RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application No. 61/078,311 entitled â€œHETEROALKYL ANTAGONISTS OF PROSTAGLANDIN D₂RECEPTORSâ€ filed on Jul. 3, 2008, which is incorporated by reference in its entirety.

FIELD OF TILE INVENTION

Described herein are compounds, methods of making such compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases or conditions associated with prostaglandin D₂.

BACKGROUND OF THE INVENTION

Prostaglandins have a diverse range of activities and have a well recognized role in pain and inflammation. Prostaglandin D₂(PGD₂) is produced by mast cells, macrophages and Th2 lymphocytes in response to local tissue damage as well as allergic inflammation in diseases such as asthma, rhinitis, and atopic dermatitis. PGD₂binds to a number of receptors, which include the thromboxane-type prostanoid (TP) receptor, PGD₂receptor (DP, also known as DP₁) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2; also known as DP₂).

SUMMARY OF THE INVENTION

Presented herein are compounds, pharmaceutical compositions, and methods, for (a) diagnosing, preventing, or treating allergic and non-allergic inflammation, (b) mitigating adverse signs and symptoms that are associated with inflammation, and/or (c) controlling immunological, proliferative disorders. These disorders may arise from one or more of a genetic, iatrogenic, immunological, infectious, oncological, toxic, surgical, and/or traumatic etiology. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of PGD₂receptors. In one aspect, the methods, compounds, pharmaceutical compositions, described herein comprise antagonists of DP₂.

In one aspect provided herein are compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, which are antagonists of DP₂, and are used to treat mammals suffering from one or more PGD₂-dependent conditions or diseases, including, but not limited to, asthma, rhinitis, allergic conjuctivitis, atopic dermatitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, wound healing, endotoxic shock, pain, inflammatory conditions, eosinophilic esophagitis, eosinophil-associated gastrointestinal disorders (EGID), idiopathic hypereosinophilic syndrome, otitis, airway constriction, mucus secretion, nasal congestion, increased microvascular permeability and recruitment of eosinophils, urticaria, sinusitis, angioedema, anaphylaxia, chronic cough and Churg Strauss syndrome.

In one aspect, provided is a compound having the structure of Formula (I), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

[Image Omitted]

- wherein,
- R^Ais H or C₁-C₆alkyl;
- R⁴is H, halogen, â€”CN, â€”OH, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy, C₁-C₄alkoxy, or C₁-C₄heteroalkyl;
- R⁶is â€”NR¹³S(â• O)₂R¹², â€”S(â• O)₂N(R¹²)(R¹³), â€”N(R¹²)(R¹³), â€”C(â• O)N(R¹²)(R¹³), â€”NHC(â• O)N(R¹²)(R¹³), â€”NR¹³C(â• O)R¹², or â€”NR¹³C(â• O)OR¹²;
- R¹¹is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted 5-membered heteroaryl, a substituted or unsubstituted 6-membered heteroaryl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl);
- R¹²is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆-fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted benzyl, a substituted or unsubstituted 6-membered heteroaryl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl);
- R¹³is H or C₁-C₄alkyl; or
- R¹²and R¹³attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl;
- x is 0, 1, or 2.

In one aspect, presented herein are the compounds of Formula (I) presented in Table 1, or pharmaceutically acceptable salts, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof.

Compounds of Formula (I) are antagonists of DP₂.

In one aspect, provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I). In some embodiments, the pharmaceutical compositions comprise at least one inactive pharmaceutically acceptable inactive ingredient selected from excipients, diluents, and carriers.

In certain embodiments, presented herein are methods for treating a PGD₂-dependent condition or disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I).

In another aspect, compounds of Formula (I) are used to treat or prevent inflammatory diseases or conditions. Inflammatory conditions include, but are not limited to, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, atherosclerosis, aortic aneurysm, myocardial infarction, and stroke.

In a specific aspect, provided herein is a method for treating asthma in a mammal comprising administering a therapeutically effective amount of a compound provided herein to the mammal in need.

In another aspect, compounds of Formula (I) are used to treat or prevent immunological disorders, including, but are not limited to, allergy or to excessive or inappropriate response to an endogenous or exogenous antigen. In certain embodiments, the immunological disorder that is characterized by immune dysregulation that is not accompanied by inflammation.

In additional aspects, such diseases or conditions are iatrogenic and increases in, or abnormal localization of, PGD₂is induced by other therapies or medical or surgical procedures. In other embodiments, the PGD₂-dependent or PGD₂mediated condition or disease is caused by surgery.

In another aspect are methods for treating respiratory diseases or conditions in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of Formula (I). In a further embodiment of this aspect, the respiratory disease is asthma. In a further embodiment of this aspect, the respiratory disease includes, but is not limited to, asthma, adult respiratory distress syndrome, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, neutrophillic asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.

In another aspect compounds described herein are used for treating rhinitis in a mammal. In a further embodiment of this aspect, compounds described herein are used for treating allergic (extrinsic) rhinitis, non-allergic (intrinsic) rhinitis, chronic rhinitis, allergen-induced rhinitis, aspirin-sensitive rhinitis, child-onset rhinitis, adult-onset rhinitis, occupational rhinitis, steroid-resistant rhinitis, seasonal rhinitis, perennial rhinitis, rhinosinusitis, and rhinopolyposis.

In another aspect are methods for treating chronic obstructive pulmonary disease comprising administering to the mammal at least once an effective amount of a compound of Formula (I). In a further embodiment of this aspect, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis and/or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.

In another aspect are methods for preventing increased mucosal secretion and/or edema in mammals comprising administering to the mammal at least once an effective amount of a compound of Formula (I).

In another aspect are methods for preventing eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte or Th2 cell recruitment comprising administering to the mammal an effective amount of a compound of Formula (I).

In another aspect are methods for treating or preventing ocular inflammation, conjunctivitis, retinitis, scleritis, uveitis, allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis comprising administering to the mammal at least once an effective amount of a compound of Formula (I).

In another aspect, compounds of Formula (I) are used to treat or prevent pain.

In another aspect are methods for preventing or treating acute or chronic disorders involving recruitment or activation of eosinophils comprising administering to the mammal at least once an effective amount of a compound of Formula (I).

In another aspect are methods for treating inflammatory responses of the skin comprising administering to the mammal at least once an effective amount of at least one compound of Formula (I). Such inflammatory responses of the skin include, by way of example, psoriasis, dermatitis, atopic dermatitis, contact dermatitis, eczema, urticaria, rosacea, bullous disorders, collagenoses, Kawasaki Disease, Sjogren-Larsso Syndrome, wound healing and scarring. In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering to the mammal an effective amount of a compound of Formula (I). In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering at least once to the mammal an effective amount of a compound of Formula (I).

In a further aspect are methods to modulate the immune response to endogenous or exogenous antigens. In a further aspect are methods to treat acute or chronic allergic responses to exogenous substances that have been ingested such as foods (e.g., peanuts) or drugs (e.g., penicillin, non-steroidal anti-inflammatory drugs or the like).

In another aspect is the use of a compound of Formula (I) in the manufacture of a medicament for treating an inflammatory disease or condition in a mammal in which the activity of at least one PGD₂-associated protein contributes to the pathology and/or symptoms of the disease or condition. In one embodiment of this aspect, the PGD₂pathway protein is DP2. In another or further embodiment of this aspect, the inflammatory disease or conditions are respiratory, cardiovascular, or proliferative diseases.

â€œCardiovascular disease or conditions,â€ refers to diseases affecting the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue.

In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound is systemically administered to the mammal; and/or (b) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound administered by inhalation; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (f) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically (dermal) to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal.

In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once daily; (ii) the compound is administered twice daily; (iii) the compound is administered in cycles that include daily administration for a period of time followed by at least 1 day without administration; (iv) the compound is administered in cycles that include daily administration for a period of time followed by at least 1 day that includes a dose reduction in the daily amount of compound that is administered.

In any of the aforementioned aspects involving the treatment of PGD₂dependent diseases or conditions are further embodiments comprising administering at least one additional agent in addition to the administration of a compound having the structure of Formula (I).

In any of the aforementioned aspects involving the prevention or treatment of inflammation are further embodiments comprising: (a) monitoring inflammation in a mammal; (b) measuring bronchoconstriction in a mammal; (c) measuring eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or lymphocyte recruitment in a mammal; (d) monitoring mucosal secretion in a mammal; (e) measuring mucosal edema in a mammal.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Illustrative examples of compounds described herein.

FIG. 2. Illustrative examples of compounds described herein.

FIG. 3. Illustrative examples of compounds described herein.

FIG. 4. Illustrative examples of compounds described herein.

FIG. 5. Illustrative examples of compounds described herein.

FIG. 6. Illustrative examples of compounds described herein.

FIG. 7. Illustrative examples of compounds described herein.

FIG. 8. Illustrative examples of compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION

Prostaglandin D₂(PGD₂) is an acidic lipid derived from the metabolism of arachidonic acid by cyclooxygenases and PGD₂synthases. PGD₂is produced by mast cells, macrophages and Th2 lymphocytes in response to local tissue damage as well as in response allergic inflammation observed in diseases such as asthma, rhinitis, and atopic dermatitis. Exogenous PGD₂applied to bronchial airways elicits many responses that are characteristic of acute asthma.

Activation of DP₂is associated with chemotaxis and activation of Th2 lymphocytes, eosinophils and basophils. PGD₂binds to DP₂and mediates many of its effects through a G_i-dependent elevation of intracellular calcium levels and reduction of cyclic AMP. In Th2 lymphocytes, IL4, IL5 and IL13 cytokine production are also stimulated by DP₂activation. These cytokines have been implicated in numerous biological actions including, by way of example only, immunoglobulin E production, airway response, mucous secretion, and eosinophil recruitment.

In the brain and central nervous system, PGD₂is produced and thought to function in pain perception and sleep regulation. In other tissues, PGD₂is produced primarily in immunoglobulin E (IgE) activated mast cells and to a lesser extent, in macrophages, dendritic cells, T helper 2 (Th2) lymphocytes and other leukocytes. In the cell, PGD₂is rapidly metabolized and converted to other downstream effectors including Î”¹²PGJ₂, 9Î±11Î²PGF₂, 13,14-dihydro-15-keto-PGD₂, and 15-deoxy-Î”^12,14PGD₂.

Mast-cell-derived PGD₂is produced in high concentrations in response to an allergen challenge. Studies in preclinical species have observed the following features when PGD₂is applied to in vivo preparations, or its overproduction is engineered by genetic manipulation: vasodilatation leading to erythema (flare) and potentiation of oedema (wheal), recruitment of eosinophils and Th2 lymphocytes, modulation of Th2-cytokine production, bronchoconstriction.

Injection of PGD₂into human skin has been shown to produce a long lasting erythema, to potentiate the effects of other mediators on induration and leukocyte infiltration in human skin and to enhance oedema formation in rat skin. It is most likely that these effects of PGD₂, like those of other vasodilator prostaglandins, are due to an increased blood flow to the inflamed lesion and are, therefore, most likely to be mediated predominantly by the DP₁receptor. Although these observations make it clear that DP₁mediates the vascular effects of PGD₂, the capacity of PGD₂to promote the cellular changes associated with inflammation is not due to an action on DP₁.

Much of PGD₂'s pro-inflammatory activity is through interaction with DP₂. DP₂is a G-protein coupled receptor and is typically highly expressed in Th2 lymphocytes, eosinophils and basophils. DP₂activation functions to directly activate and recruit Th2 lymphocytes and eosinophils. Activated Th2 lymphocytes produce and secrete inflammatory cytokines including IL4, IL5, and IL13. Despite binding PGD₂with a similar affinity as DP₁, DP₂is not structurally related to DP₁and signals through a different mechanismâ€”the effects of DP₂are mediated through Gi-dependent elevation in intracellular calcium levels and reduction in intracellular levels of cyclic AMP. DP₂activation is important in eosinophil recruitment in response to allergic challenge in such tissues as nasal mucosa, bronchial airways, and skin. The application of either PGD₂or selective DP₂agonists both exacerbate and enhance allergic responses in lung and skin. DP₂activation appears to have a crucial role in mediating allergic responses. The use of antagonists of PGD₂activation of the DP₂receptor is an approach to treat the inflammatory component of inflammatory diseases or conditions, respiratory diseases or conditions, allergic diseases or conditions, such as asthma, rhinitis, and dermatitis, among others.

Compounds

Compounds of Formula (I) have the following structure:

[Image Omitted]

- wherein,
- R^Ais H or C₁-C₆alkyl;
- R⁴is H, halogen, â€”CN, â€”OH, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy, C₁-C₄alkoxy, or C₁-C₄heteroalkyl;
- R⁶is â€”NR¹³S(â• O)₂R¹², â€”S(â• O)₂N(R¹²)(R¹³), â€”N(R¹²)(R¹³), â€”C(â• O)N(R¹²)(R¹³), â€”NHC(â• O)N(R¹²)(R¹³), â€”NR¹³C(â• O)R¹², or â€”NR¹³C(â• O)OR¹²;
- R¹¹is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted 5-membered heteroaryl, a substituted or unsubstituted 6-membered heteroaryl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl);
- R¹²is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆-fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted benzyl, a substituted or unsubstituted 6-membered heteroaryl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl);
- R¹³is H or C₁-C₄alkyl; or
- R¹²and R¹³attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C₂-C₆heterocycloalkyl;
- x is 0, 1, or 2.

For any and all of the embodiments, substituents can be selected from among from a subset of the listed alternatives.

For example, in some embodiments, R^Ais H or C₁-C₄alkyl. In other embodiments, R^Ais H, â€”CH₃, or â€”CH₂CH₃. In some embodiments, R^Ais H.

In some embodiments, x is 0 (sulfide). In some embodiments, x is 1 (sulfoxide). In some embodiments, x is 2 (sulfone).

In some embodiments, R⁴is H, F, Cl, Br, â€”OH, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄fluoroalkoxy, or C₁-C₄alkoxy. In some embodiments, R⁴is F, Cl, Br, â€”OH, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy, or C₁-C₄alkoxy.

In some embodiments, R¹¹is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted 5-membered heteroaryl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl).

In some embodiments, R¹¹is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl);

In some embodiments, the compound of Formula (I) has the structure of Formula (II):

[Image Omitted]

In some embodiments, R⁴is H, F, Cl, Br, â€”OCH₃, â€”CH₃, â€”CH₂CH₃, â€”CHCH₂, â€”CHF₂, â€”CF₃, â€”OCHF₂, or â€”OCF₃. In some embodiments, R⁴is F, Cl, Br, â€”OCH₃, â€”CH₃, â€”CH₂CH₃, â€”CHCH₂, â€”CHF₂, â€”CF₃, â€”OCHF₂, or â€”OCF₃. In some embodiments, R⁴is â€”OCH₃.

In some embodiments, R¹²is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆-fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted benzyl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl).

In some embodiments, R¹³is H or â€”CH₃. In some embodiments, R¹³is H.

In some embodiments, R⁶is â€”NR¹³S(â• O)₂R¹², â€”N(R¹²)(R¹³), â€”C(â• O)N(R¹²)(R¹³), â€”NHC(â• O)N(R¹²)(R¹³), â€”NR¹³C(â• O)R¹², or â€”NR¹³C(â• O)OR¹². In some embodiments, R⁶is â€”N(R¹²)(R¹³), â€”C(â• O)N(R¹²)(R¹³), â€”NHC(â• O)N(R¹²)(R¹³), â€”NR¹³C(â• O)R¹², or â€”NR¹³C(â• O)OR¹². In some embodiments, R⁶is â€”C(â• O)N(R¹²)(R¹³), â€”NHC(â• O)N(R¹²)(R¹³), or â€”NR¹³C(â• O)R¹². In some embodiments, R⁶is â€”C(â• O)N(R¹²)(R¹³), or â€”NR¹³C(â• O)R¹².

In some embodiments, R¹¹is C₁-C₆alkyl, C₁-C₆haloalkyl, a substituted or unsubstituted phenyl, or â€”C₁-C₄alkyl-(substituted or unsubstituted phenyl). In some embodiments, R¹¹is C₂-C₄alkyl, C₂-C₄haloalkyl, a substituted or unsubstituted phenyl, or â€”C₁-C₂alkyl-(substituted or unsubstituted phenyl). In some embodiments, R¹¹is C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments, R¹¹is C₂-C₄alkyl or C₂-C₄haloalkyl. In some embodiments, R¹¹is C₁-C₆alkyl. In some embodiments, R¹¹is C₁-C₄alkyl. In some embodiments, R¹¹is C₂-C₆alkyl. In some embodiments, R¹¹is C₂-C₄alkyl.

In some embodiments, R⁶is â€”NR¹³C(â• O)R¹².

In some embodiments, R¹²is C₁-C₆alkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted benzyl. In some embodiments, R¹²is C₁-C₆alkyl or C₃-C₆cycloalkyl In some embodiments, R¹²is C₁-C₆alkyl.

In some embodiments, R¹¹is â€”CH₂CH₃, â€”CH(CH₃)₂, â€”C(CH₃)₃, â€”CH₂CF₃, a substituted or unsubstituted phenyl, â€”C₁-C₂alkyl-(substituted or unsubstituted phenyl). In some embodiments, R¹¹is â€”CH₂CH₃, â€”CH(CH₃)₂, â€”C(CH₃)₃, or â€”CH₂CF₃.

In some embodiments, R¹²is â€”CH(CH₃)₃, â€”C(CH₃)₃, â€”CH₂CH(CH₃)₂, â€”CH₂C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted benzyl. In some embodiments, R¹²is â€”CH(CH₃)₃, â€”C(CH₃)₃, â€”CH₂CH(CH₃)₂, â€”CH₂C(CH₃)₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a substituted or unsubstituted phenyl. In some embodiments, R¹²is â€”C(CH₃)₃, or a substituted or unsubstituted phenyl. In some embodiments, R¹²is â€”C(CH₃)₃. In some embodiments, R¹²is a substituted or unsubstituted phenyl. In some embodiments, R¹²is a substituted phenyl, where the phenyl is substituted in the 4-position. In some embodiments, R¹²is a substituted or unsubstituted phenyl, where the substituted phenyl is substituted with 1 or 2 groups selected from halogen, â€”OH, â€”CN, â€”CH₃, â€”CH₂CH₃, â€”CF₃, â€”OCH₃, â€”OCH₂CH₃, and â€”OCF₃.

In some embodiments, R⁶is â€”NR¹³C(â• O)R¹²and x is 0. In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (III):

[Image Omitted]

In some embodiments, R¹¹is â€”CH₂CH₃, â€”CH(CH₃)₂, â€”C(CH₃)₃, or â€”CH₂CF₃; R¹²is â€”CH(CH₃)₂, â€”C(CH₃)₃, â€”CH₂CH(CH₃)₂, â€”CH₂C(CH₃)₃, or a substituted or unsubstituted phenyl; R¹³is H.

In some embodiments, R⁴is F, Cl, â€”OCH₃, â€”CF₃, or â€”OCF₃; R¹¹is â€”C(CH₃)₃; R¹²is â€”C(CH₃)₃; R¹³is H.

In some embodiments, R²and R³in Table 1 have the same definitions as R⁴.

In one aspect, R⁴is as defined in Table 1. In one aspect, R⁵is as defined in Table 1. In one aspect, R²⁰is as defined in Table 1. In one aspect, R¹¹is as defined in Table 1.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

In one aspect, compounds of Formula (I) include, but are not limited to, those described in Table 1:

TABLE 1

Cmpd #R²R³R⁴R⁶xR¹¹M + H1HHOCH₃4-Chloro-benzoylamino0 CH₂CF₃5402HHOCH₃2,2-Dimethyl-propionylamino0CH₂CF₃4863HHOCH₃3-Benzyl-ureido0CH₂CF₃5354HHOCH₃4-Chloro-benzoylamino04-Chlorophenyl5695HHOCH₃2,2-Dimethyl-propionylamino04-Chlorophenyl5156.HHOCH₃3-Benzyl-ureido04-Chlorophenyl5647HHOCH₃2,2-Dimethyl-propionylamino0tert-Butyl4608HHOCH₃4-Chloro-benzoylamino0tert-Butyl5159HHOCH₃2,2-Dimethyl-propionylamino0Isopropyl44610HHOCH₃2,2-Dimethyl-propionylamino2Isopropyl47811HHOCH₃2,2-Dimethyl-propionylamino1Isopropyl46212HHOCH₃2,2-Dimethyl-propionylamino2CH₂CF₃51813HHOCH₃3-Benzyl-ureido0tert-Butyl50914HHOCH₃Cyclopropanecarbonyl-amino0CH₂CF₃47015HHOCH₃Isobutyrylamino0CH₂CF₃47216HHOCH₃3,3-Dimethyl-butyrylamino0CH₂CF₃50017HHOCH₃4-Chloro-benzoylamino0Phenyl533[M âˆ’ H]18HHOCH₃4-Chloro-benzoylamino0Benzyl546[M âˆ’ H]19HHOCH₃4-Chloro-benzoylamino05-methyl-554[1,3,4]thiadiazol-2-y120HHOCH₃4-Chloro-benzoylamino0Isopropyl522[M + Na]21HHOCH₃4-Chloro-benzoylamino1Isopropyl51622HHOCH₃4-Chloro-benzoylamino2Isopropyl53223HHOCH₃4-Chloro-benzoylamino1Phenyl548[M âˆ’ H]24HHOCH₃4-Chloro-benzoylamino2Phenyl564[M âˆ’ H]25HHOCH₃C(â• O)NHCH₂CH₃0Isopropyl41826HHOCH₃4-Chloro-benzylcarbamoyl0Isopropyl51427HHOCH₃2-(4-Fluoro-phenyl)-ethylcarbamoyl0Isopropyl51228HClH2,2-Dimethyl-propionylamino0CH₂CF₃49029HClH2,2-Dimethyl-propionylamino2CH₂CF₃52230HClH2,2-Dimethyl-propionylamino0Isopropyl45131HClH2,2-Dimethyl-propionylamino2Isopropyl48232HCF₃H2,2-Dimethyl-propionylamino0CH₂CF₃52433HCF₃H2,2-Dimethyl-propionylamino2CH₂CF₃55634HHOCH₃(2,2-Dimethyl-propiony1)-methyl-0CH₂CF₃500amino35HHOCH₃Cyclopropanecarbonyl-amino0tert-Butyl44436HHOCH₃Isobutyrylamino0tert-Butyl44637HHOCH₃3,3-Dimethyl-butyrylarnino0tert-Butyl47438HHOCH₃2-Oxo-oxazolidin-3-yl0CH₂CF₃47239HHOCH₃tert-Butylcarbamoyl0tert-Butyl46040HHOCH₃2-Oxo-2-phenyl-ethylcarbamoyl0tert-Butyl52241HHOCH₃2-(4-Fluoro-phenyl)-1,1-dimethyl-0Cert-Butyl554ethylcarbamoyl42HHOCH₃Piperidine-1-carbonyl0tert-Butyl47243HHOCH₃6-Methoxy-pyridin-3-ylcarbamoyl0Cert-Butyl51144HHOCH₃2,2,2-Trifluoro-ethylcarbamoyl0tert-Butyl50845HHOCH₃Isopropyl-methyl-carbamoyl0tert-Butyl46046HHOCH₃2,2-Dimethyl-propylcarbamoyl0tert-Butyl47447HClH2,2-Dimethyl-propionylamino0tert-Butyl46448HClH2,2-Dimethyl-propionylamino2tert-Butyl49649HHOCHF₂2,2-Dimethyl-propionylamino0CH₂CF₃52250HHOCHF₂2,2-Dimethyl-propionylamino2CH₂CF₃55451HHCH32,2-Dimethyl-propionylamino0CH₂CF₃47052HHCl2,2-Dimethyl-propionylamino0Isopropyl45053HHCl2,2-Dimethyl-propionylamino0CH₂CF₃49054HCF₃H2,2-Dimethyl-propionylamino0Isopropyl48455HHCHâ• CH₂2,2-Dimethyl-propionylatnino0CH₂CF₃48256HHCH₂CH₃2,2-Dimethyl-propionylamino0CH₂CF₃48457HHOCH₃2-Oxo-imidazolidin-1-y10CH₂CF₃47158HHOCH₃4-Benzoylarnino0tert-Butyl48059HHCl2,2-Dimethyl-propionylamino0tert-Butyl46460HHCl4-Chloro-benzoylamino0tert-Butyl51861HHClIsobutyrylamino0tert-Butyl45062HHOCH₃3-Fluoro-benzoylamino0tert-Butyl49863HHOCH₃4-Fluoro-benzoylamino0tert-Butyl49864HHOCH₃2-Fluoro-benzoylamino0tert-Butyl49865HHOCH₃2,4-Dichloro-benzoylamino0tert-Butyl54966HHOCH₃3,5-Dichloro-benzoylamino0tert-Butyl54967HHOCH₃3,5-Difluoro-benzoylamino0tert-Butyl51668HHOCH₃3-Trifluoromethyl-benzoylamino0CH₂CF₃57469HHOCH₃4-Trifluoromethyl-benzoylamino0CH₂CF₃57470HHOCH₃(Pyridine-3-carbony1)-amino0CH₂CF₃50771HHOCH₃(Pyridine-4-carbonyl)-amino0CH₂CF₃50772HHOCH₃5-Dimethylamino-naphthalene-1-0tert-Butyl609sulfonylamino73HHOCH₃2,2-Dimethyl-propionylamino1tert-Butyl74HHOCH₃2,2-Dimethyl-propionylamino2tert-Butyl75HHOH2,2-Dimethyl-propionylamino0tert-Butyl76HHOH2,2-Dimethyl-propionylamino1tert-Butyl

Further Forms of Compounds

In certain embodiments, compounds of Formula (I) are prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4â€²-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

Pharmaceutically acceptable salts are also obtained by reacting a compound of Formula (I) with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.

In other embodiments, compounds of Formula (I) are prepared as a pharmaceutically acceptable salts by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like, or with an inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

Reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are optionally formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of compounds of Formula (I) are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of compounds of Formula (I) are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, ethanol, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

In some embodiments, compounds of Formula (I) are prepared as prodrugs. A â€œprodrugâ€ refers to an agent that is converted into the parent drug in vivo.

In yet another embodiment, the compounds of Formula (I) possess one or more stereocenters and each center exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, the separation of stereoisomers by chiral chromatographic columns or stereoselective synthesis.

The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds exist as tautomers.

In some embodiments, the compounds described herein exist as tautomers. All tautomers are intended to be within the scope of the molecular formulas described herein.

In some embodiments, compounds described herein are isotopically-labeled, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, one or more hydrogen atoms are replaced with deuterium. In some embodiments, metabolic sites on the compounds described herein are deuterated. In some embodiments, substitution with deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

DEFINITIONS

Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms â€œa,â€ â€œanâ€ and â€œtheâ€ include plural referents unless the context clearly dictates otherwise. In this application, the use of â€œorâ€ or â€œandâ€ means â€œand/orâ€ unless stated otherwise. Furthermore, use of the term â€œincludingâ€ as well as other forms, such as â€œincludeâ€ , â€œincludes,â€ and â€œincluded,â€ is not limiting.

â€œAlkoxyâ€ refers to (alkyl)Oâ€”, where alkyl is as defined herein.

â€œAlkylâ€ refers to an aliphatic hydrocarbon group. The alkyl may be saturated or unsaturated. In one aspect, alkyl groups are selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl, and neo-pentyl.

â€œCycloalkylâ€ refers to a monocyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

â€œHaloâ€ , â€œhalogenâ€ or â€œhalideâ€ means fluoro, chloro, bromo or iodo.

â€œFluoroalkylâ€ refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is selected from â€”CF₃, â€”CHF₂, â€”CH₂F, â€”CH₂CF₃and â€”CF₂CF₃.

â€œFluoroalkoxyâ€ refers to (fluoroalkyl)Oâ€”, where fluoroalkyl is as defined herein.

â€œHeteroalkylâ€ refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. In one aspect, heteroalkyl refers to an alkyl group in which one of the skeletal atoms of the alkyl is oxygen, nitrogen, or sulfur. In another aspect, heteroalkyl refers to an alkyl group in which one of the skeletal atoms of the alkyl is oxygen.

A â€œheterocycloalkylâ€ refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. A heterocycloalkyl is a 5-membered ring or a 6-membered ring. In some embodiments, a heterocycloalkyl includes at least one N atom in the ring. Heterocycloalkyls include oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

â€œ5-Membered heteroarylâ€ include imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, and furazanyl. In one aspect, a heteroaryl contains 0-3 N atoms.

â€œ6-Membered heteroarylâ€ includes pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

The term â€œoptionally substitutedâ€ or â€œsubstitutedâ€ means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from halogen, â€”OH, â€”CN, C₁-C₄-fluoroalkyl, C₁-C₄alkoxy, C₁-C₄-fluoroalkoxy, â€”NH₂, â€”NH(C₁-C₄alkyl), â€”N(C₁-C₄alkyl)₂, and C₁-C₄heteroalkyl. In some cases, the referenced substituted group is substituted with 1 or 2 of the aforementioned groups. For example, in some embodiments, a referenced substituted group is substituted with at least one group selected from halogen, â€”OH, â€”CN, â€”CH₃, â€”CH₂CH₃, â€”CF₃, â€”OCH₃, â€”OCH₂CH₃, and â€”OCF₃.

A â€œmetaboliteâ€ of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term â€œactive metaboliteâ€ refers to a biologically active derivative of a compound that is formed when the compound is metabolized.

â€œPGD₂-dependentâ€ refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of PGD₂. â€œPGD₂-mediatedâ€ refers to refers to conditions or disorders that might occur in the absence of PGD₂but can occur in the presence of PGD₂.

â€œEffective amountâ€ or â€œtherapeutically effective amount,â€ as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. An appropriate effective amount in any individual case may be determined using techniques, such as a dose escalation study.

The terms â€œtreat,â€ â€œtreatingâ€ or â€œtreatment,â€ as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

The term â€œsubjectâ€ or â€œpatientâ€ encompasses mammals and non-mammals. In one aspect, the â€œsubjectâ€ or â€œpatientâ€ is a mammal. In one embodiment, the mammal is a human.

Pharmaceutical Composition/Formulation

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, intramuscular injection, subcutaneous injection, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administered in a local rather than systemic manner. In other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

A pharmaceutical composition refers to a mixture of a compound of Formula (I) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to a mammal.

In some embodiments, compounds described herein are formulated for oral administration. The compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

In one embodiment, compounds of Formula (I) are formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer.

In other embodiments, compounds of Formula (I) are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.

In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions.

In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or pills. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Oral dosage forms also include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

In still other embodiments, the compounds of Formula (I) are administered topically. Topically administrable compositions include solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.

In other embodiments, the compounds of Formula (I) are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders.

The active ingredient in the pharmaceutical compositions is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.

In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

In prophylactic applications, compositions comprising the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. In this use, the precise amounts also depend on the patient's state of health, weight, and the like.

The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the mammal being treated. Doses employed for adult human treatment are typically in the range of 0.02-5000 mg per day, 0.5-1500 mg per day, or 1-500 mg per day. In one embodiment, the dose is presented in a single dose or in divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compound of Formula (I) are from about 0.01 to about 10 mg/kg per body weight. In certain embodiments, suitable unit dosage forms for oral administration comprise from about 1 to 500 mg active ingredient. In other embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein.

In certain instances, it is appropriate to administer at least one compound of Formula (I) in combination with another therapeutic agent. In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

In some embodiments, compounds of Formula (I) are administered chronically. In some embodiments, compounds of Formula (I) are administered intermittently (e.g. drug holiday that includes a period of time in which the compound is not administered or is administered in a reduced amount). In some embodiments, compounds of Formula (I) are administered in cycles that include: (a) a first period that includes daily administration of the compound of Formula (I); followed by (b) a second period that includes a dose reduction of the daily amount of compound of Formula (I) that is administered. In some embodiments, the compound of Formula (I) is not administered in the second period. In some embodiments, the duration of the first and second periods, as well as the dose amounts are determined using methods described herein or known in the art.

EXAMPLES

These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

Example 1General Oxidation Procedure for the Preparation of Sulfone Compounds

To the sulfide compound (0.06 mmol) in CH₂Cl₂(2 mL) was added 3-chloroperbenzoic acid (0.027 g, 0.12 mmol), and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated and purified by preparative HPLC to give the sulfone compound.

Example 2General Oxidation Procedure for the Preparation of Sulfoxide Compounds

To the sulfide compound (0.06 mmol) in CH₂Cl₂(2 mL) was added 3-chloroperbenzoic acid (0.014 g, 0.06 mmol), and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated and purified by preparative HPLC to give the sulfoxide compound.

Example 3Synthesis of {3-[4-(4-Chloro-benzoylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 1)Step 1: [3-(2-Formyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To 3-hydroxy-4-methoxyphenylacetic acid (5.0 g, 27.4 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical tlc, the solution was concentrated and dried under high vacuum to give (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester. A solution of (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (1 equivalent), 2-fluoro-5-nitrobenzaldehyde (1 equivalent), and potassium carbonate (2 equivalents) in 1,4-dioxane was heated overnight at 70Â° C. The mixture was partitioned between EtOAc and H₂O and acidified with 1N aqueous HCl to pH 1, and then extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and concentrated, and the residue was purified by silica gel chromatography (EtOAc in hexane gradient) to give the title compound.

Step 2: [3-(2-Hydroxymethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To [3-(2-formyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (1 equivalent) in methanol was added sodium borohydride (1.2 equivalents), and the reaction was stirred at room temperature for 15 minutes. The mixture was then concentrated and partitioned between EtOAc and H₂O. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over MgSO₄, filtered, and concentrated to give the title compound.

Step 3: [3-(2-Bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To a solution of [3-(2-hydroxymethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (15.14 g, 41.9 mmol) in DME was added phosphorus tribromide (5.92 mL, 62.8 mmol), and the reaction was stirred at room temperature overnight. After cooling to 0Â° C., the mixture was quenched with saturated aqueous NaHCO₃and extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and concentrated to give the title compound.

Step 4: {4-Methoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester

To [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (2.0 g, 4.72 mmol) and 2,2,2-trifluoroethanethiol (0.46 mL, 5.18 mmol) in 1,4-dioxane (40 mL) at 0Â° C. was added sodium hydride (60% in mineral oil; 0.207 g, 5.18 mmol), and the reaction was stirred at 0Â° C. for 30 minutes. The mixture was partitioned between EtOAc and H₂O. The aqueous layer was separated and acidified, and then extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.

Step 5: {3-[4-Amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester

A solution of {4-methoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (1.46 g, 3.18 mmol), ferric chloride (0.026 g, 0.16 mmol), 1,1-dimethylhydrazine (1.69 mL, 22.27 mmol), and DARCO (0.300 g) in EtOH (30 mL) was stirred overnight at 65Â° C. The mixture was partitioned between EtOAc and H₂O and extracted three times with EtOAc. The combined organic layers were washed with H₂O and brine, and then dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc in hexanes gradient) to give the title compound.

Step 6: {3-[4-(4-Chloro-benzoylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester

To {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.200 g, 0.47 mmol) and triethylamine (0.08 mL, 0.56 mmol) in CH₂Cl₂was added 4-chlorobenzoyl chloride (0.07 mL, 0.56 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated and used directly in the hydrolysis step.

Step 7: {3-[4-(4-Chloro-benzoylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid

To {3-[4-(4-chloro-benzoylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.47 mmol) in MeOH and H₂O was added 1N aqueous lithium hydroxide. The reaction was stirred overnight at 65Â° C., and then acidified and extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.

Following the procedures of Example 3, {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester was reacted with:

- pivaloyl chloride to provide {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to provide {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 2);
- benzyl isocyanate to provide {3-[4-(3-benzyl-ureido)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[4-(3-benzyl-ureido)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 3);
- cyclopropanecarbonyl chloride to provide {3-[4-(cyclopropanecarbonyl-amino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[4-(Cyclopropanecarbonyl-amino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 14);
- isobutyryl chloride to provide {3-[4-isobutyrylamino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[4-isobutyrylamino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 15);
- tert-butylacetyl chloride to provide {3-[4-(3,3-Dimethyl-butyrylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[4-(3,3-Dimethyl-butyrylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 16);
- 3-(trifluoromethyl)benzoyl chloride to provide {4-methoxy-3-[2-(2,2,2-trifluoro-ethylsulfanylmethyl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {4-methoxy-3-[2-(2,2,2-trifluoro-ethylsulfanylmethyl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-phenyl}-acetic acid (Compound 68)
- 4-(trifluoromethyl)benzoyl chloride to provide {4-methoxy-3-[2-(2,2,2-trifluoro-ethylsulfanylmethyl)-4-(4-trifluoromethyl-benzoylamino)-phenoxy]-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {4-methoxy-3-[2-(2,2,2-trifluoro-ethylsulfanylmethyl)-4-(4-trifluoromethyl-benzoylamino)-phenoxy]-phenyl}-acetic acid (Compound 69);
- nicotinoyl chloride hydrochloride to provide {4-methoxy-3-[4-[(pyridine-3-carbonyl)-amino]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {4-methoxy-3-[4-[(pyridine-3-carbonyl)-amino]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 70);
- isonicotinoyl chloride hydrochloride to provide {4-methoxy-3-[4-[(pyridine-4-carbonyl)-amino]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {4-methoxy-3-[4-[(pyridine-4-carbonyl)-amino]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 71).

Example 4Synthesis of {3-[4-(4-Chloro-benzoylamino)-2-(4-chloro-phenylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 4)

Following the procedure described in Example 3, Step 4, {3-[2-(4-chloro-phenylsulfanylmethyl)-4-nitro-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester was obtained from [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 4-chlorobenzenethiol. {3-[2-(4-Chloro-phenylsulfanylmethyl)-4-nitro-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester was then reduced to {3-[4-amino-2-(4-chloro-phenylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester according to Example 3, Step 5. Treatment of the amine with 4-chlorobenzoyl chloride according to the procedure of Example 3, Step 6 to provide {3-[4-(4-chloro-benzoylamino)-2-(4-chloro-phenylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester according to the procedure described in Example 3, Step 7 provided the acid.

Following the procedures described in Example 3, {3-[4-amino-2-(4-chloro-phenylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester was reacted with:

- pivaloyl chloride to provide {3-[2-(4-Chloro-phenylsulfanylmethyl)-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-(4-chloro-phenylsulfanylmethyl)-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 5);
- benzyl isocyanate to provide {3-[4-(3-benzyl-ureido)-2-(4-chloro-phenylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[4-(3-benzyl-ureido)-2-(4-chloro-phenylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 6).

Example 5Synthesis of {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 7)Step 1: [3-(2-tert-Butylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

Prepared according to the procedure described in Example 3, Step 4, using the following starting materials: [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol.

Step 2: [3-(4-Amino-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

Prepared according to the procedure described in Example 3, Step 5, using the following starting material: [3-(2-tert-butylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester.

Step 3: {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester

Prepared according to the procedure described in Example 3, Step 6, using the following starting materials: [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and pivaloyl chloride.

Step 4: {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic add

Prepared according to the procedure described in Example 3, Step 7, using the following starting material: {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester.

Following the procedures described for Example 3, [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester was reacted with:

- 4-chlorobenzoyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 8);
- benzyl isocyanate to provide {3-[4-(3-benzyl-ureido)-2-tert-butylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[4-(3-benzyl-ureido)-2-tert-butylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 13);
- cyclopropanecarbonyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(cyclopropanecarbonyl-amino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(cyclopropanecarbonyl-amino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 35);
- isobutyryl chloride to provide [3-(2-tert-butylsulfanylmethyl-4-isobutyrylamino-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was hydrolyzed to [3-(2-tert-Butylsulfanylmethyl-4-isobutyrylamino-phenoxy)-4-methoxy-phenyl]-acetic acid (Compound 36);
- tert-butylacetyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(3,3-dimethyl-butyrylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-Butylsulfanylmethyl-4-(3,3-dimethyl-butyrylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 37);
- benzoyl chloride to provide [3-(4-benzoylamino-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was hydrolyzed to [3-(4-benzoylamino-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid (Compound 58);
- 3-fluorobenzoyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(3-fluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-Butylsulfanylmethyl-4-(3-fluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 62);
- 4-fluorobenzoyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(4-fluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-Butylsulfanylmethyl-4-(4-fluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 63);
- 2-fluorobenzoyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(2-fluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-Butylsulfanylmethyl-4-(2-fluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 64);

-2,4-dichlorobenzoyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(2,4-dichloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-Butylsulfanylmethyl-4-(2,4-dichloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 65);

- 3,5-dichlorobenzoyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(3,5-dichloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester {3-[2-tert-Butylsulfanylmethyl-4-(3,5-dichloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 66);
- 3,5-difluorobenzoyl chloride to provide {3-[2-tert-butylsulfanylmethyl-4-(3,5-difluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-Butylsulfanylmethyl-4-(3,5-difluoro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 67);
- dansyl chloride to provide {3-[2-tert-Butylsulfanylmethyl-4-(5-dimethylamino-naphthalene-1-sulfonylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (the crude material was purified by silica gel chromatography), which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(5-dimethylamino-naphthalene-1-sulfonylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 72).

Example 6Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 9)

[3-(2-Bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.94 mmol), 2-propanethiol (0.11 mL, 1.13 mmol), and sodium hydride (60% in mineral oil; 0.05 g, 1.13 mmol) were combined in 1,4-dioxane and stirred at room temperature for 30 minutes. The mixture was worked-up to give [3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was then reduced to the amine as described in Example 3, Step 5 to provide [3-(4-amino-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester The amine was then treated with pivaloyl chloride according to Example 3, Step 6 to provide {3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester according to the procedure described in Example 3, Step 7 provided the acid.

Example 7Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(propane-2-sulfonylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 10)

Prepared according to the procedure described in Example 1 using {3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid.

Example 8Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(propane-2-sulfinylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 11)

Prepared according to the procedure described in Example 2 using {3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid.

Example 9Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(trifluoro-ethanesulfonylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 12)

Prepared according to the procedure described in Example 1 using {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid.

Example 10Synthesis of [3-(2-Benzylsulfanylmethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acidStep 1: [3-(4-Chloro-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

(3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (0.75 g, 4.8 mmol), 5-chloro-2-fluorobenzaldehyde (1.0 g, 4.8 mmol), and potassium carbonate (1.0 g, 7.5 mmol) were combined in 1,4-dioxane (30 mL) and heated to 100Â° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.

Step 2: [3-(4-Chloro-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To [3-(4-chloro-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.9 g, 2.6 mmol) in MeOH (30 mL) was added sodium borohydride (0.11 g, 2.9 mmol), and the mixture was stirred at room temperature for 10 minutes. The mixture was worked-up to give the title compound.

Step 3: [3-(2-Bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To [3-(4-chloro-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.9 g, 2.6 mmol) in DME was added phosphorus tribromide (0.37 mL, 3.9 mmol), and the reaction was stirred for 3 hours at room temperature. The mixture was worked-up to give the title compound.

Step 4: [3-(2-Benzylsulfanylmethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.15 g, 0.36 mmol) and benzyl mercaptan (0.06 mL, 0.4 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (60% in mineral oil; 0.05 g, 1.25 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by preparative HPLC to give the title compound.

Step 5: [3-(2-Benzylsulfanylmethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid

[3-(2-Benzylsulfanylmethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester was hydrolyzed with lithium hydroxide in MeOH and H₂O to give the title compound.

Example 11Synthesis of {3-[4-(4-Chloro-benzoylamino)-2-phenylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 17)Step 1: [4-Methoxy-3-(4-nitro-2-phenylsulfanylmethyl-phenoxy)-phenyl]-acetic acid ethyl ester

Prepared according to the procedure described in Example 10, Step 4, using the following starting materials: [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and thiophenol.

Step 2: [3-(4-Amino-2-phenylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

[4-Methoxy-3-(4-nitro-2-phenylsulfanylmethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.4 g, 0.9 mmol) and tin(II) chloride (0.6 g, 2.7 mmol) were combined in EtOH (20 mL) and stirred overnight at 70Â° C. CH₂Cl₂, H₂O, and sodium bicarbonate were added, and the mixture was filtered through Celite. The organic layer was separated and concentrated to give the title compound.

Step 3: {3-[4-(4-Chloro-benzoylamino)-2-phenylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester

[3-(4-Amino-2-phenylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester (0.4 g, 0.9 mmol) and triethylamine (1 mL) were combined in CH₂Cl₂(10 mL). 4-Chlorobenzoyl chloride (0.29 mL, 2.3 mmol) was added, and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound, which was used directly in the hydrolysis step.

Step 4: {3-[4-(4-Chloro-benzoylamino)-2-phenylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid

To {3-[4-(4-chloro-benzoylamino)-2-phenylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.9 mmol) was added lithium hydroxide (0.3 g), H₂O (5 mL), and MeOH (20 mL). The reaction was stirred at 60Â° C., and then worked up and purified by preparative HPLC to give the title compound.

Example 12Synthesis of {3-[2-Benzylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 18)

As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzyl mercaptan were reacted to provide [3-(2-benzylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-benzylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide (3-[2-benzylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl)-acetic acid ethyl ester. Hydrolysis of the ester provided Compound 18.

Example 13Synthesis of {3-[4-(4-Chloro-benzoylamino)-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 19)

As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 5-methyl-1,3,4-thiadiazole-2-thiol were reacted to form {4-methoxy-3-[2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-4-nitro-phenoxy}-phenyl]-acetic acid ethyl ester, which was reduced to {3-[4-amino-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-chloro-benzoylamino)-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid provided Compound 19.

Example 14Synthesis of {3-[4-(4-Chloro-benzoylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 20)

[3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester was reduced to the amine according to the procedure described in Example 11, Step 2. The amine was treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-Chloro-benzoylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester as outlined in Example 11, Step 4 provided the acid.

Example 15Synthesis of [3-(4-Bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl esterStep 1: (3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester

To 3-hydroxy-4-methoxyphenylacetic acid (5.0 g, 23.8 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL), and the reaction was stirred overnight at room temperature. Once no starting material was seen by analytical tlc, the mixture was concentrated to give the desired product.

Step 2: [3-(4-Bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

(3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (2.0 g, 9.5 mmol), 5-bromo-2-fluorobenzaldehyde (2.0 g, 9.5 mmol), and potassium carbonate (2.0 g, 14.3 mmol) were combined in 1,4-dioxane and heated to 90Â° C. overnight. After work-up, the crude material was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give the desired product (1.8 g).

Step 3: [3-(4-Bromo-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

Prepared according to the procedure described in Example 10, Step 2, using the following starting material: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester.

Step 4: [3-(4-Bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

Prepared according to the procedure described in Example 10, Step 3, using the following starting material: [3-(4-bromo-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester.

Step 5: [3-(4-Bromo-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

[3-(4-Bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.87 mmol) and 2-propanethiol (0.08 g, 1.0 mmol) were combined in 1,4-dioxane (20 mL). Sodium hydride (60% in mineral oil; 0.04 g, 1.0 mmol) was added, and the reaction was stirred at room temperature for 20 minutes. The mixture was worked up to give the title compound.

Example 16Synthesis of {3-[4-(4-Chloro-benzoylamino)-2-(propane-2-sulfinylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 21) and {3-[4-(4-Chloro-benzoylamino)-2-(propane-2-sulfonylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 22)

To {3-[4-(4-chloro-benzoylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid (0.17 g, 0.34 mmol) in CH₂Cl₂(20 mL) was added 3-chloroperbenzoic acid (77%; 0.076 g, 0.34 mmol), and the reaction was stirred for 10 minutes at room temperature. Additional 3-chloroperbenzoic acid (77%; 0.025 g, 0.11 mmol) was added to increase the production of the sulfone product, and then the mixture was concentrated and purified by preparative HPLC to give the title sulfoxide and sulfone compounds.

Example 17Synthesis of {3-[2-Benzenesulfinylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 23) and {3-[2-Benzenesulfonylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 24)

To {3-[4-(4-chloro-benzoylamino)-2-phenylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid (0.16 mmol) in CH₂Cl₂(3 mL) was added 3-chloroperbenzoic acid (77%; 0.036 g, 0.16 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated and purified by preparative HPLC to give the title sulfoxide and sulfone compounds.

Example 18Synthesis of [3-(4-Ethylcarbamoyl-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid (Compound 25)Step 1: [3-(4-Bromo-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 2-propanethiol in 1,4-dioxane was added sodium hydride (60% in mineral oil), and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.

Step 2: 4-(5-Ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid methyl ester

[3-(4-Bromo-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.5 g, 1.1 mmol) and triethylamine (0.5 mL) were dissolved in DMF (10 mL) and MeOH (10 mL) and degassed for 10 minutes with N₂. [1,1â€²-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.09 g, 0.11 mmol) was added, and then carbon monoxide was bubbled through the solution for 10 minutes. The reaction was stirred under a balloon of carbon monoxide at 65Â° C. overnight, and then concentrated and purified by silica gel chromatography to give the title compound.

Step 3: 4-(5-Ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid

4-(5-Ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid methyl ester (0.5 g, 1.16 mmol) and sodium methylthiolate (0.16 g, 2.3 mmol) were combined in DMF (20 mL) and stirred at 65Â° C. for 1 hour. After an acidic work-up, the crude material was purified by preparative HPLC to give the title compound.

Step 4: [3-(4-Ethylcarbamoyl-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

To 4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid (0.07 g, 0.17 mmol) in CH₂Cl₂(10 mL) and DMF (1 drop) was added oxalyl chloride (0.04 mL, 0.5 mmol), and the reaction was stirred at room temperature for 30 minutes. After concentrating to dryness, ethylamine (2M in THF; 0.25 mL, 0.5 mmol) was added, followed by CH₂Cl₂(10 mL) and diisopropylethylamine (0.5 mL), and the reaction was stirred at room temperature for 15 minutes. The mixture was worked up to give the title compound.

Step 5: [3-(4-Ethylcarbamoyl-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid

Prepared according to the procedure described in Example 11, Step 4, using the following starting material: [3-(4-ethylcarbamoyl-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester.

Example 19Synthesis of {3-[4-(4-Chloro-benzylcarbamoyl)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 26)

Following the procedure described in Example 18, Step 4, {3-[4-(4-Chloro-benzylcarbamoyl)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester was obtained from 4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid and 4-chlorobenzylamine. Hydrolysis of the ester according to the procedure described in Example 11, Step 4 provided the acid.

Example 20Synthesis of (3-{4-[2-(4-Fluoro-phenyl)-ethylcarbamoyl]-2-isopropylsulfanylmethyl-phenoxy}-4-methoxy-phenyl)-acetic acid (Compound 27)

Following the procedure described in Example 18, Step 4, (3-{4-[2-(4-Fluoro-phenyl)-ethylcarbamoyl]-2-isopropylsulfanylmethyl-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester was obtained from 4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid and 4-fluorophenethylamine. Hydrolysis of the ester according to the procedure described in Example 11, Step 4 provided the acid.

Example 21Synthesis of {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 28)Step 1: 1-Benzyloxy-3-bromo-5-chloro-benzene

To 1-bromo-3-chloro-5-fluorobenzene (25 g, 112 mmol) and benzyl alcohol (25 mL, 239 mmol) in NMP (200 mL) at room temperature was added sodium hydride (60% in mineral oil; 10.5 g, 263 mmol), and the reaction was heated to 120Â° C. for 10 hours. The mixture was acidified with 10% aqueous HCl and extracted with EtOAc to give the title compound.

Step 2: 2-(3-Benzyloxy-5-chloro-phenyl)-malonic acid dimethyl ester

To a solution of 1-benzyloxy-3-bromo-5-chloro-benzene (31 g, 101.7 mmol), dimethylmalonate (25.7 mL, 223.8 mmol), and copper(I) bromide (32 g, 223.8 mmol) in 1,4-dioxane (300 mL) at 0Â° C. under N₂was added sodium hydride (60% in mineral oil; 9 g, 223.9 mmol) portionwise. After 10 minutes, the reaction was heated to 100Â° C. and stirred for 6 hours. Analytical LCMS indicated that starting material remained, so the reaction was stirred at 100Â° C. for 24 hours. 50% Aqueous NH₄OH (1 L) was added to break up the solid, and the mixture was extracted three times with CH₂Cl₂(3 L total). The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.

Step 3: (3-Benzyloxy-5-chloro-phenyl)-acetic acid methyl ester

A mixture of 2-(3-benzyloxy-5-chloro-phenyl)-malonic acid dimethyl ester (21 g, 60.2 mmol) and lithium chloride (3.06 g, 72.2 mmol) in DMSO:H₂O (10:1; 200 mL) was stirred at 150Â° C. for 5 hours. After cooling to room temperature, H₂O (500 mL) was added, and the mixture was extracted with EtOAc:hexanes (1:10; 1.5 L total) to give the title compound.

Step 4: (3-Chloro-5-hydroxy-phenyl)-acetic acid methyl ester

To (3-benzyloxy-5-chloro-phenyl)-acetic acid methyl ester (8 g, 28 mmol) in CH₂Cl₂(100 mL) at 0Â° C. was added boron tribromide (1M in CH₂Cl₂; 56 mL, 56 mmol). The reaction mixture was warmed to room temperature over 30 minutes and stirred for 2 hours. Once no starting material was seen by analytical LCMS and tlc, the mixture was cooled to 0Â° C. and quenched with H₂O (50 mL). The volume was reduced, and the residue was diluted with EtOAc (500 mL). The solid material was filtered, and the organic layer was separated and concentrated. The crude material was purified by silica gel chromatography to give the title compound.

Step 5: [3-Chloro-5-(2-formyl-4-nitro-phenoxy)-phenyl]-acetic acid methyl ester

(3-Chloro-5-hydroxy-phenyl)-acetic acid methyl ester (2.9 g, 14.5 mmol), 2-fluoro-5-nitrobenzaldehyde (2.7 g, 15.9 mmol), and potassium carbonate (4.0 g, 28.9 mmol) were combined in 1,4-dioxane (20 mL) and stirred at 100Â° C. overnight. Once no starting material was seen by analyical LCMS and tlc, the mixture was worked up with EtOAc and 10% aqueous HCl, and the crude material was purified by silica gel chromatography to give the title compound.

Step 6: [3-Chloro-5-(2-hydroxymethyl-4-nitro-phenoxy)-phenyl]-acetic acid methyl ester

To [3-chloro-5-(2-formyl-4-nitro-phenoxy)-phenyl]-acetic acid methyl ester (3.7 g, 10.6 mmol) in MeOH (30 mL) was added sodium borohydride (0.52 g, 13.8 mmol), and the reaction was stirred at room temperature for 20 minutes. After work-up with EtOAc and H₂O, the crude material was purified by silica gel chromatography to give the title compound.

Step 7: [3-(2-Bromomethyl-4-nitro-phenoxy)-5-chloro-phenyl]-acetic acid methyl ester

To a solution of [3-chloro-5-(2-hydroxymethyl-4-nitro-phenoxy)-phenyl]-acetic acid methyl ester (2.4 g, 6.8 mmol) in DME (20 mL) was added phosphorus tribromide (0.97 mL, 10.2 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up with EtOAc and H₂O, the crude material was purified by silica gel chromatography to give the title compound.

Step 8: {3-Chloro-5-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester

To [3-(2-cromomethyl-4-nitro-phenoxy)-5-chloro-phenyl]-acetic acid methyl ester (0.5 g, 1.25 mmol) and 2,2,2-trifluoroethanethiol (0.13 mL, 1.38 mmol) in 1,4-dioxane (6 mL) was added sodium hydride (60% in mineral oil; 0.055 g, 1.38 mmol), and the reaction was stirred at room temperature overnight. After work-up with EtOAc and 10% aqueous HCl, the crude material was purified by silica gel chromatography to give the title compound.

Step 9: {3-[4-Amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-chloro-phenyl}-acetic acid methyl ester

{3-Chloro-5-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.07 g, 0.16 mmol), 1,1-dimethylhydrazine (0.08 mL, 1.09 mmol), ferric chloride (0.003 g, 0.02 mmol), and DARCO (0.016 g) were combined in EtOH and stirred at 65Â° C. for 30 hours. After work-up with EtOAc and H₂O, the crude material was purified by silica gel chromatography to give the title compound.

Step 10: {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester

To a solution of {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-chloro-phenyl}-acetic acid methyl ester (0.058 g, 0.14 mmol) in CH₂Cl₂(2 mL) was added triethylamine (0.04 mL, 0.28 mmol), followed by pivaloyl chloride (0.02 mL, 0.17 mmol), and the reaction was stirred at room temperature for 10 minutes. After work-up with CH₂Cl₂and H₂O, the crude material was purified by silica gel chromatography to give the title compound.

Step 11: {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid

To {3-chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.038 g, 0.08 mmol) in THF:H₂O:MeOH (2:1:2; 2 mL) was added 1N aqueous lithium hydroxide, and the mixture was stirred at room temperature overnight. The mixture was acidified to pH 5 with 10% aqueous HCl, and extracted with EtOAc. The crude material was purified by preparative HPLC to give the title compound.

Example 22Synthesis of {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(trifluoro-ethanesulfonylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 29)

To {3-chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (0.02 g, 0.04 mmol) in CH₂Cl₂(5 mL) was added 3-chloroperbenzoic acid (77%; 0.046 g, 0.2 mmol), and the reaction was stirred for 3 hours at room temperature. After work-up with CH₂Cl₂and H₂O, the crude material was purified by silica gel chromatography to give the title compound.

Example 23Synthesis of {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid (Compound 30)

Following the procedures described in Example 21, Step 8 (starting from [3-(2-bromomethyl-4-nitro-phenoxy)-5-chloro-phenyl]-acetic acid methyl ester and 2-propanethiol), Example 21, Step 9, and Example 21, Step 10 (using pivaloyl chloride), {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid methyl ester was obtained. Hydrolysis of the ester according to the procedure described in Example 21, Step 11 provided the acid.

Example 24Synthesis of {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(propane-2-sulfonylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 31)

To {3-chloro-5-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid methyl ester (0.05 g, 0.29 mmol) in CH₂Cl₂(3 mL) was added 3-chloroperbenzoic acid (77%; 0.12 g, 1.45 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up with EtOAc and brine, the crude material was purified by silica gel chromatography to give {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(propane-2-sulfonylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester. Hydrolysis of the ester according to the procedure described in Example 21, Step 11 provided the acid.

Example 25Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid (Compound 32)

To benzyl alcohol (1.1 g, 10 mmol) in NMP (20 mL) was added sodium hydride (60% in mineral oil; 0.44 g, 11 mmol), and the mixture was stirred for 30 minutes at room temperature. The mixture was then added to a vial containing 3-fluoro-5-(trifluoromethyl)phenylacetic acid (1 g, 4.5 mmol), and the reaction was stirred at 120Â° C. for 3 hours. Acidic work-up gave (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid the title compound.

To (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid (1.5 g, 5.4 mmol) in EtOH (30 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was worked up to give (3-Benzyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester.

(3-Benzyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester (1.7 g, 5.6 mmol) was dissolved in EtOH (30 mL) and degassed with N₂. 5% Palladium on carbon (1 g) was added, and the reaction was purged with H₂and then stirred under an H₂balloon at 50Â° C. overnight. The mixture was filtered and concentrated to give (3-Hydroxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester.

(3-Hydroxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester and 2-fluoro-5-nitrobenzaldehyde were reacted according to the procedure described in Example 21, Step 5, to give [3-(2-formyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester.

[3-(2-Formyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester was reduced to [3-(2-hydroxymethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester according to the procedure described in Example 21, Step 6 and then brominated as described in Example 21, Step 7 and then treated with 2,2,2-trifluoroethanethiol to give {3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. The amine was reduced as described in Example 21, Step 9, and then treated with pivaloyl chloride as described in Example 21, Step 10 to provide {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester as described in Example 21, Step 11 provided the acid.

Example 26Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(trifluoro-ethanesulfonylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid (Compound 33)

Prepared according to the procedure described in Example 24 using {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester.

Example 27Synthesis of {3-[4-[(2,2-Dimethyl-propionyl)-methyl-amino]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 34)

To {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.128 g, 0.26 mmol) in MeCN (3 mL) was added iodomethane (0.03 mL, 0.53 mmol), followed by sodium hydride (60% in mineral oil; 0.021 g, 0.53 mmol). The reaction was stirred at room temperature, but only starting material was seen by analytical LCMS, so the reaction was heated to 60Â° C. for 2 hours, and then cooled to room temperature and stirred for 2 days under N₂. The mixture was used directly in the hydrolysis step. To a solution of {3-[4-[(2,2-dimethyl-propionyl)-methyl-amino]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester (0.26 mmol) in MeCN was added H₂O, MeOH, and lithium hydroxide, and the reaction was heated to 65Â° C. for 1 hour to give the title compound.

Example 28Synthesis of {4-Methoxy-3-[4-(2-oxo-oxazolidin-3-yl)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy}-phenyl]-acetic acid (Compound 38)Step 1: {3-[4-(2-Chloro-ethoxycarbonylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester

Prepared according to the procedure described in Example 3, Step 6, using the following starting materials: {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 2-chloroethyl chloroformate.

Step 2: {4-Methoxy-3-[4-(2-oxo-oxazolidin-3-yl)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid

To {3-[4-(2-chloro-ethoxycarbonylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.100 g, 0.19 mmol) in EtOH (5 mL) was added sodium ethoxide (21 wt % in EtOH; 4.61 mL, 0.37 mmol), and the reaction was stirred at 65Â° C. overnight. The mixture was partitioned between EtOAc and H₂O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.

Example 29Synthesis of [3-(4-tert-Butylcarbamoyl-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid (Compound 39)Step 1: [3-(4-Bromo-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

Prepared according to the procedure described in Example 15, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester and 2-methyl-2-propanethiol.

Step 2: 3-tert-Butylsulfanylmethyl-4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-benzoic acid

[3-(4-Bromo-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (2.0 g, 4.3 mmol) and triethylamine (5.9 mL, 43 mmol) were combined in H₂O (5 mL) and DMF (50 mL) and degassed with carbon monoxide for 20 minutes. [1,1â€²-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.35 g, 0.43 mmol) was added, and the reaction was heated to 80Â° C. for 4 hours. The mixture was acidified and extracted with EtOAc to give the title compound.

Step 3: [3-(4-tert-Butylcarbamoyl-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester

3-tert-Butylsulfanylmethyl-4-(5-ethoxycarbonyl methyl-2-methoxy-phenoxy)-benzoic acid (0.2 g, 0.46 mmol), tert-butylamine (0.15 mL, 13.9 mmol), 1-ethyl-3-(3â€²-dimethylaminopropyl)carbodiimide (0.11 g, 0.55 mmol), and N-hydroxybenzotriazole (0.074 g, 0.55 mmol) were combined in CH₂Cl₂(8 mL) and stirred overnight. The mixture was concentrated and purified by preparative HPLC to give the title compound.

Step 4: [3-(4-tert-Butylcarbamoyl-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid

[3-(4-tert-Butylcarbamoyl-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.46 mmol) was treated with lithium hydroxide in MeOH and H₂O at 60Â° C. for 20 minutes to give the title compound.

Following the procedures outlined in Example 29, 3-tert-butylsulfanylmethyl-4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-benzoic acid was reacted with:

- 2-aminoacetophenone hydrochloride to provide {3-[2-tert-butylsulfanylmethyl-4-(2-oxo-2-phenyl-ethylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(2-oxo-2-phenyl-ethylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 40);
- 1-(4-fluorophenyl)-2-methyl-2-propylamine to provide (3-{2-tert-butylsulfanylmethyl-4-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylcarbamoyl]-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester, which was hydrolyzed to (3-{2-tert-butylsulfanylmethyl-4-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylcarbamoyl]-phenoxy}-4-methoxy-phenyl)-acetic acid (Compound 41);
- piperidine to provide {3-[2-tert-Butylsulfanylmethyl-4-(piperidine-1-carbonyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(piperidine-1-carbonyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 42);
- 5-amino-2-methoxypyridine to provide {3-[2-tert-Butylsulfanylmethyl-4-(6-methoxy-pyridin-3-ylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(6-methoxy-pyridin-3-ylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 43);
- 2,2,2-trifluoroethylamine hydrochloride to provide {3-[2-tert-Butylsulfanylmethyl-4-(2,2,2-trifluoro-ethylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(2,2,2-trifluoro-ethylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 44);
- N-methylisopropylamine to provide {3-[2-tert-Butylsulfanylmethyl-4-(isopropyl-methyl-carbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(isopropyl-methyl-carbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 45);
- neopentylamine to provide {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester, which was hydrolyzed to {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propylcarbamoyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 46).

Example 30Synthesis of {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-5-chloro-phenyl}-acetic acid (Compound 47)

[3-(2-tert-Butylsulfanylmethyl-4-nitro-phenoxy)-5-chloro-phenyl]-acetic acid methyl ester was prepared according to the procedure described in Example 21, Step 8, using [3-(2-bromomethyl-4-nitro-phenoxy)-5-chloro-phenyl]-acetic acid methyl ester and 2-methyl-2-propanethiol, which was reduced to [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-5-chloro-phenyl]-acetic acid methyl ester as described in Example 21, Step 9. The amine was treated with pivaloyl chloride as described in Example 21, Step 10 to provide {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-5-chloro-phenyl}-acetic acid methyl ester. Hydrolysis of the ester to the acid was carried out as outlined in Example 21, Step 11.

Example 31Synthesis of {3-Chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(2-methyl-propane-2-sulfonylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 48)

Prepared according to the procedure described in Example 22 using {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-5-chloro-phenyl}-acetic acid.

Example 32Synthesis of {4-Difluoromethoxy-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 49)

{4-Methoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (1.5 g, 3.6 mmol) was treated with 48% hydrogen bromide in acetic acid (1:1; 20 mL) at 100Â° C. overnight. After work-up with EtOAc and H₂O, the crude material was purified by preparative HPLC to give {4-hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid.

{4-Hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (3.6 mmol) and hydrogen chloride (4N in 1,4-dioxane) were combined in EtOH and stirred at 80Â° C. for 3 hours. After concentrating to dryness, the residue was purified by silica gel chromatography to give {4-hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.

{4-Hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.40 g, 0.92 mmol), sodium chlorodifluoroacetate (0.282 g, 1.86 mmol), and potassium carbonate (0.14 g, 1.02 mmol) were combined in DMF:H₂O (8.5:1; 4.6 mL) and degassed with N₂for 15 minutes. The reaction was then stirred at 100Â° C. for 4 hours. After work-up with EtOAc and 1N aqueous HCl, the residue was purified by silica gel chromatography to give {4-difluoromethoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.

{4-Difluoromethoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester was reduced to {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-difluoromethoxy-phenyl}-acetic acid methyl ester as described in Example 21, Step 9, which was treated with pivaloyl chloride as described in Example 21, Step 10 to provide {4-difluoromethoxy-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester. Hydrolysis of the ester to the acid was carried out as described in Example 21, Step 11.

Example 33Synthesis of {4-Difluoromethoxy-3-[4-(2,2-dimethyl-propionylamino)-2-(trifluoro-ethanesulfonylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 50)

Prepared according to the procedure described in Example 22 using {4-difluoromethoxy-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid.

Example 34Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methyl-phenyl}-acetic acid (Compound 51)

To {4-hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.50 g, 1.16 mmol) in DMF (10 mL) was added N-phenyl-bis(trifluoromethanesulfonimide) (0.455 g, 1.27 mmol) and cesium carbonate (0.755 g, 2.32 mmol), and the reaction was stirred at room temperature for 2 hours. After work-up with EtOAc and H₂O, the crude material was purified by silica gel chromatography to give {3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester.

{3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester (0.20 g, 0.35 mmol), trimethylboroxine (0.07 mL, 0.53 mmol), potassium carbonate (0.123 g, 0.89 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.041 g, 0.035 mmol) were combined in DME:H₂O (2:1; 4 mL) and degassed with N₂for 8 minutes. The reaction was stirred at 90Â° C. for 2 hours, and then worked up with EtOAc and 10% aqueous HCl. The residue was purified by silica gel chromatography to give {4-methyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.

Following the procedures described for Example 21, {4-methyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]phenyl}-acetic acid methyl ester was reduced to {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methyl-phenyl}-acetic acid methyl ester and then treated with pivaloyl chloride to provide {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methyl-phenyl}-acetic acid methyl ester. Hydrolysis of the ester provided the acid.

Example 35Synthesis of {4-Chloro-3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid (Compound 52)

To 4-chloro-3-fluorophenylacetic acid (5 g, 26.5 mmol) and benzyl alcohol (5.5 mL, 53.0 mmol) in NMP (50 mL) at 0Â° C. was added sodium hydride (60% in mineral oil; 2.3 g, 58.3 mmol), and the reaction was then heated to 120Â° C. and stirred overnight. The mixture was acidified to pH 4 and extracted with EtOAc to give (3-benzyloxy-4-chloro-phenyl)-acetic acid.

(3-Benzyloxy-4-chloro-phenyl)-acetic acid (8 g) was treated with hydrogen chloride (4 N in 1,4-dioxane; 6 mL) in EtOH (100 mL) at 80Â° C. for 3 hours. After concentrating to dryness, the residue was purified by silica gel chromatography to give (3-benzyloxy-4-chloro-phenyl)-acetic acid ethyl ester.

(3-Benzyloxy-4-chloro-phenyl)-acetic acid ethyl ester was reacted as outlined in Example 21, Step 4 to provide (4-chloro-3-hydroxy-phenyl)-acetic acid ethyl ester.

(4-Chloro-3-hydroxy-phenyl)-acetic acid ethyl ester was reacted with 2-fluoro-5-nitrobenzaldehyde as outlined in Example 21, Step 5, to provide [4-chloro-3-(2-formyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester.

[4-Chloro-3-(2-formyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester was reduced to [4-chloro-3-(2-hydroxymethyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester as described in Example 21, Step 6 and then brominated to provide [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester as outlined in Example 21, Step 7.

[3-(2-Bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester was treated with 2-propanethiol as described in Example 21, Step 8 to provide [4-chloro-3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-isopropylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester as described in Example 21, Step 9. Treatment of the amine with pivaloyl chloride as described in Example 21, Step 10 provided {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid was carried out as described in Example 21, Step 11.

Example 36Synthesis of {4-Chloro-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 53)

As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2,2,2-trifluoroethanethiol were reacted to provide {4-chloro-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to the amine and then treated with pivaloyl chloride to provide {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.

Example 37Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid (Compound 54)

As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester and 2-propanethiol were reacted to provide [3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester. Reduction to amine and then treatment of the amine with pivaloyl chloride was carried out to provide {3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.

Example 38Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-vinyl-phenyl}-acetic acid (Compound 55) and {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-ethyl-phenyl}-acetic acid (Compound 56)

{3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester (0.920 g, 1.63 mmol), (trimethylsilyl)acetylene (0.34 mL, 2.45 mmol), dichlorobis(triphenylphosphine)palladium (H) (0.1155, 0.16 mmol), and copper iodide (0.031 g, 0.16 mmol) were combined in triethylamine (8 mL) and degassed for 5 minutes. The reaction was heated for 8 hours, and then worked-up with CH₂Cl₂and H₂O. The crude material was purified by silica gel chromatography to give {3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trimethylsilanylethynyl-phenyl}-acetic acid methyl ester.

To a solution of {3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trimethylsilanylethynyl-phenyl}-acetic acid methyl ester (0.410 g, 0.8 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (1M in THF; 1.2 mL, 1.2 mmol), and the reaction was stirred for 30 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was worked-up with EtOAc and H₂O, and the residue was purified by silica gel chromatography to give {4-Ethynyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.

{4-Ethynyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.170 g, 0.39 mmol) was hydrogenated with 10% palladium on carbon in EtOH under 50 psi H₂, using the Parr apparatus, overnight. The mixture was filtered through Celite, and the filtrate was concentrated to give a 1:1 mixture of {3-[4-Amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-vinyl-phenyl}-acetic acid methyl ester and {3-[4-Amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-ethyl-phenyl}-acetic acid methyl ester.

Following the procedures described in Example 21, {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-vinyl-phenyl}-acetic acid methyl ester and {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-ethyl-phenyl}-acetic acid methyl ester were obtained by reacting a 1:1 mixture of {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-vinyl-phenyl}-acetic acid methyl ester and {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-ethyl-phenyl}-acetic acid methyl ester; with pivaloyl chloride. The two amides were separated by chromatography. Hydrolysis of the esters provided the acids.

Example 39Synthesis of {4-Methoxy-3-[4-(2-oxo-imidazolidin-1-yl)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (Compound 57)

{3-[4-Amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 2-chloroethyl isocyanate were reacted as described for Example 3, Step 6. The crude material was purified by silica gel chromatography.

Sodium ethoxide (20% wt/v; 2.27 mL, 0.187 mmol) was added to a solution of {3-[4-[3-(2-chloro-ethyl)-ureido]-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.050 g, 0.094 mmol) in EtOH (5 mL). The reaction was stirred at 65Â° C. overnight, and then partitioned between EtOAc and H₂O. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO₄, filtered, and concentrated. The residue was purified by preparative HPLC to give Compound 57.

Example 40Synthesis of {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-chloro-phenyl}-acetic acid (Compound 59)

As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol were reacted to provide [3-(2-tert-butylsulfanylmethyl-4-nitro-phenoxy)-4-chloro-phenyl]acetic acid ethyl ester, which was reduced to [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester. The amine was treated with trimethylacetyl chloride to provide {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-chloro-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.

Example 41Synthesis of {3-[2-tert-Butylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-chloro-phenyl}-acetic acid (Compound 60)

Following the procedures described for Example 21, {3-[2-tert-butylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-chloro-phenyl}-acetic acid ethyl ester was obtained from [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 4-chlorobenzoyl chloride. Hydrolysis of the ester provided the acid.

Example 42Synthesis of [3-(2-tert-Butylsulfanylmethyl-4-isobutyrylamino-phenoxy)-4-chloro-phenyl]-acetic acid (Compound 61)

Following the procedures described for Example 21, [3-(2-tert-butylsulfanylmethyl-4-isobutyrylamino-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester was obtained from [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and isobutyryl chloride. Hydrolysis of the ester provided the acid.

Example 43Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(2-methyl-propane-2-sulfinylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 73)

Prepared according to the procedure described in Example 2 using {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid and 3-chloroperbenzoic acid (1 equivalent).

Example 44Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(2-methyl-propane-2-sulfonylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid (Compound 74)

Prepared according to the procedure described in Example 1 using {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid and 3-chloroperbenzoic acid (2 equivalents).

Example 45Synthesis of {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-hydroxy-phenyl}-acetic acid (Compound 75)

{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.953 g, 2.07 mmol) in CH₂Cl₂was cooled to 0Â° C. Boron tribromide (1M in CH₂Cl₂; 6.21 mL, 6.21 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched, and after aqueous work-up, the crude material was purified by preparative HPLC to give the title compound.

Example 46Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(2-methyl-propane-2-sulfinylmethyl)-phenoxy]-4-hydroxy-phenyl}-acetic acid (Compound 76)

Prepared according to the procedure described in Example 2 using {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-hydroxy-phenyl}-acetic acid and 3-chloroperbenzoic acid (1 equivalent).

Example 47Synthesis of (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid (Compound 77)

{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.200 g, 0.44 mmol), (2R,3R,4R,5S,6R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.200 g, 0.7 mmol; prepared according to the procedure described in Tetrahedron 2007, 63, 7596), HATU (0.266 g, 0.7 mmol), and N-methylmorpholine (0.1 mL, 0.7 mmol) were combined in MeCN, and the reaction was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester, which was subsequently treated with palladium hydroxide on carbon and stirred under an atmosphere of H₂overnight. The crude material was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid.

Mass spectrometric data (M+H) for compounds are displayed in Table 1.

Example 48CRTH2 AssaysExample 48aDP₂/CRTH2 Binding Assay

The ability of a compound to bind to the human DP₂receptor is assessed via a radioligand binding assay using [³H]PGD₂. HEK293 cells stably expressing recombinant human DP₂are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000Ã—g to pellet the membranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10% glycerol to approximately 5 mg protein/ml. Membranes (2-10 Î¼g protein/well) are incubated in 96-well plates with 1 nM [³H]PGD₂and test compound in Assay Buffer (50 mM Hepes, 10 mM MnCl₂, 1 mM EDTA, plus or minus 0.2% human serum albumin, pH 7.4) for 60 minutes at room temperature. The reactions are terminated by rapid filtration through Whatman GF/C glass fibre filter plates. The filter plates were pre-soaked in 0.33% polythylenimine for 30 minutes at room temperature then washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH 7.4) prior to harvesting. After harvesting, the filter plates are washed 3 times with 1 ml cold Wash Buffer then dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the presence of 10 Î¼M PGD₂. IC₅₀s were determined using GraphPad prism analysis of drug titration curves. Compounds tested had an IC₅₀of less than 20 micromolar in this assay.

Example 48bGTPÎ³S Binding Assay

The ability of a compound to inhibit binding of GTP to DP₂is assessed via a membrane GTPÎ³S assay. CHO cells stably expressing the recombinant human CRTH2 receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000Ã—g to pellet the membranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10% glycerol. Membranes (Ëœ12.5 Î¼g per well) are incubated in 96-well plates with 0.05 nM [³⁵S]-GTPÎ³S, 80 nM PGD₂, 5 Î¼M GDP, and test compound in Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 5 mM MgCl₂and 0.2% human serum albumin) for 60 minutes at 30Â° C. The reactions are terminated by rapid filtration through Whatman GF/B glass fibre filter plates. The filter plates are washed 3 times with 1 ml cold Assay Buffer and dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the absence of the ligand (80 nM PGD₂). IC₅₀s were determined using Graphpad prism analysis of drug titration curves.

Example 48cWhole Blood Esoinophil Shape Change Assay

Blood is drawn from consenting human volunteers in EDTA vacutainer tubes and used within 1 hr of draw. A 98 Î¼l aliquot of blood is mixed with 2 Î¼l of test compound (in 50% DMSO) in 1.2 ml polypropylene tubes. The blood is vortexed and incubated at 37Â° C. for 15 minutes. 5 Î¼l of 1 Î¼M PGD₂in PBS is added for a final concentration of 50 nM and the tubes briefly vortexed. The reactions are incubated for exactly 5 minutes at 37Â° C. and then terminated by placing the tubes on ice and immediately adding 250 Î¼l of ice-cold 1:4 diluted Cytofix (BD Biosciences). The reactions are transferred to 12Ã—75 mM polystyrene round bottom tubes and the red blood cells lysed by the addition of 3 ml ammonium chloride lysing solution (150 mM NH₄Cl, 10 mM KHCO₃, 0.1 mM EDTA disodium salt) and incubation at room temperature for 15 minutes. The cells are pelleted by spinning at 1300 rpm for 5 minutes at 4Â° C. and washed once with 3 ml ice-cold PBS. The cells are resuspended in 0.2 ml of ice-cold 1:4 diluted Cytofix (BD Biosciences) and analyzed on a FACSCalibur (BD Biosciences) within 2 hours. Eosinophils were gated on the basis of autofluorescence in the FL2 channel and shape change on 500 eosinophils was assayed by forward scatter and side scatter analysis. The specific change in shape induced by PGD₂was calculated as the difference between the percentage of high forward scatter eosinophils in the presence and absence of PGD₂. IC₅₀s were determined using Graphpad PrismÂ® analysis of drug titration curves.

Example 48dDP₁Binding Assay

The ability of a compound to bind to the human DP1 receptor was evaluated via a radioligand membrane binding assay using the DP₁selective synthetic ligand [³H]BWA868C. Packed human platelets (Biological Specialty Corporation), were resuspended in 6 volumes of Hepes/HBSS buffer (10 mM Hepes, 1 mM DTT in Hanks Balanced Salt Solution (HBSS), lysed and centrifuged at 75,000Ã—g to pellet the membranes. Membranes were resuspended in Hepes/HBSS buffer to approximately 12 mg protein/ml. Membranes (20 Î¼g protein/well) are incubated in 96-well plates with 2 nM [³H]BWA868C and test compound in Assay Buffer (50 mM Hepes, 10 mM MnCl₂, 1 mM EDTA, plus or minus 0.2% human serum albumin, pH 7.4) for 60 minutes at room temperature. The reactions are terminated by rapid filtration through Whatman GF/C glass fibre filter plates. The filter plates were pre-soaked in 0.33% polethylenimine for 30 minutes at room temperature then washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH 7.4) prior to harvesting. After harvesting, the filter plates are washed 3 times with 1 ml cold Wash Buffer then dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the presence of 10 Î¼M BW A868C. IC₅₀s were determined using GraphPad prism analysis of drug titration curves.

Example 49Mouse Allergic Rhinitis Model

The compounds ability to inhibit allergen-induced sneezing and nasal rubbing is assessed using a mouse model of allergic rhinitis. Methods were adapted from those detailed in Nakaya, M., et al. 2006, Laboratory Investigation, 86:917-926. Female BALB/c mice (20-25 g) are immunized by an intraperitoneal injection (i.p.) of 2 Î¼g ovalbumin (OVA) complexed with alum in a volume 0.2 ml on days 0 and 14. Seven days later (day 21) mice are challenged intranasally with 20 Î¼l of a 10 mg/ml solution of OVA. The challenge period occurs daily from days 21 to day 25. Mice (5-7/group) are randomly assigned to receive either compound or vehicle and are treated by oral gavage 1-2 hour prior to each OVA challenge. The number of sneezes and nasal rubs are counted by an independent blind observe during a period of 8 minutes immediately following OVA challenge on days 21, 23 and 25. A significant increase in allergen-induced sneezing and nasal rubbing occurs over the 5-day challenge period. Inhibition of this effect by select compounds is determined statistically using Graphpad prism.

Example 50Guinea Pig IV-DKPGD2-Induced Peripheral Blood Leukocyte Influx

The compounds ability to inhibit leukocyte migration in vivo was assessed using intravenous injection of 13,14-dihydro-15-keto-prostaglandin D2 (DK-PGD2). Methods were adapted from those detailed Shichijo et al., 2003, Journal of Pharmacology and Experimental Therapeutics, 307:518-525. Male Hartley guinea pigs were immunized with ovalbumin (OVA) on day 0 by intraperitoneal (IP) injection of 1 ml of a 100 Î¼g/ml solution in Imject Alum. They were then used in the DK-PGD2 procedure between days 14 and 21. Subjects were randomly assigned to receive either vehicle (0.5% methyl cellulose, 4 ml/kg, oral (PO)) or one of three to four doses of test compound. Two hours or eighteen hours after dosing, animals were anesthetized with ketamine and challenged with DK-PGD2 (1 mg/kg, IV). Thirty minutes after IV administration, blood was collected via the marginal ear vein into EDTA tubes for cell analysis. 10 Î¼l blood was lysed in 190 Î¼l water followed by a further 20-fold dilution in PBS. A 10 Î¼A fraction was mixed with equal parts trypan blue and loaded on a hemocytometer. Cells were visualized at a magnification of 40Ã— using a LabPro light microscope and totals counted and recorded. Cells are expressed as total cellsÃ—10⁸per ml of blood. Inhibition of this effect by select compounds is determined statistically using Graphpad prism.

The compounds that were tested in Table 2 had IC₅₀below 40 Î¼M in the CRTH2 binding assay.

TABLE 2Representative Biological DataCompound NumberhDP2 (Î¼M)hDP1 (Î¼M)Compound 1ACCompound 2ACCompound 3ANDCompound 4ANDCompound 5ANDCompound 6ANDCompound 7ACCompound 8ANDCompound 9ANDCompound 10ANDCompound 11ANDCompound 12ANDCompound 13ANDCompound 14ANDCompound 15ANDCompound 16ANDCompound 17ACCompound 18AACompound 19ACCompound 20ANDCompound 21ANDCompound 22ANDCompound 23ANDCompound 24ANDCompound 25ANDCompound 26ANDCompound 27ANDCompound 28ANDCompound 29ANDCompound 30ACCompound 31ANDCompound 32ACCompound 33ANDCompound 34ANDCompound 35ANDCompound 36ANDCompound 37ANDCompound 38BNDCompound 39ANDCompound 40ANDCompound 41ANDCompound 42CNDCompound 43ANDCompound 44ANDCompound 45CNDCompound 46BNDCompound 47ANDCompound 48ANDCompound 49ANDCompound 50ANDCompound 51ANDCompound 52ANDCompound 53ANDCompound 54ANDCompound 55ANDCompound 56ANDCompound 57BCCompound 58AACompound 59AACompound 60AACompound 61AACompound 62AACompound 63AACompound 64AACompound 65AACompound 66AACompound 67AACompound 68AACompound 69AACompound 70ABCompound 71ABCompound 72BNDCompound 73AACompound 74AACompound 75AACompound 76AACompound 77AARamatrobanBCA = less than 0.3 Î¼M; B = greater than 0.3 Î¼M and less than 1 Î¼M; C = greater than 1 Î¼M.ND = Not determined

Example 51Clinical Trials in HumansStudy 1: Clinical Trial Evaluating Effect of Compound of Formula (I) on Ex Vivo PGD2-Induced Blood Eosinophil Shape Change

In this double-blind, randomized, placebo-controlled, single ascending dose study of Compound of Formula (I) in healthy volunteers the inhibition of ex vivo PGD2-induced blood eosinophil shape change is determined to show proof of biochemical mechanism of DP2 receptor antagonism. Eight subjects (6 active, 2 placebo) per dose level are used. Pre dose blood is drawn and challenged with PGD2 to determine baseline shape change as described above in Example 48. At varying times after dosing blood is drawn for both pharmacokinetic analyses of drug concentration in blood, and also for PGD2 challenge and eosinophil shape change determination. The extent of receptor blockage is determined from the relationship between drug blood concentration and percentage inhibition of eosinophil shape change.

Study 2: Clinical Trial Evaluating Effect of Compound of Formula (I) on Allergen-Induced Nasal Symptoms and Inflammatory and Allergic Biomarkers

In this double-blind, randomized, placebo-controlled study of Compound of Formula (I) in individuals with allergic rhinitis the inhibition of nasal symptoms and allergic biomarkers is determined following nasal challenge with appropriate allergen. Fifteen subjects (10 active, 5 placebo) are used. Subjects are dosed for 7 days with either placebo or an amount of compound of formula (I) that results in complete DP2 receptor block in an ex vivo PGD2-induced blood eosinophil shape change pharmacodynamic study as described above. On day 7 subjects undergo nasal allergen challenge (2 hours post-dose) and early allergic response (0.25-1.0 hr) and late allergic response (4-24 hr) are evaluated as an increase from baseline for treated vs placebo. In addition changes in inflammatory cell differentials, Th2 cytokines and other inflammatory markers are determined as increase from baseline for treated vs. placebo.

Compound of Formula (I) Assay

The plasma concentrations of compound of Formula (I) are determined by gas chromatography, giving a detection limit of 1 ngÂ·ml-1 (Ritter W. Determination of BAY u 3405, a novel thromboxane antagonist, in plasma and urine by HPLC and GC. In: Reid E, Wilson ID, eds. Bioanalytical Approaches for Drugs, Including Anti-asthmatics and Metabolites. Methodological Surveys in Biochemistry and Analysis, 1992; 22: 211-216).

Study 3â€”Vienna Challenge Chamber Study

Study design: The study is a randomised, double blind, placebo controlled, two way crossover evaluation of compound of Formula (I), given orally for eight days. There is a screening period of one week and a washout period of three weeks between the two treatment periods.

There is a follow up one week after the last dose of study drug. The group of patients who receive the study drug for the first treatment period and placebo for the second are designated group A, while the group of patients who receive placebo for the first treatment period and the study drug for the second treatment period are designated group B.

Treatment plan and methods: The subjects undergo a complete screening assessment to determine a baseline response to allergens. This screening assessment takes place one week prior to the start of dosing.

Subjects commence dosing with compound of Formula (I) or placebo on Day 1 of each treatment period of the study. Adverse events, total nasal symptom score and concomitant medications are noted.

Subjects report back to the clinic on Day 2 of each treatment period for a 6 hour allergen challenge. The following measurements are obtained:

- Total nasal symptom score (TNSS) (obstruction, rhinorrhoea, itch, sneeze) with each symptom scored on a categorical scale from 0 to 3 pre-challenge, every 15 mins from 0 to 6 h post-start of challenge
- Eye symptom score (watery eyes, itchy eyes, red eyes) with each symptom scored on a categorical scale from 0 to 3 pre-challenge, every 15 mins from 0 to 6 h post-start of challenge
- Other symptoms (cough, itchy throat, itchy ears) with each symptom scored on a categorical scale from 0 to 3 pre-challenge and every 15 mins from 0 to 6 h post-start of challenge

Subjects report back to the clinic on Day 8 of each treatment period for a 6 hour allergen challenge and the measurements obtained on Day 2 are repeated.

A final follow-up visit is conducted one after the last dose of test article in Treatment Period 2.

Example 52aParenteral Composition

To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of Formula (I) is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Example 52bOral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula (I) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.

Example 52cSublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound of Formula (I) with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.

Example 52dFast-Disintegrating Sublingual Tablet

A fast-disintegrating sublingual tablet is prepared by mixing 48.5% by weigh of a compound of Formula (I), 44.5% by weight of microcrystalline cellulose (KG-802), 5% by weight of low-substituted hydroxypropyl cellulose (50 Î¼m), and 2% by weight of magnesium stearate. Tablets are prepared by direct compression (AAPS PharmSciTech. 2006; 7(2):E41). The total weight of the compressed tablets is maintained at 150 mg. The formulation is prepared by mixing the amount of compound of Formula (I) with the total quantity of microcrystalline cellulose (MCC) and two-thirds of the quantity of low-substituted hydroxypropyl cellulose (L-HPC) by using a three dimensional manual mixer (InversinaÂ®, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the quantity of L-HPC are added 30 seconds before the end of mixing.

Example 52eInhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula (I) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Example 52fRectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of Formula (I) is mixed with 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration.

Example 52 gTopical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I) is mixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Example 52hOphthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg of a compound of Formula (I) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Example 52iNasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound of Formula (I) is mixed with 30 mL of a 0.05 M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 Î¼l of spray for each application.

The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.