of Formula (I) wherein R3 is halogen and Z is O may be prepared from the compound of Formula Q) in which R3 is OH and =Z is a ketal protecting group by, e.g., dehydration to d e olefin and hydrohalic acid addition to provide d e compound of Formula (I) in which R3 is halogen and =Z is a ketal protecting group, followed by ketone deprotection.

Compounds of Formula (I) wherein R3 is C≡CRg' and Z is O may be prepared from the compound of Formula (I) in which R3 is CHO and =Z is a ketal protecting group by reaction with a mixture of dimethyl (diazomethyl)phosphonate and potassium t-butoxide or other suitable base, in an inert solvent, such as tetrahydrofuran, at reduced temperature, followed by appropriate workup and ketone deprotection to provide the compounds of Formula (I) wherein R3 is C≡CH; alternatively, prior to ketone deprotection, alkylation of the acetylene under the appropriate conditions widi a strong base followed by an alkylating

agent, RδL, wherein L is a leaving group and R8' is not H, followed by ketone deprotection, provides compounds of Formula (I) wherein R3 is C≡CRδ'.

Compounds of Formula (I) wherein R3 is CH2F and Z is O may be prepared from the compound of Formula (I) wherein R3 is CH2OH and =Z is a ketal protecting group by treatment with diediyl-aminosulfur trifluoride (DAST) followed by ketone deprotection.

Compounds of Formula (I) wherein R3 is CHF2 and Z is O may be prepared from the compound of Formula (I) wherein R3 is CHO and =Z is a ketal protecting group by treatment with diethylaminosulfur trifluoride (DAST) followed by ketone deprotection.

Compounds of Formula (I) wherein R3 is CF3 and Z is O may be prepared from the compound of Formula (3) wherein X2 is CF3 using the procedures described above for preparation of the compounds of Formula (I) wherein R3 is CN or COOR16 and Z is O; the compound of Formula (3) wherein X2 is CF3 may be prepared in turn from the compound of Formula (2) wherein Xi is H either electrochemically by the method of Shono et al., J. Org. Chem., 56:2-4, 1991, or by treating a compound of Formula (6)

wherein X5 is, e.g., bromine, with a metalling agent, such as an alkyl lithium, in an inert solvent, such as tetrahydrofuran or 1,2-dimethoxyetiιane, at -78° C followed by the trifluoroacetic acid or difluoro acetic acid by die metiiod of Nad et α/. zvest, 71, 1959: Chem. Abstr., 53, No. 14977 and 53, No. 17933 ,1959, to provide a compound of

Formula (2) wherein Xi is CF3, which is then thioketalized with, e.g., 1,3-propanedidιiol and subsequendy subjected to desulfurization with, e.g., Raney nickel.

The compounds of Formula (I) where R3 is Ci alkyl and Z is O may be prepared from the compound of Formula (I) wherein R3 is CH2OH and =Z is a protected ketone by reductive removal of die alcohol with lithium in ammonia, widi aluminum hydride, or by conversion of the alcohol to the corresponding thiocarbamate followed by reduction with, e.g., tributyltin hydride or trialkylsilyl hydride, and ketone deprotection; alternatively, the compounds of Formula (I) wherein R3 is Ci alkyl and Z is O may be prepared from the compound of Formula (I) wherein R3 is CHO and =Z is a protected ketone by thioketal formation, desulfurization and ketal deprotection.

Compounds of Formula (I) where R3 is C2-4 alkyl or halogen substituted C2-4 alkyl and Z is O may be prepared by analogous deoxygenation procedures from the corresponding alcohol derived from reaction of the compound of Formula (I) wherein R3 is CHO and =Z is a protected ketone with a metal alkyl or a halogen substituted C2-4 metal alkyl reagent and subsequent deprotection to liberate the =Z ketone.

Compounds of Formula ( ) wherein R3 is vinyl and Z is O may be prepared by, e.g., Wittig or other olefination reaction of the compound of Formula (I) wherein R3 is CHO and =Z is a protected ketone, and subsequent deprotection to liberate the =Z ketone.

Compounds of Formula (I) wherein R3 is cyclopropyl and Z is O may be prepared from the compound of Formula (I) wherein R3 is vinyl and =Z is a protected ketone by reaction widi, e.g., mediylene iodide and zinc-copper couple, widi subsequent deprotection to liberate the =Z ketone.

Alternatively, certain compounds of Formula (I) wherein Z is O and R3 is COOR8 (or COOR16) may be prepared by reducing die double bond of die cyclohexenone synthetic intermediates produced by die method of Parkinson and Pinhey, J. Chem. Soc. Periάn Trans.1, 1053-7, 1991, incorporated herein by reference in its entirety. Similar double bond reduction of the corresponding synthetic intermediates wherein R3 is CN derived by analogous procedures using 4-cyano-3-cyclohexen-l-one and/or 4-cyano-2-cyclohexen-l- one may provide certain compounds of Formula (I) wherein Z is O and R3 is CN. Most compounds of Formula (I) wherein Z is not O are prepared from die corresponding compounds of Formula (I) wherein Z is O by reaction widi die appropriate amine , alcohol, or thiol, in the presence of a catalyst or with removal of water, if required, as described in the procedures oudined in the Examples, infra; however, when R3 is CHO, this R3 group may require protection as, e.g., a ketal, during reaction followed by deprotection. b) Compounds of Formula (I) wherein X or X3 is formyl amine and Z is O may be prepared by formylating, at the last step, a compound wherein =Z is a protected ketone and X is NH2, obtained by removal of a protecting group from the amine functionality; such protective groups are well known to those skilled in the art, See Greene, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York (1991). c) Compounds of Formula (I) wherein X or X3 is Br or I and Z is O may be prepared from a similarly deprotected amine by diazotization of die amine and diazonium displacement via Sandmeyer reaction- d) Compounds of Formula (I) wherein X or X3 is NO2 and Z is O may be prepared from a similarly deprotected amine by oxidation of die amine to d e nitro group. e) Compounds of Formula (I) wherein Y is S(O)m' when m' is 1 or 2 and Z is O may be prepared from the compounds of Formula (I) wherein Y is S by oxidation of die SR2 moiety under conditions well known to those skilled in the art. Compounds of Formula (II) wherein R14 in C(O)ORl4 of the Z" group is other than an alkyl, phenyl, or benzyl group are obtained from compounds of Formula (5) or from otiier compounds of Formula (H) by standard transesterification procedures. Similarly, other compounds of the Formula (II), e.g., Z" amides, aldehydes, ketones, hydrazides, etc., may be prepared from other compounds of the Formula (II) by, e.g.,

standard functional group manipulation of the Z" group, either proceeding or following functional group manipulation of the R3 group. In some cases, appropriate protection of certain chemically sensitive R3 groups and/or the keto (=O) moiety of the Formula (II) compound may be required during functional group manipulation of the Z" group, with subsequent deprotection providing die desired Formula (H) compound. Some such manipulations of the Z" group may be accomplished by the processes described in co- pending U.S. application serial number 862,030 filed 2 April 1992 and its corresponding continuation-in-part application USSN 968,762 filed 30 October 1992. In other cases, some compounds of Formula (II) may be converted to odier compounds of Formula (II) by manipulation of the R3 group using the general techniques described above and, when necessary, using appropriate protection and deprotection of chemically sensitive functionalities, such as the keto (=O) moiety or chemically sensitive moieties of the Z" group. Also, some compounds of Formula (II) may be prepared by reaction of an appropriate compound of Formula (I) with an appropriate base in the appropriate proportions under die appropriate conditions followed by reaction with a haloformate, such as metiiyl or ediyl chloroformate, or by treatment of an appropriate compound of Formula (I) with methyl methoxy magnesium carbonate; such compounds of the Formula (II) may then be converted to odier compounds of die Formula (II) by the techniques described above and below. In addition, some compounds of die Formula (II) may be prepared by reacting a compound of die Formula (3) wherein Rl represents Ri as defined in relation to Formula (I) or a group convertable to Rl and X, X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X, X2 or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3, and X4 is CN with an excess of acrylonitrile in the presence of a base, such as excess metal hydride, or catalytic or excess quaternary amine base, such as benzyltrimetiiylammonium hydroxide, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane when a metal hydride base is used or these sovents or acetonitrile when a quaternary amine base is used, to provide a compound of the Formula (7)

wherein X4 is CN; reaction of a compound of the Formula (7) with a base, such as excess metal hydride, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2- dimethoxyethane, at an elevated temperature then provides a compound of the Formula (8)

wherein X4 is CN and X5 and Xβ are both H; alternatively, a compound of die Formula (8) may be obtained direcdy from a compound of Formula (7) wherein X4 is as described above by reaction with an excess of optionally R2-substituted acrylonitrile, with excess base, such as a metal hydride, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at an elevated temperature.

Treatment of a compound of die Formula (8) widi an acid, e.g., 6N hydrochloric acid at ambient or elevated temperature, in a solvent, such as ethanol, with or without a co- solvent, such as chloroform, provides a compound of Formula (9).

Compounds of the Formula (10)

wherein X5 is H, are prepared by heating compounds of the Formula (9) in a solution of hydrazoic acid generated in situ by, e.g., admixture of an alkalai metal azide, such as sodium azide, widi an ammonium halide, such as triethylamine hydrochloride, in a polar non-protic solvent such as N-methylpyrrolidinone.

Using the series of reactions oudined above begining with reaction of an appropriate compound of Formula (3) but widi a 2-(R2)- or 3-(R2)-acrylate provides, respectively and sequentially, the 2,6-(R2)2- or 3,5-(R2)2-pimelates of Formula (4), the 2,6-(R2)2- or 3,5- (R2)2-2-(COORi6)-cyclohexanones of Formula (5) and then the 2,6-(R2)2- or 3,5-(R2)2- cyclohexanones of Formula (T). Similarly, starting with reaction of an appropriate compound of Formula (3) but widi a 2,3-(R2)2- or 3,3-(R2)2-acrylate provides, respectively and sequentially, the 2,3,5,6-(R2)4- or 3,3,5,5-(R2)4-pimelates of Formula

(4), the 2,3,5,6-(R2)4- or 3,3,5,5-(R2)4-2-(COORi6)-cyclohexanones of Formula (5) and then the 2,3,5,6-(R2)4- or 3,3,5,5-(R2)4-cyclohexanones of Formula (I). Likewise, starting with reaction of an appropriate compound of Formula (3) but wid a mixture of appropriate acrylates, e.g., mediyl acrylate and methyl 3-(R2)- or 2,3-(R2)2-acrylate, provides, respectively and sequentially, e.g., 3-(R2)- or 2,3-(R2)2-pύτιelates of Formula (4), the 3-(R_ -, 5-(R2H 5,6-(R2)2-, or 2,3-(R2)2-2-(COORi6)-cyclohexanones of Formula (5) and then die 3-(R2)- or 2,3-(R2)2-(R2)4-cyclohexanones of Formula (I). Alternatively, reaction of an appropriate compound of Formula (I) with an appropriate base in the appropriate proportions under the appropriate conditions followed by reaction with an alkylating agent, R2L, wherein L is a leaving group, provides die 2-(R2)-, 2,2-(R2)2-. 2,6- (R2)2- _» or 2,2,6,6-(R2)4-cyclohexanones of Formula (I); similar reaction of an appropriately alkylated compound of Formula (I), e.g., 3,5-(R2)2- or 2,6-(R2)2- cyclohexanone, provides, e.g., 2,3,5-(R2)3- or 2,2,6-(R2)3-cyclohexanone of Formula (I), respectively. Likewise, similar reaction of a compound of Formula (5) provides, e.g., 2-(R2)-, 2,6-(R2)2- _> or 2,6,6-(R2)3-2-(COORi6)-cyclohexanones of Formula (5); such compounds of Formula (5) may then be convened to the corresponding compounds of Formula (I) by ester saponification and decarboxylation as described above. Such compounds of Formula (I) may then be converted to other compounds of Formula (I) using the general techniques and, when necessary, appropriate protection and deprotection of chemically sensitive functionalities, described above; likewise, such compounds of Formula (II) may be converted to odier compounds of Formula (II) using the general techniques and, when necessary, appropriate protection and deprotection of chemically sensitive functionalities, described above.

The following examples are set out to illustrate how to make the compounds of this invention and methods for determining associated therapeutic activity. These examples are not intended to limit the invention in any manner, their purpose is illustrative radier than limiting.

EXAMPLE 1 2-Carbomethoxy-4-cvano-4-(3-cvclopentyloxy-4-methoxyphenyl)- cyclohexan-l-one la. (3-Cvclopentyloxy-4-methoxyphenyl)acetonitrile To a solution of 3- cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by die dropwise addition of trimethylsilylchloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0°C, 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and die resulting mixture was allowed to warm to room temperature. After stirring for 3h, the mixture was separated into two layers. The lower layer was removed, diluted with mediylene chloride and filtered d rough Celite. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacua

to provide a light tan oil. To a solution of this crude a-bromo-3-cyclopentyloxy-4- methoxytoluene in dimethylformamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18h, then poured into cold water (600 mL) and extracted three times with ether.. The organic extract was washed three times widi water, once with brine and was dried (potassium carbonate). The solvent was removed in vacua and die residue was purified by flash chromatography, during widi 10% ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p. 32-34°C; an additional quantity (1.3 g) of slighdy impure material also was isolated. lb. Dimethyl 4-cvano-4-(3-cyclopentyloxy-4-methoxyphenyl ^' )pimelate To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g, 30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and d e mixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) was added carefully, the reaction mixture was maintained at reflux for 5h and then cooled. The mixture was diluted widi edier, was washed once with IN hydrochloric acid and once widi brine, was dried (magnesium sulfate) and die solvent was removed in vacua. The solid residue was triturated wid 5% ethanol/hexane to provide a white solid (9 g, 74%): m.p. 81- 82°C; and additional 1.1 g (9%) was also obtained from the filtrate. Analvsis Calc. for C22H29NO6: C 65.49, H 7.25, N 3.47; found: C 65.47, H 7.11, N 3.49. lc. 2-Carbomethoxy-4-cvano-4-( ^' 3-cyclopentyloxy-4-methoxyphenyl)cycIohexan-l-one To a solution of dimediyl 4-cyaπo-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (5.9 g, 14.6 mmol) in dry 1,2-dimethoxyethane (120 mL) under an argon atmosphere was added sodium hydride (80% suspension in mineral oil, 1.05 g, 43.8 mmol). The mixture was heated to reflux for 4.5h, then was cooled to room temperature and was stirred for 16h. Water was added and the reaction mixture was partitioned between ether and acidic water. The organic extract was dried (magnesium sulfate) and die solvent was removed in vacua. The residue was purified by flash chromatography, eluting with 3 : 1 hexanes/ethyl acetate, to provide a white foam (4.9 g, 93%). Analvsis Calc. for C19H23NO3-1/4H2O: C 67.09, H 6.84, N 3.72; found: C 66.92, H 6.61, N 3.74.

EXAMPLE 2 4-(3.4-Bisdifluorometfioxyphenyl -2-carbomethoxy-4-cvanocvclohexan-l-one 2a. 3.4-Bisdifluoromethoxybenzaldehyde A vigorously stirred mixture of 3,4- dihydroxybenzaldehyde (40 g, 290 mmol) and powdered potassium carbonate (120 g, 870 mol) in dimediylformamide (500 mL) was heated under an atmosphere of chlorodifluoromediane at 80°C for 7h and then was stirred at room temperature overnight. The mixture was diluted widi ether and was filtered- The filtrate was concentrated under

reduced pressure, the residue was partitioned between ether and aqueous potassium carbonate and was extracted five times widi ether. The organic extract was washed widi aqueous potassium carbonate and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 4: 1 hexanes/ether, to provide an oil (26.2 g, 38%).

2b. 3.4-Bisdifluoromedιoxybenzyl alcohol 3,4-Bisdifluoromethoxybenzaldehyde (26.2 g, 110 mmol) in absolute ethanol (150 mL) was treated with sodium borohydride (8.32 g, 220 mmol) under an argon atmosphere at room temperature for 0.5h. Ten percent aqueous sodium hydroxide (130 mL) was added, the ethanol was removed in vacuo, the mixture was partitioned between ether and water and was exracted twice with ether. The organic extract was dried (magnesium sulfate) and evaporated to a pale yellow oil (26.4 g, 100%). 2c. 2-(3.4-Bisdifluoromethoxyphenyl)acetonitrile A solution of 3,4- bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol) and pyridine (9.79 mL, 120 mmol) in chloroform (200 mL) under an argon atmosphere was treated widi thionyl chloride (9.62 mL, 130 mmol) and die mixture was heated at reflux for lh. The solvent was removed, etiier was added and the precipitate was removed by filtration. The filtrate was concentrated to a purple oil. To a solution of this 3, 4-bisdifluoromethoxy benzyl chloride in dimethylformamide (200 mL) under an argon atmosphere was added sodium cyanide (11.86 g, 240 mmol). The resulting mixture was stirred and gently heated at 45°C for 3h, was cooled and was concentrated. The mixture was partitioned between ed er and 5% aqueous sodium carbonate and was extracted five times wid ether . The organic extract was washed once widi brine, was dried (sodium carbonate) and die solvent was removed in vacuo to provide an oil (27 g). 2d. Dimethyl 4-cyano-4-(3.4-bisdifluoromethoxyphenyl)-4-cvanopimelate To a solution of 2-(3,4-bisdifluoromethoxyphenyl)acetonitrile (27 g, 108 mmol) and a 40% solution of Triton-B in methanol (5 mL, 11 mmol) in acetonitrile (450 mL) under an argon atmosphere at room temperature was added metiiyl acrylate (48.6 mL, 540 mmol). After 20 min, aqueous hydrochloric acid (3N, 20 mL) was added and the mixture was concentrated. The residue was partitioned between water and ether, was extracted twice with ether, the ether layer was dried (magnesium sulfate) and evaporated in vacuo to provide a yellow oil (45.32 g, 99%).

2e. 4-(3.4-Bisdifluoromethoxyphenyl)-2-carbomethoxy-4-cyanocyclo hexan-l-one To a solution of dimetiiyl 4-(3,4-bisdifluorometiιoxyphenyl)-4-cyanopimelate (45.32 g, 107 mmol) in dry 1,2-dimethoxyethane (450 mL) under an argon atmosphere was added sodium hydride (80% dispersion in mineral oil, 13 g, 432 mmol). The resulting mixture was refluxed for lh, was cooled to room temperature, was quenched with water and was concentrated. The mixture was partitioned between ether and acidic brine, was extracted twice with ether, the organic layer was dried (magnesium sulfate) and the solvent was

removed in vacuo. The residue was purified by flash chromatography, eluting widi 3: 1 hexanes/ethyl acetate, to provide a pale-orange oil (19.5 g, 46.6%). Analvsis Calc. for C17H15F4NO5: C 52.45, H 3.88, N 3.60; found: C 52.60, H 4.07, N 3.22.

EXAMPLE 3 2-Carbomethoxy-4-cvano-4-f 3-_ifluoromedιoxy-4-methoxyphenyl)cvclohexan- 1 -one 3a. 3-Difluoromedιoxy-4-methoxybenzaldehyde A vigorously stirred mixture of 3- hydroxy-4-methoxybenzaldehyde (2.5 g, 16.4 mmol) and powdered cesium carbonate (5.6 g, 17.2 mol) in dimediylformamide (50 mL) was heated under an atmosphere of chlorodifluoromediane at 80°C for 4h. The mixture was allowed to cool, was poured into water and was extracted tiiree times with ediyl acetate. The organic extract was dried (sodium sulfate) and die solvent was removed in vacuo. Purification by flash chromatography, eluting widi 5% ethyl acetate/chloroform, provided an oil (2 g, 60%). 3b. (3-Difluoromedιoxy-4-medιoxyphenyl)acetonitrile To 3-difluoromethoxy-4- methoxybenzaldehyde (2 g, 9.8 mmol) was added lithium bromide (1.7 g, 19.6 mmol) and acetonitrile (11 mL). Upon dissolution, die reaction mixture was cooled to 0°C. Trimethylsilylchloride (1.86 mL, 14.7 mmol) was slowly added and die reaction mixture was allowed to warm to room temperature and was stirred for 15 min. The reaction mixture was again cooled to 0°C, 1,1,3,3-tetramethyldisiloxane (2.6 mL, 14.7 mmol) was added and die resulting mixture was allowed to warm to room temperature. After stirring for 3h, the mixture was separated into two layers. The lower layer was removed, diluted widi mediylene chloride and filtered. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide an oil, which was dissolved in dimediylformamide (10 mL) under an argon atmosphere and treated widi sodium cyanide (1.08 g, 22 mmol). The resulting mixture was stirred at room temperature overnight, then poured into cold water (250 mL) and extracted three times with ediyl acetate. The organic extract was washed three times wid water, once widi brine and was dried (potassium carbonate). The solvent was removed in vacuo to provide a yellow oil (1.54 g, 74%), which was used widiout purification.

3c. Dimethyl 4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)pimelate To a solution of (3-difluorometiιoxy-4-med oxyphenyl)acetonitrile (1.54 g, 7.2 mmol) in acetonitrile (78 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (0.33 mL, 0.72 mmol). The resulting mixture was heated to reflux and metiiyl acrylate (13 mL, 144 mmol) was added cautiously. After 3h, die reaction was cooled to room temperature, water was added and die mixture was concentrated. The residue was partitioned between aqueous hydrochloric acid and ethyl acetate, was extracted twice with ethyl acetate, the organic layer was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, provided a foam (1.7 g, 61%).

3d. 2-Carbomethoxy-4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl) cyclohexan-l- one To a suspension of sodium hydride (95%, 0.33 g, 13.2 mmol) in dry 1,2- dimethoxyethane (70 mL) under an argon atmosphere was added a solution of dimethyl 4- cyano-4-(3-difluoromethoxy-4-methoxyphenyl)pimelate (1.7 g, 4.4 mmol) in dry 1,2- dimethoxyediane (70 mL). The resulting mixture was refluxed for 5h, cooled to room temperature, stirred overnight and quenched with water. The mixture was partitioned between ethyl acetate and acidic water, extracted three times with ethyl acetate, the organic layer was dried (magnesium sulfate) and die solvent was removed in vacua. Purification by flash chromatography, eluting with 3:1 hexanes/ediyl acetate, provided an oil (0.51 g, 33%, 51 % based on recovered starting material).

EXAMPLE 4

2-Carbomethoxy-4-cvano-4-(3-cvclopropylmethoxy-4-methoxyp henyl)cvclohexan-l-one

4a. 3-Cyclopropylmethoxy-4-methoxybenzaldehvde A vigorously stirred mixture of 3- hydroxy-4-methoxybenzaldehyde (20 g, 131 mmol), chloromethylcyclopropane (18.2 mL, 197 mmol) and powdered potassium carbonate (27.3 g, 197 mol) in dimethylformamide (400 mL) was heated under an argon atmosphere at 80°C for 9h. The mixture was allowed to cool and was filtered dirough Celite. The filtrate was concentrated under reduced pressure, the residue was extracted twice with ethyl acetate, the organic extract was washed five times with saturated aqueous sodium carbonate and was dried (sodium sulfate). The solvent was removed in vacuo to provide an off-white solid (21.2 g, 78%): m.p. 67-69°C. 4b. (3-Cyclopropylmethoxy- methoxyphenyI)acetonitrile To 3-cyclopropylmethoxy-4- methoxybenzaldehyde (21.2 g, 103 mmol) was added lithium bromide (17.8 g, 206 mmol) and acetonitrile (110 mL). Upon dissolution, the reaction mixture was cooled to 0°C. Trimediylsilylchloride (19.6 mL, 154 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature and was stirred for 15 min. The reaction mixture was again cooled to 0°C, 1,1,3,3-tetramethyldisiloxane (27.2 mL, 154 mmol) was added and die resulting mixture was allowed to warm to room temperature. After stirring for 2h, the mixture was separated into two layers. The lower layer was removed, was diluted widi methylene chloride, was filtered and the filtrate was concentrated under reduced pressure; this procedure was repeated a total of three times. The resulting light tan oil was dissolved in dimethylformamide (90 mL) under an argon atmosphere and was treated with sodium cyanide (11.3 g, 232 mmol). The resulting mixture was stirred at room temperature for 2h, then poured into cold water and extracted twice with ethyl acetate. The combined organic extract was washed diree times with water, once with brine and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil (21.4 g, 96%), which was used witiiout purification.

4c. Dimethyl 4-cvano-4-(3-cvclopropylmethoxy-4-methoxyphenyl)pimelate To a solution of (3-cyclopropyImethoxy-4-methoxyphenyl)acetonitrile (21.4 g, 98.6 mmol) in acetonitrile (400 mL) under an argon atmosphere was added a 40% solution of Triton-B in medianol (4.5 mL, 9.9 mmol). The resulting mixture was heated to reflux and methyl acrylate (178 mL, 197 mmol) was added cautiously. After 3h, the reaction was cooled to room temperature and concentrated. The residue was partitioned between 10% aqueous hydrochloric acid and ediyl acetate, was extracted diree times with ediyl acetate, the organic layer was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting widi 2:1 hexanes/etiiyl acetate, provided an oil (27 g, 71%). 4d. 2-Carbomedιoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphe nyl)cyclohexan- 1-one To a solution of dimetiiyl 4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)pimelate (10.4 g, 26.7 mmol) in dry 1,2-dimethoxyetiιane (500 mL) under an argon atmosphere was added sodium hydride (80% dispersion in mineral oil, 2.5 g, 31.2 mmol). The resulting mixture was refluxed for 4h, cooled to room temperature and quenched widi water. The mixture was partitioned between ethyl acetate and acidic water, extracted tiiree times, die organic layer was dried (magnesium sulfate) and die solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide an oil (9 g, 95%). Analvsis Calc. for C20H23NO5-I/8 H2O: C 66.79, H 6.52, N 3.89; found: C 66.62, H 6.43, N 3.92.

EXAMPLE 5 2-Carbomethoxy-4-cvano-4-r3-cyclopentyloxy-4-difluoromethoxy phenyl)cyclohexan-l-one 5a. 4-Difluoromethoxy-3-hydroxybenzaldehyde A vigorously stirred mixture of 3,4- dihydroxybenzaldehyde (50 g, 362 mmol) and powdered potassium carbonate (50 g, 362 mol) in dimethylformamide (250 mL) was heated at 100°C under an atmosphere of chlorodifluoromethane using a -78°C condenser for 5.5h. An additional quantity of potassium carbonate (10 g) was added and die reaction was continued for anotiier 0.5h. The mixture was allowed to cool, was acidified to pH 5-6 with concentrated hydrochloric acid and was concentrated under reduced pressure. The residue was partitioned between edier and 3N aqueous hydrochloride and was extracted five times with etiier. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, providing a yellow solid, which was triturated with ediyl acetate/hexanes to provide, in three crops, a white solid (12.1 g, 18%): m.p. 84-86°C.

5b. 3-Cvclopentyloxy-4-difluoromethoxybenzaldehvde To a mixture of 3-hydroxy-4- difluoromethoxybenzaldehyde (2.9 g, 15 mmol) and powdered potassium carbonate (3.2 g, 23 mmol) in dimethylformamide (15 mL) under an argon atmosphere was added bromocyclopentane (2.5 mL, 23 mmol) and the mixture was stirred and heated at 50°C for

lh and at 80-85°C for 1.5h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic extract was washed three times with water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 20-30% ether/hexanes, provided a yellow soild (3.5 g, 89%). 5c. (S-Cvclopentyloxy-^difluoromedioxyphenvDacetonitrile To a solution of (3- cyclopentyloxy-4-difluoromethoxyphenyl)benzaldehyde (3.4 g, 13.4 mmol) in absolute ethanol (33 mL) under an argon atmosphere at room temperature was added sodium borohydride (1.06 g, 28 mmol). After 20 min, 10% aqueous sodium hydroxide (15 mL) was added, die etiianol was removed in vacuo and the aqueous residue was extracted diree times with ether. The organic extract was washed twice with brine, was dried (magnesium sulfate) and evaporated to a pale yellow oil (3.44 g). A solution of this alcohol (1.52 g, 5.89 mmol) and pyridine (0.48 mL, 6 mmol) in alumina-dried chloroform (15 mL) under an argon atmosphere was treated with thionyl chloride (0.52 mL, 7.08 mmol) and the mixture was heated at reflux for lh. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil, which was dissolved in dimethylformamide (10 mL) under an argon atmosphere and treated widi sodium cyanide (0.58 g, 11.8 mmol). After stirring at room temperature for 72h, the mixture was partitioned between 5% aqueous sodium carbonate and ether. The organic extract was washed four times widi water, was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 15-20% ethyl acetate/hexanes, provided a pale yellow solid (3.2 g, 90%): m.p. 39-41°C.

5d. Dimethyl 4-cvano-4-(3-cvclopentyloxy-4-difluoromethoxyphenyl)pimelate To a solution of (3-cyclopentyloxy-4-difluoromethoxyphenyl)acetonitrile (1.8 g, 6.7 mmol) in acetonitrile (35 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (0.31 mL, 0.67 mmol). The resulting mixture was heated to reflux and methyl acrylate (6.1 mL, 67.2 mmol) was added cautiously. After another 20 min, the reaction was cooled to room temperature and concentrated. The residue was partitioned between aqueous hydrochloric acid and edier, d e organic layer was dried (magnesium sulfate) and evaporated to an oil (3.1 g, 100%). 5e. 2-Carbomethoxy-4-cvano-4-(3-cvclopentyloxy-4-difluoromethoxy - phenvDcyclohexan- 1 -one To a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4- difluoromedιoxyphenyl)pimelate (3.1 g, 6.7 mmol) in dry 1,2-dimethoxyethane (50 mL) under an argon atmosphere was added sodium hydride (80% dispersion in mineral oil, 0.81 g, 27 mmol). The resulting mixture was refluxed for 20 min, additional 1,2- dimedioxyediane (50 mL) was added and the mixture was refluxed for another 70 min. The mixture was cooled to 0°C, was acidified with dilute hydrochloric acid and was concentrated. The mixture was partitioned between ether and dilute hydrochloric acid, d e organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. The

product was purified by flash chromatography, eluting with 85:15 hexanes/ethyl acetate, to provide a white solid (0.76 g, 37%): m.p. 109-110.5 ^O C.

Analvsis Calc. for C21H23F2 O5: C 61.91, H 5.69, N 3.44; found: C 61.83, H 5.66, N 3.39.

EXAMPLE 6 2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromet hoxy- phenyDcyclohexan- 1 -one 6a. 3-CVclopropylmemoxy-4-difluoromethoyyh^n7-^l^( ^» hy^^ To a mixture of 3- hydroxy-4-difluoromeriιoxybenzaldehyde (19.55 g, 104 mmol) and potassium carbonate (21.56 g, 156 mmol) in dirnethylformamide (150 mL) under an argon atmosphere at 60°C was added bromomediylcyclopropane (15.13 mL, 156 mmol) and die mixture was stirred and heated at 65°C. After 1.5h, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water and was extracted four times with ethyl acetate. The organic extract was washed twice with water and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil (26.4 g).

6b. 3-Cvclopropylmethoxy-4-difluoromethoxybenzyl alcohol Crude 3- cyclopropylmedioxy-4-difluoromedioxybenzaldehyde (26.4 g) in absolute ethanol (200 mL) was treated widi sodium borohydride (8.23 g, 217 mmol) under an argon atmosphere at room temperature for 0.33h. Ten percent aqueous sodium hydroxide (150 mL) was added, die edianol was removed in vacuo and die aqueous residue was extracted three times with ether. The organic extract was washed twice with brine, was dried (sodium sulfate), was filtered and was evaporated to a pale yellow oil (24.4 g). 6c. 3-Cvclopropylmethoxy-4-difluoromethoxybenzyl chloride A solution of crude 3- cyclopropylmethoxy-4-difluoromethoxybenzyl alcohol (24.4 g) and pyridine (9.8 mL, 120 mmol) in chloroform (150 mL) under an argon atmosphere was treated widi thionyl chloride (8.0 mL, 110 mmol) and die mixture was heated at reflux for lh. The solvent was removed, edier was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil (26 g).

6d. (3-Cvclopropylmethoxy-4-difluoromedioxyphenvDacetoni-rile To 3- cyclopropylmethoxy-4-difluoromedιoxybenzyl chloride (26 g) in dimethylformamide (150 mL) under an argon atmosphere was added sodium cyanide (9.7 g, 198 mmol). The resulting mixture was stirred at room temperature and heated gently for 2h, then cooled and concentrated. The mixture was partitioned between basic brine and edier and extracted twice. The organic extract was washed wid brine and was dried (sodium sulfate). The solvent was removed in vacuo to provide an orange-brown oil (24 g), which was used without purification.

6e. Dimethyl 4-cvano-4-(3-cvclopropylmethoxy-4-difluoromedιoxyphenyl)pim elate To a solution of crude (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)acetonitrile (24 g) in acetonitrile (500 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (4.3 mL, 9.5 mmol). The resulting mixture was heated to reflux and mediyl acrylate (43 mL, 470 mmol) was added cautiously. After 20 min, the reaction was cooled to room temperature and water and dilute hydrochloric acid were added and the mixture was concentrated. The residue was partitioned between water and edier, the organic layer was dried (magnesium sulfate) and evaporated to an orange-brown oil (41 g). 6f. 2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromed ιoxy- phenyDcyclohexan- 1 -one To a suspension of sodium hydride (80% dispersion in mineral oil, 11.6 g, 388 mmol) in dry 1,2-dimedιoxyethane (700 mL) under an argon atmosphere was added a solution of crude dimethyl 4-cyano-4-(3-cyclopropylmethoxy-4- difluoromedioxypheny pimelate (41 g) in dry 1,2-dimethoxyethane (700 mL). The resulting mixture was heated at 60°C for lh, cooled to room temperature, quenched widi dilute aqueous hydrochloric acid and concentrated. The residue was diluted with water, was acidified to pH 3 and was extracted twice with methylene chloride. The organic extract was washed widi acidic water, was dried (sodium sulfate) and die solvent was removed in vacuo. Purification by flash chromatography, eluting with methylene chloride, followed by trituration with cold edier provided a solid (17.7 g, 43% from 3-cyclopropylmethoxy-4- difluoromethoxybenzaldehyde): m.p. 115-116°C.

Analvsis Calc. for C20H21F2NO5: C 61.06, H 5.38, N 3.56; found: C 61.16, H 5.40, N 3.52.

EXAMPLE 7 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -one

A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one (0.80 g, 2.15 mmol), dimethyl sulfoxide (16 mL), water (1 mL) and sodium chloride (0.8 g) under an argon atmosphere was heated at 140-145°C for 5h. The reaction mixture was cooled and concentrated. The residue was purified by flash chromatography, eluting widi 3:1 hexanes/ethyl acetate, to provide a yellow solid.

Trituration with hexanes/ediyl acetate yielded a white solid (0.52 g, 77%): m.p. 111-112°C. Analvsis Calc. for C19H23NO3: C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39, N 4.48.

EXAMPLE 8

4-(3.4-Bisdifluoromethoxyphenyl)-4-cvanocyclohexan- 1 -one A mixture of 2-carbomethoxy-4-(3,4-bisdifluoromedιoxyphenyl)-4- cyanocyclohexan-1-one (0.55 g, 1.4 mmole), dimetiiyl sulfoxide (8 mL), water (0.5 mL) and sodium chloride (0.5 g) under an argon atmosphere was heated at 140-145°C for 4h.

The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ether and water, the organic layer was dried (magnesium sulfate) and die solvent was removed in vacuo. The product was purified by flash chromatography, eluting widi 1:1 hexanes/edier. The residue was partitioned between water and ethyl acetate and die organic layer was evaporated to yield a yellow solid. Trituration from the minimal amount of ethyl acetate hexanes provided a solid (0.3 g, 63.6%): m.p. 64-66°C. Analvsis Calc. for C15H13NO3F4: C 54.39, H 3.96, N 4.23; found: C 54.25, H 3.96, N 4.20.

EXAMPLE 9

4-Cvano-(3-difluoromethoxy-4-methoxyphenyl)cvclohexan- 1 -one A mixture of 2-carbomethoxy-4-cyano-4-(3-difluoromethoxy-4- methoxyphenyI)cyclohexan-l-one (0.51 g, 1.4 mmole), dimed yl sulfoxide (11 mL), water (1 mL) and sodium chloride (0.53 g) under an argon atmosphere was heated at 150°C for 5h. The reaction mixture was partitioned between ediyl acetate and water and extracted tiiree times wid ediyl acetate. The combined organic extract was washed twice widi water, once widi brine, was dried (potassium carbonate) and die solvent was removed in vacuo.

The product was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide an oil (0.36 g, 85%). Analvsis Calc. for Ci5Hi5NO3F2-l/8 H2O: C 60.55, H 5.17, N 4.71; found: C 60.42, H

5.07, N 4.77.

EXAMPLE 10 4-Cvano-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-l-o ne A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)cyclohexan-l-one (1.7 g, 4.7 mmole), dimethyl sulfoxide (34 mL), water (3 mL) and sodium chloride (1.6 g) under an argon atmosphere was heated at 150°C for 4h, was stirred at room temperature overnight and was concentrated. The residue was partitioned between ethyl acetate and water and extracted tiiree times with ethyl acetate. The combined organic extract was washed twice with water, once widi brine, was dried

(magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide a solid (1.09 g, 77%): m.p. II6-H8OC. Analvsis Calc. for Ci8H2lNO3-l/8 H2O: C 71.68, H 7.10, N 4.64; found: C 71.51, H 7.03, N 4.55.

EXAMPLE 11 4-Cvano-4-(3-cvclopentyloxy-4-difluoromedιoxyphenyl ^' .cvclohexan- 1 -one A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4- difluoromethoxyphenyl)cyclohexan-l-one (0.98 g, 2.4 mmole), dimethyl sulfoxide (10 mL), water (0.62 mL) and sodium chloride (0.62 g) under an argon atmosphere was heated at 145°C for 5h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ether and water, the organic layer washed with water, was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting widi 20-30% ethyl acetate/hexanes. The isolated residue was dissolved in ediyl acetate, this was washed twice widi dilute sodium hydroxide, once with water, once with brine and tiien was dried and evaporated to yield a solid (0.2 g, 23.6%): m.p. 76-78.5 ⁰ C.

Analvsis Calc. for Ci9H2lF2NO3-l/6 H2O: C 64.76, H 6.10, N 3.97; found: C 64.76, H 6.04, N 3.89.

EXAMPLE 12 4-Cvano-4-(3-cvclopropylmethoxy-4-difluoromemoxyphenyl)cvclo hexan-l-one A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4- difluoromethoxyphenyl)cyclohexan-l-one (0.5 g, 1.27 mmole), dimetiiyl sulfoxide (10 mL), water (1 mL) and sodium chloride (0.5 g) under an argon atmosphere was heated at 145-150°C for 4.5h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water, extracted twice with ethyl acetate, the organic layer was washed twice with water and once with brine, was dried (sodium sulfate) and die solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 20-25% ethyl acetate/hexanes, and the resultant solid was triturated widi edier/hexane and then with cold edier to provide a solid (0.22 g, 51.6%): m.p. 85.5-86.5°C.

Analvsis Calc. for C18H19F2NO3: C 64.47, H 5.71, N 4.18; found: C 64.28, H 5.63, N 4.20.

EXAMPLE 13 4-Cyano-4-(3-cvclopentyloxy-4-methoxyphen vDcvclohexan- 1 -one oxime To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (0.125 g, 0.4 mmol) in pyridine (2 mL) was added hydroxylamine hydrochloride (0.031 g, 0.44 mmol), the mixture was stirred at room temperature under an argon atmosphere for 4h and die solvent was evaporated. The mixture was partitioned between water and ethyl acetate, was extracted twice with ethyl acetate, die organic extract was dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography,

eluting with 25% ethyl acetate hexanes, followed by trituration of the product with edier hexanes provided a white solid (0.125 g, 95%): m.p. 50-53°C. Analvsis Calc. for C19H24N2O3: C 69.44, H7.37, N 8.53; found: C 69.35, H 7.47, N 8.28.

EXAMPLE 14 4-f 3-Cyclopentyloxy-4-methoxyphenyl)-4-form ylcvclohexaπ- 1 -one 14a. 4-Cvano-4-(3-cvclopentyloxy-4-medιoxyphenyl)cvclohexan-l-on e dimethyl ketal A mixture of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (0.5 g, 1.6 mmol), trimethyl orthoformate (0.21 mL, 1.9 mmol) and a catalytic amount of p- toluenesulfonic acid in methanoi (20 mL) was heated gendy under an argon atmosphere for 2h. The mixture was cooled, was partitioned between aqueous sodium carbonate and ediyl acetate, was extracted twice with ediyl acetate, the organic extract was dried (potassium carbonate) and die solvent was removed in vacuo to provide an oil (0.57 g, 99%). 14b. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-formylcvclohexan-l-on e dimethyl ketal A solution of 4-cyano-4-(3-cyclopentyloxy-4-medιoxyphenyl)cyclohexan-l-on e dimethyl ketal (0.57 g, 1.6 mmol) in toluene (20 mL) at room temperature under an argon atmosphere was treated with a solution of diisobutylaluminum hydride (1.5M in toluene, 2.7 mL, 4 mmol). After 2h, a solution of saturated aqueous sodium bisulfite was added and die mixture was extracted twice with ethyl acetate. The organic extract was washed widi 5% aqueous sodium carbonate, was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.55 g, 96%).

14c. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan- 1 -one 4-(3- Cyclopentyloxy-4-methoxyphenyl)-4-formylcycIohexan-l-one dimethyl ketal (0.1 g, 0.28 mmol) in ethyl acetate (2 mL) was treated widi 3N hydrochloric acid (5 mL) and the mixture was stirred vigorously and gendy heated for 10 min. The mixture was extracted twice widi ethyl acetate, the combined organic extracts were washed widi 5% aqueous sodium carbonate, dried (potassium carbonate) and die solvent was removed in vacuo. This material, combined widi that obtained from an identical reaction, was purified by flash chromatography, eluting with 2% ediyl acetate/chloroform, to provide a white solid (0.1 g, 57%): m.p. 55-57 ⁰ C. Analvsis Calc. for C19H24O4: C 72.13, H 7.65; found: C 72.09, H 7.57.

EXAMPLE 15 4-(3-Cyclopentyloxy-4-med oxyphenyl)-4-(hvdroxymethyl)cvclohexan-l-one

15a. 4-f3-Cyclopentyloxy-4-methoxyphenyl)-4-..hvdroxymethyπcvclo hexan-l-one- dimediyl ketal To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4- formylcyclohexan-1-one dimethyl ketal (0.24 g, 0.66 mmol) in 1,2-dimedιoxy-edιane (5 mL) under an argon atmosphere was added sodium borohydride (0.05 g, 1.3 mmol) and the

mixture was stirred at room temperature for 0.75h. Water was added, die mixture was partitioned between ether and water, was extracted twice widi ether, the organic extract was dried (potassium carbonate) and evaporated to an oil (0.19 g, 79%). 15b. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-. hvdroxymethyllcvclohexan- 1 -one 4-(3- Cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)-cyclohexan - 1 -one dimethyl ketal (0.15 g, 0.41 mmol) in edier (2 mL) was treated with IN hydrochloric acid (2 mL) and die mixture was stirred vigorously and gently heated for 10 min. The mixture was extracted with edier, the combined organic extracts were washed with 5% aqueous sodium carbonate, dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/chloroform, provided a wax (0.06 g, 56%). Analvsis Calc. for C19H26O4: C 71.67, H 8.23; found: C 71.81, H 8.19.

EXAMPLE 16 4-(3-Cyclopentyloxy-4-methoxyphenyl')-4-Cfluoromedιyl ^' )cyclohexan-l-one 16a. 4-(3-Cyclopentyloxy-4-methoxyphenvI)-4-(fluoromethyl)cvclohe xan-l-one dimethyl ketal A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4- (hydroxymedιyl)cyclohexan-l-one dimetiiyl ketal (0.37 g, 1.02 mmol) in methylene chloride (5 mL) was added dropwise to a solution of diediylaminosulfur trifluoride (0.14 mL, 1.02 mmol) at -78°C under an argon atmosphere. The mixture was allowed to warm to room temperature and after 0.75h, 5% aqueous sodium carbonate was added. The mixture was extracted with chloroform, the organic extract was dried (magnesium sulfate) and die solvent was removed in vacuo to provide a yellow oil (0.3 g, 80%). 16b. 4-(3-CyclopentyIoxy-4-methoxyphenyl)-4-(fluoromethyl)cvclohe xan-l-one 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohe xan- 1-one dimethyl ke-ϋl (0.35 g, 0.95 mmol) in ethyl acetate (2 mL) was treated widi IN hydrochloric acid (2 L) and the mixture was stirred vigorously and gently heated for 10 min. The mixture was extracted with ediyl acetate, the organic extract was washed with 5% aqueous sodium carbonate, dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/hexanes, followed by trituration widi ether/hexanes, provided a white solid (0.075 g, 24%): m.p. 72 - 74°C. Analysis Calc. for C19H25FO3: C 71.23, H 7.87; found: C 71.22, H 7.70.

EXAMPLE 17 4-Aminocarbonyl-4-(3-cvclopentyloxy-4-methoxyphenyl)cvclohex an- 1 -one 17a. 4-Aminocarbonyl-4-( ^' 3-cyclopentyloxy-4-me_ιoxyphenyl)cvclohexan-l-one dimethyl ketal A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l- one dimethyl ketal (0.34 g, 0.95 mmol) and powdered potassium carbonate (0.7 g, 5.1 mmol) in methanol (20 mL) and water (4 mL) at 0°C was treated with hydrogen peroxide (30% solution, 2.55 mL). The mixture was allowed to warm to room temperature and, after

seven days, brine was added and the mixture was extracted with methylene chloride. The organic extract was washed twice wid brine, dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography provided the amide (0.055 g, 15%) along widi recovered starting material (0.25 g). 17b. 4-Aminocarbonyl-4-(3-cvclopentyloxy-4-methoxyphenyl)cyclohex an-l-one A mixture of 4-aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex - 1-one dimetiiyl ketal (0.055 g, 0.15 mmol) and p-toluenesulfonic acid (catalytic amount) in 20% aqueous acetone (5 mL) was stirred under an argon atmosphere at reflux for 8h. The mixture was cooled, diluted widi water and extracted with metiiylene chloride. The organic extract was dried (magnesium sulfate) and die solvent was removed in vacuo to provide a hygroscopic, amorphous material (0.035 g, 72%).

Analvsis Calc. for C19H25NO4-3/8 H2O: C 67.48, H 7.67, N 4.14; found: C 67.38, H 7.54, N 3.86.

EXAMPLE 18

4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-ethvnylcyclohexan- 1 -one 18a. 4-f3-CvcIopentyloxy-4-methoxyphenyl)-4-ethvnylcvclohex- 1-one dimethyl ketal To a solution of potassium t-butoxide (0.155 g, 1.38 mmol) in dry tetrahydrofuran (5 mL) under an argon atmosphere at -78°C was added a solution of dimethyl (diazomethyl)phosphonate (ca. 88% pure, 0.24 g, 1.38 mmol). After 0.25h, a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-l-on e dimethyl ketal (0.42 g, 1.15 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the mixture was allowed to stir at -78°C under an argon atmosphere for 5h. Aqueous acetic acid was added, die mixture was concentrated, partitioned between methylene chloride and water and extracted twice. The organic extract was dried (magnesium sulfate) and evaporated.

Purification by flash chromatography, eluting wid 3:1 hexanes/ethyl acetate, provided an oil (0.13 g, 32%).

18b. 4-(3-CvcIopentyloxy-4-methoxyphenyl)-4-ethynylcvclohexan-l-o ne A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-edιynylcyclohex-l-on e dimetiiyl ketal (0.13 g, 0.36 mmol) and p-toluenesulfonic acid (catalytic amount) in acetone (5 mL) was stirred under an argon atmosphere at room temperature for 1.5h. The mixture was concentrated, diluted widi ediyl acetate and washed widi water. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo to provide an oil (0.11 g, 97%). Analvsis Calc. for C20H24O3 /2 H2O: C 74.74, H 7.84; found: C 74.81, H 7.84.

EXAMPLE 19 4-(3.4-Bisdifluoromethoxyphenyl)-4-ethynylcvclohexan-l-one 19a. 4-G.4-Bisdifluoromethoxyphenyl)-4-cvanocvclohexan-l-one dimethyl ketal A mixture of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-l-one (1.34 g, 4.05

mmol), trimediyl orthoformate (0.53 mL, 4.85 mmol) and a catalytic amount of p- toluenesulfonic acid in medianol (40 mL) was heated gendy under an argon atmosphere for 2h. The mixture was cooled and then concentrated. The residue was partitioned between 5% aqueous sodium carbonate and ediyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (1.5 g, 98%).

19b. 4-(3.4-Bisdifluoromethoxyphenyl'.-4-formylcyclohexan-l-one dimethyl ketal A solution of 4-cyano-4-(3,4-bisdifluoromedιoxyphenyl)cyclohexan-l-one dimetiiyl ketal (1.5 g, 3.98 mmol) in toluene (50 mL) at room temperature under an argon atmosphere was treated widi a solution of diisobutylaluminum hydride (1M in toluene, 10 mL, 10 mmol). After 4h, a solution of saturated aqueous sodium bisulfite was added and die mixture was extracted twice with ediyl acetate. The combined organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (1.5 g, 99%). 19c. 4-(3.4-Bisdifluoromed oxy)-4-ethynylcvclohex-l-one dimethyl ketal To a suspension of potassium t-butoxide (0.18 g, 1.6 mmol) in dry tetrahydrofuran (5 mL) under an argon atmosphere at -78°C was added a solution of dimethyl (diazomethyl)phosphonate (ca. 90% pure, 0.27 g, 1.6 mmol) in tetrahydrofuran (5 mL). After 0.25h, a solution of 4- (3,4-bisdifluoromedioxyphenyl)-4-formylcyclohexan-l-one dimethyl ketal (0.5 g, 1.3 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the mixture was allowed to stir at -78°C under an argon atmosphere for 10 min. Aqueous acetic acid was added, die mixture was concentrated and was partitioned between methylene chloride and water. The organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an oil (0.2 g, 41%). 19d. 4-(3.4-Bisdifluoromethoxyphenyl)-4-edιvnylcyclohexan- 1 -one A mixture of 4- (3,4-bisdifluoromethoxyphenyl)-4-ethynylcyclohex-l-one dimetiiyl ketal (0.2 g, 0.53 mmol) and p-toluenesulfonic acid (catalytic amount) in acetone (10 mL) was stirred under an argon atmosphere at room temperature for 0.5h. The mixture was concentrated, was diluted widi med ylene chloride and was washed widi water. The organic extract was dried (magnesium sulfate) and die solvent was removed in vacuo to provide an oil (0.17 g, 98%). Analvsis Calc. for C16H14F4O3: C 58.19, H 4.27; found: C 58.30, H 4.40.

EXAMPLE 20 4-(3.4-Bisdifluoromedιoxyphenyl)-4-(oxamidomethyl)cyclohexa n-l-one 20a. 4-Aminomethyl-4-(3.4-bisdifluoromethoxyphenyl)cyclohexan- 1 -one dimetiiyl ketal A solution of 4-(3,4-bisdifluoromedιoxyphenyl)-4-cyanocyclohexan- 1 -one dimetiiyl ketal (0.5 g, 1.33 mmol) in tetrahydrofuran (3 mL) at room temperature under an argon atmosphere was added to a suspension of lithium aluminum hydride (0.1 g, 2.66 mmol) in tetrahydrofuran (4.5 mL). After 6h, ethyl acetate and saturated aqueous sodium potassium tartrate were added, followed by saturated aqueous sodium carbonate, and die mixture was

extracted four times with ediyl acetate. The organic extract was dried (potassium carbonate) and die solvent was removed in vacuo to provide an oil (0.43 g, 85%). 20b. 4-(3.4-Bisdifluoromethoxyphenyl')-4-foxamidomethyl')cvclohex an-l-one To a solution of 4-aminomethyl-4-(3,4-bisdifluorometiιoxyphenyl)cyclohexan- 1-one dimethyl ketal (0.43 g, 1.13 mmol) and trietiiylamine (0.16 mL, 1.13 mmol) in methylene chloride (7 mL) under an argon atmosphere at -78°C was added metiiyl oxalyl chloride (0.12 mL, 1.07 mmol). After 5 min, water was added and the mixture was partitioned between methylene chloride and acidic water and was extracted twice. The organic extract was dried (potassium carbonate) and evaporated to an oil (0.59 g). This oil in methanol (ca. 2 mL) in a pressure tube was cooled to -78°C and an equal volume of anhydrous ammonia was condensed into the tube. The tube was sealed, was allowed to come to room temperature and was stirred underpressure for 6h. The ammonia was allowed to evaporate, the mixture was partitioned between chloroform and water and was extracted tiiree times. The organic extract was dried (potassium carbonate) and evaporated to die ketal, an oil (0.6 g). This oil in tetrahydrofuran (13 mL) was treated widi 5% hydrochloric acid (7.6 mL) and the mixture was stirred under an argon atmosphere at room temperature for 20h. The mixture was poured into acidic water, was extracted tiiree times with methylene chloride, d e organic extract was dried (potassium carbonate) and die solvent was removed in vacuo. Purification by flash chromatography, eluting with 5% ether/chloroform, followed by trituration with ether/methylene chloride, provided a white solid (0.21 g, 45%): m.p. 164-165°C.

Analvsis Calc. for C17H18F4N2O5: C 50.25, H 4.47, N 6.89; found: C 50.04, H 4.45, N 6.64.

EXAMPLE 21 4-Cvano-4-(3-cyclopropylmethoxy-4-difluoromedιoxyphenyI -2-r2-

(trimethylsilvDetiioxycarbonvDlcvclohexan-l-one A solution of 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxy-phenyl)cyclohexan-l-one (0.18 g, 0.45 mmol) in 2-(trimethylsilyl)- ethanol (1.0 mL) was heated at 180°C under an argon atmosphere for 2.5h. The mixture was cooled, was concentrated and die product was purified by flash chromatography, eluting with 3:1 hexanes/ether, to provide a colorless oil (0.2 g, 95%).

EXAMPLE 22 4-Cvano-4-r3-cyclopentyloxy-4-( ^' 4-fluorobenzyloxy)phenvπcyclohexan-l-one A solution of 4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one

(0.75 g, 2.4 mmol) and concentrated hydrochloric acid (2 L) in methanol (10 mL) was heated at reflux under an argon atmosphere for 2h- The mixture was cooled, was diluted widi water and was extracted tiiree times wid methylene chloride. The organic extract was dried (magnesium sulfate) and was evaporated to the phenol (0.54 g, 92%). A vigorously

stirred mixture of this phenol, 4-fluorobenzyl bromide (0.83 mL, 6.6 mmol) and potassium carbonate (0.92 g, 6.6 mmol) in dimediylformamide (12 mL) was heated under an argon atmosphere at 90°C for 2h. The mixture was allowed to cool, was diluted with water and was extracted tiiree times with ether. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 30% ethyl acetate/hexanes, provided a white solid (0.6 g, 78%): m.p. 145-146°C. Analvsis Calc. for C2lH20FNO3-l/5 H2O: C 70.65, H 5.76, N 3.92; found: C 70.59, H

5.59, N 3.99.

EXAMPLE 23

4-Cvano-4-r3-cyclopentyloxy-4-f4-fluorobenzyloxy .phenyllcyclohexan- 1 -one oxime A solution of 4-cyano-4-[3-cyclopentyloxy-4-(4- fluorobenzyloxy)phenyl)cyclohexan-l-one (0.525 g, 1.49 mmol) and hydroxylamine hydrochloride (0.114 g, 1.63 mmol) in pyridine (5 mL) was was stirred at room temperature under an argon atmosphere for 18h. The mixture was partitioned between IN hydrochloric acid and methylene chloride, the organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 35% ethyl acetate/hexanes, provided a white solid (0.45 g, 82%): m.p. 55-57°C.

EXAMPLE 24

4-(3-Cvclopropylmethoxy-4-difluoromethoxyphenyl)-4-ethyny lcyclohexan-l-one The tide compound, prepared substantially as described above for 4-(3,4- bisdifluoromethoxyphenyl)-4-ethynylcyclohexan-l-one in EXAMPLE 19, was isolated as a solid: m.p. 75-77 ⁰ C . Analvsis Calc. for C19H20F2O3: C 68.25, H 6.03; found: C 67.93, H 6.10.

EXAMPLE 25 4-Cyano-4-(3-cyclopropmethoxy-4-methoxyphenyl)cvcIohexan-l-o ne oxime

The title compound, prepared substantially as described above for 4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one oxime in EXAMPLE 13, was isolated as a solid: m.p. 75-77°C .

Analvsis Calc. for C18H22N2O3 /4 H2O: C 67.80, H 7.11, N 8.78; found: C 68.03, H

7.08, N 8.59.

EXAMPLE 26

2-Aminocarbonyl-4-cvano-4-(3-cyclopropylmethoxy-4-methoxy phenvπcvclohexan-l-one 26a. 2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphen yl)-l- (methoxymethyloxy)cyclohex- 1 -ene A solution of 2-carbomethoxy-4-cyano-4-(3- cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-l-one (1.0 g, 2.8 mmol) and sodium hydride (80% dispersion in mineral oil, 0.09 g, 3.1 mmol) in dry hexamethylphosphoric

triamide (8 mL) was stirred under an argon atmosphere at room temperature for 0.5h. Chloromethylmediyl ether (0.26 mL, 3.4 mmol) was added and stirring was continued for 4.5h. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, was extracted three times, the organic layer was dried (sodium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting widi 3:1 hexanes/etiiyl acetate, to provide a white solid (0.5 g, 44%): m.p. 98-99°C. 26b. 2-Carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyπ- 1 - (methoxymethyloxy cyclohex-l -ene A solution of 2-carbomethoxy-4-cyano-4-(3- cyclopropylmethoxy-4-metiιoxyphenyI)-l-(medιoxymethyloxy)c yclohex-l-ene (0.5 g, 1.25 mmol) and potassium hydroxide (0.21 g, 3.75 mmol) in medianol (13 mL), tetrahydrofuran (5 mL) and water (7.5 mL) under an argon atmosphere was heated at 65°C for 3h. The mixture was partitioned between methylene chloride and acidic water, was extracted twice, die organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 5% metiianol chloroform, provided an oil (0.26 g, 54%).

26c. 2-Aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphe nyl)- 1 - fmethoxymethvIoxy)cvcIohex-l-ene A mixture of 2-carboxy-4-cyano-4-(3- cyclopropylmethoxy-4-methoxyphenyl)-l-(methoxymethyloxy)cycl ohex-l-ene (0.26 g, 0.67 mmol), N-methyl morpholine (0.09 ml, 0.8 mmol) and isobutyl chloroformate (0.1 mL, 0.77 mmol) in diy 1,2-dimethoxyedιane (7 mL) was stirred under an argon atmosphere at room temperature for 10 min. Ammonium hydroxide (0.07 mL, 1.0 mmol) was added and stirring was continued for 0.5h. The mixture was partitioned between mediylene chloride and 5% aqueous sodium carbonate, was extracted tiiree times, die organic layer was dried (potassium carbonate) and die solvent was removed in vacuo to provide a white solid (0.22 g, 85%): m.p- 120-122°C.

26d. 2-Aminocarbonyl-4-cyano-4-(3-cvclopropylmethoxy-4-methoxyphe nyl ^' )cvclohexan- 1-one A solution of 2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)-l-(methoxymedιyloxy)cyclohex-l-ene (0.22 g, 0.57 mmol) in 50% aqueous acetic acid (12 mL, containing 9 drops concentrated sulfuric acid per 30 mL) was heated at 75°C under an argon atmosphere for 2h. The mixture was cooled, was partitioned between methylene chloride and water, was extracted twice, die organic layer was dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 5% metiianol/chloroform, followed by crystallization from ether/methylene chloride, provided a white powder (0.07 g, 51%): m.p. 154-155°C. Analysis Calc. for C19H22N2O4-1/2 H ₂ O: C 64.94, H 6.60, N 7.97; found: C 64.93, H 6.56, N 7.61.

EXAMPLE 27 2-Carboxy-4-cvano-4-('3-cvclopropylmethoxy-4-difluoromethoxy -phenvI)cvclohexan-l-one 27a. 4-Cvano-4-f3-cvclopropylmethoxy-4-difluoron.ethoxyphenyl)-2- r2- (trimethylsilv ethoxycarbonvDlcvclohexan-l-one A solution of 2-carbomethoxy-4-cyano- 4-(3-cyclopropylmethoxy"4-difluoromethoxy-phenyl)cyclohexan- l-one (0.18 g, 0.45 mmol) in 2-(trimethylsilyl)ethanol (1.0 mL) was heated at 180°C under an argon atmosphere for 2.5h. The mixture was cooled, was concentrated and the product was purified by flash chromatography, eluting with 3:1 hexanes/ether, to provide a colorless oil (0.2 g, 95%).

27b. 2-Carboxy-4-cvano-4-(3-cvclopropylmethoxy-4-difluoromethoxyp henyl)- cvclohexan-1-one A solution of 4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)-2-[2-(rrimethylsilyl)ethoxycarbonyl)] cyclohexan- 1 -one (0.2 g, 0.42 mmol) and tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 2 mL, 2 mmol) was stirred at room temperature under an argon atmosphere for 2.5h. The mixture was poured into cold dilute aqueous hydrochloric acid, was extracted twice with edier, the organic extract was washed tiiree times widi ice water, was dried (sodium sulfate) and the solvent was removed in vacuo. Trituration of die residue provided a white powder (0.12 g, 77%): m.p. 110-112°C (dec). Analysis Calc. for C19H19F2NO5: C 60.16, H 5.05, N 3.69; found: C 60.25, H 5.07, N 3.57.

EXAMPLE 28 4- ⁽ 3-Cvclopropylmethoxy-4-difluoromethoxyphenyl)-2.4-dicv anocvclohexan-l-one To a stirred solution of l-amino-4-(3-cyclopropylmethoxy-4- difluoromedιoxyphenyl])-2,4-dicyanocyclohex-l-ene (0.25 g, 0.696 mmol) in ethanol (2 mL) was added 6N hydrochloric acid (0.6 mL) and the mixture was stirred for 1.5h at ambient temperature. The reaction was poured into ice water, was extracted three times with ether and die combined organic phase was washed wid water, brine and was dried (sodium sulfate). The solvent was evaporated and the residue was purified by flash chromatography, eluting with 4% methanol/toluene, and the residue was triturated with ether to provide a white powder (0.08 g, 32%): m.p. 142-143°C. Analysis Calc. for C19H18F2N2O3.I/4 H2O: C 62.55, H 5.11, N 7.68; found: C 62.69, 62.39, H: 5.05, 5.04, N 7.47, 7.43.

EXAMPLE 29 2-Aminocarbonyl-4-cvano-4-f3-cvclopropylmethoxy-4-difluorome thoxyphenyl)cvclohexan-

1-one 29a. 2-Carbome oxy-4-cvano-4-(3-cvclopropylme oxy-4-difluoromethoxyphenyl)- 1 - f methox vmeth yloxytevclohex- 1 -ene The title compound, prepared substantially as described above for 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphen yl)- l-(methoxymedιyloxy)cyclohex-l-ene in EXAMPLE 26a, was triturated wid ether to provide white crystals (0.334 g, 77%): m.p. 81-82.5°C. Analysis Calc. for C22H25F2NO6: C 60.41, H 5.76, N 3.20; found: C 60.32, H 5.80, N 3.21.

29b. 2-Carboxy-4-cyano-4-f3-cyclopropylmethoxy-4-difluoromethoxyp henyl)-l- (methoxymethyloxy)cyclohex-l-ene The tide compound, prepared substantially as described above for 2-carboxy-4-cyano-4-(3-cycIopropylmethoxy-4-methoxyphenyl)-l - (methoxymethyloxy)cyclohex-l-ene in EXAMPLE 26b, was isolated as an oil.

29c. 2-Aminc arbonyl-4-cyano-4-r3-cvclopropylmethoxy-4-difluoromedιoxyph enylV 1 - fmemoxymethyloxy)cyclohex-l-ene The title compound, prepared substantially as described above for 2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)-l-(medιoxymedιyloxy)cyclohex-l-ene in EXAMPLE 26c, was isolated as an oil.

29d. 2-AminocarbonyI-4-cyano-4-(3-cyclopropylmethoxy-4-difluorome thoxyphenyl)- cvclohexan-l-one The title compound, prepared substantially as described above for 2- ammocarbonyl-4-cyano-4-(3-cycIopropylmethoxy-4-metiioxypheny l)cyclohexan- 1-one in EXAMPLE 26d, was isolated as a white powder (0.025 g, 24%): m.p. 157-159°C. Analysis Calc. for C19H20F2N2O4.I/2 H2O: C 58.91, H 5.46, N 7.23; found: C 58.86, H 5.32, N 6.95.

METHODS OF TREATMENT Li order to use a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance widi standard pharmaceutical practice as a pharmaceutical composition.

The compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for die prophylatic or therapeutic treatment of any disease state in a human or odier mammal which is mediated by inhibition of PDE IV, such as but not limited to asthma, allergic, or inflammatory diseases. The compounds of Formula CD or (II) are administered in an amount sufficient to treat such a disease in a human or odier mammal.

For die purposes herein all methods of treatment and dosage regimens apply equally to both die compounds of Formula (T) or (II).

In order to use a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof for the treatment of humans and odier mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

The amount of a compound of Formula (I) or (II) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, die nature and severity of the condition and die animal undergoing treatment, and is ultimately at the discretion of the physician.

The daily dosage regimen for oral administration is suitably about .001 mg/kg to lOOmg/kg, preferably 0.01 mg Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.

No toxic effects are expected when tiiese compounds are administered in accordance with the present invention.

UTILΠΎ EXAMPLES

EXAMPLE A Inhibitory effect of compounds of Formula (I) or (II) on in vitro TNF production by human monocytes The inhibitory effect of compounds of Formula (I) or (II) 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 TΝF activity for the compounds of Formula (I) or (II). The protocol used in tiiese 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 TΝF induced by the injection of endotoxin.

EXAMPLE C Isolation of PDE Isozymes The phosphodiesterase inhibitory activity and selectivity of die compounds of Formula CD or (H) can be determined using a battery of five distinct PDE isozymes. The tissues used as sources of die different isozymes are as follows: 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 "Ia"), canine trachealis. PDEs Ia, lb, Ic and in 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 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 (D or (II) have been demonstrated.

EXAMPLE D The ability of selected PDE IV inhibitors to increase cAMP accumulation in intact tissues is assessed using U-937 cells, a human monocyte cell line that has been shown to contain a large amount of PDE IV. To assess the activity of PDE IV inhibition in intact cells, nondifferentiated U-937 cells (approximately 10-5 cells/reaction tube) were incubated with various concentrations (0.01-1000 μM) of PDE inhibitors for one minute and lμM prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by die addition of 17.5% perchloric acid, die pH was neutralized by die addition of 1M potassium carbonate and cAMP content was assessed by RIA. A general protocol for this assay is described in Brooker et al., Radioimmunassay of cyclic AMP and cyclic GMP., Adv. Cyclic Nucleotide Res., 10: 1-33, 1979. The compounds of die working examples as described herein for Formula (I) or (H) have demonstrated a positive EC5QS in the μM range in the above assay.