Field of the Invention

The present invention relates to novel compounds, pharmaceutical compositions containing these compounds, the use of these compounds in treating allergic and __n_l___mmatσry diseases, and to the use of these compounds to inhibit 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 components of chronic bronchial asthma. An alternative to the "mediator approach" is to regulate the activity of cells responsible for the pathophysiology of asthma. Cyclic AMP (cAMP, adenosine cyclic 3\5'- monophosphate) modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. 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 monocyte and macrophage activation. Cyclic AMP has been shown to mediate cellular responses to a wide range of hormones, neurotransmitters and drugs; (Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973). One potential means to regulate the activity of cells responsible for the pathophysiology of asthma is to control the intracellular levels of cyclic AMP. Cellular cAMP levels are elevated when an appropriate agonist binds to particular cell surface receptors, thereby activating adenylate cyclase to convert Mg ⁺ 2-ATP to cAMP at an accelerated rate. The principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (cyclic nucleotide phosphodiesterase hereinafter "PDE"s). Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing undesirable activation of airway smooth muscle and a wide variety of inflammatory cells. It has been shown that a distinct 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. The beneficial effects of PDE IV inhibition are markedly potentiated when the adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids. Thus, PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (both activators of adenylate cyclase) are elevated. PDE IV inhibitors offer a unique approach to the phaπnacotherapy of bronchial asthma, and possess significant therapeutic advantages over agents currently on the market The compounds of this invention have the ability to inhibit PDE IV. The compounds of this invention also inhibit the production of TNF, a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of undesirable physiological conditions, such as diseases, and 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, human acquired immune deficiency syndrome (AIDS), cachexia secondary to AIDS, AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with human immunodeficiency virus (HTV). At least three types or strains of HTV have been identified: HTV-l, HIV-2 and HTV-3. As a consequence of HTV infection, T-cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HTV entry into a T lymphocyte requires prior T lymphocyte activation. Once an activated T lymphocyte has been infected with HTV, the T lymphocyte must be maintained in an activated state in order to permit HTV gene expression and/or HTV replication. Cytokines, including TNF, are implicated in activated T-cell-mediated HTV protein expression and/or virus replication as playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity in an HTV-infected individual, such as by inhibition of TNF production, aids in limiting the maintenance of T cell activation, and thereby mitigates the progression of HTV infection to previously uninfected cells. When HTV infection of previously uninfected cells is diminished, a slowing or elimination of the progression of immune dysfunction caused by HTV infection results.

Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in the maintenance of HTV infection. These cells, like T cells, are targets

for viral replication, where the level of viral replication is dependent upon the activation state of the cells. (See Rosenberg et al., The Immunopathogenesis of HTV Infection, Advances in Immunology, Vol. 57, 1989). Monokines, such as TNF, have been shown to activate HTV replication in monocytes and/or macrophages (See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990), therefore, inhibition of monokine production or activity aid in limiting HTV progression as stated above for T cells.

TNF has also been implicated in various roles with other viral infections, such as that of cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for simila 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, 1990; and Luke e al, Journal of Infectious Diseases, 162:211-214, 1990). Summary of the Invention

This invention relates to the novel compounds of Formula (I) as shown below, and the pharmaceutically acceptable salts thereof. These compounds are useful in the mediatio or inhibition of the enzymatic activity or catalytic activity of PDE IV. These compounds also have TNF inhibitory activity. The compounds of Formula (I) are represented by the following structure:

α) or a pharmaceutically acceptable salt thereof, wherein:

Rl is -(CR ₄ R ₅ ) _n C(=O)O(CR4R ₅ ) _m R ₆ , -(CR ₄ R ₅ ) _n C(=O)NR4(CR4R ₅ ) _m R6, - (CR4R5) _n O(CR4R5) R or -(CR4R5)rR6, wherein any alkyl moiety may be optionally substituted with one or more halogens;

R2 is independently methyl or ethyl, where either methyl or ethyl may be optionally substituted by 1 or more halogens; each R4 and each R5 are independently -H or a C1.2 alkyl; R is -H, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCι.3 alkyl, halo substituted aryloxyCι .3 alkyl, indanyl, indenyl, C7.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3.6 cycloalkyl or a C4.6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups, one ethyl group or an hydroxyl group;

provided that: a) when R is hydroxyl, then m is 2: or b) when Rg is hydroxyl or -H, then r is 2 to 6; or c) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2- tetrahydrofuranyl,or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R is 2-tetrahydropyranyl, 2tetrahydrothiopyranyl, 2- tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; each R7 is independently -(CR4R5)qRi2 or C\. alkyl wherein the R 2 or C\. alkyl group is optionally substituted one or more times by Cj_2 alkyl optionally substituted by one to three groups selected from -F, -Br, -Cl, -NO2, -NRIQRJ J, - C(=O)R ₈ , -C(=O)OR ₈ , -OR ₈ , -CN, -C(=O)NRιoRn, -OC(=O)NR ₁₀ R ₁ ι, - OC(=O)R ₈ , -NR ₁₀ C(=O)NRιoR ₁₁ , -NRι ₀ C(=O)Rn, -NRι ₀ C(=O)OR ₉ , - NR ₁₀ C(=O)Rι ₃ , -C(=NRιo)NR ₁₀ Rn, -C(=N-CN)NR ₁₀ R ₁₁ , -C(=N-CN)SR ₉ , - NRlθC(=N-CN)NRιoRι ι, -N ₁₀ S(=O) ₂ R9, -S(=O) _m .R ₉ , - NR ₁ oC(=O)C(=O)NRιoRil, -NRιoC(=O)C(=O)Rιo, or Rι ₃ ; each Rg is independently -H or R _9; each R ₉ is independently Cι_4 alkyl optionally substituted by one to three -F; each R o s independently -ORg or Rjj; each Ri 1 is independently -H or C 1.4 alkyl optionally substituted by one to three -F; or when RIQ and Ri 1 are as NRIQRI 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; each R 2 is independently C3.7 cycloalkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazolyl, 1-imidazolyl, 2-imidazolyl, thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, 2-thienyl, 3-thienyl, 4-thiazolyl, 5- thiazolyl, quinolinyl, naphthyl or phenyl; each R 3 is a heterocyclic ring independently selected from oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl or thiadiazolyl, where R13 is appended to a compound of Formula (I) through a carbon atom of the heterocyclic ring, and where each heterocyclic ring may be unsubstituted or substituted by one or two Cι_2 alkyl groups; each R14 is independently H or R7, or when RIQ and R14 are as NR10R14, they may together with the nitrogen atom form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S; each m is independently 0 to 2; each m' is independently 0 to 2; n is 1 to 4;

r is 0 to 6; each q is independently 0 to 2.

Xl is YRβ, halogen, nitro, NR4R5 or formyl .unino;

X2 is O oτ NR ₈ ; X3 is hydrogen or X 1 ;

Y is O or S(=O) _m - _;

Y' is O or S;

Z, Z2 and Z3 are independently H, (CH2)ι_3CN, (CH2)i-3(C=O)ORi4, C(=O)H, C(=O)NR ₈ NR ₈ C(=O)R ₈ , C(=O)NR ₈ NRιoR ₁₄ , C(=NORι ₄ )R ₈ , C(=NR ₈ )NRιoR ₁₄ , C(=NR ₁₄ )NR ₈ R ₈ , C(=N- C J IORM' C(=N-CN)SR ₉ , 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 4-triazolyl[ 1,2,3], 5-triazolyl[l,2,3], 3-triazolyl[ 1,2,4], 5- triazolyl[l,2,4], 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 3-oxadiazolyl[ 1,2,4], 5-oxadiazolyl[ 1,2,4], 2- oxadiazolyU 1,3,4], 2-thiadiazolylf 1,3,4], 5-thiadiazolyl[ 1,2,4], 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4- thiazolidinyl or 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, or 5- imidazolidinyl; wherein all of the heterocyclic ring systems may be optionally substituted one or more times by R14; Zi is H, OH, CN, C(=O)OH, C(=O)OCH3 OR C(=O)NH2; with the provisos that: a) at least one of Z, Z2 and Z3 is other than H; b) at least one of Z, Z2 and Z3 is H; and c) when Zi is -C(=O)OH, then X2R1 is not methoxy; and d) when Z2 is (CH2)i-3CN, or (CH2)ι_3C(C=)ORi4, then Z3 is H.

This invention also relates to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable excipient

This invention also relates to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable excipient This 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 a pharmaceutically acceptable salt thereof.

This invention also relates to a method for the treatment of allergic and ijriflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method for the treatment of asthma which comprise administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention further relates to a method of inhibiting TNF production in a mammal, including humans, which comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states effected thereby.

This invention further relates to a method of treating a human afflicted with a huma immunodeficiency virus (HIV), which method comprises administering to a human in need of such treatment, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Compounds of Formula (I) are useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF, or will elicit TNF production in vivo.

In addition, compounds of Formula (I) are useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF, or will elicit TNF production in vivo.

Detailed Description of the Preferred Embodiments DEFINITIONS

As used herein, the following terms and expressions have the indicated meaning. "Aryl" or "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. The alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms. The term "Cι_2 alkyl", "C1.4 alkyl", "Cι_6 alkyl" or "alkyl groups" includes both straight or branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited thereto, including, but not limited to methyl, ethyl, Λ-propyl, isopropyl, n butyl, sec-butyl, isobutyl, rerr-butyl, and the like.

The term "C3.7 cycloalkyl" means groups of 3-7 carbon atoms where some or all o them form a ring, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.

"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 lympho-rines regardless of which cells produce them. The cytokine inhibited by the present invention for use in the treatment of an 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.

"Halo" includes all halogen radicals, i.e., chloro, fluoro, bromo, or iodo.

"Heteroaryl" means an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl or thienyl. "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 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 IL- 1 or TNF levels 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

"Percentage" and "%" refers to percentage by weight of a component or ingredient based on the weight of the total composition containing such component or ingredient

'TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance, is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-β (also known as lymphotoxin) has close structural homology with TNF-α (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-α and TNF-β are inhibited by the compounds of the present invention and thus are herein referred to collectively as 'TNF" unless specifically delineated otherwise.

This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for 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 a pharmaceutically acceptable salt thereof.

PDE rV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic ihinitis, 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 α ^' stress syndrome. In addition, PDE IV inhibitors are useful in the treatment o

diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HTV-1, HTV-2 and HTV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.

This invention more specifically relates to a method of treating a ____ammal, afflicted with a human immunodeficiency virus (HTV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of this invention may also be used in association with the veterinary treatment of animals, other than humans, in need of inhibition of TNF production. TNF mediated diseases for treatment therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to feline immunodeficiency virus (FTV) or other retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses. The compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fiingal meningitis. Additionally, a compound of Formula (I) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections. Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymycins, 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 compounds called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B. A compound of Formula (I) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) to a mammal in need of such treatment. Preferably, a compound of Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B. PREFERRED COMPOUNDS

Preferred compounds of Formula I are as follows:

Preferred Ri substituents for the compounds of the Formula (I) are C4-6 cycloalkyl with or without an hydroxyl group, CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C7.11

polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)l-3θ(CH2)0-2CH3, and -(CH2)2-4OH. When Ri for the compounds of the Formula (I) is or contains an alkyl moiety substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine. A preferred alkyl moiety substituted by 1 or more halogens is C 1-4 alkyl substituted by 1 or more fluorines. A more preferred halo- substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3, and -CH2CHF2

When the Ri term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of any individual methylene un to be independent of branching in any other methylene unit, e.g., (CR4Rs)n wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can 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[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, _ricyclo[5.2.1.0 ² .6]decyl, etc., where 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 Xi groups are those wherein Xi is YR2 and Y is oxygen. The preferred

X2 group is that wherein X2 is oxygen. The preferred X3 group is that wherein X3 is hydrogen.

Preferred R2 groups are a Ci-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 fluoro-substituted alkyls, specifically a Cl-2 alkyl, such as a -CF3, -CHF2. or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.

Preferred rings when Rio and R14 are as -NR10R14 and together with the nitrogen atom 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, 1 -pyrazolyl, 1 -triazolyl, 2- triazolyl, 1-tetrazolyl, 2-tetrazolyl, mσrpholinyl, piperazinyl, and pyrrolyl.

Preferred groups for -NR10 14 which contain a heterocyclic ring are 5-(Rl4)-l-tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(R 14)- 1 -piperazinyl or 4-(R 15)- 1 -piperazinyl.

Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4-, or 5-pyrazolyl), (4- or 5-tri__zolyl[ 1,2,3]), (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[ 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).

Preferred are those compounds of Formula (I) wherein Ri is -C4-6 cycloalkyl with or without an hydroxyl group, -CH2-cyclopropyl, -CH2-C5-6 cycloalkyl, tetrahydrofuran- 3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl and Xi is YR2-

Most preferred are those compounds wherein Ri is cyclopentyl, 3-hydroxycyclopent-l-yl, -CH2-cyclopropyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl It will be recognized that some of the compounds of Formula (I) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. Furthermore, some of the compounds of Formula (I) may exist in more than one tautomeric form, e.g., imines are a tautomeric form of enamines. All of these compounds are considered to be within the scope of the present invention.

Exemplified compounds of Formula (I) are:

3-(3'-cyclopentyloxy-4'-methoxy[l,l ^r |biphenyl-3yl)-5-methyl[l^,4]oxadiazole;

5-(3'-cyclopentyloxy-4'-methoxy [ 1 , 1 ^* ]biphenyl-3yl)-3-methyl[l ,2,4]oxadiazole;

5-(3 ^, -cyclopentyloxy-2,6-difluoro-4 ^, methoxy [ 1 , l']biphenyl-3yl)-3- methyl[l,2,4]ox_-diazole;

5-(4-cyano-3'-cyclopen tyloxy-4'-methoxy[ 1 , 1 ^* ]biphenyl-3yl)-3- methyl[ 1 ,2,4] oxadiazole;

2-(3 ^, -cyclopentyloxy-4'-methoxy[l,l ^, ]biphenyl-3yl)-5-methyl[l,3,4]oxadiazole;

2-(3'-cyclopen_yloxy-4'-methoxy[l,l ^, ]biphenyl-3yl)-5-methyl[l,3,4]thiadiazole; 5-(3'-cyclopentyloxy-4 ^, -methoxy [ 1 , 1 ']biphenyl-3yl)-3-methyl[ 1 ,2,4] thiadiazole;

5-(3'-cyclopentyloxy-4'-methoxy[ 1 , 1 ']biphenyl-3yl)-l-methyl- lH-tetrazole;

5-(3 ^, -cyclopentyloxy-4-'methoxy[ 1 , 1 ']biphenyl-3yl)-2-methyl-2H-tetrazole;

S'-cyclopropylmethoxy-^-methoxyt 1 , 1 ^* ]biphenyl-3-acetonitrile;

S'-cyclopropylmethoxy^'-methoxy [ 1 , 1 ^r )biphenyl-2-acetonitrile; or 3'-cyclopropylmethoxy-4-hydroxy-4'-methoxy[l,l']biphenyl-3-c arboxaldehyde.

All of the compounds of Formulas (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocyte in a mammal, including humans, in need thereof. All of the compounds of Formulas (I) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE I and in treatment of disease states mediated thereby. METHODS OF PREPARATION

Preparation of the compounds of Formula (I) can be carried out by one of skill in the art according to the procedures outlined in the Examples, infra. The remaining

compounds of the Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise:

(a) reacting a compound of Formula (II)

wherein Z, Zi , Z2 and Z3 represents Z, Z 1 , Z2 and Z3 as defined in relation to Formula (I) or a group convertible to ZJ _t Z2 and Z3 by standard synthetic methods, and T represents bromo, iodo or trifluoromethylsulfonoxy;

(b) with a compound of

(πi) wherein Ri, Xl and X2 represent Rj, Xi and X2 respectively, as previously defined in relation to Formula (I) or a group convertible to Rj, Xi and X2 respectively, by standard synthetic methods, and L is a metallic group or a group convertible to a metallic group, such as a boronic acid in the presence of a suitable base, a trialkyl tin, a magnesium halide, lithium cyanocuprate complex, a mercury salt, or a zinc derivative as prepared, for example by the transmetallation of the corresponding lithium compound with a zinc halide;

(c) in a suitable non-reacting solvent under a suitable inert atmosphere, and in the presence of a suitable catalyst

The procedure to react the compounds of Formulas (II) and (HI) to form a biphenyl compound of Formula (I), or a biphenyl precursor to a compound of Formula (I), may be referred to as a coupling reaction.

According to a presently preferred method of preparation, aqueous ethylene glycol dimethyl ether, argon and palladium (II) acetate are preferred as the solvent, atmosphere and catalyst respectively. Boronic acid is a presently preferred L group, and bromo is a presently preferred T group. To form a compound of Formula (I), palladium (II) acetate is dissolved in ethylene glycol dimethyl ether, and the solution is purged of oxygen by bubbling with argon. To the solution is added a compound of Formula (II), a compound o Formula (HI), an alkali metal carbonate or bicarbonate such as sodium bicarbonate, and water to facilitate dissolution of the reactants. The mixture is again purged of oxygen by bubbling with argon, and then stirred at a temperature of between about 20 °C and about 100 °C until the reaction is complete. According to a presently preferred procedure, approximately 1.1 moles of a compound of Formula (HI) are charged for each mole of a compound of Formula (II). According to a presently preferred procedure, the solvent comprises from about 5% to about 60% water as needed to maximize reactant solubility.

According to a presently preferred procedure, the palladium acetate catalyst is present at about 5 to about 30 molar percent, and the base is present at about 200 to about 300 mole percent, calculated on the moles of a compound of Formula (HI).

Another presently preferred procedure for the preparation of compounds of the Formula (I), wherein Z is 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4- pyrazolyl, 5-pyrazolyl, 4-triazolyl[ 1,2,3], 5-triazolyl[l,2,3], 3-triazolyl[l,2,4], 5- triazolyl[l,2,4], 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 3-oxadiazolyl[ 1,2,4], 5-ox__diazolyl[ 1,2,4], 2- oxadiazolyl[l,3,4], 2-thiadiazolyl[ 1,3,4], 5-thiadiazolyl[ 1,2,4], 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl or S-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, or 5-___nidazolidinyl; wherein all of the heterocyclic ring systems may be optionally substituted one or more times by Ri4 _> utilizes a palladium catalyst, dissolved in a suitable solvent, having stabilizing ligands where the ligands are chosen from, for example, triphenylphosphine, 1,1'- bis(diphenylphosphino)ferrocene or 1,4-bisdiphenylphosphinylbutane.

Alternatively the stabilized catalyst is prepared in situ from a mixture of a palladium salt such as the acetate or the bromide, with a stabilizing ligand such as one of the phosphine ligands hereabove exemplified, dissolved in a suitable solvent and the mixture heated in the range of about 50 °C to about 70 °C until the catalyst solution has formed, where exemplary solvents are dimethyl formamide, toluene, tetrahydrofiiran or preferably ethylene glycol dimethyl ether. Compounds of Formula (II) and Formula (D3) where L is preferably boronic acid are then added together with an appropriate base such as a trialkylamine, or preferably with an alkali metal bicarbonate or carbonate and about 5 to about 25% water to maximize reagent solubility, to the catalyst solution, and the mixture heated under an appropriate atmosphere, for example argon, to provide a compound of Formula (I).

Compounds of Formula (II) wherein Z is 3-methyl[l,2,4]oxadiazole, 5- __oethyl[l,2,4]oxadi__zole, 5-methyl[l,3,4]oxadiazole, or 5-meώyl[l,3,4]thiadiazole are prepared by the procedures described in W. Tully, C. Gardener, R. Gillespie, and R. Westwood, J. Medicinal Chem.24. 2060-2067 (1991), as exemplified herein.

Compounds of Formula (II) wherein Z is 1 -alkyl tetrazole are prepared by heating the corresponding N-alkyl carboxamides with thionyl chloride and treating the resulting N-alkyl imidoyl chlorides with sodium azide by the procedure of A. Padwa, et al., J. Org. Chem., 44. 3281-3287 (1979), as exemplified herein. Compounds of Formula (II) wherein Z is 2-alkyl tetrazole are prepared by alkylation of the unsubstituted tetrazole with an alkyl iodide. The compounds of Formula (II) where Z is an unsubstituted tetrazole are prepared from the corresponding

nitriles by the procedure of S.Wittenberger and B. Donner, J. Org. Chem., 5 £, 4139- 4140 (1993), as exemplified herein.

Compounds of Formula (II) wherein Z is 3-__l___yl[l,2,4]thiadiazote are prepared by treatment of the corresponding thioamides sequentially with a N ,N- di-tnethylalkylaimde, i.e., N,N-dimemy_al___aneamide followed by an amino transfer reagent such as hydroxylamine-O-sulfonic acid by the procedure of Y. Iin, S. Lang, Jr., S. Petty, J. Org. Chem., 5, 3750-3753 (1980), as exemplified herein.

Some compounds of Formula (I) may be prepared from other compounds of Formula (I) by, e.g., functional group manipulation of the Z, Zj, Z2 or Z3 group. Additional manipulations of the Z, Zi , Z2 or Z3 groups may be accomplished by the processes described in co-pending U.S. application Serial Number 862,030, filed 2 April 1992 and its corresponding U.S. continuation-in-part application Serial Number 968,762, filed 30 October 1992.

Compounds of Formula (3) may be prepared as illustrated in Scheme 1, and as described in detail in Synthetic Example 1. A brominated anisaldehyde (4) may be reduced to a corresponding hydroxy derivative (5) , and the hydroxy derivative (5) can be converted to a corresponding ether compound of Formula (6), followed by conversion of the bromide to a metallic group L to form a compound of Formula (3).

Scheme I

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

SYNTHETIC EXAMPLES Example 1 Preparation of 3'-cvclopentvloxv-4'-methoxvπ.nbiphenvl-3-carboxvlic acid 1(a) 5-bromo-2-methoxyphenol To a stirred solution of 5-bromo-o-anisaldehyde (Aldrich Chemical Company Inc., 2 g, 116 mmol) in methanol (233 mL) was added cold hydrogen peroxide (30%, 27.7 mL, 24 mmol) followed by concentrated sulfuric acid (5.4 mL, 97 mmol). The reaction mixture wa maintained at 70 °C for 6.5 h, stirred at ambient temperature for 72 h and concentrated in vacuo. The residue was poured into ice-water and extracted with ethyl ether (three times). The combined organic phase was washed with 3 N hydrochloric acid (twice), water, saturat brine, dried over magnesium sulfate and stripped in vacuo to afford an oily orange solid. 1(b) 3-cyclopentyloxy-4-methoxyphenyl bromide

To a stirred solution of 5-bromo-2-methoxyphenol (11.9 g, 58.6 mmol) in dry dimethyl formamide (65 mL) was added cyclopentyl bromide (9.52 mL, 88 mmol) and powdered potassium carbonate (12.15 g, 88 mmol). The reaction mixture was maintained 70 °C for 2 h, 90 °C for 1 h, and stimed at ambient temperature for 72 h. The volatiles we removed in vacuo and the residue partitioned between water and ether. The organic phase was washed with water (three times), saturated brine, dried over anhydrous sodium sulfate and stripped in vacuo. The residue was purified by chromatography (silica gel, 33-40% methylene chloride / hexanes) to afford the titled compound as a colorless oil (11.33 g, 82 !H NMR (400 MHz, CDCI3) 67.00 (dd, Jι=8.5 Hz, J2=2.4 Hz) superimposed upon 6.97 J=2.1 Hz) (2H total), 6.72 (d, J=8.4 Hz, 1H, 4.73 (dt, Jι=J ₂ =6.0 Hz, 1H), 3.82 (s, 3H), 1. 1.81 (m, 6H), 1.63-1.56 (m, 2H). 1(c) 3-cyc_opentyloxy-4-methoxypheny 1-1 -boronic acid To a stirred solution of 3-cyclopentyloxy-4-methoxyphenyl bromide (9.0 g, 33.2 mmol) in dry tetrahydrof iran (105 mL) under an argon atmosphere at -78 °C was added dropwise a 2.58 M solution of Λ-butyl lithium in hexanes (14.6 mL, 36.5 mmol) followed after 2 h stirring by trimethyl borate (4.52 mL, 39.8 mmol). After stirring at ambient temperature for 72 h, the reaction mixture was treated with a solution of 10% aqueous hydrochloric acid (50 mL), stirred for 20 min, and extracted with ethyl acetate three times. The combined organic phase was washed with saturated brine, dried over sodium sulfate (anhydrous) and concentrated in vacuo. The residue was purified by chromatography, preabsorbing on silica gel, and removing the impurities with 0-2% methanol in 10% ethyl acetate / methylene chloride. The tided compound was eluted with 5% methanol in ethyl acetate / methylene chloride (1:10) and concentrated in vacuo to afford a white solid (5.0 g, 64%). mp 173-174.5 °C. 1(d) S'-cyclopentyloxy^'-methoxyf πbiphenyl-S-carboxylic acid

To dimethoxyethane (6 mL) and water (6 mL), deoxygenated with argon and at room temperature, was added palladium acetate (0.016 g, 0.07 mmol), then, as a mixture of solids, 3-iodobenzoic acid (0.22 g, 0.87 mmol), 3-cyclopentyloxy-4- methoxyphenyl boronic acid (0.23 g, 0.96 mmol) and sodium bicarbonate (0.30 g, 3.5 mmol). The reaction was stirred in the dark under an argon atmosphere for 24 h, then diluted with 5:95 methano dichloromethane, washed with 10% hydrochloric acid, water, and brine, was dried (MgSO4), was filtered and was concentrated. The crude mixture was purified by flash chromatography, eluting with 1:9 methano dichloromethane, to afford the title compound (0.22 g, 81%), which was further triturated with dichloromethane:hexanes to provide a white solid, mp 146-148 °C. Anal. (C19H20O4 ^• 0.5 H2O) calcd: C, 71.01; H, 6.59; found: C, 70.93; H, 6.35.

Example 2 Preparation of methvl 3'-cvclopentvloxv-4'-methoxvr .nbiphenvl-3-carhoxvlate A solution of 3'-cyclopentyloxy-4'-methoxy[l,l']biphenyl-3-C-Ut)oxylic acid (0.15 g, 0.47 mmol) in methanol (5 mL) was treated with chlorotrimethylsilane (0.1 mL, 0.79 mmol), was stirred at room temperature under an argon atmosphere for 3 days and was concentrated. The crude mixture was purified by flash chromatography, eluting with 5:95 ethyl acetate:hexanes, to afford the title product (0.08 g, 53 %), which was further triturated with dichloromethane:hexanes to provide a white solid, mp 84-85 °C. Anal. (C ₂ oH ₂ 2θ4 ^• 0.75 H2O) calcd: C, 70.67; H, 6.82; found: C, 70.79 H, 6.45.

Example 3

Preparation of 3'-cvclopentvloxv-4'-methoxvri .1 lbiphenvl-3-carhoxamide To a solution of S'-cyclopentyloxy-^-methoxytl.πbiphenyl-S-carboxylic acid (0.3 g, 0.96 mmol) in dry ethylene glycol dimethyl ether (8 mL) was added N-methyl morpholin (0.13 mL, 1.2 mmol) followed by isobutyl chloroformate (0.14 mL, 1.08 mmol). After 15 min stirring at ambient temperature, ammonium hydroxide (0.6mL, 4.6 mmol) was added dropwise, and the mixture stirred for another 2 h. The reaction mixture was concentrated vacuo, and the residue partitioned between aqueous sodium carbonate solution and methyl chloride. The organic phase was washed with aqueous sodium carbonate solution, dried o anhydrous sodium sulfate, and stripped in vacuo to give the titled compound as a tan solid (0.197 g, 66%). mp 134.5-136 °C. -Η NMR (400 MHz, CDCI3) δ 8.01 (t, J=1.7 Hz, 1H 7.72-7.69 (m, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.16-7.12 (m, 2H), 6.95 (d, J=8.1, 1H), 6.15 (b 0.78H), 5.68 (br s, 0.76H), 4.87 (m, J=0.3, 1H), 3.89 (s, 3H), 2.02-1.82 (m, 6H), 1.68-1.5 (m, 7H with H2O). Example 4

Preparation of 3'-cvclopentvloxv-4'-methoxv.1.11biphenvl-3-N-methvl carboxamide Following the procedure of Example 3 except substituting a 40% aqueous solution of memylamine for ammonium hydroxide and purifying the product by chromatography

(silica gel, 1% methanol / chloroform) afforded the tide compound as an off-white solid (0.272 g, 52%). mp 112-114 °C; Anal. (C20H23NO3 • 1/8 H ₂ O) calcd: C 73.31, H 7.15, N 4.27; found: C 73.26, H 7.13, N 4.33.

Example 5 Preparation of methvl 3'-cvclopentvloxv-4'-π.ethoxv. l.nbiphenvl-3-acetate

5(a) 3-bromσphenyl acetic acid methyl ester

To a solution of 3-bromophenyl acetic acid (Aldrich Chemical Company, Inc., 0.50 g, 2.33 mmol) in dry methanol (2.5 mL) at ambient temperature was added trimethylsilyl chloride (0.9 mL, 7.0 mmol) dropwise. After stirring for 24 h at ambient temperature, the reaction mixture was heated to reflux for 30 min, and then partitioned between iced 5% sodium carbonate solution and ethyl acetate. The combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate and stripped in vacuo to afford an oil. 5(b) methyl 3'-cyclopentyloxy-4'-me oxy[l,l']biphenyl-3-acetate To an argon purged solution of palladium acetate (0.0097 g, 0.043 mmol) dissolved in dry ethylene glycol dimethyl ether (4.8 mL) was added with stirring 3-bromophenyl acetic acid methyl ester (0.103 mL, 0.576 mmol), a powdered mixture of 3- cyclopentyloxy-4-methoxyphenylboronic acid (0.15 g, 0.636 mmol) and sodium bicarbonate (0.118 g, 1.41 mmol) and water (1.5 mL) followed by repurging with argon. The reaction mixture was stirred at ambient temperature for 18 h, then concentrated in vacuo. The residue was absorbed onto silica gel and purified by chromatography (silica gel, 5-10% ethyl acetate / hexanes) and dried at 50 °C in vacuo to afford the tided compound as white crystals (0.163 g, 83%). mp 59-60.5°C; Anal. (C21H24O4) calcd: C 74.09, H 7.11; found: C 74.20, H 7.20. Example 6

Preparation of 3'-cvclopenrvloxv-4'-methoxv.1.nbiphenvl-4-carbonitrile Following the procedure of Example 5(b), except substituting 4-bromobenzonitrile (Aldrich Chemical Company, Inc.) for 3-bromophenyl acetic acid methyl ester and recrystallizing from methanol gave the titled compound as white crystals (0.124 g, 73%). mp 97-98.5 °C; Anal. (Ci^^NC^) calcd: C 77.79, H 6.53, N 4.77; found: C 77.83, H 6.58, N 4.64.

Example 7 Preparation of 3'-cvclopentyloxy-4'-methoxyrL11biphenyl-3-carbonitrile Following the procedure of Example 5(b), except substituting 3-bromobenzonitrile (Aldrich Chemical Company, Inc.) for 3-bromophenyl acetic acid methyl ester and chromatographing (15- 20% ethyl acetate / hexanes) gave the tided compound as white crystals (0.471 g, 76%). mp 66-67.5 °C; Anal. (Cι ₉ Hι ₉ NO ₂ ) calcd: C 77.79, H 6.53, N 4.77; found: C 77.80, H 6.54, N 5.13.

Example 8 Preparation of methvl 4-cvano-3'-cvclopentvloxv-4'-methoxvri .l1hiphenvl-3- carboxvlate 8(a) methyl 2-hydroxy-5-bromobenzoate A solution of methyl 2-hydroxybenzoate (8.0 g, 52.6 mmol) in acetic acid (200 mL) at room temperature was treated dropwise over 1 h with a solution of bromine (5.15 mL, 100 mmol) in acetic acid (50 mL), stirred for 8 h, was diluted with ether, was washed with aqueous sodium bisulfite, aqueous sodium carbonate, and water, was dried (MgSO4), was filtered and was concentrated to afford the tide intermediate as a white solid (11.4 g, 94 %). mp 57- 58 °C.

80-0 methyl S'-cyclopentyloxy- hydroxy^'-methoxyfl.llbiphenyl-S-carboxylate

The tide intermediate was prepared following the procedure of Example 1(d), except substituting methyl 2-hydroxy-5-bromobenzoate for 3-iodobenzoic acid. 8(c) methyl S'-cyclcpentyloxy^'-methoxy-^trifluoromethylsu-fonatofl.llbi phenyl-S- carboxylate

To methyl 3'-cyclopentyloxy-4-hydroxy-4'-methoxy[l, ]biphenyl-3-carboxylate (0.33 g, 0.59 mmol) in pyridine (3 mL) at 0 °C under an argon atmosphere was added trifluoromethane sulfonic anhydride (0.12 mL, 0.71 mmol). The reaction was stirred at room temperature for 2.5 h, was quenched with 10% hydrochloric acid, was extracted three times with ethyl acetate, was dried (MgSO4), was filtered and was concentrated. The crude mixture was purified by flash chromatography, eluting with 1:9 ethyl acetate exanes to afford the tide intermediate as a colorless liquid (0.15g, 44%). *H NMR (400 MHz, CDCI3) d 8.22 (d, J=2.4 Hz, 1H), 7.75 (dd, J=8.5, 2.4 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.13 (dd, J= 8.2, 2.1 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 4.87 (m, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 1.8-2.0 (m, 6H), 1.6-1.7 (m, 2H). 8(d) Methyl 4-cyano-3 ^, -cyclopentyloxy-4'-methoxy[l, ]biphenyl-3-carboxylate

A solution of methyl S'-cyclopentyloxy^'-methoxy- trifluoromethylsulfonatotl.πbiphenyl-S-carboxylate (0.45 g, 0.95 mmol) in deoxygenated dimethylformamide (9.5 mL) was treated with potassium cyanide (0.09 g, 1.43 mmol), palladium acetate (0.032 g, 0.14 mmol), triphenylphosphine (0.075 g, 0.29 mmol) and coarsely ground potassium hydroxide (0.08 g, 1.43 mmol). The reaction was heated at 100-105 °C for 15 min, cooled, diluted with water, and extracted twice with ethyl acetate. The combined organic layers were washed three times with water, with aqueous sodium carbonate and brine, were dried (MgSO4), were filtered and were concentrated. The crude mixture was purified by flash chromatography, eluting with 2:8 ethyl acetate:hexanes to afford the tide product as a colorless oil (0.19g, 57 %), which was further triturated with dichloromethane:hexanes to provide a white solid, mp 101-

103 °C; Anal. (C21H21NO4 ^• 0.125 H2O) calcd: C, 71.32; H, 6.06; N, 3.96; found: C, 71.32; H, 6.03; N, 3.87.

Example 9

Preparation of 3'-cvclopen_vloxv-2.6-difluoro-4'-methoxvri . 1hiphenvl-3-carboxvUc acid

9(a) 2,4-difluoro-3-iodobenzoic acid

A solution of di-iswpropylamine (1.55 mL, 11.1 mmol) in tetrahydrofiiran (15 mL) at 0 °C under an argon atmosphere was treated with 2.5 M n-butyllithium in hexanes (4.20 mL, 10.5 mmol), stirred for 30 min, and cooled to -78 °C. A solution of 2,4-difluorobenzoic acid (0.79 g, 5.0 mmol) in tetrahydrofiiran (8 mL) was added over 15 min, followed after 30 min by the addition of a solution of iodine ( 1.4 g, 5.5 mmol) in tetrahydrofiiran over 15 min. After 30 min the reaction was quenched with 1 _K hydrochloric acid, warmed to room temperature, extracted three times with 5:95 methanol :dichloromethane, dried (MgSO4), filtered, and concentrated. Recrystallization from dichloromethane:hexanes provided the tide intermediate as a white solid (1.15 g, 81%). mp 206-208 °C. 9(b) 3'-cyclopentyloxy-2,6-difluoro-4'-methoxy[l, ]biphenyl-3-carboxyUc acid

To dimethoxyethane (5 mL) and water (5 mL), deoxygenated with argon and at room temperature, was added palladium acetate (0.013 g, 0.06 mmol), then as a mixture of solids 2,4-difluoro-3-iodobenzoic acid (0.20 g, 0.72 mmol), 3- cyclσpentyloxy-4-methoxyphenyl boronic acid (0.19 g, 0.79 mmol) and sodium carbonate (0.24 g, 2.3 mmol). The reaction was stirred in the dark under an argon atmosphere for 24 h, then diluted with 5:95 methanol:dichloromethane, washed with 10% hydrochloric acid, water and brine, dried (MgSO4), filtered, and concentrated. The crude mixture was purified by flash chromatography, eluting with 0.2:2:98 acetic acid:methanol:dichloromethane to afford the tide compound as a white solid (0.17 g, 67%). mp 154-155 °C. Anal. (Cι ₉ H oθ4 ) calcd: C, 65.51; H, 5.21; found: C, 65.11; H, 5.20.

Example 10 Preparation of methvl '-cvclopen_vloxv-2.6-difluoro-4'-methoxvri.l'1biphenvl-3- carboxvlate A solution of 3'-cyclopentyloxy-2,6-difluoro-4'-methoxy[l, ]biphenyl-3- carboxylic acid (0.15 g, 0.42 mmol) in methanol (2.5 mL) was treated with chlorotrimethylsilane (0.16 mL, 1.26 mmol) and stirred at room temperature under an argon atmosphere for 48 h. The reaction was diluted with water, extracted three times with dichloromethane, dried (MgSO4), filtered, and concentrated. The crude mixture was purified by flash chromatography, eluting with 1:9 ethyl acetate:hexanes to afford the tide compound as a colorless oil (0.13 g, 84%) which turned gummy with time.

Anal. (C20H20F2O4 ^• 0.5 H2O.) calcd: C, 64.68; H, 5.70; found: C, 64.51; H, 5.44. iH NMR (400 MHz, CDCI3) 57.9-8.0 (m, 1H), 6.9-7.1 (m, 4H), 4.78 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 1.8-2.0 (m, 6H), 1.6-1.7 (m, 2H).

Example 11 Preparation of 3'-cvclopentvloxv-4'-methoxvr 1.11biphenvl-3.4-dicarhoni.rile

11(a) 4-bromophthalic anhydride

Crystalline 4-bromophthalic acid (Aldrich) was distilled at atmospheric pressure, collecting the material of bp >290 °C, drying in vacuo and grinding to afford the tided compound as a white powder (5.8 g, 78%). mp 100-104 °C. 11(b) 4-bromophthalimide

A powdered mixture of 4-bromophthalic anhydride (5.7 g, 25.1 mmol) and urea (1.51 g, 25.1 mmol) was heated to melting under argon atmosphere and maintained at 150 °C for 10 minutes after gas evolution terminated. The solid obtained on cooling was heated in glacial acetic acid, cooled, filtered, washed with cold water and dried in vacuo to afford the tided compound (5.03 g, 89%). mp 228-230 °C (Waldman in J. fur Practische Chemie, 12& 65 (1930) reports mp 229.5 °C). 11 (c) 4-bromophthalamide

A rapidly stirred suspension of 4-bromophthaUmide (2.5 g, 11.06 mmol) in concentrated ammonium hydroxide (75 mL) was gendy heated to dissolve. The mixture was then chilled with the formation of a white precipitate. The chilled mixture was filtered, washed with cold water and the white solid dried in vacuo to afford the tided compound (2.08 g, 77%) as a white powder which partially melts at 197 °C, evolves a gas and changes to crystals which melt at 227-229 °C. 11(d) 4-bromo-2-cyanobenzonitrile A stirred mixture of 4-bromophthalamide (0.400 g, 1.65 mmol) in dry tetrahydrofiiran (4.0 mL) under an argon atmosphere was treated sequentially at 0 °C with dry pyridine (1.15 mL, 14.3 mmol) and then, over 0.5 h, dropwise with trifluoroacetic acid anhydride (1.01 mL, 7.14 mmol). After 3 h stirring at ambient temperature, the reaction mixture was added to ice water and partitioned between methylene chloride and water. The organic extract was washed with water, brine dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica; 15-20% ethyl acetate/hexanes) to afford the tided compound as a white solid (0.30 g 88%). mp 138.5-140 °C. 11(e) 3'-cyclopentyloxy-4'-me±oxy[l,l']biphenyl-3,4-dic_ιrbonitr ile

Following the procedure of Example 5(b), except substituting 4-bromo-2- cyanobenzonitrile for 3-bromophenyl acetic acid methyl ester, employing 5 rather than 24 percent of water (v/v) in the solvent and heating the reaction mixture at 55 °C for an additional 2 h resulted in only about 75% consumption of the bromide by thin layer chromatography (silica; 1:3; ethyl acetate /hexanes). Another 25% of 3-cyclopentyloxy-

4-methoxyphenylboronic acid (0.0375 g, 0.159 mmol), palladium acetate (0.0025 g, 0.011 mmol), and sodium carbonate (0.049 g, 0.46 mmol) was then added, stirring at ambient temperature for an additional 72 h followed by heating for 3 h at 60 °C. The reaction mixture was concentrated in vacuo, partitioned between methylene chloride / water, and the organic phase washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (silica; hexanes methylene chloride; 1:2 containing 2-4% ethyl acetate) followed by recrystallization (ethyl acetate/petroleum ether) and drying at 130 °C in vacuo to afford the tided compound as a white solid . mp 157.5-159 °C; Anal. (C20HI8N2O2 ^• 1/8 H2O) calcd: C 74.94, H 5.74, N 8.74; found (two measurements were made): C 74.92, 75.00, H 5.62, 5.60, N 8.58, 8.56; MS:(CI, NH3) [M+NH4] ⁺ 336.1, and [M+H- C5H ₈ ]+ 250.0.

Example 12 Preparation of 3'-cvclopropvlmethoxv-4'-methoxvri.nhiphenvl-3-carhoxvlic acidl2(a) 3- cyclopropylmethoxy-4-methoxyphenyl bromide

Following the procedure of Example 1(b), except substituting cyclopropylmethyl bromide for cyclopentyl bromide, maintaining the reaction mixture at 70 °C for 3 h follow by ambient temperature for 72 h and purifying by chromatography (silica gel, 33-50% methylene chloride/hexanes) gave the tided compound as a white solid (11.5 g, 76%). mp 53-54 °C

12(b) 3-cyclopropylmethoxy-4-methoxyphenyl-l -boronic acid

Following the procedure of Example 1(c), except substituting 3-cyclopropylmetho 4-methoxyphenyl bromide for 3-cyclopentyloxy-4-methoxyphenyl bromide, and purifying chromatography (silica gel, 2-5% methanol/methylene chloride) gave the tided compound white solid (1.74 g, 50%). mp 205-206 °C.

12(c) S'-cyclopropylmethoxy^'-methoxytl.πbiphenyl-S-carboxylic acid

Following the procedure of Example 1(d), except utilizing a 50:50 solution of wateπethylene glycol dimethyl ether, substituting 3-cyclopropylmethoxy-4-methoxyphenyl 1 -boronic acid for 3-cyclopentyloxy-4-methoxyphenyl-l -boronic acid, substituting ethyl ether for ethyl acetate as the extraction solvent and crystallizing from ethyl ether and dryin following chromatography gave the tided compound as white crystals (0.131 g, 72%). m 147-148 °C; Anal. (Cι ₈ Hι ₈ O ) calcd: C 72.47, H 6.08; found: C 72.18, H 6.12.

Example Preparation of 3'-cvclonropvlme_hoxv-4'-methoxvn .TlhiphRnvl-3-carhoxami e Following the procedure of Example 3, except substituting 3'-cyclopropylmethoxy

4'-methoxy[l,l ^f ]biphenyl-3-carboxylic acid for 3'-cyclopentyloxy-4'-methoxy[l,l']biphenyl 3-carboxylic acid, purifying the dried, and stripped residue by chromatography (silica gel, 5% methanol / toluene) and crystallizing from ethyl ether gave the tided compound as a

white powder (0.046 g, 60%). mp 148-150 °C; Anal. (Ci ₈ Hi NO3) calcd: C 72.71, H 6.44, N 4.71; found: C 72.54, H 6.43, N 4.49.

Example 14 Preparation of 3'-cvc_opropvlme_hoxv-4'-methoxvπ .11biphenvl-3-c_uτ)onitrile To a stirred mixture of 3 ^, -cyclc*propylmemoxy-4'--_-_ethoxyphenyl- 1-boronic acid

(0.20 g, 0.90 mmol), 3-broπ-θbenzonitrile (0.149 g, 0.82 mmol), and tetrakis- triphenylphosphinyl palladium (0.047 g, 0.041 mmol) in dimethylformamide (6 mL) under argon was added triethylamine (0.354 mL, 2.54 mmol). The reaction mixture was purged with argon bubbling, heated at 90-100 °C for 7 h and then partitioned between methylene chloride and dilute aqueous hydrochloric acid. The organic phase was washed with water, dilute aqueous sodium carbonate solution, water, saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 60-80% methylene chloride/hexanes), recrystallized from methanol and dried in vacuo to afford the tided compound as white crystals (0.067 g, 29%). mp 101-102 °C; Anal. (CigHπNC^) calcd: C 77.40, H 6.13, N 5.01; found: C 77.30, H 6.11, N 4.96.

Example 15 Preparation of 3'-cvclopτσpvlmethoxv-4'-methoxv.1.11hiphenvl-3-acetonitri le Following the procedure of Example 14, except substituting 3- bromophenylacetonitrile (Aldrich Chemical Company, Inc.) for 3-bromobenzonitrile, chromatographing (silica gel, 80-100% methylene chloride/hexanes) and recrystallizing from ethyl ether gave the tided compound as a white powder (0.041 g, 25%). mp 75-76 °C; Anal. (Cι^^NC- ^• 1/10 H ₂ O) calcd: C 77.32, H 6.56, N 4.75; found (measured twice): C 77.34, 77.38, H 6.47, 6.52, N 4.65, 4.58.

Example 16 Preparation of 3'-cvclopropvlmethoxv-4'-methoxv.1.1 'lhiphenvl-2-acetonitrile

Following the procedure of Example 14, except substituting 2- bromophenylacetonitrile (Aldrich Chemical Company, Inc.) for 3-bromobenzonitrile, and evaporating the solvent in vacuo from the fractions collected from the chromatography, rather than recrystallizing from methanol, gave the tided compound as a resin (0.054 g, 33%). Anal. (Ci ₉ Hi ₉ NO2 ^• 1/10 H ₂ O) calcd: C 77.32, H 6.56, N 4.75; found: C 77.36, H 6.59, N 4.51. MS (CI/NH3) mle 311 [M+NH3] ⁺ , 294 [M+H] ⁺ .

Example 17 Preparation of methyl 3 '-cyclopropylmethoxy-4'-methox vf 1.11 biphenyl- 3-carboxylate Following the procedure of Example 14, except substituting methyl 3-iodobenzoate for 3-bromobenzonitrile, and following a first chromatography (silica gel, 40-60% methylene chloride / hexanes) with a second chromatography in which the impure tided compound was preabsorbed onto silica gel (silica gel, 15-20% ethyl acetate / hexanes), and

recrystallizing from ethyl ether gave the tided compound as a white powder (0.057 g, 32%). mp 71-72.5 °C; Anal. (C1QH20O4) calcd: C 73.06, H 6.45; found: C 73.02, H 6.54.

Example 18 Preparation of 3'-cvclopropvlmethoxv-4-hvdroxv-4'-methoxvri .1 Ibiphenvl

Following the procedure of Example 12(c), except substituting 4-iodophenol (Aldrich Chemical Company, Inc.) for 3-iodobenzoic acid, chromatographing (silica gel, 1% methanol methylene chloride) and crystallizing from ethyl ether gave the tided compound as white crystals (0.083 g, 63%). mp 117.5-118.5 °C; Anal. (CπHιgθ3) calcd: C 75.53, H 6.71; found: C 75.45, H 6.76.

Example 1 Preparation of 3'-cvclopropvlmethoxv-4-hvdroxv-4'-methoxvπ .nhinhenvl-3- carboxaldehvde Following the procedure of Example 18, except substituting 5- bromo-2-hydroxybenzaldehyde (Aldrich Chemical Company, Inc.) for 4-iodophenol, chromatographing twice (silica, 50 to 80% methylene chloride:hexane; silica, 0 to 1% methanol:toluene) and crystallizing from methylene chlσride:ethyl ether gave the tided compound as a white crystals (0.047 g, 32%). mp 85-86 °C; Anal. (Ci ₈ Hi ₈ O4) calcd: C 72.47, H 6.08; found: C 72.27, H 6.03.

Example 20 Preparation of methvl 3'-cvclopropvlmethoxv-4'-methoxvπ .11biphenvl-4-caτboxvlate

To a stirred solution of 3'-cyclopropylmethoxy-4'-me_hoxyphenyl-l-boronic acid (0.81 g, 3.65 mmol) dissolved in aqueous (13.6 mL) sodium bicarbonate (0.605 g, 7.20 mmol), under an argon atmosphere ,was added tetrakis-triphenylphosphinyl palladium (0.126 g, 0.109 mmol) and a solution of methyl 4-bromobenzoate (0.774 g, 3.60 mmol) in toluene (8 mL). The suspension was heated at 70 °C for 22 h, cooled and partitioned between methylene chloride and a solution of 5% sodium carbonate also containing concentrated ammonium hydroxide. The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 1:1:8 ethyl acetate:toluene:hexanes) to afford the tided compound as a white solid (0.210 g, 17%). mp 138 °C; Anal. (Cι ₉ H2θθ4 ^• 1/8 H2O) calcd: C 72.54, H 6.49; found: C 72.77, H 6.45.

Example 21 Preparation of 3'-cvclopropvlmethoxv-4'-methoxvπ.Tlbiphenvl-4-carboxvlic acid To a stirred suspension of 3'-cyclopropylmethoxy-4'-methoxy[l,llbiphenyl-4- carboxylic acid methyl ester (0.150 g, 0.48 mmol) in methanol (4.8 mL) was added a solution of potassium hydroxide (0.081 g, 1.44 mmol) in water (2.8 mL) and tetrahydrofiiran (0.5 mL). After 6 days, sufficient tetrahydrofuran was added to give a homogeneous reaction mixture. After stirring another 2 days, the reaction was poured into

aqueous dilute hydrochloric acid, extracted (4 times) with chloroform containing a trace of methanol, dried over magnesium sulfate and concentrated in vacuo. Trituration with methylene chloride/ethyl ether afforded die tided compound as a solid (0.10 g, 70%). mp 212 °C; Anal. (Cι ₈ Hι ₈ O • 1/4 H ₂ O) calcd: C 71.39, H 6.16; found: C 71.60, H 6.04. Example 22

Preparation of 3'-cvclopropvlmethoxv-4'-methoxvπ .llbiphenvl-4-caτhoxamide Following the procedure of Example 3, except substituting 3'-cyclopropylmethoxy- 4'-methoxy[l,l']biphenyl-4-carboxylic acid for S'-cyclopentyloxy-^'-methoxyfl.llbiphenyl- 3-carboxylic acid, and triturating from methylene chloride/ethyl ether gave the tided compound as a white solid (0.040 g, 79%). mp 200-201 °C; Anal. (CigHi NO3 • 1/2 H ₂ O) calcd: C 70.57, H 6.58, N 4.57; found: C 70.46, H 6.19, N 4.45.

Example 23

Prep__ration of 5-f3 ^, -cvclopentvloxv-4'-methoxvri.l1biphenvl-3-vn-3-methvir i.2.41oxadiaz A solution of 3'-cyclor_«ntyloxy-4 ^? -methoxy[l,l ^, ]biphenyl-3-c_-rt>oxamide (0.171 g, 0.55 mmol) prepared as described in Example 3 in dimethylacetamide dimethyl acetal (1.7 mL, 10.5 mmol) was heated at 100 °C in a sealed tube for 1 h. The resulting mixture was concentrated in vacuo . The residue was dissolved in dioxane (2.0 mL), treated with hydroxylamine hydrochloride (0.54 mg, 0.77 mmol), acetic acid (2.0 mL), 2 M aqueous sodium hydroxide (0.475 mL, 0.95 mmol) and heated at 90 °C in a sealed tube for 2 h. The reaction mixture was cooled, poured into cold water, made alkaline with aqueous sodium carbonate, and extracted four times with ethyl acetate. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with ethyl ether and recrystallized twice from methanol to give the tided compound as a white solid (0.131 g, 68% ). mp 101.5-102.5 °C; Anal. (C21H22N2O3) calcd: C 71.98, H 6.33, N 7.99; found: C 71.80, H 6.26, N 7.92.

Example 24

Preparation of 3-f3'-cvclopentvloxv-4'-methoxvri ■11biphenvl-3-vlV5-methviπ .2.41oxadiaz 24(a) 3-bromo-N-hydroxybenzamidine To a stirred mixture of 3-bromobenzonitrile (0.80 g, 4.4 mmol), hydroxyl__mine hydrochloride (0.458 g, 6.59 mmol) and pulverized potassium hydroxide (0.37 g, 6.60 mmol) in a pyrex tube under an argon atmosphere was added absolute ethanol (12 mL) and the suspension was sealed and heated at 75 °C for 14 h. After cooling, the reaction mixture was concentrated in vacuo and the residue partitioned between methylene chloride and water containing dilute sodium carbonate. The organic phase was washed with saturated brine, dried over sodium sulfate, stripped in vacuo to afford white crystals (0.72g, 77%). mp 117-124 ^© C. 24(b) 3-(3-bromophenyl)-5-methyl[ 1 ,2,4]oxadiazole

A solution of 3-bromo-N-hydiOxybenzamidine (0.71 g, 3.3 mmol) in dimethylacetamide dimethyl acetal (10 mL of 90% solution in methanol) was heated at 100 °C for 1 h and stripped in vacuo. The residue, preabsorbed onto silica (5 mL), was purified by chromatography (silica gel, 2.5% ethyl acetate/hexanes) and concentrated in vacuo to afford white crystals (0.65 g, 82%). mp 80-81 °C.

24(c) 3-(3'-cyclopentyloxy-4 ^, -methoxy[l,l']biphenyl-3-yl)-5-methyl[l^,4]oxadiazole

A solution of palladium acetate (0.013 g, 0.059 mmol) and bis(diphenylphosphin6)butane (0.028 g, 0.065 mmol) in ethylene glycol dimethylether (7 mL) was heated for 1 min at 60 °C with argon bubbling, cooled, and treated with a powdered mixture of 3-cyclopentyloxy-4-methoxyphenylboronic acid (0.20 g, 0.847 mmol), 3-(3-bromophenyl)-5-methyl[l,2,4]oxadiazole (0.188 g, 0.788 mmol) and sodium bicarbonate (0.213 g, 2.54 mmol) followed by addition of water (0.27 mL) and repurged with argon bubbling. This mixture was sealed in a pressure tube and heated for 7 h at 100 °C. The reaction mixture was cooled, concentrated in vacuo, the residue partitioned in methylene chloride vs water, the organic phase washed with saturated brine and dried over anhydrous potassium carbonate. The mixture was deposited onto silica gel and purified by chromatography (silica gel, 10% ethyl acetate/hexanes), crystallized from ethyl ether and dried in vacuo to afford a white powder (0.172 g, 62%). mp 67-70 °C; Anal. (C21H22N2O3) calcd: C 71.98, H 6.33, N 7.99; found: C 72.04, H 6.47, N 7.73.

Example 25 Preparation of 5-f3'-cvclopentvloxv-4'-methoxvπ .1 hiphenvl-3-vlV l-methvl-lH-tetrazol 25(a) 3-bromo-N-methylbenzamide

To an-ice cold stirred suspension of 40% aqueous methylamine (4 mL) and methyle chloride (4 mL, 52 mmol) was added dropwise 3-bromobenzoyl chloride (0.50 mL, 3.79 mmol). After 10 min, the suspension was partitioned between cold water and methylene chloride and the combined organic layers were washed successively with water, dilute aque acetic acid, dilute aqueous sodium carbonate, water and saturated brine. The solvent was removed in vacuo to afford a white solid (0.726 g, 90%). mp 91-92 °C. 25(b) 5-(3-bromophenyl)-l-me_hyl-lH-tetrazole

A solution of 3-bromo-N-methylbenzamide (0.305 g, 1.42 mmol) in thionyl chloride (1.2 mL, 16.4 mmol) was refluxed for 40 min under argon and the excess thionyl chloride removed in vacuo. A solution of the residue dissolved in dimethyl formamide (3 mL) was added dropwise to a stirred suspension of sodium azide (0.277 g, 4.3 mmol) in dimethyl formamide at 0 °C and the mixture was maintained at this temperature for 16 h. The reaction mixture was poured into ice- water, made alkaline with 5% aqueous sodium carbonate and extracted (3 times) with ethyl acetate. The combined organic layer was washed with water (3 times), saturated brine, dried over

sodium sulfate (anhydrous) and stripped in vacuo to afford a white crystalline solid (0.323 g, 95%). mp 107-108 ^© C.

25(c) 5-(3 ^, -cyclopentyloxy-4'-methoxy[ 1 , 1 ^* ]biphenyl-3-yl)- 1-methyl- lH-tetrazole Following the procedure of Example 24(c), except substituting 5-(3- bromophenyl)-l-methyl-lH-tctr__zole for 3-(3-bromophenyl)-5-methyl[l^,4]oxadiazole and eluting with ethyl acetate hloroform (2:98) gave the tided compound as white crystals (0.188 g, 57%). mp 120-121 °C; Anal. (C20H21N4O2 • 4/10 H2O) calcd: C 67.17, H 6.43, N 15.67; found: C 67.18, H 6.32, N 15.60

Example 26 Preparation of 5-(3'-cvclopentv_oxv-4'-methoxvr 1.11h.phenvl-3-vπ-2-methvl-2H-tetrazole

26(a) 5-(3-bromophenyl)-lH-tetπ_zole

A mixture of 3-bromo-benzonitrile (0.546 g, 3.00 mmol), dry toluene (6 mL), azidotrimethylsilane (0.796 mL, 6.00 mmol), and dibutyltin oxide (0.0136 g, 0.055 mmol) was stirred at 90 °C for four days in a sealed tube. The reaction mixture was cooled and then concentrated in vacuo and treated twice with methanol, followed each time by reconcentration. The residue was partitioned between ethyl acetate and sodium carbonate solution (5%). The organic phase was extracted with an additional portion of sodium carbonate solution, and the combined aqueous phase was acidified with 6N HC1 and extracted with ethyl acetate. The organic extract was dried (sodium sulfate) and concentrated in vacuo to afford the tided compound as a pale yellow solid (0.597 g, 88%). mp 150-151 °C. 26(b) 5-(3-bromophenyl)-2-methyl-2H-tetrazole

A stirred solution of 5-(3-bromophenyl)-lH-tetrazole (0.4 g, 1.78 mmol) in acetone (3.2 mL) was treated with pulverized potassium hydroxide (0.15 g, 2.67 mmol), water (0.72 mL), and iodomethane (0.166 mL, 2.67 mmol), sealed under argon and stirred for 72 h at ambient temperature. The reaction mixture was poured into ice- water, extracted with methylene chloride (three times), and the combined organic phase washed with water, dried (sodium sulfate) and concentrated in vacuo. The residue, a mixture of 5-(3-bromophenyl)-l- methyl-2H-tetrazole and 5-(3-bromophenyl)-2-methyl-2H-tetrazole, was purified by chromatography (silica gel, 50% methylene chloride/hexanes), eluting the tided compound as the faster isomer, a white solid (0.327 g, 77%). mp 93-94.5 °C. 26(c) 5-(3'-cyclopentyloxy-4'methoxy[ 1 , 1 "]biphenyl-3-yl)-2-methyl-2H- tetrazole

Following the procedure of Example 25(c), except substituting 5-(3- bromophenyl)-2-methyl-2H-tetrazole for 3-(3-bromophenyl)-5-methyl[ l,2,4]oxadiazole and sodium carbonate for sodium bicarbonate, heating the mixture for 16 h at 85 °C followed by 4 h at 90 °C, washing the organic extract with 5% aqueous sodium carbonate solution, water and saturated brine, and purifying by chromatography (silica gel, 100:0 to 98:2 methylene chloride:ethyl acetate) afforded the tided compound as a

white powder (0.158 g, 67%). mp 105-106 °C; Anal. (C20H22N4O2) calcd: C 68.55, H 6.33, N 15.99; found: C 68.39, H 6.41, N 15.94.

Example 27

Preparation of 2-r3'-cvclopentvloxv-4'-methoxvn.l1biphenvl-3-vlV5-methviπ .3.41oxadia7 le 27(a) 3-bromobenzoyl-N'-acetyl hydrazine

A stirred mixture of 3-bromobenzoyl hydrazine (2.0 g, 9.3 mmol) in absolute ethanol (20 mL) was treated with triethylamine (2.0 mL, 14.3 mmol) followed by acetic anhydride (1.35 mL, 14.0 mmol) and the resulting solution was refluxed for 2 h. The mixture was allowed to cool, and then water was added to the cooled solution resulting in the precipitation of a white solid. The white solid was isolated by filtration, then washed with water and dried in vacuo to afford the tided compound as a mixture of rotational isomers (2.3 g, 96%). mp 151-170 °C. 27(b) 2-(3-bromophenyl)-5-methyl[l,3,4]oxadiazole

A stirred mixture of 3-bromobenzoyl-N'-acetyl hydrazine (0.5 g, 1.94 mmol), phosphorus oxychloride (2.0 mL, 21.4 mmol), and toluene (15 mL) was refluxed for 1.5 h under an argon atmosphere. The cooled mixture was partitioned between chloroform and water, and d e organic phase was washed with aqueous 5% sodium carbonate solution (twice), and water, then dried over sodium sulfate. After filtering, the organic phase was concentrated in vacuo, and the residue purified by chromatography (silica, 2 to 5% ethyl acetate/methylene chloride) to afford the tided compound as cream colored crystals (0.35 g, 76%). mp 76-77.5 °C. 27(c) 2-(3'-cyclopentyloxy-4 ^, -methoxy[l,l ^r ]biphenyl-3-yl)-5-methyl[l,3,4]oxadia--θle

Following the procedure of Example 24(c), except substituting 2-(3-bromophenyl)- 5-methyl[l,3,4]oxadiazole for 3-(3-bromophenyl)-5-methyl[l,2,4]oxadiazole, heating the mixture for 10 h at 100 °C, washing the organic extract with 5% aqueous sodium carbonate solution, drying over sodium sulfate, purifying by chromatography (silica gel, 35 to 40% ethyl acetate hexanes), and crystallizing from ethyl ether gave the tided compound as a white solid containing traces of solvents (mp 111.5-113 °C) which was melted in vacuo to afford a cream colored glass (0.127 g, 53%). Anal. (C21H22 2O3 • 1/8 H2O) calcd: C 71.52, H 6.36, N 7.94; found (measured twice): C 71.55, 71.51, H 6.31, 6.28, N 7.86, 7.78; MS: (CI, NH3) [M+NH4]+ 368.2, [M+H]+ 351.2, [M+H-CH3CN]+ 311.2.

Example 28 Preparation of 2-f3'-cvclopentvloxv-4'-methoxvri.l1biphenvl-3-vlV5-methviri .3.41thiadiazole 28(a) 2-(3-bromophenyl)-5-methyl[ 1 ,3,4]thiadiazole A stirred mixture of 3-bromobenzoyl-N'-acetyl hydrazine (0.5 g, 1.94 mmol), prepared as described in Example 28(a) above, toluene (19 mL) and Lawessons's reagent (1.0 g, 2.47 mmol) was refluxed for 1.5 h under an argon atmosphere. The cooled mixture was diluted with chloroform (10 mL), basified with a 5% sodium carbonate solution, and

the organic phase washed with water dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 2 to 3% ethyl acetate/methylene chloride) to afford the tided compound as a white solid (0.349 g, 70%). mp 63-64.5 °C. 28(b) 2-(3 ^, -cyclopentyloxy-4'-methoxy [ 1 , 1 ^* ]biphenyl-3-yl)-5-methyl[ 1 ,3,4] thiadiazole Following the procedure of Example 24(c), except substituting 2-(3-bromophenyl)-

5-methyl[l,3,4]thiadiazole for 3-(3-bromophenyl)-5-methyl[l,2,4]oxadiazole and sodium carbonate for sodium bicarbonate, heating the mixture for 12 h at 100 °C, filtering an ethyl acetate solution of d e reaction mixture through Celite, purifying the residue by chromatography (silica gel, 30 to 40% ethyl acetate/hexanes), and crystallizing from ethyl ether gave the tided compound as a white solid (0.127 g, 50%). mp 109.5-110.5 °C; Anal. (C21H22N2O2S) calcd: C 68.82, H 6.05, N 7.64; found: C 68.80, H 6.05, N 7.56.

Example 29

Preparation of 5-(3'-cvclopentvloxv-4'-methoxvπ .Tlhiphenvl-3-vn-3- ci yiπ .2.41 hia iazplc 29(a) 3-bromothiobenzamide

A solution of 3-bromobenzonitrile (1.02 g, 5.5 mmol), methanol (50 mL) and 24% aqueous ammonium sulfide (30 mL) was heated at 65-70 °C in a sealed pressure vessel for 1 h, then was purged widi argon. After diluting with cold water, the mixture was extracted three times with dichloromethane, the combined extracts were washed twice with water, were dried (MgSO4), were filtered and were concentrated to afford the tide intermediate as a pale yellow solid (1.06 g, 89 %). mp 116-117 °C. 29(b) 5-(3-bromophenyl)-3-methyl[ 1 ,2,4]thiadiazole

A solution of 3-bromothiobenzamide (0.94 g, 4.37 mmol) in dimethylacetamide dimethylacetal (15 mL) was stirred for 1 h at room temperature under an argon atmosphere, then was evaporated and was redissolved in ethanol (10 mL). After rapid addition of pyridine (0.72 mL) and a solution of hydroxylamine-O-sulfonic acid (0.54 g, 4.81 mmol) in methanol (6.5 mL), the solution was stiired at room temperature for 3 h, was partially concentrated, was diluted with water and was extracted twice with dichloromethane. The combined extracts were washed with 0.3 ϋ sodium hydroxide and water, dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography, eluting with 5:95 ethyl acetate:hexanes, to afford the tide intermediate as a very viscous, pale orange oil (0.70 g, 63%). Also isolated was slighdy impure intermediate (0.25 g, 22%). -1H NMR (400 MHz, CDCI3) δ 8.13 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 2.74 (s, 3H). 29(c) 5-(3'-cyclopentyloxy-4'-methoxy [ 1 , 1 ']biphenyl-3-yl)-3-methyl[ 1 ,2,4] thiadiazole A solution of palladium acetate (0.02 g, 0.09 mmol) and bis(l,4- diphenylphosphino)butane (0.42 g, 0.10 mmol) in deoxygenated dimethoxyethane was heated at 45-50 °C for 1 min, then was cooled. After rapid addition of a solution of 5-

(3-__romophenyl)-3-methyl[l,2,4]thiadiazole (0.38 g, 1.5 mmol) in dimethoxyethane (3 mL), a solid mixture of 3-cyclopentyloxy-4-methoxyphenylboronic acid (0.39 g, 1.65 mmol) and sodium bicarbonate (0.42 g, 5.0 mmol), and water (2.5 mL) the vessel was sealed and was heated at 85-90 °C for 4 h, then the mixture was cooled, was diluted with 10% hydrochloric acid, was extracted three times with ether, was dried (MgSO4), was filtered and was concentrated. The crude product was purified by two successive flash chromatographies, eluting with 5:95 and with 1:9 ethyl acetate:hexanes to afford the tide product as a gummy solid (0.33 g, 59%). Trituration with etheπhexanes provided a white solid, mp 83-84 °C. Anal. (C21H22NO2S ) calcd: C, 68.82; H, 6.05; N, 7.64; found: C, 68.58; H, 6.07; N, 7.55.

Example 30

Preparation of 5-f4-cyano-3'-gyclp ^p eπtyloχy-4'-me_ gχy[ 1.1 'l >iphenyl-3-yl)-3- me-hyiri_2.4]Qxa_liazple. Route A 30(a) methyl 2-(2-methoxyethoxymethyl)-5-bromobenzoate A solution of methyl 2-hydroxy-5-bromobenzoate (2.6 g, 11.3 mmol) in tetrahydrofiiran (10 mL) was added dropwise over 15 min to a suspension of 80% sodium hydride in mineral oil (0.38 g, 12.4 mmol) suspended in tetrahydrofiiran (40 mL) at 0 °C under an argon atmosphere and was stirred for 30 min. 2-Methoxyethoxymethyl chloride (1.55 mL, 13.6 mmol) was added over 5 min and the reaction was stirred at room temperature for 6 h, quenched widi ammonium chloride, was extracted three times with dichloromethane, was dried (MgSO4), was filtered and was concentrated. The crude mixture was purified by flash chromatography, eluting with 3:7 ethyl acetate:hexanes to afford the tide intermediate as a colorless liquid (2.46 g, 68%). *H NMR (400 MHz, CDCI3) δ 7.89 (d, J=2.7 Hz, 1H), 7.53 (dd, J=8.8, 2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 5.32 (s, 2H), 3.88 (s, 3H), 3.86 (m, 2H), 3.55 (m, 2H), 3.36 (s, 3H). 30 ) 2-(2--___ethoxyethoxymeΛyl)-5-broπ_oben__amide

A mixture of methyl 2-(2-methoxyethoxymethyl)-5-bromobenzoate (0.96 g, 3 mmol) and several crystals of sodium cyanide (catalytic) in liquid ammonia (-3 mL) was heated in a sealed pressure vessel at 45-50 °C for 48 h, cooled, concentrated, diluted with an aqueous solution of potassium carbonate, extracted with 5:95 methanol:dichloromethane, dried (MgSO4), filtered, and concentrated to provide the tide intermediate as a colorless oil (0.83 g, 91%). 1H NMR (400 MHz, CDCI3) δ 8.30 (d, J=2.6 Hz, 1H), 7.65 (br, 1H), 7.54 (dd, J=8.8, 2.6 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.70 (br, 1H), 5.42 (s, 2H), 3.86 (m, 2H), 3.50 (m, 2H), 3.37 (s, 3H). 30(c) 5-(l-(2-memoxyethoxymethyl)-4-bromophenyl-2-yl)-3-methyl[l,2 ,4]oxadiazole

2-(2-methoxyethoxymethyl)-5-bromobenzamide (0.83 g, 2.72 mmol) was dissolved in dimethylacetamide dimethylacetal (4 mL), stirred at 100 °C for 1 h, then concentrated. A solution of this residue in 1,4-dioxane (5 mL) and acetic acid (5 mL) was treated with

hydroxylamine hydrochloride (0.29 g, 4.2 mmol) and a solution of sodium hydroxide (0.18 g, 4.5 mmol) in water (1 mL), stirred at 90-95 °C for 1 h, cooled, diluted with water, extracted tiiree times with dichloromethane, dried (MgSO4), filtered, and concentrated. The crude mixture was purified by flash chromatography, eluting with 3:7 ethyl acetate:hexanes to afford the tide intermediate (0.75 g, 80%), as a white solid, mp 80-81 °C. 30(d) 5-(l-hydroxy-4-bromophenyl-2-yl)-3-methyl[l^,4]oxadiazole

A solution of 5-( 1 -(2-me_hoxyethoxymethyl)-4-bromophenyl-2-yl)-3- methyl[l,2,4]oxadiazole (0.72 g, 1.4 mmol) and trifluoromethanesulfonic acid (1.5 mL, 16.9 mmol) in dichloromethane (10 mL) was stirred at room temperature under an argon atmosphere for 8 h, quenched with aqueous sodium bicarbonate solution, extracted twice with dichloromethane, dried (MgSO4), filtered, and concentrated. The crude mixture was combined with a previous run (0.94 g) and purified by flash chromatography, eluting with 5:95 ethyl acetate exanes to afford the tide intermediate as a white solid (0.47 g, 100%). mp 83-84 °C.

30(e) 5-(3'-cyclopentyloxy-4'-methoxy-4-hydroxy [ 1 , 1 ^* ]biphenyl-3-yl)-3- methyl[l,2,4]oxadiazole

Following the procedure of Example 29(c), except substituting 5-(l-hydroxy-4- _jromophenyl-2-yl)-3-methyl[l,2,4]oxadiazole for 5-(3-bromophenyl)-3- methyl[ 1,2,4] thiadiazole the tide intermediate was prepared as a pale yellow gum (0.21 g, 32%). !H NMR (400 MHz, CDCI3) δ 10.45 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.16 (dd, J=8.4, 2.1 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.11 (dd, J=8.1, 1.8 Hz, 2H), 6.95 (d, J=8.1 Hz, 1H), 4.88 (m, 1H), 3.90 (s, 3H), 2.52 (s, 3H), 1.8-2.0 (m, 6H), 1.6-1.7 (m, 2H). 30(f) S-fS'-cyclopentyloxy^'-methoxy^-trifluoromethylsulfonator 1 , 1 ^" ]biphenyl-3-yl)-3- methyl[ 1 ,2,4]oxadia__ole

Following the procedure of Example 8(c), except substituting 5-(3'-cyclopentyloxy- 4'-methoxy-4-hydroxy[l,llbiphenyl-3-yl)-3-methyl[l^,4]oxadia zole for methyl 3'- cyclopentyloxy^'-methoxy-^hydroxytLllbiphenyl-S-carboxylate the tide intermediate was prepared as a colorless oil (0.18 g, 65%). *H NMR (400 MHz, CDCI3) d 8.33 (d, J=2.4 Hz, 1H), 7.79 (dd, J=8.6, 2.4 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.16 (dd, J=8.4, 2.1 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 4.88 (m, 1H), 3.90 (s, 3H), 2.50 (s, 3H), 1.8-2.0 (m, 6H), 1.6-1.7 (m, 2H). 30(g) 5-(3'-cyclopentyloxy-4'-methoxy-4-cyano[ 1 , 1 lbiphenyl-3-yl)-3- methyl[l,2,4]oxadiazole

Following the procedure of Example 8(d), except substituting 5-(3'-cyclopentyloxy- 4'-methoxy-4-trifluσromethylsulfonato[ 1 , 1 ^* ]biphenyl-3-yl)-3-methyl[ 1 ,2,4]oxadiazole for

methyl 3'-cyclopen_yloxy-4'-methoxy-4-trifluoromethylsulfonato[l, ]biphenyl-3- carboxylate the tide product was prepared as a white solid (0.013 g, 13%). mp 130-132 °C.

Example 31 Preparation of 5-f4-cvano-3'-cvclopentvloxv-4'-methoxvri.l1hiphenvl-3-vn-3- methvl. L2.41oxadiazole. Route B 31(a) 5-bro____o-2-c_-_i>omeώoxy_>en_amide

A solution of 4-bromophthalic acid (5 g, 20.5 mmol), sulfuric acid (5 mL), and methanol (100 mL) was refluxed for 24 h, cooled, neutralized with sodium bicarbonate, concentrated, diluted with dichloromethane, and extracted three times with 10% sodium hydroxide. The aqueous phase was acidified, extracted with 1:9 methanol:dichloromethane, dried (MgSO4), filtered, and concentrated to provide a 1:1 mixture of acids. A solution of tiiis mixture (4.36 g, 17.4 mmol) and N-methylmorpholine (2.1 mL, 19.2 mmol) in dimethoxyethane (70 mL) was treated dropwise with isobutylchloroformate (2.40 mL, 18.3 mmol), stirred 7 min, then treated with concentrated ammonium hydroxide (5 mL) and stirred for 1.5 h. The mixture was acidified, extracted three times with 1:9 methanol:dichloromethane, dried (MgSO4), filtered, and concentrated. The crude mixture was purified by flash chromatography, eluting with 7:3 ethyl acetate:hexanes to afford the tide intermediate as a white solid (0.90 g, 17%). mp 126-128 °C. 31(b) 5-(5-bromo-2-carbomethoxyphenyl)-3-methyl[l^,4]oxadiazole

Following the procedure of Example 8c, except substituting 2-carbomethoxy-5- bromobenzamide for 2-(2-____et__κ)xyethoxymethyl)-5-bromobenzamide the tide intermediate was prepared as a colorless oil (0.08 g, 27%). *H NMR (400 MHz, CDCI3) δ 7.98 (s, 1H), 7.78 (s, 2H), 3.85 (s, 3H), 2.50 (s, 3H). 31 (c) 5-(2-carboxamido-5-bromophenyl)-3-methyl[ 1 ,2,4]oxadiazole

A solution of 5-(2-carbomethoxy-5-bromophenyl)-3-methyl[l,2,4]oxadiazole (0.076 g, 0.25 mmol) and potassium hydroxide (0.016 g, 0.28 mmol) in tetrahydrofuran (1.25 mL), methanol (1.25 mL), and water (0.5 mL) was stirred at room temperature for 24 h, acidified with 10% hydrochloric acid, extracted three times with 5:95 methanol:dichloromethane, dried (MgSO4), filtered, and concentrated. The residue and N- methylmorpholine (0.03 mL, 0.28 mmol) in dimethoxyethane (1.5 mL) at room temperature under an argon atmosphere was treated dropwise with isobutylchloroformate (0.034 mL, 0.26 mmol), stirred 5 min, then treated with concentrated ammonium hydroxide (3 drops) and stirred for 1 h. The mixture was diluted with water, extracted three times with 5:95 methano dichloromethane, dried (MgSO4), filtered, and concentrated to afford the tide intermediate as a white solid (0.056 g, 79%). mp 195-198 °C. 31 (d) 5-(2-cyano-5-bromophenyl)-3-methyl[ 1 ,2,4]oxadiazole

A solution of 5-(2-ca_rboxamido-5-bromophenyl)-3-methyl[ 1 ,2,4]oxadiazole (0.05 g, 0.18 mmol), pyridine (0.032 mL, 0.39 mmol), and trifluoroacetic anhydride (0.03 mL, 0.20 mmol) in tetrahydrofiiran (2 mL) was stirred at room temperature under argon for 5 h. Pyridine (0.032 mL, 0.039 mmol) and trifluoroacetic anhydride (0.03 mL, 0.20 mmol) was added, and stirring continued for 1 h. The mixture was diluted with ether, washed twice with 10% hydrochloric acid, water, and brine, dried (MgSO4), filtered, and concentrated to afford die tide intermediate as an oil (0.046 g, 96%). -1H NMR (400 MHz, CDCI3) d 8.40 (s, 1H), 7.84 (d, J=8.2Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 2.54 (s, 3H). 31 (e) 5-(3'-cyclopentyloxy-4'-methoxy-4-cyano[ 1 , 1 ^" Jbiphenyl-S-yl)^- ____ethyl[l,2,4]ox__diazole

Following the procedure of Example 29(c), except substituting 5-(2-cyano-5- bromophenyl)-3-methyl[ 1 ,2,4]oxadiazole for 5-(3-bromophenyl)-3-methyl[ 1 ,2,4]thiadiazole the tide product was prepared (0.038 g, 68%), then further triturated from dichloromethane:hexanes to provide a white solid, mp 132-134 °C. Anal. (C22H21 3O3 ^• 0.25 H2O) calcd: C, 69.55; H, 5.70; N, 11.06, found: C, 69.30; H, 5.58; N, 10.94.

Example 32 Preparation of 5-f3'-cvclopentvloxv-2.6-difluoro-4'-methoxvri .11biphenv1-3-vtt-3- methvl.1.2.4.oxariiazole 32(a) 5-(2,4-difluoro-3-iodophenyl-3-yl)-3-methyl[ 1 ,2,4]oxadiazole A solution of 2,4-difluoro-3-iodobenzoic acid (0.54 g, 1.9 mmol), and N- me ylmorpholine (0.23 mL, 2.1 mmol) in dimethoxyethane at room temperature under an argon atmosphere was treated dropwise with isobutylchloroformate (0.26 mL, 2.0 mmol). After 5 min cone, ammonium hydroxide (7 drops) was added and stirring continued for 1 h. The reaction was acidified with 10% hydrochloric acid, extracted three times with 5:95 methanohmethylene chloride, dried (MgSO4), and concentrated. The residue was dissolved in dimethylacetamide dimethylacetal (3 mL), stirred at 90-95 °C for 1 h, then concentrated. A solution of this residue in 1,4-dioxane (4 mL) and acetic acid (4 mL) was treated with hydroxylamine hydrochloride (0.18 g, 2.66 mmol) and a solution of sodium hydroxide (0.11 g, 2.85 mmol) in water (1 mL), stirred at 90-95 °C for 1 h, cooled, diluted witii water, extracted diree times with dichloromethane, dried (MgSO4), filtered, and concentrated. The crude mixture was purified by flash chromatography, eluting with 1:9 ethyl acetate:hexanes to afford d e tide intermediate as a white solid (0.22 g, 36%). mp 131-133 ^O Q 32(b) 5-(3'-cyclopentyloxy-4'-methoxy-2,6-difluoro[ 1 , 1 ]biphenyl-3-yl)-3- methyl[l,2,4]oxadiazole

Following the procedure of Example 29(c), except substituting 5-(2,4-difluoro-3- iodophenyl-3-yl)-3-methyl[l,2,4]oxadiazole for 5-(3-bromophenyl)-3- methyl[l,2,4]thiadiazole, the tide compound was prepared as a white solid, mp 101-102

°C. Anal. (C.2lH ₂ oF2 ^N 2θ3 ^• 0.375 H2O ) calcd: C, 64.15; H, 5.32; N, 7.13; found: C,

64.19; H, 5.26; N, 6.89.

METHODS OF TREATMENT

The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can be used as discussed above in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human or other mammal which is mediated by inhibition of PDE IV, such as, but not limited to, asthma, allergic, or inflammatory diseases. The compounds of Formula (I) are administered in an amount sufficient to treat such a disease in a human or other mammal. In order to use a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition using appropriate pharmaceutically acceptable excipients, such as carriers and diluents.

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

The daily dosage regimen for oral administration is suitably about 0.001 mg/kg to

100 mg/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 acid or base, whichever is appropriate. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity. Administration by inhalation is preferred for treatment of asthma conditions.

No unacceptable toxic effects are expected when these compounds are administered in accordance witii the present invention. Compounds of this invention were found to have useful activity as per the utility examples below.

TΠTLΓΓY EXAMPLES

The utility of these compounds can be determined using the assays described in prior published patent applications. For example see /PCT/US93/01991 published as WO93/19749. That application is incorporated herein by reference in so far as its disclosure is useful for preparing and running assays which prove the putative utility of these compounds.