WO2011109679A2 - Inhibitors of 5-lipoxygenase - Google Patents

Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of 5-lipoxygenase (5-LO). Also described herein are methods of using such 5-LO inhibitors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions, diseases, or disorders.

Description

INHIBITORS OF 5-LIPOXYGENASE

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S provisional patent application no. 61/311,184 entitled "INHIBITORS OF 5-LIPOXYGENASE" filed on March 5, 2010, which is

incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0001] Described herein are compounds, methods of making such compounds,

pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with 5-lipoxygenase activity.

BACKGROUND OF THE INVENTION

[0002] The protein 5-lipoxygenase (5-LO) is associated with the pathway of leukotriene synthesis. Upon presentation of inflammatory stimuli from the exterior of the cell, calcium is released and binds to phospholipase A₂ (PLA2) and 5-lipoxygenase. Cell activation results in the translocation of PLA₂ and 5-lipoxygenase from the cytoplasm to the endoplasmic reticulum and/or nuclear membranes, where in the presence of 5-lipoxygenase-activating protein (FLAP), 5-lipoxygenase can then catalyze the two-step oxygenation and dehydration of arachidonic acid, converting it into the intermediate compound 5-HPETE (5- hydroperoxyeicosatetraenoic acid), and in the presence of FLAP convert the 5-HPETE to Leukotriene A₄ (LTA₄).

[0003] Leukotrienes are biological compounds formed from arachidonic acid in the leukotriene synthesis pathway (Samuelsson et ah, Science, 220, 568-575, 1983; Cooper, The Cell, A Molecular Approach, 2nd Ed. Sinauer Associates, Inc., Sunderland (MA), 2000). They are synthesized primarily by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and monocytes. Leukotrienes have been implicated in biological actions including, by way of example only, smooth muscle contraction, leukocyte activation, cytokine secretion, mucous secretion, and vascular function.

SUMMARY OF THE INVENTION

[0004] Presented herein are methods, compounds, pharmaceutical compositions, and medicaments for (a) diagnosing, preventing, or treating allergic and non-allergic inflammation, (b) controlling signs and symptoms that are associated with inflammation, and/or (c) controlling proliferative or metabolic disorders. These disorders may arise from genetic, iatrogenic, immunological, infectious, metabolic, oncologic, toxic, and/or traumatic etiology. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein include 5-lipoxygenase inhibitors described herein.

[0005] Compounds, pharmaceutically acceptable salts, pharmaceutically acceptable N- oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and/or pharmaceutically acceptable solvates thereof, which antagonize or inhibit 5-lipoxygenase and may be used to treat mammals suffering from leukotriene-dependent conditions or diseases, including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders, inflammatory conditions and painful conditions, are provided.

[0006] Compounds described herein, or pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvates thereof may be used to treat leukotriene dependent or leukotriene -mediated diseases, disorders, or conditions in a mammal, or 5- lipoxygenase dependent or 5-lipoxygenase-mediated diseases, disorders, or condition in a mammal.

[0007] In one aspect, provided herein are compounds that have a structure represented by Formula (I), or a pharmaceuticall acceptable salt, solvate, prodrug or metabolite thereof:

Formula (I)

R¹ is Ci-C₆alkyl, Ci-C₆fluoroalkyl, C3-C₆cycloalkyl, substituted or unsubstituted

monocyclic heteroaryl, or substituted or unsubstituted bicyclic heteroaryl;

R² is H, C C₆alkyl, CrC₆fluoroalkyl, C₃-C₆cycloalkyl, -C C₄alkylene-R³, -CN, halogen, -C0₂R¹⁰, -CON(R⁹)₂, -CHO, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, or - S0₂N(R⁹)₂;

R³ is -C0₂H, -C0₂R¹⁰, -C(0)R¹⁰, -C(OH)(R⁹)₂, -CON(R⁹)₂, -C(0)NHS0₂R¹⁰, tetrazolyl, -OH, C C₄alkoxy, halide, -CN, -SR⁹, -S(0)R¹⁰, -S(0)₂R¹⁰, - S0₂NHC(0)R¹⁰, -N(R⁹)₂, or -NHC(0)R¹⁰;

ring A is a triazolyl, oxadiazolyl or thiazolyl;

X is C(R²) or N;

L¹ is -0-, -NR⁸-, -S-, C C₃alkylene, -NR⁸C C₃alkylene -, or C C₃heteroalkylene R⁴ is H, C C₄alkyl, or -C(=0)R⁷;

R⁵ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkyl- Ci-C₄alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl;

R⁶ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl or C₃-

C₆cycloalkyl-Ci-C₄alkyl;

R⁷ is H, Ci-C₄alkyl, Ci-C₄fluoroalkyl, or C₃-C₆cycloalkyl, substituted or unsubstituted phenyl;

R⁸ is H, C C₄alkyl;

each R⁹ is independently selected from H, Ci-C₆alkyl, Ci-C₆fluoroalkyl, C₃-

Cscycloalkyl, substituted or unsubstituted phenyl, and a substituted or unsubstituted heteroaryl; or both R⁹ are optionally joined to form a heterocycloalkyl

R¹⁰ is selected from Ci-C₆alkyl, Ci-C₆fiuoroaikyl, C₃-C₈cycloalkyl, substituted or

unsubstituted phenyl, and a substituted or unsubstituted heteroaryl;

where each substituted phenyl or substituted heteroaryl is substituted with 1 or 2 R¹¹, where each R¹¹ is independently selected from halogen, -OH, Ci-C₄alkyl, Ci- C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, -

CN, -C0₂H, -C0₂R¹⁰, -CON(R⁹)₂, tetrazolyl, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, - S0₂N(R⁹)₂, and -N(R⁹)₂.

[0008] For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives. For example, in some embodiments, L¹ is -S-, -CH₂-, -NHCH₂-. In some embodiments, L¹ is -CH₂-. In some embodiments, L¹ is -NHCH₂-.

[0009] In some embodiments, L¹ is -S-, -CH₂-, -NHCH₂-.

[0010] In some embodiments, R⁴ is H.

[0011] In some embodiments, R⁵ is Ci-C₄alkyl, or Ci-C₄fluoroalkyl.

[0012] In some embodiments, R⁶ is Ci-C₄alkyl, or Ci-C₄fluoroalkyl.

[0013] In some embodiments, R⁴ is H; R⁵ is C C₄alkyl, or Ci-C₄fluoroalkyl; R⁶ is C_r

C₄alkyl, or Ci-C₄fluoroalkyl.

[0014] In some embodiments, ring A is oxadiazolyl.

[0015] In some embodiments, the com ound of Formula (I) has the structure of Formula (II):

Formula (II). [0016] In some embodiments, ring A is triazolyl.

[0017] In some embodiments, the com ound of Formula (I) has the structure of Formula (III):

Formula (III).

[0018] In some embodiments, R² is -H, -CN, CHO, halide, -C0₂R¹⁰, COR¹⁰, -CON(R⁹)₂, - S0₂R¹⁰, or -S0₂N(R⁹)₂.

[0019] In some embodiments, each R⁹ is independently selected from H and Ci-C₆alkyl; R¹⁰ is Ci-C₆alkyl.

[0020] In some embodiments, R⁵ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃. In some

embodiments, R⁵ is -CH₂CH₃.

[0021] In some embodiments, R⁶ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃. In some

embodiments, R⁶ is -CF₃.

[0022] In some embodiments, R⁵ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃; R⁶ is -CH₃, -

CH₂CH₃, -CF₃, or -CH₂CF₃. In some embodiments, R⁵ is -CH₂CH₃; R⁶ is -CF₃.

[0023] In some embodiments, R¹ is Ci-C₆alkyl, Ci-C₆fluoroalkyl, or C₃-C₆cycloalkyl.

[0024] In some embodiments, R¹ is -CH₃, -CH₂CH₃, -CH(CH₃)₂, -C(=CH₂)CH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

[0025] In some embodiments, R¹ is -CH(CH₃)₂, or -C(=CH₂)CH₃.

[0026] In some embodiments, R¹ is -CH(CH₃)₂, or -C(=CH₂)CH₃; R² is -CN, -C0₂R¹⁰, - CON(R⁹)₂, -S0₂R¹⁰, or -S0₂N(R⁹)₂; each R⁹ is independently selected from H and d-C₄alkyl;

R¹⁰ is Ci-C₄alkyl.

[0027] In some embodiments, R¹ is a substituted or unsubstituted monocyclic heteroaryl or a substituted or unsubstituted bicyclic heteroaryl.

[0028] In some embodiments, R¹ is substituted or unsubstituted monocyclic heteroaryl.

[0029] In some embodiments, R¹ is substituted or unsubstituted monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0030] In some embodiments, R¹ is substituted or unsubstituted monocyclic heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl. In some embodiments, R¹ is substituted or unsubstituted pyridinyl. [0031] In some embodiments, R¹ is substituted or unsubstituted pyridinyl; R² is -CN, - C0₂R¹⁰, -CON(R⁹)₂, -S0₂R¹⁰, or -S0₂N(R⁹)₂; each R⁹ is independently selected from H and C C₄alkyl; R¹⁰ is C C₄alkyl.

[0032] In some embodiments, R⁵ is C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; R⁶ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, or C3-C₆cycloalkyl.

[0033] Any of the combinations of the groups described above for the various variables is contemplated herein.

[0034] Also provided is a compound selected from compounds disclosed in Table 1 , Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, provided are pharmaceutical compositions that include a compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of any compound described herein. In a further aspect, provided are compositions further including a pharmaceutically acceptable diluent, excipient or binder. In a further aspect, provided are compositions further including a second pharmaceutically active ingredient.

[0036] In certain embodiments, provided herein is a pharmaceutical composition containing: i) a physiologically acceptable carrier, diluent, and/or excipient; and ii) one or more compounds provided herein.

[0037] In another aspect, described herein is a pharmaceutical composition that includes a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable excipient.

[0038] In another aspect, described herein is a method for treating inflammation in a mammal comprising administering a therapeutically effective amount of a compound described herein to the mammal in need.

[0039] In another aspect, described herein is a method for treating respiratory disease in a mammal comprising administering a therapeutically effective amount of a compound described herein to the mammal in need. In one aspect, the respiratory disease is asthma.

[0040] In another aspect, described herein is a method for treating cardiovascular disease in a mammal comprising administering a therapeutically effective amount of a compound described herein to the mammal in need.

[0041] In another aspect, described herein is a method for treating pain in a mammal by administering a therapeutically effective amount of a compound described herein to the mammal in need. In one aspect, the pain is associated with arthritis, including rheumatoid arthritis and osteaoarthritis and ankylosing spondylitis. In some embodiments, the pain is acute pain or chronic pain. In some embodiments, the pain is nociceptive pain, neuropathic pain, inflammatory pain, or non-inflammatory pain. In some embodiments, the pain is central pain or peripheral pain. In some embodiments, the pain is peripheral neuropathic pain.

[0042] In one aspect, provided herein are methods for treating a mammal by administering a compound provided herein. In some embodiments, provided herein is a method of inhibiting the activity of 5-LO or of treating a disease, disorder, or condition, which would benefit from inhibition of 5-LO activity in a mammal, which includes administering to the mammal a therapeutically effective amount of at least one of any of the compounds herein, or

pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate.

[0043] In another aspect, provided herein are methods of treating a leukotriene dependent or leukotriene-mediated disease or condition in a mammal, that includes administering to the mammal a therapeutically effective amount of the compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of any compound described herein, which inhibits the activity of 5-LO. In a further embodiment, the disease or condition is respiratory disease or cardiovascular disease or diseases in which pain occurs. In an alternative embodiment, the disease or condition is asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, aortic aneurysm, myocardial infarction, stroke or arthritis. In an alternative embodiment, the disease or condition is asthma. In an alternative embodiment, the disease or condition is osteoarthritis. In an alternative embodiment, the disease or condition is cancer or a non-cancerous disorder. In an alternative embodiment, the disease or condition is a non-cancerous disorder involving the skin or lymphatic tissues. In an alternative embodiment, the disease or disorder is a metabolic disorder. In an alternative embodiment, the disease or disorder relates to bone remodeling, loss or gain. In an alternative embodiment, the disease or condition is iatrogenic.

[0044] In some embodiments, the inflammatory conditions to be treated with the compounds described herein include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, aortic aneurysm, myocardial infarction, stroke and arthritis. In other embodiments the proliferative disorders include, but are not limited to, cancer and non-cancerous disorders, including, but not limited to, those involving the skin or lymphatic tissues. In other embodiments the metabolic disorders include, but are not limited to, bone remodeling, loss or gain. In additional embodiments, such conditions are iatrogenic and increases in, or abnormal localization of, leukotrienes may be induced by other therapies or medical or surgical procedures. [0045] In other embodiments, the methods, compounds, pharmaceutical compositions, and medicaments described herein are used to prevent the cellular activation of 5-lipoxygenase, while in other embodiments the methods, compounds, pharmaceutical compositions, and medicaments described herein may be used to limit the formation of leukotrienes. In other embodiments, such methods, compounds, pharmaceutical compositions, and medicaments include compounds disclosed herein, which inhibit the activity of 5-lipoxygenase, for the treatment of asthma by: (a) lowering the concentrations of leukotrienes in certain tissue(s) of the body or in the entire body of a mammal, (b) modulating the activity of enzymes or proteins in a mammal wherein such enzymes or proteins are involved in the leukotriene pathway such as, by way of example, 5-lipoxygenase, or (c) combining the effects of (a) and (b). In yet other embodiments, the methods, compounds, pharmaceutical compositions, and medicaments described herein may be used in combination with other medical treatments or surgical modalities.

[0046] In some embodiments, provided herein are methods for reducing/inhibiting the leukotriene synthetic activity of 5-lipoxygenase in a mammal comprising administering to the mammal at least once an effective amount of a compound described herein.

[0047] In other embodiments, provided herein are methods for modulating, including reducing and/or inhibiting, the activity of 5-lipoxygenase, directly or indirectly, in a mammal comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0048] In further embodiments, provided herein are methods for treating leukotriene- dependent or leukotriene mediated conditions or diseases, comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0049] In yet further embodiments, provided herein are methods for treating inflammation comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0050] In other embodiments, provided herein are methods for treating respiratory diseases comprising administering to the mammal at least once an effective amount of at least one compound described herein. 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, adult respiratory distress syndrome and 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, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma or seasonal asthma. [0051] In yet other embodiments, provided herein are methods for preventing chronic obstructive pulmonary disease comprising administering to the mammal at least once an effective amount of at least one compound described herein. In a further embodiment of this aspect, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.

[0052] In yet other embodiments, provided herein are methods for preventing pain in diseases including, but not limited to, arthritis, comprising administering to the mammal at least once an effective amount of at least one compound described herein. In a further embodiment of this aspect, the painful disease includes, but is not limited to, osteoarthritis, rheumatoid arthritis and ankylosing spondilitis. In another aspect the disease is any musculoseletal disease and the pain associated with these diseases. In another aspect the disease is endometriosis and pain associated with endometriosis and menstruation. In another embodiment the pain is associated with sickle cell disease. In another aspect, the disease is cancer and the pain associated with cancer. In another aspect the disease is fibromyalgia and the pain associated with fibroyalgia. In another embodiment the pain is associated with herpes virus infection of the skin in the disease commonly known as shingles.

[0053] In some embodiments, provided herein are methods for preventing increased mucosal secretion and/or edema in a disease or condition comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0054] Yet in other embodiments, provided herein are methods for preventing or treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke comprising administering to the mammal an effective amount of a compound described herein.

[0055] Additional embodiments provided herein include methods for reducing organ reperfusion injury following organ ischemia and/or endotoxic shock comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0056] Still further embodiments provided herein include methods for reducing the constriction of blood vessels in a mammal comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0057] Some other embodiments are methods for lowering or preventing an increase in blood pressure of a mammal comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0058] Other embodiments provided herein include methods for preventing eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte recruitment comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0059] Some further embodiments provided herein include methods for the prevention or treatment of abnormal bone remodeling, loss or gain, including diseases or conditions as, by way of example, osteopenia, osteoporosis, Paget's disease, cancer and other diseases comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0060] Additional embodiments provided herein include methods for preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary

conjunctivitis comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0061] Still further embodiments provided herein include methods for preventing CNS disorders comprising administering to the mammal at least once an effective amount of at least one compound described herein. CNS disorders include, but are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and head injury.

[0062] Some additional embodiments provided herein include methods for the treatment of cancer comprising administering to the mammal at least once an effective amount of at least one compound described herein. The type of cancer may include, but is not limited to, pancreatic cancer and other solid or hematological tumors.

[0063] In some embodiments, provided herein are methods for preventing endotoxic shock and septic shock comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0064] In further embodiments, provided herein are methods for preventing rheumatoid arthritis and osteoarthritis comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0065] In other embodiments, methods for preventing increased GI diseases comprising administering to the mammal at least once an effective amount of at least one compound described herein, are provided. Such diseases include, by way of example only, chronic gastritis, eosinophilic gastroenteritis, and gastric motor dysfunction.

[0066] In further embodiments, provided herein are methods for treating kidney diseases comprising administering to the mammal at least once an effective amount of at least one compound described herein. Such diseases include, by way of example only,

glomerulonephritis, cyclosporine nephrotoxicity renal ischemia reperfusion. [0067] In still further embodiments, provided herein are methods for preventing or treating acute or chronic renal insufficiency comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0068] In yet further embodiments, provided herein are methods for treating type II diabetes comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0069] In other embodiments, provided herein are methods to diminish the inflammatory aspects of acute infections within one or more solid organs or tissues such as the kidney with acute pyelonephritis comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0070] In further embodiments, provided herein 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 at least one compound described herein.

[0071] In another aspect, provided herein are methods for preventing or treating acute or chronic erosive disease or motor dysfunction of the gastrointestinal tract caused by nonsteroidal anti-inflammatory drugs (including selective or non-selective cyclooxygenase -1 or -2 inhibitors) comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0072] Other embodiments provided herein include methods for the prevention or treatment of rejection or dysfunction in a transplanted organ or tissue comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0073] Further embodiments provided herein include methods for treating inflammatory responses of the skin comprising administering to the mammal at least once an effective amount of at least one compound described herein. Such inflammatory responses of the skin include, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, 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 described herein.

[0074] In another aspect, provided herein are methods for the treatment of cystitis, including, by way of example only, interstitial cystitis, comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0075] Other further embodiments provided herein include methods for the treatment of metabolic syndromes such as Familial Mediterranean Fever or inflammatory pancreatitis comprising administering to the mammal at least once an effective amount of at least one compound described herein. [0076] Additional further embodiments provided herein include methods to treat hepatorenal syndrome comprising administering to the mammal at least once an effective amount of at least one compound described herein.

[0077] In another embodiment, compounds described herein are used in the manufacture of a medicament for treating an inflammatory disease or condition in an animal in which the activity of at least one leukotriene protein contributes to the pathology and/or symptoms of the disease or condition. In one embodiment of this aspect, the leukotriene pathway protein is 5- lipoxygenase. In another or further embodiment of this aspect, the inflammatory disease or conditions are respiratory, cardiovascular, arthritic or proliferative diseases. In one embodiment, the respiratory disease is asthma.

[0078] In any of the aforementioned embodiments are further embodiments in which administration is enteral, parenteral, or both, and wherein (a) the effective amount of the compound is systemically administered to the mammal; (b) the effective amount of the compound is administered orally to the mammal; (c) the effective amount of the compound is intravenously administered to the mammal; (d) the effective amount of the compound administered by inhalation; (e) the effective amount of the compound is administered by nasal administration; or (f) the effective amount of the compound is administered by injection to the mammal; (g) the effective amount of the compound is administered topically (dermal) to the mammal; (h) the effective amount of the compound is administered by ophthalmic

administration; or (i) the effective amount of the compound is administered rectally to the mammal.

[0079] In any of the aforementioned embodiments are further embodiments in which the mammal is a human, including embodiments wherein (a) the human has an asthmatic condition or trait selected from the group consisting of 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, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid- resistant asthma, or seasonal asthma, or chronic obstructive pulmonary disease, or pulmonary hypertension or interstitial lung fibrosis. In any of the aforementioned embodiments are further embodiments in which the mammal is an animal model for pulmonary inflammation, examples of which are provided herein.

[0080] In any of the aforementioned embodiments 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. [0081] In any of the aforementioned embodiments are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours;. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. The length of the drug holiday can vary from 2 days to 1 year.

[0082] In any of the aforementioned embodiments involving the treatment of leukotriene dependent diseases or conditions are further embodiments comprising administering at least one additional agent, including, by way of example, an anti-inflammatory agent, a different compound having the structure of Formula (I), a CysLTi receptor antagonist, or a

CysLTi/CysLT₂ dual receptor antagonist. In further or alternative embodiments, the CysLTi antagonist is selected from montelukast ([l-[[l-[3-[2-[(7-chloro-2-quinolyl)]vinyl]phenyl]-3-[2- (1 -hydroxy- 1 -methyl-ethyl)phenyl] -propyl] sulfanylmethyl] cyclopropyl] acetic acid), zafirlukast (3-[[2-methoxy-4-(o-tolylsulfonylcarbamoyl)phenyl]methyl]-l -methyl- lH-indol-5- yl] amino formic acid cyclopentyl ester) or pranlukast (Onon: 4-oxo-8-[p-(4- phenylbutyloxy)benzoylamino]-2-tetrazol-5-yl)-4H-l-benzopyran).

[0083] In further or alternative embodiments, the anti-inflammatory agent includes, but is not limited to, non-steroidal anti-inflammatory drugs such as a cyclooxygenase inhibitor (COX-1 and/or COX-2), lipoxygenase inhibitors and steroids such as prednisone or dexamethasone. In further or alternative embodiments, the anti-inflammatory agent is selected from the group consisting of diclofenac, 5-aminosalicyclic acid, antipyrine, sulfasalazine, oxaprozin, etodolac, mefenamic acid, methylprednisolone, aspirin, indomethacin, rofecoxib, celecoxib, valdecoxib, diclofenac, etodolac, ketoprofen, meloxicam, nabumetone, naproxen, piroxicam,

betamethasone, prednisone.

[0084] In any of the aforementioned embodiments involving the treatment of pain, including but not limited to arthritic pain, are further embodiments comprising administering at least one additional agent selected from the group consisting of opiod drugs like morphine, fentanyl, bupivacaine and anesthetic compounds such as lidocaine

[0085] In any of the aforementioned embodiments involving the treatment of proliferative disorders, including cancer, are further embodiments comprising administering at least one additional agent selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5- fluorouracil, gemtuzumab, methotrexate, paclitaxel, temozolomide, thioguanine, or classes of drugs including hormones (an antiestrogen, an antiandrogen, or gonadotropin releasing hormone analogues, interferons such as alpha interferon, nitrogen mustards such as busulfan or melphalan or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents to treat signs or symptoms induced by such therapy including allopurinol, filgrastim,

granisetron/ondansetron/palonosetron, dronabinol.

[0086] In any of the aforementioned embodiments involving the therapy of transplanted organs or tissues or cells are further embodiments that include administering at least one additional agent selected from the group consisting of azathioprine, a corticosteroid, cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, or thymoglobulin.

[0087] In any of the aforementioned embodiments involving the therapy of interstitial cystitis are further embodiments that include administering at least one additional agent selected from dimethylsulfoxide, omalizumab, and pentosan polysulfate.

[0088] In any of the aforementioned embodiments involving the therapy of disorders of bone are further embodiments that include administering at least one additional agent selected from the group consisting of minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analogs, and cathepsin K inhibitors, dronabinol.

[0089] In any of the aforementioned embodiments 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; (e) measuring levels of LTB₄ in the calcium ionophore-challenged blood of a mammal; (f) measuring levels of LTE₄ in the urinary excretion of a mammal; or (g) identifying a mammal by measuring leukotriene-driven inflammatory biomarkers such as LTB₄, LTC₄, 11-6, CRP, SAA, MPO, EPO, MCP-1 , ΜΙΡ-α, sICAMs, 11-4, 11-13.

[0090] In any of the aforementioned embodiments the leukotriene-dependent or leukotriene mediated diseases or conditions include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis, allergy, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, and endotoxic shock.

[0091] In some embodiments, compounds provided herein are administered to a human. [0092] In some embodiments, compounds provided herein are orally administered. In some embodiments, compounds provided herein are topically administered.

[0093] In some embodiments, compounds provided herein are used for inhibiting the activity of 5-LO. In some embodiments, compounds provided herein are used for inhibiting the activity of 5-LO or for the treatment of a disease or condition that would benefit from inhibition of 5-LO activity.

[0094] In other embodiments, compounds provided herein are used for the formulation of a medicament for the inhibition of 5-LO activity.

[0095] Articles of manufacture containing packaging material, a compound described herein, or composition or pharmaceutically acceptable derivative thereof, which is effective for inhibiting the activity of 5-LO, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting the activity of 5-LO, are provided.

[0096] Other objects, features and advantages of the methods, compounds, 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. All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference for the purposes cited.

DETAILED DESCRIPTION

[0097] Described herein are compounds, methods of making such compounds,

pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with 5-lipoxygenase activity. Described herein are compounds that inhibit the activity of 5-lipoxygenase (5-LO).

[0098] Leukotrienes (LTs) are potent contractile and inflammatory mediators produced by release of arachidonic acid from cell membranes and conversion to leukotrienes by the action of 5-lipoxygenase, 5-lipoxygenase-activating protein, LTA₄ hydrolase and LTC₄ synthase. The leukotriene synthesis pathway, or 5-lipoxygenase pathway, involves a series of enzymatic reactions in which arachidonic acid is converted to leukotriene LTB₄, or the cysteinyl leukotrienes, LTC₄, LTD₄, and LTE₄.

[0099] Protein components dedicated to the leukotriene synthesis pathway include 5- lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP), LTA₄ hydrolase, and LTC₄ synthase. Leukotrienes are synthesized directly from arachidonic acid by different cells including eosinophils, neutrophils, basophils, lymphocytes, macrophages, monocytes and mast cells. Excess LTA₄, for example from an activated neutrophil, may enter a cell by a transcellular pathway. Most cells in the body have LTA₄ hydrolase so can produce LTB₄. Platelets and endothelial cells have LTC₄ synthase, so can make LTC₄ when presented with LTA₄ by a transcellular pathway.

[00100] Arachidonic acid is a polyunsaturated fatty acid and is present mainly in the membranes of the body's cells. Upon presentation of inflammatory stimuli from the exterior of the cell, calcium is released and binds to phospholipase A₂ (PLA2) and 5-LO. Cell activation results in the translocation of PLA and 5-LO from the cytoplasm to the endoplasmic reticulum and/or nuclear membranes, where in the presence of FLAP, the released arachidonic acid is converted via a 5-HPETE intermediate to the epoxide LTA₄. Depending on the cell type, the LTA₄ may be immediately converted to LTC₄ by the nuclear-bound LTC₄ synthase or to LTB₄ by the action of cytosolic LTA₄ hydrolase. LTB₄ is exported from cells by an as yet

uncharacterized transporter and may activate other cells, or the cell it was made in, via high affinity binding to one of two G protein-coupled receptors (GPCRs), namely BLTiR or BLT₂R. LTC₄ is exported to the blood via the MRP- 1 anion pump and rapidly converted to LTD₄ by the action of γ-glutamyl transpeptidase and LTD₄ and is then converted to LTE₄ by the action of dipeptidases. LTC₄, LTD₄ and LTE₄, which are collectively referred to as the cysteinyl leukotrienes (or previously as slow reacting substance of anaphylaxis, SRS-A). The cysteinyl leukotrienes activate other cells, or the cells they are made in, via high affinity binding to one of two GPCRs, namely CysLTiR or CysLT R. CysLTi receptors are found in the human airway eosinophils, neutrophils, macrophages, mast cells, B-lymphocytes and smooth muscle and induce bronchoconstriction. CysLT₂ receptors are located in human airway eosinophils, macrophages, mast cells the human pulmonary vasculature.

[00101] 5-Lipoxygenase-activating protein has been shown to form two distinct multimeric complexes that regulate the formation of leukotrienes in RBL-2H3 cells; Mandal et al, Proc Natl Acad Sci., 101, 6587-6592 (2004). The first complex is the formation of homodimers or homotrimers of 5-lipoxygenase-activating protein, the second is the formation of heterodimers or heterotrimers involving 5-lipoxygenase-activating protein and LTC₄ synthase. The tight association of LTC₄ synthase with 5-lipoxygenase-activating protein and the low expression level of LTC₄ synthase implies that all the LTC₄ synthase is tied up in the heteromultimers with 5-lipoxygenase-activating protein. The formation of LTC₄ is likely regulated through the heterodimer or heterotrimer while the homodimer or homotrimer of 5-lipoxygenase-activating protein regulates the generation of LTA₄ that is then available for the conversion to LTB₄. Inhibition of 5-lipoxygenase results in the complete downstream inhibition of the formation of leukotrienes. In contrast, the existence of different multimeric complexes of 5-lipoxygenase- activating protein offers the possibility of differentially regulating the inhibition of the production of LTB₄ or the cysteinyl leukotrienes LTC₄, LTD₄ and LTE₄ through the preparation of 5-lipoxygenase-activating protein inhibitors selective for each multimeric complex.

Involvement of Leukotrienes in Diseases or Conditions

[00102] The involvement of leukotrienes in disease is described in detail in the literature. See e.g., Busse, Clin. Exp. Allergy 26:868-79, 1996; O'Byrne, Chest 11 l(Supp. 2): 27S-34S, 1977; Sheftell, F.D., et al, Headache, 40: 158-163, 2000; Klickstein et al, J. Clin. Invest., 66: 1166- 1170, 1950; Davidson et ah, Ann. Rheum. Dis., 42:677-679, 1983. Leukotrienes produce marked inflammatory responses in human skin. Evidence for the involvement of leukotrienes in a human disease is found in psoriasis, in which leukotrienes have been detected in psoriatic lesions.

[00103] For example, inflammatory responses have been suggested to reflect three types of changes in the local blood vessels. The primary change is an increase in vascular diameter, which results in an increase in local blood flow and leads to an increased temperature, redness and a reduction in the velocity of blood flow, especially along the surfaces of small blood vessels. The second change is the activation of endothelial cells lining the blood vessel to express adhesion molecules that promote the binding of circulating leukocytes. The

combination of slowed blood flow and induced adhesion molecules allows leukocytes to attach to the endothelium and migrate into the tissues, a process known as extravasation. These changes are initiated by cytokines and leukotrienes produced by activated macrophages. Once inflammation has begun, the first cells attracted to the site of infection are generally neutrophils. They are followed by monocytes, which differentiate into more tissue macrophages. In the latter stages of inflammation, other leukocytes, such as eosinophils and lymphocytes also enter the infected site. The third major change in the local blood vessels is an increase in vascular permeability. Instead of being tightly joined together, the endothelial cells lining the blood vessel walls become separated, leading to exit of fluid and proteins from the blood and their local accumulation in the tissue.

[00104] LTB₄ produces relatively weak contractions of isolated trachea and lung parenchyma, and these contractions are blocked in part by inhibitors of cyclooxygenase, suggesting that the contraction are secondary to the release of prostaglandins. However, LTB₄ has been shown to be a potent chemotactic agent for eosinophils and progenitors of mast cells; and the LTB₄ receptor BLT1-/- knockout mouse is protected from eosinophilic inflammation and T-cell mediated allergic airway hyperreactivity. LTB₄ has also been shown to be elevated in synovial fluid in rheumatoid arthrits (Davidson et al, Annals Rheum. Diseases 42:677-679 (1983) and to be involved in arthritic joint pain in both rats (Castro da Rocha et al, Eur. J. Pharm. 497:81-86 (2004) and mice (Guerrero et al, J. Leuk. Biol 83: 122-130 (2008). In addition, LTB₄ mediates the itch-associated pain and inflammation responses of intradermal nocioceptin (Andoh et al, J. Invest. Dermatol. 123: 196-201 (2004). LTB₄ enhances atherosclerotic progression in two atherosclerotic mouse models, namely low density receptor lipoprotein receptor deficient (LDLr-/-) and apolipoprotein E-deficient (ApoE-/-) mice (Aiello et al, Arterioscler. Thromb. Vase. Biol .22:443-449 (2002); Subbarao et al, Arterioscler. Thromb. Vas.c Biol.24:369-37 '5 (2004); Heller et ah, Circulation 112:578-586 (2005). LTB₄ has also been shown to increase human monocyte chemoattractant protein (MCP-1) a known enhancer of atherosclerotic progression (Huang et al, Arterioscler. Thromb. Vase. Biol.lA: 1783-1788, 2004).

[00105] Leukotrienes C₄ and D₄ are potent smooth muscle contractile agents, promoting bronchoconstriction in a variety of species, including humans. These compounds have profound hemodynamic effects, constricting coronary blood vessels, and resulting in a reduction of cardiac output efficiency. Leukotrienes also act as vasoconstrictors, however, marked differences exist for different vascular beds. There are reports suggesting that leukotrienes contribute to cardiac reperfusion injury following myocardial ischemia (Barst and Mullane, Eur. J. Pharmacol, 114: 383-387, 1985; Sasaki et al, Cardiovasc. Res., 22: 142-148, 1988). LTC₄ and LTD₄ directly increase vascular permeability probably by promoting retraction of capillary endothelial cells via activation of the CysLT₂ receptor and possibly other as yet undefined CysLT receptors [Lotzer et al Arterioscler Thromb Vase Biol 23: e32-36.(2003)]. Urinary LTE₄ is a measurement of production of cysteinyl leukotrienes in disease and has been shown to be elevated in respiratory disease (Taylor et al, Lancet 584-588 (1989), cardiovascular disease (Carry et al, Circulation 85:230-236 (1992) and in sickle cell disease (Field et al, Am. J.

Hematol. 84:231-233 (2009).

[00106] The role of 5-lipoxygenase in the leukotriene synthesis pathway is significant because 5-lipoxygenase in concert with 5-lipoxygenase-activating protein performs the first step in the pathway for the synthesis of leukotrienes. Therefore, the leukotriene synthesis pathway provides a number of targets for compounds useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions, including, by way of example, vascular and inflammatory disorders, proliferative diseases, and non-cancerous disorders.

[00107] Leukotriene-dependent or leukotriene mediated conditions treated using the methods, compounds, pharmaceutical compositions and medicaments described herein, include, but are not limited to, bone diseases and disorder, cardiovascular diseases and disorders, inflammatory diseases and disorders, dermatological diseases and disorders, ocular diseases and disorders, cancer and other proliferative diseases and disorders, respiratory diseases and disorders, such as, for example, asthma, and non-cancerous disorders.

Treatment Options

[00108] Leukotrienes contribute to the inflammation of the airways of mammals with asthma. CysLTi receptor antagonists such as montelukast have been shown to be efficacious in asthma and allergic rhinitis. CysLTiR antagonists pranlukast and zafirlukast have also been shown to be efficacious in asthma.

[00109] Several inhibitors of 5-lipoxygenase have been described: zileuton; ZD2138 (6-[(3- fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy- methyl] -l-methyl-2- quinolone), which has shown efficacy in inhibiting the fall of FEV1 resulting from aspirin- induced asthma (Nasser et al, Thorax, 49, 749-756, 1994); CJ- 13,610 (Mano et al, Chem.

Pharm. Bull, 53, 965-973, 2005); MK0633; ABT-761 (atreleuton; Stewart et al, J. Med. Chem. , 1997, 40, 1955-1968); AZD-4407 [5-((4-((2S,4R)-tetrahydro-4-hydroxy-2-methyl-2H-pyran-4- yl)thiophen-2-yl)sulfanyl)- 1 -methylindolin-2-one] (European Patent EP 623614); L-739,010 ([lS,5R]-3-cyano-l-(3-furyl)-6-{6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-yl- methoxyl} naphthalene) (Hamel et al, J. Med. Chem., 40, 2866-2875, 1997); Wy-50,295 ((S)-2- (2-((quinolin-2-yl)methoxy)naphthalen-7-yl)propanoate tromethamine) (Musser and Kreft, Drugs of the Future, 15, 73-80, 1990) and TMK688 (Tohda et al, Clin. Exp. Allergy, 27, 110- 118, 1997). See also Young, Eur. J. Med. Chem., 34, 671-685, 1999 and Werz Expert Opin. Ther. Patents, 15, 505-519, 2005. Several inhibitors of 5-lipoxygenase-activating protein have also been described: MK886 (2-((l-(4-chlorobenzyl)-3-(tert-butylthio)-5-isopropyl-lH-indol-2- yl)methyl)-2-methylpropanoic acid); MK591 (2-((5-((quinolin-2-yl)methoxy)-l-(4- chlorobenzyl)-3-(tert-butylthio)-lH-indol-2-yl)methyl)-2-methylpropanoic acid); BAY X1005 ((R)-2-(4-((quinolin-2-yl)methoxy)phenyl)-2-cyclopentylacetic acid); VML-530 (Abt-080; Kolasa et al, J. Med. Chem., 43, 3322-3334, 2000); and ETH615 (Kirstein et al,

Pharm. Toxicol, 68, 125-130, 1991). See also: Musser et al, J. Med. Chem., 35, 2501-2524, 1992; Brooks et al. J. Med. Chem., 1996, Vol. 39, No. 14, 2629-2654; Steinhilber, Curr. Med. Chem. 6(l):71-85, 1999; Riendeau, Bioorg Med Chem Lett., 15(14):3352-5, 2005; Flamand, et al, Mol. Pharmacol. 62(2):250-6, 2002; Folco, et al., Am. J. Respir. Crit. Care Med. 161(2 Pt 2):S112-6, 2000; Hakonarson, JAMA, 293(18):2245-56, 2005); 3-[5-(pyrid-2-ylmethoxy)-3-(2- methyl-2-propylthio)-l-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid; 3-[3-tert-butylsulfanyl- 1 -[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2- ylmethoxy)-lH-indol-2-yl]-2,2-dimethyl-propionic acid, 3-{5-((S)-l-Acetyl-2,3-dihydro-lH- indol-2-ylmethoxy)-3-tert-butylsulfanyl-l-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-lH-indol-2- yl}-2,2-dimethyl-propionic acid, 3-[3-tert-Butylsulfanyl-l-[4-(5-methoxy-pyrimidin-2-yl)- benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-lH-indol-2-yl]-2,2-dimethyl-propionic acid; CJ- 13610.

[00110] 5-Lipoxygenase inhibition will decrease LTB₄ from monocytes, neutrophils and other cells involved in vascular inflammation and thereby decrease atherosclerotic progression. The FLAP inhibitor MK-886 has been shown to decrease the post-angioplasty vasoconstrictive response in a porcine carotid injury model. Provost et ah, Brit. J. Pharmacol. 123: 251-258 (1998). MK-886 has also been shown to suppress femoral artery intimal hyperplasia in a rat photochemical model of endothelial injury. Kondo et al. Thromb. Haemost. 79:635-639 (1998). The 5-lipoxygenase inhibitor zileuton has been shown to reduce renal ischemia in a mouse model. Nimesh et ah, Mol. Pharm. 66:220-227 (2004). The 5-lipoxygenase inhibitor CJ-13610 has been shown to reduce chronic inflammatory pain in a rat model of osteoarthritis (Cortes- Burgos et ah, Eur. J. Pharm. 617:59-67 (2009).

[00111] Leukotriene pathway modulators have been used for the treatment of a variety of diseases or conditions, including, by way of example only, (i) inflammation; (ii) respiratory diseases including asthma, adult respiratory distress syndrome and 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, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma; (iii) chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis; (iv) increased mucosal secretion and/or edema in a disease or condition; arthritic disease and pain associated with arthritic disease;

cardiovascular disease including vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke; (vi) reducing organ reperfusion injury following organ ischemia and/or endotoxic shock; (vii) reducing the constriction of blood vessels; (viii) lowering or preventing an increase in blood pressure; (ix) preventing eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte recruitment; (x) abnormal bone remodeling, loss or gain, including osteopenia, osteoporosis, Paget's disease, cancer and other diseases; (xi) ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis; (xii) CNS disorders, including, but are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine; (xiii) peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and head injury; (xiv) cancer, including, but is not limited to, pancreatic cancer and other solid or hematological tumors; (xv) endotoxic shock and septic shock; (xvi) rheumatoid arthritis and osteoarthritis; (xvii) preventing increased GI diseases, including, by way of example only, chronic gastritis, eosinophilic gastroenteritis, and gastric motor dysfunction; (xviii) kidney diseases, including, by way of example only, glomerulonephritis, cyclosporine nephrotoxicity renal ischemia reperfusion; (xix) preventing or treating acute or chronic renal insufficiency; (xx) type II diabetes; (xxi) diminish the inflammatory aspects of acute infections within one or more solid organs or tissues such as the kidney with acute pyelonephritis; (xxii) preventing or treating acute or chronic disorders involving recruitment or activation of eosinophils; (xxiii) preventing or treating acute or chronic erosive disease or motor dysfunction of the gastrointestinal tract caused by non-steroidal antiinflammatory drugs (including selective or non-selective cyclooxygenase -1 or -2 inhibitors); (xxiv) treatment of metabolic syndromes, including, by way of example only, Familial

Mediterranean Fever; and (xxv) treat hepatorenal syndrome.

Identification of Leukotriene Synthesis Pathway Inhibitors

[00112] The development and testing of novel 5-lipoxygenase inhibitors, which are effective either alone or in combination with other drugs, and which result in minimal negative side effects would be beneficial for treating leukotriene-dependent or leukotriene mediated diseases, disorders, or conditions. Inhibitors of the leukotriene synthesis pathway described herein may target any step of the pathway to prevent or reduce the formation of leukotrienes. Such leukotriene synthesis inhibitors can, by way of example, inhibit at the level of 5-lipoxygenase, or 5-lipoxygenase-activating protein, thus minimizing the formation of various products in the leukotriene pathway, thereby decreasing the amounts of such compounds available in the cell. Leukotriene synthesis inhibitors are identified based on their ability to bind to proteins in the leukotriene synthesis pathway. For example, 5-lipoxygenase inhibitors are identified based on the inhibition of formation of the intermediate product 5-HPETE/5-HETE in cytosol fractions or purified 5-lipoxygenase, with product measured by HPLC or spectrophotometry, or by the inhibition of LTB₄ production from stimulated human leukocytes or by the inhibition of LTB₄ production from stimulated human blood (with product LTB₄ measured in both cases by LTB₄ specific ELISA.

Compounds

[00113] Described herein are compounds that inhibit the activity of 5-lipoxygenase. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound are provided. [00114] In one aspect, provided herein are compounds of Formula (I). Formula (I) is as follows:

R¹ is Ci-C₆alkyl, Ci-C₆fiuoroalkyl, C₃-C₆cycloalkyl, substituted or unsubstituted

monocyclic heteroaryl, or substituted or unsubstituted bicyclic heteroaryl;

R² is H, C C₆alkyl, CrC₆fluoroalkyl, C₃-C₆cycloalkyl, -C C₄alkylene-R³, -CN,

halogen, -C0₂R¹⁰, -CON(R⁹)₂, -CHO, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, or - S0₂N(R⁹)₂;

R³ is -C0₂H, -C0₂R¹⁰, -C(0)R¹⁰, -C(OH)(R⁹)₂, -CON(R⁹)₂, -C(0)NHS0₂R¹⁰,

tetrazolyl, -OH, C C₄alkoxy, halide, -CN, -SR⁹, -S(0)R¹⁰, -S(0)₂R¹⁰, - S0₂NHC(0)R¹⁰, -N(R⁹)₂, or -NHC(0)R¹⁰;

ring A is a triazolyl,oxadiazolyl or thiazolyl;

X is C(R²) or N;

L¹ is -0-, -NR⁸-, -S-, Ci-C₃alkylene, -NR⁸Ci-C₃alkylene -, or C C₃heteroalkylene; R⁴ is H, C C₄alkyl, or -C(=0)R⁷;

R⁵ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkyl- Ci-C₄alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl;

R⁶ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl or C₃-

C₆cycloalkyl-Ci-C₄alkyl;

R⁷ is H, Ci-C₄alkyl, Ci-C₄fluoroalkyl, or C₃-C₆cycloalkyl, substituted or unsubstituted phenyl;

R⁸ is H, CrQalkyl;

each R⁹ is independently selected from H, Ci-C₆alkyl, Ci-C₆fiuoroaikyl, C₃-

Cscycloalkyl, substituted or unsubstituted phenyl, and a substituted or unsubstituted heteroaryl; or both R⁹ are optionally joined to form a heterocycloalkyl

R¹⁰ is selected from Ci-C₆alkyl, Ci-C₆fiuoroaikyl, C₃-C₈cycloalkyl, substituted or

unsubstituted phenyl, and a substituted or unsubstituted heteroaryl;

where each substituted phenyl or substituted heteroaryl is substituted with 1 or 2 R¹¹, where each R¹¹ is independently selected from halogen, -OH, Ci-C₄alkyl, Ci- C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, - CN, -C0₂H, -C0₂R¹⁰, -CON(R⁹)₂, tetrazolyl, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, - S0₂N(R⁹)₂, and -N(R⁹)₂;

n is 0, 1, or 2.

[00115] For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives. For example, in some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[00116] In some embodiments, n is 0 and the compound of Formula (I) has the following structure:

[00117] In some embodiments, L¹ is -S-, -CH₂-, -NHCH₂-. In some embodiments, L¹ is -CH₂-.

In some embodiments, L¹ is -NHCH₂-.

[00118] In some embodiments, L¹ is -S-, -CH₂-, -NHCH₂-.

[00119] In some embodiments, X is C(R²). In some embodiments, X is N.

[00120] In some embodiments, R⁴ is H.

[00121] In some embodiments, R⁵ is Ci-C₄alkyl, or Ci-C₄fiuoroaikyl.

[00122] In some embodiments, R⁶ is Ci-C₄alkyl, or Ci-C₄fluoroalkyl.

[00123] In some embodiments, R⁴ is H; R⁵ is d-C₄alkyl, or Ci-C₄fiuoroaikyl; R⁶ is d-

C₄alkyl, or Ci-C₄fluoroalkyl.

[00124] In some embodiments, ring A is oxadiazolyl. In some embodiments, ring A is oxadiazolyl and X is N. In some embodiments, ring A is oxadiazolyl and X is C(R²).

[00125] In some embodiments, the com ound of Formula (I) has the structure of Formula (II):

Formula (II).

[00126] In some embodiments, ring A is triazolyl. In some embodiments, ring A is triazolyl and X is N. In some embodiments, ring A is triazolyl and X is C(R²).

[00127] In some embodiments, the compound of Formula (I) has the structure of Formula (III)

Formula (III).

[00128] In some embodiments, R² is -H, -CN, CHO, halide, -C0₂R¹⁰, COR¹⁰, -CON(R⁹)₂, - S0₂R¹⁰, or -S0₂N(R⁹)₂.

[00129] In some embodiments, each R⁹ is independently selected from H and Ci-C₆alkyl; R¹⁰ is Ci-C₆alkyl.

[00130] In some embodiments, R⁵ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃. In some

embodiments, R⁵ is -CH₂CH₃.

[00131] In some embodiments, R⁶ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃. In some

embodiments, R⁶ is -CF₃.

[00132] In some embodiments, R⁵ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃; R⁶ is -CH₃, -

CH₂CH₃, -CF₃, or -CH₂CF₃. In some embodiments, R⁵ is -CH₂CH₃; R⁶ is -CF₃.

[00133] In some embodiments, R¹ is Ci-C₆alkyl, Ci-C₆fluoroalkyl, or C₃-C₆cycloalkyl.

[00134] In some embodiments, R¹ is -CH₃, -CH₂CH₃, -CH(CH₃)₂, -C(=CH₂)CH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

[00135] In some embodiments, R¹ is -CH(CH₃)₂, or -C(=CH₂)CH₃.

[00136] In some embodiments, R¹ is -CH(CH₃)₂, or -C(=CH₂)CH₃; R² is -CN, -C0₂R¹⁰, -

CON(R⁹)₂, -S0₂R¹⁰, or -S0₂N(R⁹)₂; each R⁹ is independently selected from H and d-C₄alkyl;

R¹⁰ is C C₄alkyl.

[00137] In some embodiments, R¹ is a substituted or unsubstituted monocyclic heteroaryl or a substituted or unsubstituted bicyclic heteroaryl.

[00138] In some embodiments, R¹ is substituted or unsubstituted monocyclic heteroaryl.

[00139] In some embodiments, R¹ is substituted or unsubstituted monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1 ,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[00140] In some embodiments, R¹ is substituted or unsubstituted monocyclic heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl. In some embodiments, R¹ is substituted or unsubstituted pyridinyl.

[00141] In some embodiments, R¹ is substituted or unsubstituted pyridinyl; R² is -CN, -

C0₂R¹⁰, -CON(R⁹)₂, -S0₂R¹⁰, or -S0₂N(R⁹)₂; each R⁹ is independently selected from H and C C₄alkyl; R¹⁰ is C C₄alkyl. [00142] In some embodiments, R⁵ is C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; R⁶ is Ci-C4alkyl, Ci-C4iluoroalkyl, or C3-C₆cycloalkyl.

[00143] In some embodiments, each R¹¹ is independently selected from halogen, -OH, Ci- C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄fiuoroaikoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, -CN, -C0₂H, -C0₂R¹⁰, -CON(R⁹)₂, tetrazolyl, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, -S0₂N(R⁹)₂, and -N(R⁹)₂. In some embodiments, each R¹¹ is independently selected from halogen, -OH, C C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, -CN, -C0₂H, -C0₂R¹⁰, tetrazolyl, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, -S0₂N(R⁹)₂, and -N(R⁹)₂. In some embodiments, each R¹¹ is independently selected from halogen, -OH, Ci-C₄alkyl, C C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, -CN, -

C0₂H, and -C0₂R¹⁰. In some embodiments, each R¹¹ is independently selected from halogen, - OH, Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, and -CN. In some embodiments, each R¹¹ is independently selected from halogen, -OH, Ci-C₄alkyl, C C4iluoroalkyl, Ci-C4iluoroalkoxy, and Ci-C4alkoxy. In some embodiments, each R¹¹ is independently selected from halogen, -OH, Ci-C₄alkyl, Ci-C₄fluoroalkyl, and Ci-C₄alkoxy.

[00144] In some embodiments, each R¹¹ is independently selected from halogen, -OH, -CH₃, - CH₂CH₃, -CH₂CH₂CH₃, -CH(CH₃)₂, -CH₂CH₂CH₂CH₃, -C(CH₃)₃, -CF₃, -CH₂CF₃, -OCF₃, - OCH₂CF₃, -OCH₃, -OCH₂CH₃, -OCH(CH₃)₂, -OC(CH₃)₃, -CH₂OH, -CH₂OCH₃, -CH₂NH₂, - CH₂NHCH₃, -CH₂N(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CN, -C0₂H, - C0₂CH₃, -C0₂CH₂CH₃, -CONH₂, -CONHCH₃, -CON(CH₃)₂, tetrazolyl, -C(=0)CH₃, -

C(=0)CH₂CH₃, -C(OH)(CH₃)₂, -C(OH)(CH₂CH₃)₂, -S0₂CH₃, -S0₂CH₂CH₃, -S0₂NH₂, -NH₂, - NHCH₃, and -N(CH₃)₂. In some embodiments, each R¹¹ is independently selected from halogen, -OH, -CH₃, -CH₂CH₃, -CF₃, -CH₂CF₃, -OCF₃, -OCH₂CF₃, -OCH₃, -OCH₂CH₃, -CN, - C0₂H, -C0₂CH₃, and -C0₂CH₂CH₃. In some embodiments, each R¹¹ is independently selected from halogen, -OH, -CH₃, -CH₂CH₃, -CF₃, -CH₂CF₃, -OCF₃, -OCH₃, -OCH₂CH₃, and -CN. In some embodiments, each R¹¹ is independently selected from F, CI, -OH, -CH₃, -CH₂CH₃, -CF₃, -CH₂CF₃, -OCF₃, -OCH₃, and -OCH₂CH₃. In some embodiments, each R¹¹ is independently selected from F, CI, -OH, -CH₃, -CH₂CH₃, -CF₃, -OCF₃, -OCH₃, and -OCH₂CH₃.

[00145] In some embodiments, R¹ is as described in Table 1, Table 2, Table 3, Table 4 and/or Table 5.

[00146] In some embodiments, R² is as described in Table 1, Table 2, Table 3, Table 4 and/or Table 5.

[00147] In some embodiments, R⁵ is as described in Table 3, Table 4 and/or Table 5.

[00148] In some embodiments, R⁶ is as described in Table 3, Table 4 and/or Table 5.

[00152] Non- limiting representative compounds of Formula (I), Formula (II), Formula (III) include compounds disclosed in Table 1, Table 2, Table 3, Table 4 and Table 5.

Table 1:

# single enantiomer, prepared by using Enantiomer B of Intermediate B

* single enantiomer, prepared by using Enantiomer A of Intermediate B

Table 2:

single enantiomer, resolved by chiral chromatography Table 3:

single enantiomer, resolved by chiral chromatography Table 4:

Cmpd

R¹ R⁵ R⁶ No.

4-16 6-Methylpyridin-3 -yl Phenyl CF₃

4-17 2-propyl Cyclopropyl Cyclopropyl

4-18 2-propyl Cyclopropyl CF₃

4-19 2-propyl Ethyl CF₃

4-20 2-propyl Phenyl CF₃

4-21 2-Methylpyridin-4-yl Cyclopropyl Cyclopropyl

4-22 2-Methylpyridin-4-yl Cyclopropyl CF₃

4-23 2-Methylpyridin-4-yl Ethyl CF₃

4-24 2-Methylpyridin-4-yl Phenyl CF₃

4-25 6-Fluoropyridin-3-yl Cyclopropyl Cyclopropyl

4-26 6-Fluoropyridin-3-yl Cyclopropyl CF₃

4-27 6-Fluoropyridin-3-yl Ethyl CF₃

4-28 6-Fluoropyridin-3-yl Phenyl CF₃

4-29 Pyridin-3-yl Cyclopropyl Cyclopropyl

4-30 Pyridin-3-yl Cyclopropyl CF₃

4-31 Pyridin-3-yl Ethyl CF₃

4-32 Pyridin-3-yl Phenyl CF₃

4-33 Pyrimidin-5-yl Cyclopropyl Cyclopropyl

4-34 Pyrimidin-5-yl Cyclopropyl CF₃

4-35 Pyrimidin-5-yl Ethyl CF₃

4-36 Pyrimidin-5-yl Phenyl CF₃

# single enantiomer, using Enantiomer B of Intermediate B

Cmpd

R¹ R⁵ R⁶

No.

5-17 2-propyl Cyclopropyl Cyclopropyl

5-18 2-propyl Cyclopropyl CF₃

5-19 2-propyl Ethyl CF₃

5-20 2-propyl Phenyl CF₃

5-21 2-Methylpyridin-4-yl Cyclopropyl Cyclopropyl

5-22 2-Methylpyridin-4-yl Cyclopropyl CF₃

5-23 2-Methylpyridin-4-yl Ethyl CF₃

5-24 2-Methylpyridin-4-yl Phenyl CF₃

5-25 6-Fluoropyridin-3-yl Cyclopropyl Cyclopropyl

5-26 6-Fluoropyridin-3-yl Cyclopropyl CF₃

5-27 6-Fluoropyridin-3-yl Ethyl CF₃

5-28 6-Fluoropyridin-3-yl Phenyl CF₃

5-29 Pyridin-3-yl Cyclopropyl Cyclopropyl

5-30 Pyridin-3-yl Cyclopropyl CF₃

5-31 Pyridin-3-yl Ethyl CF₃

5-32 Pyridin-3-yl Phenyl CF₃

5-33 Pyrimidin-5-yl Cyclopropyl Cyclopropyl

5-34 Pyrimidin-5-yl Cyclopropyl CF₃

5-35 Pyrimidin-5-yl Ethyl CF₃

5-36 Pyrimidin-5-yl Phenyl CF₃

[00153] Any of the combinations of the groups described above for the various variables is contemplated herein.

Further Forms of Compounds

[00154] Compounds described herein may possess one or more stereocenters and each center may exist in the R or S configuration. The compounds presented herein include all

diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of steroisomers may be performed by chromatography. Alternatively, individual stereoisomers may be obtained by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers is optionally carried out using covalent diastereomeric derivatives of the compounds described herein, dissociable complexes are also possible (e.g., crystalline diastereomeric salts).

Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are optionally readily separated by taking advantage of these dissimilarities. The diastereomers are optionally separated by chiral chromatography, or by

separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, herein incorporated by reference for such disclosures.

Stereoisomers may also be obtained by stereoselective synthesis.

[00155] In some situations, compounds may exist as tautomers. All tautomers are included within the formulas described herein.

[00156] The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity. In addition, the compounds described herein can exist in 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.

[00157] In some embodiments, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is

enzymatically metabolized by one or more steps or processes to the biologically,

pharmaceutically or therapeutically active form of the compound.

[00158] To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).

[00159] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[00160] In some cases, a prodrug has improved solubility in pharmaceutical compositions over the parent drug. In some cases, prodrugs are designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et ah, Am. J. Physiol, 269:G210-218 (1995); McLoed et al, Gastroenterol, 106:405-413 (1994); Hochhaus et al, Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein by reference for such disclosures.

[00161] In some embodiments, sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, such as, by way of example only, halogens can reduce, minimize or eliminate this metabolic pathway.

[00162] In some embodiments, compounds described herein are labeled isotopically (e.g. with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[00163] Compounds described herein include isotopically-labeled compounds, 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. Examples of isotopes that are optionally incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, O, S, F, CI, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. [00164] In additional or further embodiments, the compounds described herein are

metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[00165] In some embodiments, compounds described herein are prepared as pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a

pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tnfluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l- carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[00166] It should be understood that a 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 may be 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, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are optionally conveniently prepared or formed during the processes described herein. 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.

[00167] In some embodiments, compounds described herein are prepared in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[00168] The screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates is accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include, but are not limited to, Differential scanning calorimetry (DSC), Modulated Differential Scanning Calorimetry

(MDCS), Thermogravimetric analysis (TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

Preparation of Compounds

[00169] The synthesis of compounds described herein is accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof.

[00170] Compounds described herein are synthesized using standard synthetic techniques or using such methods in combination with methods described herein. In addition, solvents, temperatures and other reaction conditions presented herein may vary according to those of skill in the art.

[00171] The starting material used for the synthesis of the compounds described herein are optionally synthesized or obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, Fluka, Acros Organics, Alfa Aesar, and the like. The compounds described herein, and other related compounds having different substituents are optionally synthesized using techniques and materials described herein as well as those that are known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 ^rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosures). As a guide the following synthetic methods are optionally utilized.

Scheme 1

[00172] In some embodiments, benzothiophene formation begins with 4-bromo-2-fluoro- benzaldehyde. Introduction of the R¹ group is achieved by reacting the benzaldehyde with a suitable nucleophile followed by oxidation of the alcohol to the ketone. Suitable nucleophiles include organometallic reagents, such as, but not limited to, R'-MgX or R'-Li, where X is halogen. Reaction of the ketone 1-1 with HS-CH2CO2R¹⁰ in the prence of a base and a suitable solvent provides benzothiophenes of structure 1-2. In some embodiments, the ester is converted to a cyano group using suitable methods. In some embodiments, the ester is not converted to the cyano.

[00173] The bromo group of the benzothiophene 1-3 is then converted to the methyl ester 1-4 using standard carbonylation conditions. Selective reduction of the methyl ester provides the benzyl alcohol 1-5. The benzyl alcohol is converted to the corresponding azide under standard conditions.

[00174] Copper iodide induced cyclization of the benzylic azide with alkyne (see scheme 6 for the preparation of the alkyne) provides the corresponding triazole. The 4-nitrobenzoyl group is then hydrolyzed to provide the tertiary alcohol 1-8.

[00175] In some embodiments, compounds of Formula (I) where R² is an amide are prepared as outlined in Scheme 2.

Scheme 2

[00176] Partial hydrolysis of the cyano group of compound 2-1 provides amides of structure 2- 2.

[00177] In some embodiments, compounds of Formula (I) where ring A is an oxadiazole are prepared as outlined in Scheme 3.

Scheme 3

[00178] The methyl ester is hydrolyzed to the carboxylic acid and the intermediate carboxylic acid is decarboxylated to provide compound 3-1. In some embodiments, decarboxylation of the carboxylic acid is achieved by treatment with copper in refluxing quinoline. Standard carbonylation is performed as described in Scheme 1 to provide methyl ester 3-2. Selective bromination of the benzothiophene employing bromine in acetic acid yields the 2- bromobenzothiophene 3-3. Reduction of the methyl ester provides the alcohol which is then oxidized to provide the aldehyde. Reductive amination with the amine substituted oxadiazole provides compound 3-6. The 2-bromobenzothiophene can be converted into a methyl sulphone by treatment with methyl sulfinic acid sodium salt and Cul in polar solvent, such as n- methylpyrrolidinone (NMP).

[00179] In some embodiments, amides are prepared as outlined in Scheme 4a. Scheme 4a

[00180] In some embodiments, the 2-bromothiophene 4-1 is treated with CuCN to provide the cyano compound 4-2. Oxidation of the cyano group provides the amide as shown.

[00181] In some embodiments, 2-bromothiophenes are converted to 2-(alkyl

ester)benzothiophenes as shown in scheme 4b.

Scheme 4b.

[00182] Standard carbonyaltion conditions are used to converted the bromo compound to the alkyl ester. In some embodiments, the carbonylation conditions comprise a palladium catalyst in the presence of carbon monoxide.

[00183] In some embodiments, 2-bromothiophenes are converted to methylsulphones as shown in Scheme 4c and Scheme 3.

Scheme 4c

[00184] Scheme 5 outlines another approach to the synthesis of compounds of Formula (I). Scheme 5

[00185] Benzylic brommation followed by azide displacement generates the azide 5-3. Copper iodide induced cyclization of the benzylic azide 5-3 with the protected alkyne generates the corresponding triazole, which is treated with a suitable base in a suitable solvent to remove the alcohol protecting group to furnish compound 5-4. Metal mediated reaction conditions are then used to introduce suitable R¹ groups. In some embodiments, a Suzuki cross-coupling reaction is used to introduce suitable R¹ groups into the molecule.

[00186] Other metal mediated coupling reactions contemplated include, but are not limited to Suzuki reactions, Stille cross couplings, Negishi couplings, Kumada couplings, Ullmann reactions, Hiyama Coupling, and variants thereof (Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere (Editor), Francois Diederich (Editor), John Wiley & Sons; 2nd edition, 2004; Ozdemir, et ah, Tetrahedron, 2005, 61, 9791-9798; Ackermann, et ah, Org. Lett., 2006, 8, 3457-3460; Blakey, et al, J. Am. Chem. Soc, 2003, 125, 6046-6047; Dai, et al, Org. Lett., 2004, 6, 221-224; Yoshikai, et al, J. Am. Chem. Soc, 2005, 127, 17978-17979; Tang, et al, J. Org. Chem., 2006, 71, 2167-2169; Murata, et al, Synthesis, 2001, 2231-2233).

[00187] The synthesis of the requisite alkyene used in the synthesis of triazoles described herein is outlined in Scheme 6. Scheme 6.

3.TBAF

Certain Terminology

[00188] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet.

[00189] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless otherwise stated.

Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[00190] Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4^th ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of mammals. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.

[00191] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein.

[00192] As used herein, C C_x includes C C₂, C C₃ . . . C C_x.

[00193] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl or an unsaturated alkyl. The alkyl, whether saturated or unsaturated, may be branched or straight chain. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[00194] The "alkyl" moiety may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group of the compounds described herein may be designated as "Ci-C₆ alkyl" or similar designations. By way of example only, "C₁-C6 alkyl" indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[00195] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein. A "lower alkoxy" has 1 to 6 carbon atoms.

[00196] The term "alkylamine" refers to the -N(alkyl)_xH_y group, where alkyl is as defined herein and x and y are selected from the group x=l , y=l and x=2, y=0. When x=2, the alkyl groups taken together with the nitrogen atom to which they are attached can optionally form a heterocyclic ring system.

[00197] An "amide" is a chemical moiety with formula -C(=0)NHR or -NHC(=0)R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). An amide may be an amino acid or a peptide molecule attached to a compound described herein, such as, for example, a compound of Formula (I), thereby forming a prodrug. Any amine, or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are found in sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^r Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference for such disclosures.

[00198] The term "ester" refers to a chemical moiety with formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are found in sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference for such disclosures.

[00199] As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.

[00200] The term "membered ring" can embrace any cyclic structure. The term "membered" is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.

[00201] The term "fused" refers to structures in which two or more rings share one or more bonds.

[00202] The term "carbocyclic" or "carbocycle" refers to a ring wherein each of the atoms forming the ring is a carbon atom. Carbocycle includes aryl and cycloalkyl. The term thus distinguishes carbocycle from heterocycle ("heterocyclic") in which the ring backbone contains at least one atom which is different from carbon (i.e a heteroatom). Heterocycle includes heteroaryl and heterocycloalkyl. Carbocycles and heterocycles can be optionally substituted.

[00203] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term "aromatic" includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[00204] As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fiuorenyl, and indenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). In some embodiments, an aryl is a phenyl.

[00205] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[00206] The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N- containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be

monoradical or a diradical (i.e., a heteroarylene group). In some embodiments, the heteroaryl is a monocyclic heteroaryl. In some embodiments, the heteroaryl is a Ci-Cgheteroaryl. In some embodiments, the heteroaryl is a Ci-Csheteroaryl. In some embodiments, the heteroaryl includes 0-4 Ν atoms, 0- 1 O atoms and 0- 1 S atoms in the ring. In some embodiments, the heteroaryl includes 1-4 Ν atoms, 0-1 O atoms and 0-1 S atoms in the ring. In some embodiments, the heteroaryl includes 1-2 Ν atoms, 0-1 O atoms and 0-1 S atoms in the ring. In some

embodiments, the heteroaryl is a bicyclic heteroaryl.

[00207] The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from O, S and Ν, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10- membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,

dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazohnyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, may be C- attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-l-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (=0) moieties such as pyrrolidin-2-one.

Depending on the structure, a heterocycle group can be a monoradical or a diradical (i.e., a heterocyclene group).

[00208] A "heteroalicyclic" or "heterocycloalkyl"group refers to a cycloalkyl group that includes at least one ring atom that is not a carbon, i.e. at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The heterocycloalkyl radicals may be fused with an aryl or heteroaryl. Illustrative examples of heterocycloalkyl groups, also referred to as non- aromatic heterocycles, include:

term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same at the total number of atoms (including the heteratoms) that make up the heterocycloalkyl (i.e skeletal atoms of the heterocycloalkyl ring). In some embodiments, heterocycloalkyls have 0-2 Natoms, 0-1 O atoms and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have 1 -2 Natoms, 0- 1 O atoms and 0- 1 S atoms in the ring.

[00209] The terms "halo", "halide", and "halogen" mean fluoro, chloro, bromo and iodo.

[00210] The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halogens. The halogens may the same or they may be different.

[00211] The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[00212] The terms "heteroalkyl" "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen (-NH-, -Nalkyl-, - N(C(=0)alkyl)-), sulfur, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH₂-0- CH₃, -CH₂-CH₂-0-CH₃, -CH₂-NH-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-N(CH₃)-CH₃, -CH₂-CH₂- NH-CH₃, -CH₂-CH₂-N(CH₃)-CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂,-S(0)-CH₃, -CH₂-CH₂-S(0)₂- CH₃, -CH=CH-0-CH₃, -CH₂-CH=N-OCH₃, and -CH=CH-N(CH₃)-CH₃. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH₂-NH-OCH₃.

[00213] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

[00214] The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [00215] As used herein, the substituent "R" appearing by itself and without a number designation refers to a substituent selected from among from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).

[00216] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from Ci-C₆alkyl, C₃-C₈cycloalkyl, phenyl, monocyclic heteroaryl, C₂-C₆heteroalicyclic, hydroxy, Ci-C₆alkoxy, phenyloxy, Ci-C₆alkylthio, phenylthio, Ci-C₆alkylsulfoxide,

phenylsulfoxide, Ci-C₆alkylsulfone, phenylsulfone, cyano, halo, C₂-Csacyl, C₂-Csacyloxy, nitro, Ci-C₆haloalkyl, Ci-C₆fiuoroaikyl, and amino, including Ci-C₆alkylamino, and the protected derivatives thereof. By way of example, an optional substituents may be L^SR^S, wherein each L^s is independently selected from a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0)₂-, -NH-, -NHC(=0)-, -C(=0)NH-, S(=0)₂NH-, -NHS(=0)₂-, -OC(=0)NH-, -NHC(=0)0-, -(C C₆alkyl)-, or -(C₂- C₆alkenyl)-; and each R^s is independently selected from H, (Ci-C₄alkyl), (C₃-C₈cycloalkyl), heteroaryl, aryl, and Ci-C₆heteroalkyl. In some embodiments, an optional substituent is C C₄alkyl, hydroxy, C C₄alkoxy, Ci-C₄alkylthio, Ci-C₄alkylsulfoxide, Ci-C₄alkylsulfone, cyano, halo, C₂-C₄acyl, Ci-C₄haloalkyl, Ci-C₄fluoroalkyl, amino, Ci-C₄alkylamino, or di(Cr

C₄alkyl)amino. In some embodiments, an optional substituent is halogen, -CN, -NH₂, -OH, - NH(CH₃), -N(CH₃)₂, -CH₃, -CH₂CH₃, -CH(CH₃)₂, -CF₃, -OCH₃, -OCH₂CH₃, or -OCF₃. In some embodiments, substituted groups are substituted with 1 or 2 of the preceding groups. Optionally substituted non-aromatic groups may be substituted with one or more oxo (=0). The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.

[00217] The compounds presented herein may possess one or more stereocenters and each center may exist in the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by, for example, the separation of individual stereoisomers by chiral chromatographic columns or by stereoselective synthesis.

[00218] The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of any of Formula (I), Formula (II), or Formula (III), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, the compounds described herein can exist in 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.

[00219] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[00220] As used herein, the term "target protein" refers to a protein or a portion of a protein capable of being bound by a selective binding compound. In certain embodiments, a target protein is 5-LO.

[00221] As used herein, the term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target proteins.

[00222] As used herein, the term "selectively binds" refers to the ability of a selective binding compound to bind to a target protein, such as, for example, 5-LO, with greater affinity than it binds to a non-target protein. In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000 or more times greater than the affinity for a non-target.

[00223] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[00224] The term "modulate," as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[00225] As used herein, the term "modulator" refers to a compound that alters an activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.

[00226] As used herein, the term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

[00227] As used herein, the term "agonist" refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the protein, such as, for example, 5-LO.

[00228] As used herein, the term "antagonist" refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a protein. In certain

embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a protein, such as, for example, 5-LO. In certain embodiments, an antagonist is an inhibitor.

[00229] The terms "inhibits", "inhibiting", or "inhibitor" of 5-LO, as used herein, refer to inhibition of 5-lipoxygenase activity.

[00230] The term "asthma" as used herein refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with airway constriction of whatever cause

(intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma is sometimes used with one or more adjectives to indicate cause.

[00231] The term "bone disease,' as used herein, refers to a disease or condition of the bone, including, but not limited to, inappropriate bone remodeling, loss or gain, osteopenia, osteomalacia, osteofibrosis, and Paget's disease.

[00232] The term "cardiovascular disease," as used herein refers to diseases affecting the heart or blood vessels or both, including but not limited to: arrhythmia; atherosclerosis and its sequelae; angina; 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.

[00233] The term "cancer,' as used herein refers to an abnormal growth of cells, which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The types of cancer include, but is not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma) or hematological tumors (such as the leukemias). [00234] The term "dermatological disorder," as used herein refers to a skin disorder. Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin such as, atopic dermatitis, bullous disorders, collagenoses, contact dermatitis eczema, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.

[00235] The terms "fibrosis" or "fibrosing disorder," as used herein, refers to conditions that follow acute or chronic inflammation and are associated with the abnormal accumulation of cells and/or collagen and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, joints, lung, or skin, and includes such disorders as idiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis.

[00236] The term "iatrogenic" means a leukotriene-dependent or leukotriene-mediated condition, disorder, or disease created or worsened by medical or surgical therapy.

[00237] The term "inflammatory disorders" refers to those diseases or conditions that are characterized by one or more of the signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat {color, from vasodilatation), redness {rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and loss of function (functio laesa, which may be partial or complete, temporary or permanent). Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more of the following: acute, adhesive, atrophic, catarrhal., chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disorders further include, without being limited to those affecting the blood vessels (polyarteritis, temporal arteritis); joints (arthritis: crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's); gastrointestinal tract (Crohn's Disease, ulcerative colitis); skin

(dermatitis); or multiple organs and tissues (systemic lupus erythematosus).

[00238] The term "interstitial cystitis" refers to a disorder characterized by lower abdominal discomfort, frequent and sometimes painful urination that is not caused by anatomical abnormalites, infection, toxins, trauma or tumors.

[00239] The terms "neurogenerative disease" or "nervous system disorder," as used herein, refers to conditions that alter the structure or function of the brain, spinal cord or peripheral nervous system, including but not limited to Alzheimer's Disease, cerebral edema, cerebral ischemia, multiple sclerosis, neuropathies, Parkinson's Disease, those found after blunt or surgical trauma (including post-surgical cognitive dysfunction and spinal cord or brain stem injury), as well as the neurological aspects of disorders such as degenerative disk disease and sciatica. The acronym "CNS" refers to disorders of the central nervous system, i.e., brain and spinal cord.

[00240] The terms "ocular disease" or "ophthalmic disease," as used herein, refer to diseases which affect the eye or eyes and potentially the surrounding tissues as well. Ocular or ophthalmic diseases include, but are not limited to, conjunctivitis, retinitis, scleritis, uveitis, allergic conjunctivitis, vernal conjunctivitis, papillary conjunctivitis.

[00241] The term "skin disease", as used herein, includes but is not limited to eczema, psoriasis, scleroderma, neurodermatitis, pruritis, exfoliative dermatitis, allergic dermatitis, dermatitis, pemphigus and hypersensitivity reactions.

[00242] The term "respiratory disease," as used herein, refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, trachea, bronchi, and lungs. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and 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, 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.

[00243] The term "leukotriene-driven mediators," as used herein, refers to molecules able to be produced in a mammal that may result from excessive production of leukotriene stimulation of cells, such as, by way of example only, LTB₄, LTC₄, LTE₄, cysteinyl leukotrienes, monocyte inflammatory protein (ΜΙΡ-Ια), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin- 13 (IL- 13), monocyte chemoattractant protein (MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM), myeloperoxidase (MPO), eosinophil peroxidase (EPO), and general inflammation molecules such as interleukin-6 (11-6), C-reactive protein (CRP), and serum amyloid A protein (SAA).

[00244] The term "leukotriene-dependent", as used herein, refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of one or more leukotrienes.

[00245] The term "leukotriene-mediated", as used herein, refers to refers to conditions or disorders that might occur in the absence of leukotrienes but can occur in the presence of one or more leukotrienes.

[00246] The term "leukotriene-responsive mammal," as used herein, refers to a mammal who has been identified by either genotyping of FLAP haplotypes, or genotyping of LTA₄ hydrolase haplotypes or genotyping of one or more other genes in the leukotriene pathway and/or, by phenotyping of mammals either by previous positive clinical response to another leukotriene modulator, including, by way of example only, zileuton, montelukast, pranlukast, zafirlukast, and/or by their profile of leukotriene-driven mediators that indicate excessive leukotriene stimulation of inflammatory cells, as likely to respond favorably to leukotriene modulator therapy.

[00247] The term "carrier," as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

[00248] The terms "co-administration" or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single mammal, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[00249] The term "diluent" refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.

[00250] The terms "effective amount" or "therapeutically effective amount," 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. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.

[00251] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[00252] The terms "kit" and "article of manufacture" are used as synonyms.

[00253] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism may be obtained from The

Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[00254] By "pharmaceutically acceptable," as used herein, refers a material., such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[00255] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.

[00256] The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula (I), Formula (II), or Formula (III), and a co- agent, are both administered to a mammal simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula (I), Formula (II), or Formula (III), and a co-agent, are administered to a mammal as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the mammal. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[00257] The term "pharmaceutical composition" refers to a mixture of a compound of Formula (I), Formula (II), or Formula (III), with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to:

intravenous, oral., aerosol, parenteral., ophthalmic, pulmonary and topical administration.

[00258] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[00259] The terms "treat," "treating" or "treatment," 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.

Pharmaceutical Composition/Formulation

[00260] For convenience, the pharmaceutical compositions and formulations described in this section and other parts herein use a single formula, such as "Formula (I)," by way of example. In addition, the pharmaceutical compositions and formulations described herein apply equally well to all formulae presented herein that fall within the scope of Formula (I). For example, the pharmaceutical compositions and formulations described herein can be applied to compounds having the structure of Formula (I), Formula (II), or Formula (III), as well as to all of the specific compounds that fall within the scope of these generic formulae.

[00261] Pharmaceutical compositions are formulated in conventional manners using one or more physiologically acceptable carriers including 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. A summary of pharmaceutical compositions described herein is found, for example, in 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,

Pennsylvania 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 & Wilkinsl999), herein incorporated by reference for such disclosures. [00262] Provided herein are pharmaceutical compositions that include a compound described herein, such as a compound of Formula (I) and a pharmaceutically acceptable diluent(s), excipient(s), and/or carrier(s). In addition, the compounds described herein can be administered as pharmaceutical compositions in which compounds described herein, such as compounds of Formula (I), are mixed with other active ingredients, as in combination therapy.

[00263] A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein, such as a compound of Formula (I) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein, such as compounds of Formula (I) provided herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[00264] In some embodiments, for intravenous injections, compounds described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal

administration, penetrants appropriate to the barrier to be permeated are used in the formulation. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.

[00265] For oral administration, compounds described herein can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients. Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a mammal to be treated.

[00266] Pharmaceutical preparations for oral use can be 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 dragee cores. Suitable excipients are, but not limited to, 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. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[00267] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions are used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. In some cases, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00268] Pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. All formulations for oral administration are in dosages suitable for such administration.

[00269] For buccal or sublingual administration, the compositions take the form of tablets, lozenges, or gels formulated in a conventional manner.

[00270] Parental injections involve bolus injection or continuous infusion. In some embodiments, formulations for injection are presented in unit dosage form, e.g. , in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition of the compounds described herein are in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound(s) in water-soluble form. Additionally, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In some cases, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient is in powder form for constitution with a suitable vehicle, e.g. , sterile pyrogen- free water, before use. [00271] The compounds described herein, such as compounds of Formula (I), can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[00272] In some embodiments, formulations suitable for transdermal administration of compounds described herein employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In certain embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein is accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches can provide controlled delivery of the compounds described herein. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers are used to increase absorption. In certain cases, an absorption enhancer or carrier includes absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[00273] For administration by inhalation, the compounds described herein are in a form as an aerosol, a mist, or a powder. Pharmaceutical compositions of compounds described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g. , dichlorodifiuoromethane,

trichlorofluoromethane, dichlorotetrafiuoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol the dosage unit is determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[00274] In some embodiments, the compounds described herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted. [00275] Pharmaceutical compositions are formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which are pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Pharmaceutical compositions that include a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[00276] The pharmaceutical compositions will include at least one pharmaceutically acceptable carrier, diluent and/or excipient and a compound described herein, such as a compound of Formula (I) as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.

[00277] In addition, the pharmaceutical compositions may include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. In some embodiments, the pharmaceutical compositions also include other therapeutically valuable substances.

[00278] Methods for the preparation of compositions that include the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.

Liquid compositions include solutions in which a compound is dissolved, emulsions that include a compound described herein, or a solution containing liposomes, micelles, or nanoparticles that include a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. In some cases, the compositions are in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[00279] A composition that includes a compound described herein, such as a compound of Formula (I) illustratively takes the form of a liquid where the agents are present in solution, in suspension, or both. Typically when the composition is administered as a solution or suspension, a first portion of the compound is present in solution and a second portion of the compound is present in particulate form, in suspension in a liquid matrix. In some

embodiments, a liquid composition may include a gel formulation. In other embodiments, the liquid composition is aqueous. [00280] In some embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl- containing polymers. In some embodiments, compositions also include a mucoadhesive polymer, selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate, and dextran.

[00281] In some embodiments, compositions also include solubilizing agents to aid in the solubility of a compound described herein, such as a compound of Formula (I). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[00282] In some embodiments, compositions include one or more pH adjusting agents or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[00283] In some embodiments, compositions include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[00284] In some embodiments, compositions include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[00285] Still other compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g. , polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. [00286] Still other compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[00287] In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.

[00288] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as N-methylpyrrolidone also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds are delivered using a sustained-release system, such as semipermeable matrices of solid

hydrophobic polymers containing the therapeutic agent. Sustained-release capsules, depending on their chemical nature, release the compounds over the course of 4-24 hours. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

Methods of Dosing and Treatment Regimens

[00289] For convenience, the methods of dosing and treatment regimens described in this section and other parts herein use a single formula, such as "Formula (I)," by way of example. In addition, the methods of dosing and treatment regimens described herein apply equally well to all formulae presented herein that fall within the scope of Formula (I). For example, the methods of dosing and treatment regimens described herein can be applied to compounds having the structure of Formula (I), Formula (II), or Formula (III), as well as to all of the specific compounds that fall within the scope of these generic formulae.

[00290] The compounds described herein, such as compounds of Formula (I), can be used in the preparation of medicaments for the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable N- oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or

pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject

[00291] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a mammal 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 will depend on the severity and course of the disease or condition, previous therapy, the mammars health status, weight, and response to the drugs, and the judgment of the treating physician. Such therapeutically effective amounts are optionally determined by a dose escalation clinical trial.

[00292] In prophylactic applications, compositions containing the compounds described herein are administered to a mammal susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the mammal's state of health, weight, and the like. Such therapeutically effective amounts are optionally determined by a dose escalation clinical trial. When used in a mammal, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal's health status and response to the drugs, and the judgment of the treating physician.

[00293] In the case wherein the mammal's condition does not improve, upon the doctor's discretion the administration of the compounds described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the mammal's life in order to ameliorate or otherwise control or limit the symptoms of the mammal's disease or condition.

[00294] In the case wherein the mammal's status does improve, upon the doctor's discretion the administration of the compounds described herein are given continuously; alternatively, the dose of the compounds described herein being administered may be temporarily reduced or temporarily suspended for a certain length of time {i.e., a "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday may be from 10%- 100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[00295] Once improvement of the mammal's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved state of the disease, disorder or condition is maintained. Mammals can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[00296] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity {e.g., age, weight, gender, etc.) of the subject or host in need of treatment, but can nevertheless be determined in a manner 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 subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, in some embodiments 1-1500 mg per day. The desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00297] In some embodiments, the pharmaceutical composition described herein is in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. In some embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation. Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single- dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[00298] The daily dosages appropriate for the compounds described herein are from about 0.01 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form. Suitable unit dosage forms for oral administration include from about 1 mg to about 50 mg active ingredient. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00299] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD5₀ and ED₅₀. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating

concentrations that include the ED5₀ with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

Combination Treatments

[00300] For convenience, the combination treatments described in this section and other parts herein use a single formula, such as "Formula (I)," by way of example. In addition, the combination treatments described herein apply equally well to all formulae presented herein that fall within the scope of Formula (I). For example, the combination treatments described herein can be applied to compounds having the structure of Formula (I), Formula (II), or Formula (III), as well as to all of the specific compounds that fall within the scope of these generic formulae.

[00301] In certain instances, it may be appropriate to administer at least one compound of Formula (I) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a mammal upon receiving one of the compounds herein is inflammation, then it may be appropriate to administer an anti-inflammatory agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant {i.e., by itself the adjuvant may have minimal therapeutic benefit, but in

combination with another therapeutic agent, the overall therapeutic benefit to the mammal is enhanced). Or, by way of example only, the benefit experienced by a mammal may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for asthma involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the mammal with other therapeutic agents or therapies for asthma. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the mammal may simply be additive of the two therapeutic agents or the mammal may experience a synergistic benefit.

[00302] Therapeutically-effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens include, for example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.

[00303] A combination treatment regimen encompasses treatment regimens in which administration of a 5-lipoxygenase inhibitor described herein is initiated prior to, during, or after treatment with a second agent described above, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a 5-lipoxygenase inhibitor described herein and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment futher includes periodic treatments that start and stop at various times to assist with the clinical management of the mammal. For example, a 5-lipoxygenase inhibitor described herein in the combination treatment can be administered weekly at the onset of treatment, decreasing to biweekly, and decreasing further as appropriate.

[00304] Compositions and methods for combination therapy are provided herein. In accordance with one aspect, the pharmaceutical compositions disclosed herein are used to treat leukotriene-dependent or leukotriene mediated conditions. In accordance with another aspect, the pharmaceutical compositions disclosed herein are used to treat respiratory diseases, where treatment with a 5-lipoxygenase inhibitor is indicated, in particular asthma, and to induce bronchodilation in a subject. In one embodiment, pharmaceutical compositions disclosed herein are used to treat a subject suffering from a vascular inflammation-driven disorder. In one embodiment, the pharmaceutical compositions disclosed herein are used to treat a subject susceptible to myocardial infarction (MI).

[00305] Combination therapies described herein can be used as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of a 5-lipoxygenase inhibitors described herein and a concurrent treatment. It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, can be modified in accordance with a variety of factors. These factors include the type of respiratory disorder and the type of bronchodilation from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein.

[00306] For combination therapies described herein, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific compound employed, on the disease or condition being treated and so forth. In addition, when co-administered with one or more biologically active agents, the compound provided herein is administered either simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering the compound described herein, such as a compound of Formula (I), in combination with the biologically active agent(s).

[00307] In any case, the multiple therapeutic agents (one of which is one of the compounds described herein, such as a compound of Formula (I) are administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents are provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations are also envisioned.

[00308] In addition, the compounds described herein, such as compounds of Formula (I), are used in combination with procedures that provide additional or synergistic benefit to the mammal. By way of example only, mammals are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of Formula (I) and /or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.

[00309] The compounds described herein, such as compounds of Formula (I), and combination therapies can be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition(s) containing a compound can vary. Thus, for example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, in some embodiments within the first 48 hours of the onset of the symptoms, in other embodiments within the first 6 hours of the onset of the symptoms, and yet in other embodiments within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, a solution, suspension, and the like, or combination thereof. A compound is preferably administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 day to about 3 months. The length of treatment can vary for each subject, and the length can be determined using known criteria. For example, the compound or a formulation containing the compound can be administered for at least 2 weeks, in some embodiments from about 1 month to about 5 years, and in other embodiments from about 1 month to about 3 years.

[00310] By way of example, therapies which combine compounds of Formula (I) with inhibitors of leukotriene synthesis or leukotriene receptor antagonists, either acting at the same or other points in the leukotriene synthesis pathway, could prove to be particularly useful for treating leukotriene-dependent or leukotriene mediated diseases or conditions. In addition, by way of example, therapies which combine compounds of Formula (I) with inhibitors of inflammation could prove to be particularly useful for treating leukotriene-dependent or leukotriene mediated diseases or conditions.

Anti-Inflammatory Agents

[00311] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases include administering to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with an anti-inflammatory agent including, but not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids).

[00312] NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate,

meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337 and NS398).

[00313] Corticosteroids, include, but are not limited to: betamethasone (Celestone), prednisone (Deltasone), alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, formocortal, halcinonide,

halometasone, hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, and ulobetasol.

[00314] Corticosteroids do not directly inhibit leukotriene production, therefore co-dosing with steroids could provide additional anti-inflammatory benefit.

[00315] Some commercially available anti-inflammatories include, but are not limited to: diclofenac and misoprostol, 5-aminosalicyclic acid, antipyrine and benzocaine, sulfasalazine, oxaprozin, etodolac, mefenamic acid, methylprednisolone, aspirin, indomethacin, rofecoxib, celecoxib, valdecoxib, etoricoxib, lumiracoxib, ibuprofen, diclofenac, ketoprofen, meloxicam, nabumetone, naproxen, piroxicam.

[00316] By way of example, asthma is a chronic inflammatory disease characterized by pulmonary eosinophilia and airway hyperresponsiveness. In mammals with asthma, leukotrienes are released from mast cells, eosinophils, and basophils. The leukotrienes are involved in contraction of airway smooth muscle, an increase in vascular permeability and mucus secretions, and have been reported to attract and activate inflammatory cells in the airways of asthmatics (Siegel et ah, ed., Basic Neurochemistry, Molecular, Cellular and Medical Aspects, Sixth Ed., Lippincott Williams & Wilkins, 1999). Thus, in another embodiment described herein, the methods for treatment of respiratory diseases include administering to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with an anti-inflammatory agent.

Leukotriene Receptor Antagonists

[00317] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases include administering to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with leukotriene receptor antagonists including, but are not limited to, CysLTi/CysLT₂ dual receptor antagonists and CysLTi receptor anatagonists. In another embodiment described herein, methods for treatment of leukotriene-dependent or leukotriene mediated conditions or diseases include administering to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with a CysLT i/CysLT dual receptor antagonist. CysLTi/CysLT₂ dual receptor antagonists include, but are not limited to, BAY u9773 (4- ((4S,5R,6E,8E, 10Z, 13Z)- 1 -carboxy-4-hydroxynonadeca-6,8, 10, 13-tetraen-5-ylthio)benzoic acid) (EP 00791576), DUO-LT (6-((4-(2-carbamoylacetyl)phenyl)sulfanyl)-6-(4-nonylphenyl)- 5-oxohexanoic acid). For a particular mammal, the most appropriate formulation or method of use of such combination treatments depends on the type of leukotriene-dependent or leukotriene mediated disorder, the time period in which the 5-lipoxygenase inhibitor acts to treat the disorder and the time period in which the CysLT i/CysLT₂ dual receptor antagonist acts to inhibit CysLT receptor activity. By way of example only, such combination treatments are used for treating a mammal suffering from a respiratory disorder.

[00318] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases include administering to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with a CysLTi receptor antagonist. CysLTi receptor antagonists include, but are not limited to, zafirlukast, montelukast, prankulast (ONO-1078), and derivatives or analogs thereof. Such combinations are used to treat leukotriene-dependent or leukotriene mediated disorder, including respiratory disorders.

[00319] In some embodiments, the co-administration of a 5-lipoxygenase or FLAP inhibitor described herein with a CysLTi receptor antagonist or a dual CysLTi/CysLT₂ receptor antagonist has therapeutic benefit over and above the benefit derived from the administration of a either a 5-lipoxygenase or FLAP inhibitor or a CysLTiR antagonist alone. In the case that substantial inhibition of leukotriene production has undesired effects, partial inhibition of this pathway through the amelioration of the effects of the proinflammatory LTB₄ and cysteinyl leukotrienes combined with the block of the CysLTi receptor and/or dual CysLTyCysLT₂ receptor block may afford substantial therapeutic benefits, particularly for respiratory diseases.

Other Combination Therapies

[00320] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases, such as proliferative disorders, including cancer, include administration to a mammal compounds, pharmaceutical

compositions, or medicaments described herein in combination with at least one additional agent selected from among: alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine,

daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, paclitaxel (Taxol), temozolomide, thioguanine, or classes of drugs including hormones (an antiestrogen, an antiandrogen, or gonadotropin releasing hormone analogues), interferons such as, but not limited to, alpha interferon; nitrogen mustards such as, but not limited to, busulfan, melphalan, and mechlorethamine; retinoids such as, but not limited to, tretinoin; topoisomerase inhibitors such as, but not limited to, irinotecan, and topotecan;

tyrosine kinase inhibitors such as, but not limited to, gefinitinib, and imatinib; or agents to treat signs or symptoms induced by such therapy including, but not limited to, allopurinol, filgrastim, granisetron/ ondansetron/ palonosetron, and dronabinol.

[00321] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases, such as the therapy of transplanted organs or tissues or cells, include administration to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from among azathioprine, a corticosteroid, cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, and thymoglobulin.

[00322] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases, such as atherosclerosis, include administration to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from among HMG- CoA reductase inhibitors (e.g., statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin; simvastatin; dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof; fluvastatin, particularly the sodium salt thereof; atorvastatin, particularly the calcium salt thereof; nisvastatin, also referred to as NK- 104; rosuvastatin); agents that have both lipid-altering effects and other pharmaceutical activities; HMG-CoA synthase inhibitors; cholesterol absorption inhibitors such as ezetimibe; cholesterol ester transfer protein (CETP) inhibitors, for example JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors); acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT- 1 or ACAT-2 as well as dual inhibitors of ACAT- 1 and-2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example adenosine diphosphate (ADP) receptor (P2Y12 receptor) inhibitors such as clopidogrel

(Plavix®), glycoprotein Ilb/IIIa fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPARy) agonists, including the compounds commonly referred to as glitazones, for example troglitazone, pioglitazone and rosiglitazone and including those compounds included within the structural class known as thiazolidinediones as well as those PPARy agonists outside the thiazolidinedione structural class; PPARa agonists such as clofibrate, fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dual α/γ agonists such as 5-[(2, 4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4- (trifluoromethyl)phenyl]methyl]-benzamide, known as KRP-297; vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCI salt; vitamin B 12 (also known as cyanocobalamin); folic acid or a pharmaceutically acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt; anti-oxidant vitamins such as vitamin C and E and beta carotene; beta-blockers; angiotensin II antagonists such as losartan; angiotensin converting enzyme inhibitors such as enalapril and captopril; calcium channel blockers such as nifedipine and diltiazam; endothelian antagonists; agents that enhance ABC1 gene expression; FXR and LXR ligands including both inhibitors and agonists; bisphosphonate compounds such as alendronate sodium; and cyclooxygenase-2 inhibitors, such as, for example, rofecoxib, celecoxib, etoricoxib, and lumiracoxib.

[00323] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases, such as the therapy of stroke, include administration to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from COX-2 inhibitors; nitric oxide synthase inhibitors, such as, but not limited to, N-(3- (aminomethyl)benzyl) acetamidine; Rho kinase inhibitors, such as, but not limited to, fasudil; angiotension II type-1 receptor antagonists, including, but not limited to, candesartan, losartan, irbesartan, eprosartan, telmisartan, and valsartan; glycogen synthase kinase 3 inhibitors; sodium or calcium channel blockers, including, but not limited to, crobenetine; p38 MAP kinase inhibitors, including, but not limited to, SKB 239063; thromboxane AX- synthetase inhibitors, including, but not limited to, isbogrel, ozagrel, ridogrel and dazoxiben; statins (HMG CoA reductase inhibitors), including, but not limited to, lovastatin, simvastatin, dihydroxy open-acid simvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin, and rosuvastatin; neuroprotectants, including free radical scavengers, calcium channel blockers, excitatory amino acid antagonists, growth factors, antioxidants, such as edaravone, vitamin C, vitamin E, 6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid, citicoline and minicycline, and reactive astrocyte inhibitors, such as (2R)-2-propyloctanoic acid; beta andrenergic blockers, such as, but not limited to, propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol and acebutolol; NMDA receptor antagonists, including memantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists; adenosine diphosphate (ADP) receptor (P2Y12 receptor) inhibitors such as clopidogrel; aspirin; receptor platelet fibrinogen receptor antagonists, including tirofiban and lamifiban; thrombin inhibitors; antithrombotics, such as argatroban; antihypertensive agents, such as enalapril; vasodilators, such as cyclandelate; nociceptin antagonists; DPIV antagonists; GABA 5 inverse agonists; and selective androgen receptor modulators.

[00324] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases, such as the therapy of pulmonary fibrosis, include administration to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from among anti-inflammatory agents, such as corticosteroids, azathioprine, and cyclophosphamide.

[00325] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases, such as the therapy of interstitial cystitis, include administration to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from among dimethylsulfoxide, omalizumab, and pentosan polysulfate.

[00326] In another embodiment described herein, methods for treatment of leukotriene- dependent or leukotriene mediated conditions or diseases, such as the therapy of disorders of bone, include administration to a mammal compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from among minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analogs, and cathepsin K inhibitors.

[00327] In another embodiment, described herein, methods for treatment of leukotriene- dependent or leukotriene-mediated conditions or diseases, such as the therapy of painful disorders such as arthritis, including administration to a mammal compounds, pharmaceutical compositions, topically applied gels or ointments or medicaments described herein in combination with at least one additional agent selected from among NSAIDs, opiods or anesthetics.

Diagnostic Methods for Mammal Identification

[00328] For convenience, the diagnostic and/or mammal identification methods and treatment methods resulting therefrom that are described in this section and other parts herein use a single formula, such as "Formula (I)," by way of example. In addition, the diagnostic and/or mammal identification methods and treatment methods resulting therefrom that are described herein apply equally well to all formulae presented herein that fall within the scope of Formula (I). For example, the diagnostic and/or mammal identification methods and treatment methods resulting therefrom that are described herein can be applied to compounds having the structure of Formula (I), Formula (II), or Formula (III), as well as to all of the specific compounds that fall within the scope of these generic formulae.

[00329] The screening of "leukotriene-responsive mammals" which are selected for treatment with compounds described herein, such as compounds of Formula (I), or pharmaceutical compositions or medicaments described herein which include compounds of Formula (I), or other 5-lipoxygenase modulators, is accomplished, in some embodiments, using techniques and methods described herein. Such techniques and methods include, by way of example, evaluation of gene haplotypes (genotype analysis), monitoring/measurement of biomarkers (phenotype analysis), monitoring/measurement of functional markers (phenotype analysis), which indicate mammal response to known modulators of the leukotriene pathway, or any combination thereof.

Phenotype Analysis: Biomarkers

[00330] In some embodiments, mammals who are under consideration for treatment with compounds described herein, such as compounds of Formula (I), or drug combinations described herein that include compounds described herein, such as compounds of Formula (I), are screened for potential responsiveness to treatment based on leukotriene-driven inflammatory biomarker phenotypes.

[00331] Mammal screening based on leukotriene-driven inflammatory biomarker phenotypes can be used as an alternative to, or it may be complimentary with, mammal screening by leukotriene pathway gene haplotype detection. The term "biomarker" as used herein refers to a characteristic which can be measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacological responses to therapeutic intervention. Thus a biomarker may be any substance, structure or process which can be measured in the body, or its products, and which may influence or predict the incidence of outcome or disease. Biomarkers may be classified into markers of exposure, effect, and susceptibility. Biomarkers can be physiologic endpoints, by way of example blood pressure, or they can be analytical endpoints, by way of example, blood glucose, or cholesterol concentrations. Techniques, used to monitor and/or measure biomarkers include, but are not limited to, NMR, LC-MS, LC-MS/MS, GC-MS, GC-MS/MS, HPLC-MS, HPLC-MS/MS, FT-MS, FT-MS/MS, ICP-MS, ICP-MS/MS, peptide/protein sequencing, nucleic acid sequencing, electrophoresis techniques, immunoassays, immuno-blotting, in-situ hybridization, fluorescence in-situ hybridization, PCR, radio- immuno assays, and enzyme-immuno assays. Single nucleotide polymorphisms (SNPs) have also been useful for the identification of biomarkers for propensity to certain diseases and also susceptibility or responsiveness to drugs such as chemotherapeutic agents and antiviral agents. These techniques, or any combination thereof, may be used to screen mammals for leukotriene- dependent or leukotriene mediated diseases or conditions, wherein such mammals may be beneficially treated with compounds described herein, such as compounds of Formula (I), or drug combinations described herein that include compounds described herein, such as compounds of Formula (I).

[00332] In some embodiments, mammals are selected for treatment with compounds described herein, such as compounds of Formula (I), or drug combinations described herein that include compounds described herein, such as compounds of Formula (I), by screening for enhanced inflammatory blood biomarkers such as, but not limited to, stimulated LTB₄, LTC₄, LTE₄, myeloperoxidase (MPO), eosinophil peroxidase (EPO), C-reactive protein (CRP), soluble intracellular adhesion molecule (sICAM), monocyte chemoattractant protein (MCP-1), monocyte inflammatory protein (ΜΙΡ-Ια), interleukin-6 (IL-6), the TH2 T cell activators interleukin 4 (IL-4), and 13 (IL-13) and other inflammatory cytokines. In certain embodiments, mammals with inflammatory respiratory diseases, including but not limited to, asthma and COPD, or with cardiovascular diseases, are selected as those most likely to be responsive to leukotriene synthesis inhibition using compounds described herein, such as compounds of Formula (I), by using a panel of leukotriene driven inflammatory biomarkers.

Phenotype Analysis: Functional Markers

[00333] In some embodiments, mammals who are under consideration for treatment with compounds described herein, such as compounds of Formula (I), or drug combinations described herein that include compounds described herein, such as compounds of Formula (I), are screened for response to known modulators of the leukotriene pathway. Mammal screening by evaluation of functional markers as indicators of a mammal's response to known modulators of the leukotriene pathway may be used as an alternative to, or it may be complimentary with, mammal screening by leukotriene pathway gene haplotype detection (genotype analysis) and/or monitoring/measurement of leukotriene-driven inflammatory biomarker phenotypes. Functional markers include, but are not limited to, any physical characteristics associated with a leukotriene dependent condition or disease, or knowledge of current or past drug treatment regimens.

[00334] In some embodiments, the evaluation of lung volume and/or function is used as a functional marker for leukotriene-dependent or leukotriene mediated diseases or conditions, such as respiratory diseases. In some embodiments, lung function tests are used to screen mammals, with such leukotriene-dependent or leukotriene mediated diseases or conditions, for treatment using compounds described herein, such as compounds of Formula (I) or

pharmaceutical compostitons or medicaments which include compounds of Formula (I). Such tests include, but are not limited to, evaluation of lung volumes and capacities, such as tidal volume, inspiratory reserve volume, expiratory reserve volume, residual volume, inspiratory capacity, functional residual capacity, vital capacity, total lung capacity, respiratory minute volume, alveolar ventilation, timed vital capacity, and ventilatory capacity. Method of measurement of lung volumes and capacities include, but are not limited to, maximum expiratory flow volume curve, forced expiratory volume in 1 sec. (FEV1), peak expiratory flow rate. In addition, other lung function tests used as functional markers for mammal evaluation described herein include, but are not limited to, respiratory muscle power, maximum inspiratory pressure, maximum expiratory pressure, transdiaphragmatic pressure, distribution of ventilation, single breath nitrogen test, pulmonary nitrogen washout, and gas transfer.

[00335] Additionally, the knowledge of a mammals past or current treatment regimen is used as a functional marker to assist in screening mammals for treatment of leukotriene dependent conditions or diseases using compounds of Formula (I) or pharmaceutical compositions or medicaments that include compounds of Formula (I). By way of example only, such treatment regimens include past or current treatment using zileuton, montelukast, pranlukast, zafirlukast.

[00336] In some cases, mammals who are under consideration for treatment with compounds described herein, such as compounds of Formula (I), or drug combinations described herein that include compounds described herein, such as compounds of Formula (I), are screened for functional markers which include, but are not limited to, reduced eosinophil and/or basophil, and/or neutrophil, and/or monocyte and/or dendritic cell and/or lymphocyte recruitment, decreased mucosal secretion, decreased mucosal edema, and/or increased bronchodilation. [00337] It is expected that one skilled in the art will use this information in conjunction with other mammal information, including, but not limited to age, weight, sex, diet, and medical condition, to choose a treatment method. It is also expected that each piece of information will be given a particular weight in the decision process. In certain embodiments, the information obtained from the diagnostic methods described above and any other mammal information, including, but not limited to age, weight, sex, diet, and medical condition, are incorporated into an algorithm used to elucidate a tretment method, wherein each piece of information will be given a particular weight in the decision process.

[00338] In certain embodiments a mammal sample is analyzed for leukotriene gene haplotypes and the information obtained identifies a mammal in need of treatment using various treatment methods. Such treatment methods include, but are not limited to, administering a therapeutic effective amount of a compound of Formula (I) or pharmaceutical composition or medicament which includes a compound of Formula (I), administering a therapeutic effective amount of a compound of Formula (I) or pharmaceutical composition or medicament which includes a compound of Formula (I), in combination with a therapeutic effective amount of a leukotriene receptor antagonist (by way of example, CysLTi/CysLT₂ antagonist or CysLTi antagonist), or administering a therapeutic effective amount of a compound of Formula (I) or pharmaceutical composition or medicament which includes a compound of Formula (I), in combination with a therapeutic effective amount of another anti-inflammatory agent. In other embodiments a mammal sample is analyzed for leukotriene gene haplotypes, and/or phenotype biomarkers, and/or phenotype functional marker responses to leukotriene modifying agents. The mammal may then be treated using various treatment methods. Such treatment methods include, but are not limited to, administering a therapeutic effective amount of a compound of Formula (I) or pharmaceutical composition or medicament which includes a compound of Formula (I), administering a therapeutic effective amount of a compound of Formula (I) or pharmaceutical composition or medicament which includes a compound of Formula (I), in combination with a therapeutic effective amount of a leukotriene receptor antagonist (by way of example,

CysLTi/CysLT₂ antagonist or CysLTi antagonist), or administering a therapeutic effective amount of a compound of Formula (I) or pharmaceutical composition or medicament which includes a compound of Formula (I), in combination with a therapeutic effective amount of another anti-inflammatory agent. In still other embodiments a mammal sample is analyzed for leukotriene gene haplotypes, and phenotype biomarkers, and phenotype functional marker responses to leukotriene modifying agents. The mammal is then treated using various treatment methods; such treatment methods include, but are not limited to, administering a therapeutic effective amount of a 5-lipoxygenase inhibitor, or pharmaceutical composition or medicament that includes a 5-lipoxygenase inhibitor, administering a therapeutic effective amount of a 5- lipoxygenase inhibitor, or pharmaceutical composition or medicament which includes a 5- lipoxygenase inhibitor, in combination with a therapeutic effective amount of a leukotriene receptor antagonist (by way of example, CysLTyCysUI^ antagonist or CysLTi antagonist), or administering a therapeutic effective amount of a 5-lipoxygenase inhibitor, or pharmaceutical composition or medicament that includes a 5-lipoxygenase inhibitor in combination with a therapeutic effective amount of another anti-inflammatory agent.

Kits/ Articles of Manufacture

[00339] For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic.

[00340] The articles of manufacture provided herein contain packaging materials. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by inhibition of 5-LO or in which 5-LO activity is a mediator or contributor to the symptoms or cause.

[00341] For example, the container(s) include one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[00342] In some embodiments, a kit includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non- limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. [00343] A label is on or associated with the container. A label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[00344] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. For example, the pack contains metal or plastic foil, such as a blister pack. The pack or dispenser device is accompanied by instructions for administration. The pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Compositions containing a compound provided herein are formulated into suitable forms for adminstration, placed in an appropriate container, and labeled for treatment of an indicated condition.

EXAMPLES

[00345] The person skilled in the art may further appreciate various aspects and advantages the present disclosure upon review of the following illustrative and non- limiting examples. Intermediate A: Trifluoromethyl-pent-l- -3-ol

Step 1: 3-Trifluoromethyl-l-trimethylsilanyl-pent-l-yn-3-ol

[00346] To (trimethylsilyl)acetylene (2.45g, 25mmol) in THF (lOOmL) at -78°C was added n- butyllithium (1.6M in hexanes; 19mL, 30mmol) dropwise. After stirring for 1 hour at -78°C, l,l,l-trifluoro-2-butanone (4mL, 30mmol) in THF (lOmL) was added dropwise, and the reaction was slowly warmed to room temperature. The mixture was diluted with Et₂0 (300mL) and washed with H₂0, and then dried, filter concentrated to give the title compound.

Step 2: 3-Trifluoromethyl-pent-l-yn-3-ol

[00347] 3-Trifluoromethyl-l-trimethylsilanyl-pent-l-yn-3-ol (3.67g, 16.4mmol) in MeCN (lOOmL) was treated with cesium fluoride (2.62g, 17.2mmol), and the reaction was stirred at room temperature for 15 minutes. The mixture was diluted with Et₂0 (300mL) and washed with ¾0 and brine. The combined aqueous layers were back-extracted with Et₂0, and the mixture was concentrated to ~300mL. THF (500mL) was added, and the mixture was concentrated to - lOOmL and then used directly in the following step.

Intermediate B: 4-Nitro-benzoic acid l-ethyl-l-trifluoromethyl-prop-2-ynyl ester

0₂

[00348] A solution of 3-trifluoromethyl-l-trimethylsilanyl-pent-l-yn-3-ol (0.500g, 2.23mmol) in DMF (15mL) was treated with sodium hydride (60% in mineral oil; 0.090g, 2.25mmol), followed by 4-nitrobenzoyl chloride (0.414g, 2.23mmol), and the reaction was stirred at room temperature. Aqueous work-up provided the title compound as a racemate.

[00349] Resolution: The racemic nitrobenzoate ester (30.2 g) was resolved (Chiral

Technologies, Inc., West Chester, PA) by preparative HPLC using a D-Star HPLC unit with a 5cm ID x 25cm L column. The stationary phase was CHIRALCEL® OD 20 μηι and the mobile phase was hexane/IPA 95:5 with a flow rate of 160 mL/min. The racemate was dissolved at a concentration of 25g/L in the mobile phase and the injection volume was 200 mL. Fractions were collected, combined and the solvent removed using a rotary evaporator to afford the first eluting enantiomer, Enantiomer A, 13.5g (99.8% e.e.) and the second eluting enantiomer, Enantiomer B, 12.9 g (>99.9% e.e.).

Intermediate C: 2-(5-Amino-[l,3,4]ox ,l-trifluoro-butan-2-ol

Step 1: 2-Hydroxy-2-trifluoromethyl-butyric acid ethyl ester

[00350] To a solution of ethyl 3,3,3-trifluoropyruvate (50g, 294mmol) in Et₂0 (500mL) at - 78°C was added ethylmagnesium bromide (3M in Et₂0; 98mL, 294mmol) over 90 minutes. The reaction was allowed to warm to -10°C and then poured in saturated aqueous NH₄C1 (1L). The aqueous layer was extracted 5 times with Et₂0, and the combined organic layers were dried over MgS0₄, filtered, and concentrated to give the title compound.

Step 2: 2-Hydroxy-2-trifluoromethyl-butyric acid hydrazide

[00351] 2-Hydroxy-2-trifluoromethyl-butyric acid ethyl ester (48g, 224mmol) and hydrazine hydrate (25mL) were combined, and the reaction was stirred at 80°C for 18 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (70% EtOAc in hexanes) to give the title compound as an orange oil.

Step 3: 2-(5-Amino-[l,3,4]oxadiazol-2-yl)-l,l,l-trifluoro-butan-2-ol

[00352] To 2-Hydroxy-2-trifluoromethyl -butyric acid hydrazide (28g, 150mmol) in ¾0 (250mL) was added NaHC0₃ (12.6g, 150mmol). Cyanogen bromide (15.93g, 150mmol) was added over 5 minutes, and the reaction was stirred at room temperature overnight, with a precipitate forming after 10 minutes. The mixture was filtered, and the isolated solids were washed with H₂0 and dried to give the title compound.

Example 1: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-isopropyl-benzo[6]thiop le (Compound 1-1)

Step 1: l-(4-Bromo-2-fluoro-phenyl)-2-methyl-propan-l-ol

[00353] To a stirred solution of 4-bromo-2-fluorobenzaldehyde (10.0 g, 49.3 mmol) in anhydrous THF (200 mL) at 0°C was added isopropylmagnesium chloride (25.0 mL of a 2.0M solution in THF, 50.0 mmol) slowly via syringe. After 30 minutes, an additional 20.0 mL isopropylmagnesium chloride was added, and stirring continued for 5 minutes. TLC analysis indicated that the starting material had been consumed, and the reaction was then quenched with 100 mL H₂0. The resulting mixture was diluted with 200 mL EtOAc, and the aqueous layer was separated. The organic layer was washed with an additional 100 mL H₂O, then dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 100% EtOAc in hexanes) to give the title compound.

Step 2: l-(4-Bromo-2-fluoro-phenyl)-2-methyl-propan-l-one

[00354] To a stirred solution of 1 -(4-bromo-2-fluoro-phenyl)-2-methyl-propan- 1 -ol (3.52 g, 14.25 mmol) and 4-methylmorpholine N-oxide (2.5 g, 21.4 mmol) in DCM (120 mL) and ACN (20 mL) at room temperature was added tetrapropylammonium perruthenate (150 mg, 0.43 mmol). After 1 hour, an addition portion of tetrapropylammonium perruthenate (100 mg, 0.28 mmol) was added, and stirring was continued for 10 minutes. TLC analysis indicated that the starting material had been consumed, and the reaction was then quenched with the addition of silica gel. The resulting mixture was concentrated to dryness, and loaded on top of a short plug of silica gel. The product was eluted with 30% EtOAc in hexanes (500 mL) to give the title compound.

Step 3: 6-Bromo-3-isopropyl-benzo[6]thiophene-2-carboxylic acid methyl ester

[00355] To a mixture of 1 -(4-bromo-2-fluoro-phenyl)-2-methyl-propan- 1 -one (3.2 g, 13.1 mmol) and CS2CO₃ (8.5 g, 26.2 mmol) in THF (100 mL) at room temperature was added methyl thioglycolate (1.42 mL, 15.7 mmol). The resulting mixture was heated at reflux for 18 hours, then cooled to room temperature and partitioned with EtOAc (200 mL) and ¾0 (100 mL). The aqueous layer was separated, and the organic layer was washed with additional H₂0 (50 mL) and brine (50 mL), then dried over MgS0₄, filtered, and concentrated to give the title compound.

Step 4: 6-Bromo-3-isopropyl-benzo[6]thiophene-2-carbonitrile

[00356] Ammonium chloride (1.43 g, 26.8 mmol) was suspended in dry toluene (26.8 mL) at 0°C. To this was added trimethylaluminum (13.4 mL of 2.0M solution in toluene, 26.8 mmol) slowly by syringe. The resulting mixture was stirred at room temperature for 1 hour, then transferred to a sealed reaction vessel containing 6-bromo-3-isopropyl-benzo[ ?]thiophene-2- carboxylic acid methyl ester (3.1 g, 9.9 mmol). The resulting mixture was capped tightly and stirred at 80°C for 18 hrs. The vessel was cooled to 0°C and diluted with toluene (100 mL), then quenched by the slow addition of solid sodium sulfate decahydrate (40 g) and stirred for 30 minutes. The resulting slurry was filtered, concentrated, and the residue was purified on silica gel (0% to 20% EtOAc in hexanes) to give the title compound.

Step 5: 2-Cyano-3-isopropyl-benzo[6]thiophene-6-carboxylic acid methyl ester

[00357] [l, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (629 mg, 0.86 mmol) was added to a nitrogen-purged mixture of 6-bromo-3-isopropyl-benzo[ ?]thiophene-2- carbonitrile (2.42 g, 8.6 mmol) and triethylamine (2.99 mL, 21.5 mmol) in DMF (50 mL) and MeOH (20 mL) at room temperature. The mixture was bubbled with carbon monoxide via balloon for 5 minutes, then warmed to 75°C and stirred with the carbon monoxide balloon needle placed in reaction flask head-space. After 18 hrs, TLC analysis showed disappearance of starting material. The mixture was cooled to room temperature, diluted with 1 : 1

EtOAc:hexanes (300 mL) and washed with water (2X50 mL) and brine (2X50 mL). The combined aqueous layers were back-extracted with 1 : 1 EtOAc:hexanes (100 mL) and the combined organic layers were dried over MgSC , filtered and concentrated. The residue was purified on silica gel (0% to 30% EtOAc in hexanes) to give the title compound.

Step 6: 2-Cyano-3-isopropyl-benzo[6]thiophene-6-carboxylic acid

[00358] To a stirred solution of 2-cyano-3-isopropyl-benzo[ ?]thiophene-6-carboxylic acid methyl ester (500 mg, 1.93 mmol) in 1 : 1 MeOH:THF (12 mL) at room temperature was added LiOH (1.0 N, 5.0 mL, 5.0 mmol). The resuting mixture was stirred for 3 hours, then neutralized with 1.0 N HC1 (7.5 mL) and diluted with EtOAc (50 mL). The aqueous layer was separated, and the organic layer was washed with H₂0 (20 mL), then dried over MgSC , filtered, and concentrated to give the title compound.

Step 7: 2-Cyano-3-isopropyl-benzo[6]thiophene-6-carbonyloxylformate isobutyl ester

[00359] To a solution of 2-cyano-3-isopropyl-benzo[ ?]thiophene-6-carboxylic acid (443 mg, 1.8 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) in DCM (15 mL) at 0°C was added isobutyl chloroformate (0.31 mL, 2.34 mmol) followed by 4-dimethylaminopyridine (21 mg, 0.18 mmol). The cold bath was removed, and the reaction was stirred for 10 minutes at room temperature, after which time analytical LCMS analysis showed disappearance of starting material. The mixture was diluted with 200 mL EtOAc and transferred to a separatory funnel, where it was washed with H₂0 (2X50 mL) and brine (50 mL), then dried over MgS0₄, filtered, and concentrated to give the title compound.

Step 8 : 6-Hydroxymethyl-3-isopropyl-benzo [b] thiophene-2-carbonitrile

[00360] To a stirred solution of 2-cyano-3-isopropyl-benzo[ ?]thiophene-6- carbonyloxylformate isobutyl ester (630 mg, 1.83 mmol) in absolute EtOH (15 mL) at 0°C was added sodium borohydride (153 mg, 4.0 mmol) in one portion. TLC analysis after 5 minutes showed disappearance of starting material. The reaction was quenched by dropwise addition of IN HC1, until gas evolution was no longer observed. The resulting mixture was diluted with EtOAc (100 mL) and partitioned with H₂0 (50 mL). The aqueous layer was separated, and the organic layer was dried over MgS0₄ ed to give the title compound.

Step 9: 6-Azidomethyl-3-isopropyl-benzo[6]thiophene-2-carbonitrile

[00361] To a solution of 6-hydroxymethyl-3-isopropyl-benzo[ ?]thiophene-2-carbonitrile (462 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.04 mL, 6.0 mmol) in DCM (20 mL) at 0°C was added methanesulfonyl chloride (0.234 mL, 3.0 mmol) dropwise via syringe. After stirring for 5 minutes, analytical LCMS of reaction aliquot showed full conversion to intermediate methanesulfonate. The reaction was poured in to EtOAc (150 mL), washed with saturated NaHC0₃ (20 mL) and H₂0 (50 mL), then dried over MgS0₄, filtered, and concentrated. The crude residue was dissolved in DMF (10 mL) and to this was added sodium azide (195 mg, 3.0 mmol). The mixture was stirred for 1 hour at room temperature, after which time LCMS analysis of the reaction showed disappearance of the intermediate. The mixture was then diluted with 1 : 1 EtOAc:hexanes (200 mL), washed with H₂0 (50 mL) and brine (2X50 mL), dried over MgS0₄, filtered and concentrated to give the title compound.

Step 10: 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-isopropyl- benzo[6]thiophene-2-carbonitrile

[00362] A solution of 3-trifluoromethyl-l-trimethylsilanyl-pent-l-yn-3-ol (0.775g, 3.46 mmol) in acetonitrile (30 mL) was treated with cesium fluoride (0.522g, 3.46 mmol) and the reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with ether (100 mL) and partitioned with ¾0 (50 mL). The ether layer was dried (MgS0₄) and concentrated to one third its original volume. THF (50 mL) was added, and the mixture was further concentrated to approximately 20 mL total volume. To this mixture was then added 6-azidomethyl-3-isopropyl- benzo[ ?]thiophene-2-carbonitrile (0.443 g, 1.73 mmol), followed by Cul (0.493 g, 2.6 mmol) and DIEA (1.8 mL, 10.4 mmol). The resulting mixture was stirred at room temperature for 0.5 hr, then diluted with EtOAc (100 mL), washed with saturated NH₄C1 (3X50 mL) and H₂0 (50 mL), dried (MgS0₄), filtered, and concentrated. The crude residue was purified on silica gel (0% to 100% EtOAc in hexanes) to afford the title compound. Mass spectrometric data: [M+H] = 409.

Example 2: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-isopropyl-benzo[6]thiophene-2-carbonitrile (Compound 1-2)

Step 1: 4-Nitro-benzoic acid l-[l-(2-cyano-3-isopropyl-benzo[6]thiophen-6-ylmethyl)-lH- [l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester

[00363] To a solution of 6-azidomethyl-3-isopropyl-benzo[ ?]thiophene-2-carbonitrile (510 mg, 2.0 mmol) and enantiopure 4-nitro-benzoic acid 1 -ethyl- 1 -trifluoromethyl-prop-2-ynyl ester (Enantiomer B; 903 mg, 3.0 mmol) in THF (20 mL) was added Cul (570 mg, 3.0 mmol) followed by N,N-diisopropylethylamine (2.1 mL, 12.0 mmol). The reaction was left to stir for 18 hrs, after which time LCMS analysis showed nearly full conversion to product. The mixture was diluted with EtOAc (100 mL), washed with saturated NH₄C1 (2x20 mL), dried over MgS0₄, filtered and concentrated to give the title compound which was determined to be sufficiently pure by analytical LCM to move forward to the next step.

Step 2: 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-isopropyl- benzo[6]thiophene-2-carbonitrile

[00364] To a solution of 4-nitro-benzoic acid l-[l-(2-cyano-3-isopropyl-benzo[ ?]thiophen-6- ylmethyl)-lH-[l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester (1.1 g, 2.0 mmol) in MeOH (30 mL) at room temperature was added aqueous LiOH (5.4 mL of 1.0 N, 5.4 mmol). After stirring for 10 minutes, LCMS analysis showed disappearance of starting material and conversion to product of desired mass. The reaction was quenched by addition of 1.0 N HC1 (7 mL), and the resulting mixture was diluted with EtOAc (100 mL) and H₂0 (50 mL). The aqueous layer was separated, and the organic layer was dried over MgS0₄, filtered, and concentrated. The residue was purified on silica gel (0% to 100% EtOAc in hexanes) to give the title compound. Mass spectrometric data: [M+H] = 409.

Example 3: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-isopropyl-benzo[6]thiophene-2-carboxylic acid amide (Compound 1-13)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-isopropyl- benzo[6]thiophene-2-carboxylic acid amide

[00365] To a solution of 6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]- 3-isopropyl-benzo[ ?]thiophene-2-carbonitrile (Example 1; 100 mg, 0.25 mmol) in acetone (3 mL) and H₂0 (3 mL) was added sodium percarbonate (0.60 g, 3.8 mmol). The mixture was refluxed for 4 hrs, then cooled to room temperature and partitioned with EtOAc (30 mL) and H₂0 (15 mL). The organic layer was dried (MgS0₄), filtered, and concentrated. The crude residue was purified on reverse-phase preparative HPLC to give the title compound. Mass spectrometric data: [M+H] = 427.

Example 4: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-isopropyl-benzo[6]thiophene-2-carboxylic acid amide (Compound 1-14)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-isopropyl- benzo[6]thiophene-2-carboxylic acid amide

[00366] To a solution of 6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]- 3-isopropyl-benzo[ ?]thiophene-2-carbonitrile (Example 2; 207 mg, 0.5 mmol) in absolute EtOH (5 mL) in a screw-cap vial was added KOH (90 mg, 1.5 mmol) as a solution in H₂0 (2 mL). The vial was capped tightly, and the reaction was stirred at 70°C for 24 hours. LCMS analysis showed disappearance of starting material and full conversion to product. The reaction was acidified by the addition of 1.0 N HC1 (3 mL) and diluted with EtOAc (100 mL) and H₂0 (50 mL). The aqueous layer was separated, and the organic layer was dried over MgS0₄, filtered, and concentrated. The crude residue was purified on reverse-phase preparative HPLC to give the title compound. Mass spectrometric data: [M+H] = 427.

Example 5: Synthesis of 3-Cyclopropyl-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)- [l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carbonitrile (Compound 1-4)

Step 1: (4-Bromo-2-fluoro-phenyl)-cyclopropyl-methanol

[00367] 4-Bromo-2-fluorobenzaldehyde (lg, 5.0mmol) was dissolved in THF (50mL) and cooled to 0°C. Cyclopropylmagnesium bromide (0.5M in THF; 12mL, 6mmol) was added dropwise, and the reaction was stirred at 0°C for 30 minutes. Additional cyclopropylmagnesium bromide (0.5M in THF; 12mL, 6mmol) was added, and the reaction was stirred at 0°C for 1.5 hours and then quenched with H 0. The mixture was extracted three time with EtOAc, and the combined organic layers were washed with H₂0 and brine, and then dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.

Step 2: (4-Bromo-2-fluoro-phenyl)-cyclopropyl-methanone

[00368] (4-Bromo-2-fluoro-phenyl)-cyclopropyl-methanol (0.662g, 2.7mmol) in CH₂C1₂ (18mL) and CH₃CN( 2mL) was treated with N-methylmorpholine N-oxide (0.349g, 2.97mmol), followed by tetrapropylammonium perruthenate (0.047g, 0.14mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness on silica, and the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.

Step 3: 6-Bromo-3-cyclopropyl-benzo[6]thiophene-2-carboxylic acid methyl ester

[00369] To (4-bromo-2-fluoro-phenyl)-cyclopropyl-methanone (0.593g, 2.44mmol) in THF (20mL) was added cesium carbonate (1.6g, 4.88mmol), followed by methyl thioglycolate (0.29mL, 3.17mmol), and the reaction was stirred at 70°C overnight. The mixture was diluted with EtOAc and washed three times with H₂0 and brine. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated to give the

Step 4: 6-Bromo-3-cyclopropyl-benzo[6]thiophene-2-carboxylic acid amide and 6-Bromo- 3-cyclopropyl-benzo[6]thiophene-2-carbonitrile

[00370] To ammonium chloride (0.450g, 8.4mmol) in toluene (8.4mL) at 0°C was added trimethylaluminum (2M in toluene; 4.2mL, 8.4mmol), and the reaction was stirred until clear at room temperature, and then added to 6-bromo-3-cyclopropyl-benzo[ ?]thiophene-2-carboxylic acid methyl ester (0.780g, 2.5mmol). The reaction was stirred at 75°C overnight, and then quenched with H 0 and extracted three times with EtOAc. The combined organic layers were washed with IN aqueous HC1 and brine, and then dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compounds as separate products.

Step 5: 6-Bromo-3-cyclopropyl-benzo[6]thiophene-2-carbonitrile

[00371] 6-Bromo-3-cyclopropyl-benzo[ ?]thiophene-2-carboxylic acid amide (0.370g, 1.25mmol) in CH2CI2 (20mL) was treated with triethylamine (0.38mL, 2.75mmol), followed by trifluoromethanesulfonic anhydride (0.023mL, 1.38mmol) dropwise, and the reacton was stirred for 30 minutes at room temperature. The mixture was quenched with H₂0 (lmL) and extracted with EtOAc. The combined organic layers were washed with H 0 and brine, and then dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (0- 50% EtOAc in hexanes) to give the title compound, which was combined with the nitrile compound isolated in Example 5, Step 4.

Step 6: 2-Cyano-3-cyclopropyl-benzo[6]thiophene-6-carboxylic acid methyl ester

[00372] 6-Bromo-3-cyclopropyl-benzo[ ?]thiophene-2-carbonitrile (0.352g, 1.26mmol) was dissolved in DMF (15mL) and MeOH (lOmL). Triethylamine (0.44mL, 3.15mmol) was added, and the mixture was purged with N₂ for 10 minutes. Pd(dppf)₂ (0.092g, 0.13mmol) was added, and the reaction was purged with CO for 5 minutes and then stirred at 70°C for 1 hour. The mixture was quenched with H₂0 and diluted with 1 : 1 EtOAc :hexanes, and the organic layer was washed four times with H 0 and brine. The combined aqueous layers were back-extracted with 1 : 1 EtOAc:hexanes, and the combined organic layers were dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.

Step 7: 2-Cyano-3-cyclopropyl-benzo[6]thiophene-6-carboxylic acid

[00373] 2-Cyano-3-cyclopropyl-benzo[ ?]thiophene-6-carboxylic acid methyl ester (0.322g, 1.25mmol) in MeOH (5mL) and THF (5mL) was treated with IN aqueous LiOH (6.25mL, 6.25mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was quenched with IN aqueous HC1 (lOmL) and extracted twice with EtOAc. The combined organic layers were dried, filtered, and concentrated to give the title compound.

Step 8: 2-Cyano-3-cyclopropyl-benzo[6]thiophene-6-carbonyloxylformate isobutyl ester

[00374] To 2-cyano-3-cyclopropyl-benzo[ ?]thiophene-6-carboxylic acid (0.330g, 1.36mmol) in CH₂C1₂ (15mL) was added diisopropylethylamine (0.47mL, 2.72mmol), and the mixture was cooled to 0°C. Isobutyl chloroformate (0.23mL, 1.77mmol) was added slowly, and the reaction was stirred for 10 minutes at 0°C. The mixutre was quenched with H₂0 and diluted the EtOAc. The organic layer was washed three times with H 0 and brine, and the combined aqueous layers were back-extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated to give the title compo nd.

Step 9: 3-Cyclopropyl-6-hydroxymethyl-benzo[6]thiophene-2-carbonitrile

[00375] 2-Cyano-3-cyclopropyl-benzo[ ?]thiophene-6-carbonyloxylformate isobutyl ester (0.413g, 1.2mmol) was dissolved in EtOH (20mL) and cooled to 0°C. Sodium borohydride (0.09 lg, 2.4mmol) was added, and the reaction was stirred for 10 minutes. The mixture was quenched with IN aqueous HC1 (5mL) at 0°C, and then diluted with EtOAc. The organic layer was washed with H₂0 and brine, and the combined aqueous layers were back-extracted with EtOAc. The combined organic layers wre dried, filtered, and concentrated, and the residue was purified by silica gel chromatograph - 100% EtOAc in hexanes) to give the title compound.

Step 10: 6-Azidomethyl-3-cyclopropyl-benzo[6]thiophene-2-carbonitrile

[00376] 3-Cyclopropyl-6-hydroxymethyl-benzo[ ?]thiophene-2-carbonitrile (0.080g,

0.35mmol) was dissolved in CH₂CI₂ (5mL) and cooled to 0°C. Diisopropylethylamine (0.18mL, 1.05mmol) was added, followed by methanesulfonyl chloride (0.041mL, 0.53mmol), and the reaction was stirred for 5 minutes. The mixture was quenched with saturated aqueous NaHC0₃ and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHC0₃, and then dried and filtered. To the solution was added DMF (5mL), followed by sodium azide (0.035g, 0.53mmol), and the reaction was concentrated to remove CH₂C1₂ and then stirred at room temperature for 2 hours. The mixture was diluted with 1 : 1 EtOAc:hexanes and washed three times with H₂0 and brine. The combined aqueous layers were back-extracted with 1 : 1 EtOAc :hexanes, and the combined organic layers were dried, filtered, and concentrated to give the title compound.

Step 11: 4-Nitro-benzoic acid l-[l-(2-cyano-3-cyclopropyl-benzo[6]thiophen-6-ylmethyl)- lH-[l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester

[00377] 6-Azidomethyl-3-cyclopropyl-benzo[ ?]thiophene-2-carbonitrile (0.089g, 0.35mmol) was dissolved in THF (lOmL). 4-Nitro-benzoic acid 1 -ethyl- 1 -trifluoromethyl-prop-2-ynyl ester (Enantiomer B; 0.11 lg, 0.36mmol) was added, followed by copper iodide (0.068g, 0.36mmol) and diisopropylethylamine (0.37mL, 2.1mmol). The reaction was stirred overnight at room temperature, and then diluted with EtOAc and washed three times with aqeous NH₄CI and once with brine. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated to give the title compound.

Step 12: 3-Cyclopropyl-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl] -benzo [b] thiophene-2-carbonitrile

[00378] 4-Nitro-benzoic acid l-[l-(2-cyano-3-cyclopropyl-benzo[ ?]thiophen-6-ylmethyl)-lH- [l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester (0.146g, 0.26mmol) in MeOH (5mL) and THF (lmL) was treated with IN aqueous LiOH (2mL), and the reaction was stirred at room temperature for 1 hour. The mixture was quenched with IN aqueous HC1 (5mL) and diluted with EtOAc. The organic layer was washed three times with H₂0 and brine, and the combined aqueous layers were back-extracted with EOAc. The combined organic layers were dried, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. Mass spectrometric data: [M+H] = 407.

Example 6: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid methyl ester (Compound 1-31)

Step 1: 6-Bromomethyl-3-chloro-benzo[6]thiophene-2-carboxylic acid methyl ester

[00379] To methyl 3-chloro-6-methylbenzo[b]thiophene-2-carboxylate (10. Og, 41.54mmol) in CC1₄ (250mL) at 70°C was added N-bromosuccinimide (8.13g, 45.7mmol) and benzoyl peroxide (0.502g, 2.08mmol), and the reaction was refluxed for 1 hour. The mixture was concentrated, and the residue was H₂0 to give the title compound.

Step 2: 6-Azidomethyl-3-chloro-benzo[6]thiophene-2-carboxylic acid methyl ester

[00380] 6-Bromomethyl-3-chloro-benzo[ ?]thiophene-2-carboxylic acid methyl ester (9.0g, 28.13mmol) and sodium azide (3.66g, 56.26mmol) were combined in DMF (lOOmL) and stirred overnight at room temperature. After work-up, the crude material was purified by silica gel chromatography to give the title compound.

Step 3: 3-Chloro-6-{4-[l-(4-nitro-benzoyloxy)-l-trifluoromethyl-propyl]-[l,2,3]triazol-l- ylmethyl}-benzo[6]thiophene-2-carboxylic acid methyl ester

[00381] 6-Azidomethyl-3-chloro-benzo[ ?]thiophene-2-carboxylic acid methyl ester (l.Og, 3.5mmol), 4-nitro-benzoic acid 1 -ethyl- 1 -trifluoromethyl-prop-2-ynyl ester (Enantiomer B; 1.106g, 3.67mmol), and copper iodide (1.05g, 5.52mmol) were combined in THF (30mL). Diisopropylethylamine (3.65mL, 21mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was worked-up with EtOAc and aqueous NH₄C1, and the organic layer was dried over MgS to give the title compound.

Step 4: 3-Chloro-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]- benzo[6]thiophene-2-carboxylic acid methyl ester

[00382] 3-Chloro-6- {4-[ 1 -(4-nitro-benzoyloxy)- 1 -trifluoromethyl-propyl]-[ 1 ,2,3]triazol- 1 - ylmethyl}-benzo[ ?]thiophene-2-carboxylic acid methyl ester (2.22g, 3.81mmol) in 10: 1 MeOH:THF was treated with IN aqueous LiOH (3.8 lmL, 3.81mmol), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. After work-up, the crude material was purified by silica gel chromatography to give the title compound.

Step 5: 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid methyl ester

[00383] 3-Chloro-6-[4-( 1 -hydroxy- 1 -trifluoromethyl-propyl)-[ 1 ,2,3]triazol- 1 -ylmethyl] - benzo[ ?]thiophene-2-carboxylic acid methyl ester (0.216g, 0.5mmol), 2-methoxypyridine-5- boronic acid (0.230g, 1.5mmol), Pd(OAc)₂ (0.01 lg, 0.05mmol), 2-dicyclohexylphosphino-2'- (N,N-dimethylamino)biphenyl (0.030g, 0.08mmol), and cesium fluoride (0.456g, 3.0mmol) were combined in deoxygenated l,4-dioxane:H₂0 (100: 1; lOmL), and the reaction was stirred at 57°C overnight. After work-up, the crude material was purified by silica gel chromatography to give the title compound. Mass spectrometric data: [M+H] = 507.

Example 7: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide

(Compound 1-20) and 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carbonitrile (Compound 1-8)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide and 6-[4-(l-Hydroxy-l- trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6-methoxy-pyridin-3-yl)- benzo[6]thiophene-2-carbonitrile [00384] Prepared according to the procedure described in Example 5, Step 4, using the following starting material: 6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[ ?]thiophene-2-carboxylic acid methyl ester; the title compounds were separated by preparative HPLC. Mass spectrometric data: [M+H] = 492 (Compound 1-20) and 474 (Compound 1-8).

Example 8: Synthesis of 2-[l-(2-Bromo-3-cyclopropyl-benzo[6]thiophen-6-ylmethyl)-lH- [l,2,3]triazol-4-yl]-l,l,l-trifluoro-but -2-ol (Compound 1-48)

Step 1: 6-Bromo-3-cyclopropyl-benzo[6]thiophene

[00385] 6-Bromo-3-cyclopropyl-benzo[ ?]thiophene-2-carboxylic acid methyl ester (0.990g, 3.18mmol) was dissolved in MeOH (15mL) and THF (15mL), and the solution was treated with IN aqueous LiOH (15mL). The reaction was stirred at room temperature for 30 minutes, and then quenched with IN aqueous HCl (20mL) and diluted with EtOAc. The organic layer was washed with three times with H₂0 and brine, and the combined aqueous layers were back- extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated, and the residue was dissolved in quinoline (lOmL). Copper powder (0.120g, 1.89mmol) was added, and the reaction was stirred at 160°C overnight. The mixture was extracted three times with EtOAc, and the combined organic layers were washed with IN aqueous HCl, dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.

Step 2: 3-Cyclopropyl-benzo[6]thiophene-6-carboxylic acid methyl ester

[00386] Prepared according to the procedure described in Example 5, Step 6, using the following starting material: 6-bromo-3-cyclopropyl-benzo[ ?]thiophene.

Step 3: 2-Bromo-3-cyclopropyl-benzo[6]thiophene-6-carboxylic acid methyl ester

[00387] 3-Cyclopropyl-benzo[ ?]thiophene-6-carboxylic acid methyl ester (0.293g, 1.26mmol) in AcOH (7mL) was treated with bromine (0.13mL, 2.52mmol) in CH2CI2 (7mL), and the reaction was stirred at room temperature for 10 minutes. The mixture was quenched with H₂0 and diluted with EtOAc, and the organic layer was washed three times with aqueous Na₂S203. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried, filtered, and conentrated to give the title compound.

Step 4: (2-Bromo-3-cyclopropyl-benzo[6]thiophen-6-yl)-methanol

[00388] 2-Bromo-3-cyclopropyl-benzo[ ?]thiophene-6-carboxylic acid methyl ester (0.392g, 1.26mmol) was dissolved in THF (lOmL) and cooled to -78°C. Diisobutylaluminium hydride (1.0M in toluene; 3.78mL, 3.78mmol) was added dropwise, and the reaction was stirred at - 78°C for 30 minutes. Additional diisobutylaluminium hydride (1.0M in toluene; 7.56mL, 7.56mmol) was added, and the reacction was stirred at -78°C for 1 hour. The mixture was quenched with aqueous HC1 and diluted with EtOAc. The organic layer was washed with aqueous HC1 and brine, and the combined aqueous layers were back-extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated onto silica, and the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.

Step 5: 6-Azidomethyl-2-bromo-3-cyclopropyl-benzo[6]thiophene

[00389] Prepared according to the procedure described in Example 5, Step 10, using the following starting materials: (2-bromo-3-cyclopropyl-benzo[ ?]thiophen-6-yl)-methanol and sodium azide.

Step 6: 4-Nitro-benzoic acid l-[l-(2-bromo-3-cyclopropyl-benzo[6]thiophen-6-ylmethyl)- lH-[l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester

[00390] Prepared according to the procedure described in Example 5, Step 1 1 , using the following starting materials: 6-azidomethyl-2-bromo-3-cyclopropyl-benzo[ ?]thiophene and 4- nitro-benzoic acid 1 -ethyl- 1 -trifluoromethyl-prop-2-ynyl ester (Enantiomer B).

Step 7: 2-[l-(2-Bromo-3-cyclopropyl-benzo[6]thiophen-6-ylmethyl)-lH-[l,2,3]triazol-4-yl]- l,l,l-trifluoro-butan-2-ol

[00391] Prepared according to the procedure described in Example 5, Step 12, using the following starting material: 4-nitro-benzoic acid l-[l-(2-bromo-3-cyclopropyl- benzo[ ?]thiophen-6-ylmethyl)- lH-[ 1 ,2,3]triazol-4-yl]- 1 -trifluoromethyl-propyl ester. Mass spectrometric data: [Μ+Η] = 461.

Example 9: Synthesis of 2-[l-(3-Cyclopropyl-2-methanesulfonyl-benzo[6]thiophen-6- ylmethyl)-lH-[l,2,3]triazol-4-yl]- -trifluoro-butan-2-ol (Compound 1-38)

Step 1: 2-[l-(3-Cyclopropyl-2-methanesulfonyl-benzo[6]thiophen-6-ylmethyl)-lH- [l,2,3]triazol-4-yl]-l,l,l-trifluoro-butan-2-ol

[00392] 2-[l-(2-Bromo-3-cyclopropyl-benzo[b]thiophen-6-ylmethyl)-lH-[l ,2,3]triazol-4-yl]- 1 ,1 ,1 -trifluoro-butan-2-ol (0.103g, 0.22mmol) was dissolved in NMP (5mL), and the solution was purged with N2 for 5 minutes. Copper iodide (0.190g, 1.Ommol) and sodium

methanesulfinate (0.102g, 1. Ommol) were added, and the reaction was stirred at 100°C in a sealed tube for 5 hours. The mixture was diluted with 1 : 1 EtOAc:hexanes (200mL) and washed three times with aqueous NH₄C1. The organic layer was dried, filtered, and concentrated, and the crude material was purified by silica gel chromtagraphy (0- 100% EtOAc in hexanes) to give the title compound. Mass spectrometric data: [M+H] = 460.

Example 10: Synthesis of 2-[l-(3-Cyclopropyl-benzo[6]thiophen-6-ylmethyl)-lH- [l,2,3]triazol-4-yl]-l,l,l-trifluoro d 1-47)

Step 1: 2-[l-(3-Cyclopropyl-benzo[6]thiophen-6-ylmethyl)-lH-[l,2,3]triazol-4-yl]-l,l,l- trifluoro-butan-2-ol

[00393] A solution of 2-[l-(2-bromo-3-cyclopropyl-benzo[b]thiophen-6-ylmethyl)-lH- [l ,2,3]triazol-4-yl]-l ,l ,l-trifluoro-butan-2-ol (0.023g, 0.05mmol) in EtOAc (lmL) and MeOH (0. lmL) was purged with N₂ for 5 minutes. 10% Palladium on carbon (50% wet with H₂0; 0.01 lg, 0.005mmol) was added, and the reaction was stirred under an atmosphere of H₂ at room temperature for 20 minutes. Additional 10%) palladium on carbon (50%> wet with H₂0; 0.020g, O.Olmmol) was added, and the reaction was stirred under an atmosphere of H for 2 hours. The mixture was filtered through a syringe filter, diluted with EtOAc (lOOmL), and washed twice with H₂0 and brine. The organic layer was dried, filtered, and concentrated, and the residue was purified by silica gel chromatography (0- 100%> EtOAc in hexanes) to give the title compound. Mass spectrometric data: [M+H] = 382.

Example 11: Synthesis of 3-Cyclopentyl-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)- [l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carbonitrile (Compound 1-6)

Step 1: (4-Bromo-2-hydroxy-phenyl)-cyclopentyl-methanone

[00394] To 3-bromophenol (2.75g, 15.9mmol) in dichloroethane (15mL) at room temperature was added aluminum chloride (3.18g, 23.8mmol) slowly in three equal portions, and the mixture was stirred for 5 minutes. Cyclopentanecarbonyl chloride (1.98mL, 16.22mmol) was added dropwise, and the reaction was stirred at reflux for 2 hours. After cooling to room temperature, the mixture was poured onto ice/ΙΝ aqueous HC1 (lOOmL), and then extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated onto silica and the residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to give the title compound.

Step 2: Dimethyl-thiocarbamic acid 0-(5-bromo-2-cyclopentanecarbonyl-phenyl) ester

[00395] (4-Bromo-2-hydroxy-phenyl)-cyclopentyl-methanone (3. lg, 11.5mmol) was dissolved in DMF (30mL). l,4-Diazabicyclo(2,2,2)octane (2.58g, 23mmol) was added, followed by dimethylthiocarbamoyl chloride (2.85g, 23mmol), and the reaction was stirred for 1 hour at room temperature. Aftetr aqueous work-up, the crude material was purified by silica gel chromatography to give the title compound.

Step 3: (4-Bromo-2-mercapto-phenyl)-cyclopentyl-methanone

[00396] Neat dimethyl-thiocarbamic acid (9-(5-bromo-2-cyclopentanecarbonyl-phenyl) ester (3.5g, 9.8mmol) was stirred at 190°C for 5 hours, and then cooled to room temperature overnight. The mixture was diluted with MeOH (50mL), and potassium hydroxide (3.6g, 64mmol) was added. The reaction was refluxed for 2 hours, and then diluted with EtOAc, acidified with IN aqueous HC1, and washed with H₂0 and brine. The crude material purified by silica gel chromatography to give the title compound.

Step 4: (5-Bromo-2-cyclopentanecarbonyl-phenylsulfanyl)-acetic acid methyl ester

[00397] To (4-bromo-2-mercapto-phenyl)-cyclopentyl-methanone (1.5g, 5.26mmol) in acetone (50mL) was added methyl bromoacetate (0.58mL, 6.31mmol), followed by cesium carbonate (5.85g, 17mmol), and the reaction was stirred at room temperature for 30 minutes. After aqueous work-up, the crude material was purified by silica gel chromatography to give the title compound.

Step 5: 6-Bromo-3-cyclopentyl-benzo[6]thiophene-2-carboxylic acid

[00398] (5-Bromo-2-cyclopentanecarbonyl-phenylsulfanyl)-acetic acid methyl ester (1.2g, 3.36mmol) in acetone (50mL) was treated with cesium carbonate (4.0g, 12.3mmol), and the reaction was stirred at 40°C for 3 hours. Aqueous work-up provided the title compound.

Step 6: 6-Bromo-3-cyclopentyl-benzo[6]thiophene-2-carboxylic acid amide and 6-Bromo- 3-cyclopentyl-benzo[6]thiophene-2-carbonitrile

[00399] Prepared according to the procedure described in Example 5, Step 4, using the following starting material: 6-bromo-3-cyclopentyl-benzo[ ?]thiophene-2-carboxylic acid; the title compounds were isolated by silica gel chromatography.

Step 7: 2-Cyano-3-cyclopentyl-benzo[6]thiophene-6-carboxylic acid methyl ester

[00400] Prepared according to the procedure described in Example 5, Step 6, using the following starting material: 6-bromo-3-cyclopentyl-benzo[ ?]thiophene-2-carbonitrile.

Step 8: 2-Cyano-3-cyclopentyl-benzo[6]thiophene-6-carboxylic acid

[00401] Prepared according to the procedure described in Example 5, Step 7, using the following starting material: 2-cyano-3-cyclopentyl-benzo[ ?]thiophene-6-carboxylic acid ester.

Step 9: 2-Cyano-3-cyclopentyl-benzo[6]thiophene-6-carbonyloxylformate isobutyl ester

[00402] Prepared according to the procedure described in Example 5, Step 8, using the following starting materials: 2-cyano-3-cyclopentyl-benzo[ ?]thiophene-6-carboxylic acid methyl ester and isobutyl chloroformate.

Step 10: 3-Cyclopentyl-6-hydroxymethyl-benzo[6]thiophene-2-carbonitrile

[00403] Prepared according to the procedure described in Example 5, Step 9, using the following starting material: 2-cyano-3-cyclopentyl-benzo[ ?]thiophene-6-carbonyloxylformate isobutyl ester.

Step 11: 6-Azidomethyl-3-cyclopentyl-benzo[6]thiophene-2-carbonitrile

[00404] Prepared according to the procedure described in Example 5, Step 10, using the following starting materials: 3-cyclopentyl-6-hydroxymethyl-benzo[ ?]thiophene-2-carbonitrile and sodium azide.

Step 12: 4-Nitro-benzoic acid l-[l-(2-cyano-3-cyclopentyl-benzo[6]thiophen-6-ylmethyl)- lH-[l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester

[00405] Prepared according to the procedure described in Example 5, Step 11 , using the following starting materials: 6-azidomethyl-3-cyclopentyl-benzo[ ?]thiophene-2-carbonitrile and 4-nitro-benzoic acid 1 -ethyl- 1 -trifl romethyl-prop-2-ynyl ester (Enantiomer B).

Step 13: 3-Cyclopentyl-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl] -benzo [b] thiophene-2-carbonitrile

[00406] Prepared according to the procedure described in Example 5, Step 12, using the following starting material: 4-nitro-benzoic acid l-[l-(2-cyano-3-cyclopentyl-benzo[ ?]thiophen- 6-ylmethyl)-lH-[l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester. Mass spectrometric data: [Μ+Η] = 435.

Example 12: Synthesis of 3-Cyclopentyl-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)- [l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carboxylic acid amide (Compound 1-18)

Step 1: 3-Cyclopentyl-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-benzo[6]thiophene-2-carboxylic acid amide

[00407] Prepared according to the procedure described in Example 4, Step 1, using the following starting material: 3 -cyclopentyl-6-[4-(l -hydroxy- 1 -trifluoromethyl-p ropyl)-

[l,2,3]triazol-l-ylmethyl]-benzo[ ?]thiophene-2-carbonitrile. Mass spectrometric data: [M+H] = 453.

Example 13: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl] -3-(6-trifluoromethyl-pyridin-3-yl)-benzo [b] thiophene-2-carboxylic acid methyl ester (Compound 1-35)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid methyl ester

[00408] 3-Chloro-6-[4-( 1 -hydroxy- 1 -trifluoromethyl-propyl)-[ 1 ,2,3]triazol- 1 -ylmethyl] - benzo[ ?]thiophene-2-carboxylic acid methyl ester (0.216g, 0.5mmol), 2- trifluoromethylpyridine-5-boronic acid (0.286g, 1.5mmol), Pd(OAc)2 (0.01 lg, 0.05mmol), 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (0.030g, 0.08mmol), and cesium fluoride (0.456g, 3.0mmol) were combined in 1,4-dioxane (5mL) and H₂0 (50mL), and the reaction was purged with N2 for 10 minutes, and then stirred at 60°C overnight. The mixture was diluted with EtOAc and washed three times with ¾0 and once with brine. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated. The crude material was purified by preparative HPLC to give the title compound. Mass spectrometric data: [M+H] = 545.

Example 14: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl] -3-(6-trifluoromethyl-pyridin-3-yl)-benzo [b] thiophene-2-carbonitrile (Compound 1-12)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2-carbonitrile

[00409] Prepared according to the procedure described in Example 5, Step 4, using the following starting material: 6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-benzo[ ?]thiophene-2-carboxylic acid methyl ester. Mass spectrometric data: [M+H] = 512.

Example 15: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl] -3-(6-trifluoromethyl-pyridin-3-yl)-benzo [b] thiophene-2-carboxylic acid amide (Compound 1-24)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide

[00410] Prepared according to the procedure described in Example 4, Step 1, using the following starting material: 6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-benzo[ ?]thiophene-2-carbonitrile. Mass spectrometric data: [M+H] = 530.

Example 16: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide

(Compound l-20a)

Step 1: 6-Methyl-benzo[6]thiophene-2-carboxylic acid methyl ester

[00411] 2-Fluoro-4-methylbenzaldehyde (10.35g, 75.0mmol) and cesium carbonate (49.0g, 150.0mmol) were combined in THF (300mL). Methyl thioglycolate (7.16mL, 79.0mmol) was added, and the reaction was stirred at reflux for 12 hours. After aqueous work-up, the crude material was purified by silica gel chromatography, and the isolated material was triturated with hexanes to give the title compound.

Step 2: (6-Methyl-benzo[6]thiophen-2-yl)-methanol

[00412] A solution of 6-methyl-benzo[ ?]thiophene-2-carboxylic acid methyl ester (9.2g,

44.6mmol) in THF (300mL) was cooled to 0°C. Lithium aluminum hydride (1.1 lg, 29.3mmol) was added in 3 portions, with 2 minutes between each addition. The reaction was stirred at 0°C for 1 hour, and at room temperature for 1 hour. The mixture was diluted with Et 0 (500mL) and cooled to 0°C, and then quenched with H₂0 (1.2mL), followed by 15% w/v aqueous NaOH (1.2mL), and then additional H 0 (3mL). The mixture was stirred at room temperature for 30 minutes, and then treated with excess MgS0₄ and left sitting over the weekend. The mixture was filtered and concentrated to give the title compound.

Step 3: (3-Bromo-6-methyl-benzo[6]thiophen-2-yl)-methanol and 3-Bromo-2- bromomethyl-6-methyl-benzo [b] thiophene

[00413] (6-Methyl-benzo[ ?]thiophen-2-yl)-methanol (8.9g, 44.6mmol) was dissolved in AcOH (150mL) and CH₂C1₂ (200mL), and cooled to 0°C. Bromine (2.17mL, 42.4mmol) in CH₂C1₂ (150mL) was added via a dropping funnel, and the reaction was stirred at 0°C for 30 minutes. Silica gel chromatography provided he title compounds as separate compound.

Step 4a: 3-Bromo-6-methyl-benzo[6]thiophene-2-carbaldehyde

[00414] Prepared according to the procedure described in Example 5, Step 1, using following starting material: (3-bromo-6-methyl-benzo[ ?]thiophen-2-yl)-methanol.

Step 4b: 3-Bromo-6-methyl-benzo[6]thiophene-2-carbaldehyde

3-Bromo-2-bromomethyl-6-methyl-benzo[ ?]thiophene (3.55g, 10.6mmol) in 1,4-dioxane (lOOmL) was treated with N-methylmorpholine N-oxide (3.73g, 31.7mmol), and the reaction was stirred at reflux for 30 minutes. Aqueous work-up provided the title compound, which was combined with the isolated material from Example 16, Step 4a.

Step 5: 3-Bromo-6-methyl-benzo[6]thiophene-2-carbaldehyde oxime

[00415] 3-Bromo-6-methyl-benzo[ ?]thiophene-2-carbaldehyde (5.4g, 20.0mmol) was dissolved in pyridine. Hydroxylamine hydrochloride (6.95g, 100. Ommol) was added, and the reaction was stirred for 1 hour at room temperature. After aqueous work-up, which included ten washes with IN aqueous HC1 to remove pyridine, the organic layer was dried, filtered, and concentrated to give the title compoun of oxime isomers.

Step 6: 3-Bromo-6-methyl-benzo[6]thiophene-2-carbonitrile

3-Bromo-6-methyl-benzo[ ?]thiophene-2-carbaldehyde oxime (5.68g, 20. Ommol) in acetic anhydride (70mL) was stirred at 145°C for 24 hours. The mixture was concentrated to dryness, and the crude material was purified by silica gel chromatography to give the title compound.

Step 7: 3-Bromo-6-bromomethyl-benzo[6]thiophene-2-carbonitrile

[00416] To 3-bromo-6-methyl-benzo[ ?]thiophene-2-carbonitrile (4.0g, 15.75mmol) in CC1₄ (lOOmL) was added N-bromosuccinimide (3.09g, 17.4mmol) and benzoyl peroxide (0.191g, 0.79mmol), and the reaction was refluxed for 2 hour. The mixture was concentrated, and aqueous work-up, followed by silica gel chromatography (0-20% EtOAc in hexanes), gave the title compound.

Step 8: 6-Azidomethyl-3-bromo-benzo[6]thiophene-2-carbonitrile

[00417] Prepared according to the procedure described in Example 6, Step 2, using the following starting materials: 3-bromo-6-bromomethyl-benzo[ ?]thiophene-2-carbonitrile and sodium azide.

Step 9: 4-Nitro-benzoic acid l-[l-(3-bromo-2-cyano-benzo[6]thiophen-6-ylmethyl)-lH- [1,2,3] triazol-4-yl] -1 -trifluor omethyl-pr opyl ester

[00418] Prepared according to the procedure described in Example 5, Step 11, using the following starting materials: 6-azidomethyl-3-bromo-benzo[ ?]thiophene-2-carbonitrile and 4- nitro-benzoic acid 1 -ethyl- 1 -trifluoromethyl-prop-2-ynyl ester (Enantiomer A).

Step 10: 4-Nitro-benzoic acid l-{l-[2-cyano-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophen- 6-ylmethyl]-lH-[l,2,3]triazol-4-yl}-l-trifluoromethyl-propyl ester

[00419] 4-Nitro-benzoic acid l-[l-(3-bromo-2-cyano-benzo[ ?]thiophen-6-ylmethyl)-lH- [l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester (0.360g, 0.61mmol), 2-methoxypyridine-5- boronic acid (0.140g, 0.92mmol), and sodium bicarbonate (0.13 lg, 1.53mmol) were combined in 2: 1 DME:H₂0 (6mL), and the solution was purged with N₂ for 5 minutes. PdCl₂(dppf)₂ (0.045g, 0.06mmol) was added, and the reaction was stirred at 80°C for 30 minutes. The mixture was cooled to room temperature overnight, and then diluted with EtOAc and washed three times with H 0 and brine. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried over MgS0₄, filtered, and concentrated. The crude material was purified by silica gel chromatography (0- 100% EtOAc in hexanes) to give the title compound.

Step 11: 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- methoxy-pyridin-3-yl)-benzo [b] thiophene-2-carboxylic acid amide

[00420] Prepared according to the procedure described in Example 4, Step 1, using the following starting material: 4-nitro-benzoic acid l-{l-[2-cyano-3-(6-methoxy-pyridin-3-yl)- benzo[ ?]thiophen-6-ylmethyl]-lH-[l,2,3]triazol-4-yl}-l-trifluoromethyl-propyl ester; the title compound was purified by preparative HPLC. Mass spectrometric data: [M+H] = 492.

Example 17: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carbonitrile (Compound l-8a)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- methoxy-pyridin-3-yl)-benzo [b] thiophene-2-carbonitrile

[00421] Prepared according to the procedure described in Example 5, Step 12, using the following starting material: 4-nitro-benzoic acid l- { l-[2-cyano-3-(6-methoxy-pyridin-3-yl)- benzo[ ?]thiophen-6-ylmethyl]-lH-[l ,2,3]triazol-4-yl}-l-trifluoromethyl-propyl ester; the title compound was purified by preparative HPLC. Mass spectrometric data: [M+H] = 473.

Example 18: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methyl-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide

(Compound 1-22)

Step 1: 4-Nitro-benzoic acid l-[l-(3-bromo-2-cyano-benzo[6]thiophen-6-ylmethyl)-lH- [1,2,3] triazol-4-yl] -1 -trifluor omethyl-pr opyl ester

[00422] Prepared according to the procedure described in Example 5, Step 1 1 , using the following starting materials: 6-azidomethyl-3-bromo-benzo[ ?]thiophene-2-carbonitrile and 4- nitro-benzoic acid 1 -ethyl- 1 -trifluoromethyl-prop-2-ynyl ester (Enantiomer B).

Step 2: 3-Bromo-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]- benzo[6]thiophene-2-carboxylic acid amide

[00423] Prepared according to the procedure described in Example 5, Step 12, using the following starting material: 4-nitro-benzoic acid l-[l-(3-bromo-2-cyano-benzo[ ?]thiophen-6- ylmethyl)-lH-[l,2,3]triazol-4-yl]-l-trifluoromethyl-propyl ester; the isolated compound was further hydrolyzed according to the procedure described in Example 4, Step 1, to give the title compound.

Step 3: 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6-methyl- pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide

[00424] Prepared according to the procedure described in Example 16, Step 10, using the following starting materials: 3-bromo-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol- l-ylmethyl]-benzo[ ?]thiophene-2-carboxylic acid amide and 2-methylpyridine-5-boronic acid; the title compound was purified by preparative HPLC. Mass spectrometric data: [M+H] = 476. Example 19: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(6-methyl-pyridin-3- -benzo[6]thiophene-2-carbonitrile (Compound 1-10)

Step 1: 3-Bromo-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]- benzo[6]thiophene-2-carbonitrile

[00425] Prepared according to the procedure described in Example 5, Step 12, using the following starting material: 4-nitro-benzoic acid l-[l-(3-bromo-2-cyano-benzo[ ?]thiophen-6- ylmethyl)- lH-[ 1 ,2,3]triazol-4-yl]- 1 -trifluoromethyl-propyl ester.

Step 2: 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(6-methyl- pyridin-3-yl)-benzo [b] thiophene-2-carbonitrile

[00426] Prepared according to the procedure described in Example 16, Step 10, using the following starting materials: 3-bromo-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[ l,2,3]triazol- l-ylmethyl]-benzo[ ?]thiophene-2-carbonitrile and 2-methylpyridine-5-boronic acid; the title compound was purified by preparative HPLC. Mass spectrometric data: [M+H] = 458.

Example 20: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(2-methyl-pyridin-4-yl)-benzo[6]thiophene-2-carboxylic acid amide

(Compound 1-21)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(2-methyl- pyridin-4-yl)-benzo[6]thiophene-2-carboxylic acid amide

[00427] Prepared according to the procedure described in Example 16, Step 10, using the following starting materials: 3-bromo-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l ,2,3]triazol- l-ylmethyl]-benzo[ ?]thiophene-2-carboxylic acid amide and 2-methylpyridine-4-boronic acid. Mass spectrometric data: [M+H] = 476.

Example 21: Synthesis of 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l- ylmethyl]-3-(2-methyl-pyridin-4- -benzo[6]thiophene-2-carbonitrile (Compound 1-9)

Step 1 : 6-[4-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol-l-ylmethyl]-3-(2-methyl- pyridin-4-yl)-benzo [b] thiophene-2-carbonitrile

[00428] Prepared according to the procedure described in Example 16, Step 10, using the following starting materials: 3-bromo-6-[4-(l-hydroxy-l-trifluoromethyl-propyl)-[l,2,3]triazol- l-ylmethyl]-benzo[ ?]thiophene-2-carbonitrile and 2-methylpyridine-4-boronic acid; the title compound was purified by preparative HPLC. Mass spectrometric data: [M+H] = 458.

Example 22: Synthesis of 3-Cyclopropyl-6-{[5-(l-hydroxy-l-trifluoromethyl-propyl)- [1,3,4] oxadiazol-2-ylamino]-methyl -benzo[6]thiophene-2-carbonitrile (Compound 2-3)

Step 1: 3-Cyclopropyl-6-formyl-benzo[6]thiophene-2-carbonitrile

[00429] Prepared according to the procedure described in Example 5, Step 2, using the following starting material: 3-cyclopropyl-6-hydroxymethyl-benzo[ ?]thiophene-2-carbonitrile.

Step 2: 3-Cyclopropyl-6-{[5-(l-hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2- ylamino]-methyl}-benzo[6]thiophene-2-carbonitrile

[00430] To a solution of 3-cyclopropyl-6-formyl-benzo[ ?]thiophene-2-carbonitrile (0.053g, 0.23mmol) in toluene (5ml) was added pyridinium p-toluenesulfonate (0.006g, 0.023mmol) and 2-(5-amino-[l,3,4]oxadiazol-2-yl)-l,l,l-trifluoro-butan-2-ol (0.058g, 0.28mmol), and the reaction was refluxed using a Dean-Stark apparatus overnight. After cooling to room temperature, the mixture was concentrated, and the residue was dissolved in EtOH (5mL) and cooled to 0°C. Sodium borohydride (0.0 lOg, 0.25mmol) was added, and the reaction was stirred for 5 minutes at 0°C. The mixture was quenched with IN aqueous HCl and diluted with EtOAc. The organic layer was washed three times with H₂0 and brine, and then dried, filtered, and concentrated. The crude material was purified by preparative HPLC, and the isolated material was repurified by silica gel chromatography (0- 100% EtOAc in hexanes) to give the title compound. Mass spectrometric data: [M+H] = 423.

Example 23: Synthesis of 6-{[5-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2- ylamino]-methyl}-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carbonitrile

(Compound 2-7)

Step 1: 3-Bromo-6-formyl-benzo[6]thiophene-2-carbonitrile

[00431] 3-Bromo-6-bromomethyl-benzo[ ?]thiophene-2-carbonitrile (0.412g, 1.2mmol) in 1,4- dioxane (15mL) was treated with N-methylmorpholine N-oxide (0.436g, 3.7mmol), and the reaction was stirred at 120°C for 30 minutes. The mixture wa diluted with EtOAc and ¾0, and the organic layer was washed with H₂0 and brine, and then dried over MgS0₄, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title co

Step 2: 3-Bromo-6-{[5-(l-hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2-ylamino]- methyl}-benzo[6]thiophene-2-carbonitrile

[00432] To a solution of 3-bromo-6-formyl-benzo[ ?]thiophene-2-carbonitrile (0.255g, 0.96mmol) in benzene (10ml) was added pyridinium p-toluenesulfonate (0.025g, 0.096mmol) and 2-(5-amino-[l,3,4]oxadiazol-2-yl)-l,l,l-trifluoro-butan-2-ol (0.242g, 1.15mmol), and the reaction was refluxed using a Dean-Stark apparatus for 5 hours. After cooling to room temperature, the mixture was concentrated, and the residue was dissolved in EtOH (5mL). Sodium cyanoborohydride (0.090g, 1.44mmol) was added, and the reaction was stirred at room temperature overnight. Additional sodium cyanoborohydride (0.06 lg, 0.96mmol) was added, and the reaction was stirred for 45 minutes. Another portion of sodium cyanoborohydride (0.06 lg, 0.96mmol) was added, and the reaction was stirred for 1.5 hours. The mixture was quenched with IN aqueous HC1 and extracted with EtOAc. The organic layer was dried over MgS0₄, filtered, and concentrated. The crude material was purified by silica gel

chromatography (0- 100% EtOAc in hexanes) to give the title compound.

Step 3: 6-{[5-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2-ylamino]-methyl}- 3-(6-methoxy-pyridin-3-yl)-benzo [b] thiophene-2-carbonitrile

[00433] Prepared according to the procedure described in Example 16, Step 10, using the following starting materials: 3-bromo-6-{[5-(l-hydroxy-l-trifluoromethyl-propyl)-

[l,3,4]oxadiazol-2-ylamino]-methyl}-benzo[ ?]thiophene-2-carbonitrile and 2-methoxypyridine - 5-boronic acid. Mass spectrometric data: [M+H] = 490.

Example 24: Synthesis of 6-{[5-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2- ylamino]-methyl}-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 1) (Compound 2-18a) and 6-{[5-(l-Hydroxy-l-trifluoromethyl-propyl)- [l,3,4]oxadiazol-2-ylamino]-methyl}-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2- carboxylic acid amide (Enantiomer 2) (Compound 2-18b)

Enantiomer 1 and 2

Step 1: 6-{[5-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2-ylamino]-methyl}- 3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 1) and 6-{[5-(l-Hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2-ylamino]-methyl}-3-(6- methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 2)

[00434] Prepared according to the procedure described in Example 4, Step 1, using the following starting material: 6-{[5-(l-hydroxy-l-trifluoromethyl-propyl)-[l,3,4]oxadiazol-2- ylamino] -methyl} -3-(6-methoxy-pyridin-3-yl)-benzo[ ?]thiophene-2-carbonitrile; the title compounds were resolved by preparative HPLC. The stationary phase was a ChiralPak® AD column and the mobile phase was hexane/IPA 50:50 with a flow rate of 8 mL/min. The racemate was dissolved at a concentration of lOmg/mL in the mobile phase. Fractions were collected, combined and the solvent removed using a rotary evaporator to afford the first eluting enantiomer, Enantiomer 1, and the second eluting enantiomer, Enantiomer 2. Mass

spectrometric data: [M+H] = 508 (Compound 2- 18a) and 508 (Compound 2- 18b).

Example 25: Synthesis of 6-[4-(Dicyclopropyl-hydroxy-methyl)-[l,2,3]triazol-l-ylmethyl]- 3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carbonitrile (Compound 3-1) and 6-[4- (Dicyclopr opyl-hydroxy-methyl)- [1,2,3] triazol-1 -ylmethyl] -3-(6-methoxy-pyridin-3-yl)- benzo[6]thiophene-2-carboxylic acid amide (Compound 3-2)

Step 1: l,l-Dicyclopropyl-3-trimethylsilanyl-prop-2-yn-l-ol

[00435] (Trimethylsilyl)acetylene (5.0g, 51.0mmol) was dissolved in THF (400mL) and cooled to -78°C. n-Butyllithium (1.6M in hexanes; 38.25mL, 61.2mmol) was added dropwise over 10 minutes, and the mixture was stirred for 1 hour. Dicyclopropyl ketone (6.98mL, 61.2mmol) in THF (lOmL) was added dropwise, and the reaction was warmed to room temperature and stirred overnight. The mixture was quenched with IN aqueous HCl (200mL), concentrated to a volume of 1 OOmL, and diluted with EtOAc. The organic layer was washed three times with H 0 and once with brine, and then dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.

Step 2: l,l-Dicyclopropyl-prop-2-yn-l-ol

[00436] l,l-Dicyclopropyl-3-trimethylsilanyl-prop-2-yn-l-ol (l. lg, 5.3mmol) in MeCN (50mL) was treated with cesium fluoride (0.860g, 5.7mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with Et 0 and washed twice with H 0 and brine. The combined aqueous layer was back-extracted with Et 0, and the combined organic layers were dried, filtered, and concentrated to give the title product.

- I l l -

Step 3 : 3-C hloro-6- [4-(dicyclopr opyl-hydr oxy-methyl)- [1,2,3] triazol-1 -ylmethyl] - benzo[6]thiophene-2-carboxylic acid methyl ester

[00437] To a solution of 1 , 1 -dicyclopropyl-prop-2-yn- 1 -ol (5.3mmol) in THF (30mL) was added 6-azidomethyl-3-chloro-benzo[ ?]thiophene-2-carboxylic acid methyl ester (l.Og, 3.54mmol), and copper iodide (l.Og, 5.3mmol), followed by diisopropylethylamine (3.6mL, 21.2mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was quenched with H₂0 and diluted with EtOAc, and the organic layer was washed three times with aqueous NH₄C1 and brine, and then dried, filtered, and concentrated. The crude material was purified by silica gel chromatogr es) to give the title compound.

Step 4: 6-[4-(Dicyclopropyl-hydroxy-methyl)-[l,2,3]triazol-l-ylmethyl]-3-(6-methoxy- pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid methyl ester

[00438] Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: 3-chloro-6-[4-(dicyclopropyl-hydroxy-methyl)-[l,2,3]triazol-l- ylmethyl]-benzo[ ?]thiophene-2-carboxylic acid methyl ester and 2-methoxypyridine-5-boronic acid; the title compound was further purified by preparative HPLC.

Step 5: 6-[4-(Dicyclopropyl-hydroxy-methyl)-[l,2,3]triazol-l-ylniethyl]-3-(6-methoxy- pyridin-3-yl)-benzo [b] thiophene-2-carbonitrile and 6- [4-(Dicyclopropyl-hydroxy-methyl)- [l,2,3]triazol-l-ylmethyl]-3-(6-niethoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide

[00439] Prepared according to the procedure described in Example 5, Step 4, using the following starting material: 6-[4-(Dicyclopropyl-hydroxy-methyl)-[l,2,3]triazol-l-ylmethyl]-3- (6-methoxy-pyridin-3-yl)-benzo[ ?]thiophene-2-carboxylic acid methyl ester; the title compounds were separated by preparative HPLC. Mass spectrometric data: [M+H] = 458 (Compound 3-1) and 476 (Compound 3-2).

Example 26: Synthesis of 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l- phenyl-ethyl)-[l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carbonitrile (Compound 3-9) and 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)- [l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carboxylic acid methyl ester (Compound 3- 10)

Step 1: l,l,l-Trifluoro-4-triisopropylsilanyl-but-3-yn-2-one

[00440] Prepared according to the procedure described in Example 25, Step 1, using following starting materials: ethyl tri sopropylsilyl)acetylene.

Step 2: l,l,l-Trifluoro-2-phenyl-4-triisopropylsilanyl-but-3-yn-2-ol

[00441] To l,l,l-trifluoro-4-triisopropylsilanyl-but-3-yn-2-one (2g, 7.2mmol) in CH2CI2 (50mL) at 0°C was added phenylmagnesium bromide (1M in THF; 14.4mL, 14.4mmol), and the reaction was stirred at 0°C for 2.5 hours. The mixture was quenched with aqueous NH₄C1 and diluted with CH2CI2, and the organic layer was separated and washed with H₂0, dried, filtered, and concentrated to give the title compound.

Step 3: 3-Chloro-6-[4-(2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)-[l,2,3]triazol-l-ylmethyl]- benzo[6]thiophene-2-carboxylic acid methyl ester

[00442] l,l,l-Trifluoro-2-phenyl-4-triisopropylsilanyl-but-3-yn-2-ol (1.25g, 3.5mmol) in THF (35mL) was treated with tetrabutylammonium fluoride (1M in THF; 3.33mL, 3.33mmol), and the mixture was stirred for 10 minutes, until no starting material was seen by analytical tic. 6- Azidomethyl-3-chloro-benzo[ ?]thiophene-2-carboxylic acid methyl ester (l.Og, 3.5mmol) and copper iodide (l.Og, 5.25mmol) were added, followed by diisopropylethylamine (3.65mL, 21mmol), and the reaction was stirred at room temperature for 3 hours. The mixture was diluted with 1 : 1 EtOAc:hexanes (200mL) and washed three times with aqueous NH4CI. The combined aqueous layers were back-extracted, and the combined organic layers were dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (0- 100% EtOAc in hexanes) to give the title compound.

Step 4: 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)- [l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carboxylic acid methyl ester

[00443] Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: 3-chloro-6-[4-(2,2,2-trifluoro-l -hydroxy- 1 -phenyl-ethyl)- [l,2,3]triazol-l-ylmethyl]-benzo[ ?]thiophene-2-carboxylic acid methyl ester and 2- metho

Step 5: 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)- [l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carbonitrile and 3-(6-Methoxy-pyridin-3- yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)-[l,2,3]triazol-l-ylmethyl]- benzo[6]thiophene-2-carboxylic acid methyl ester and 3-(6-Methoxy-pyridin-3-yl)-6-[4- (2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)-[l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2- carboxylic acid amide (racemic)

[00444] Prepared according to the procedure described in Example 5, Step 4, using the following starting material: 3-(6-methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l -hydroxy- 1 - phenyl-ethyl)-[l,2,3]triazol-l-ylmethyl]-benzo[ ?]thiophene-2-carboxylic acid methyl ester; the title compounds were separated by silica gel chromatography and further purified by preparative HPLC. Mass spectrometric data: [M+H] = 522 (Compound 3-9) and 555 (Compound 3-10). Example 27: Synthesis of 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l- phenyl-ethyl)-[l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 1) (Compound 3-11) and 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l- hydroxy-l-phenyl-ethyl)-[l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer

Enantiomer 1 and 2

Step 1 : 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)- [l,2,3]triazol-l-ylmethyl]-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 1) and 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro-l-hydroxy-l-phenyl-ethyl)-[l,2,3]triazol- l-ylmethyl]-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 2)

[00445] 3-(6-Methoxy-pyridin-3-yl)-6-[4-(2,2,2-trifluoro- 1 -hydroxy- 1 -phenyl-ethyl)- [l,2,3]triazol-l-ylmethyl]-benzo[ ?]thiophene-2-carboxylic acid amide (racemic) was resolved by preparative HPLC. The stationary phase was a ChiralPak® AD column and the mobile phase was hexane/IPA 50:50 with a flow rate of 8 mL/min. The racemate was dissolved at a concentration of 20mg/mL in the mobile phase. Fractions were collected, combined and the solvent removed using a rotary evaporator to afford the first eluting enantiomer, Enantiomer 1 , and the second eluting enantiomer, Enantiomer 2. Mass spectrometric data: [M+H] = 540 (Compound 3-11) and 540 (Compound 3-12).

Example 28: Synthesis of 6-[4-(l-Cyclopropyl-2,2,2-trifiuoro-l-hydroxy-ethyl)- [l,2,3]triazol-l-ylmethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2- carbonitrile (Compound 3-13)

Step 1 : 6-Methyl-3-(6-trifluoromethyl-pyridin-3-yl)-benzo [b] thiophene-2-carbonitrile

[00446] Prepared according to the procedure described in Example 16, Step 10, using the following starting materials: 3-bromo-6-methyl-benzo[ ?]thiophene-2-carbonitrile and trifluoromethylpyridine-5-boronic acid.

Step 2 : 6-Bromomethyl-3-(6-trifluoromethyl-pyridin-3-yl)-benzo [b] thiophene-2- carbonitrile

[00447] Prepared according to the procedure described in Example 6, Step 1, using the following starting materials: 6-methyl-3-(6-trifluoromethyl-pyridin-3-yl)-benzo[ 7]thiophene-2- carbonitrile and N-bromosuccinimid

Step 3: 6-Azidomethyl-3-(6-trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2- carbonitrile

[00448] Prepared according to the procedure described in Example 6, Step 2, using the following starting materials: 6-bromomethyl-3-(6-trifluoromethyl-pyridin-3-yl)- benzo[ ?]thiophene-2-carbonitrile and sodium azide.

Step 4: 2-Cyclopropyl-l,l₉l-trifluoro-4-triisopropylsilanyl-but-3-yn-2-ol

[00449] Prepared according to the procedure described in Example 26, Step 2, using the following starting materials: l,l,l-trifluoro-4-triisopropylsilanyl-but-3-yn-2-one and cyclopropylmagnesium bromide (0.5M in THF).

Step 5: 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3-

(6-trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2-carbonitrile

[00450] Prepared according to the procedure described in Example 26, Step 3, using the following starting materials: 6-azidomethyl-3-(6-trifluoromethyl-pyridin-3-yl)- benzo[ ?]thiophene-2-carbonitrile and 2-cyclopropyl- 1,1,1 -trifluoro-4-triisopropylsilanyl-but-3- yn-2-ol. Mass spectrometric data: [M+H] = 524.

Example 29: Synthesis of 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)- [l,2,3]triazol-l-ylmethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2- carboxylic acid amide (Enantiomer 1) (Compound 3-14) and 6-[4-(l-Cyclopropyl-2,2,2- trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3-(6-trifluoromethyl-pyridin-3-yl)- benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 2) (Compound 3-15)

1 and 2

Step 1: 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3- (6-trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 1) and 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- trifluoromethyl-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 2)

[00451] Prepared according to the procedure described in Example 4, Step 1, using the following starting material: 6-[4-(l -cyclopropyl-2,2,2-trifluoro- 1 -hydroxy-ethyl)-[ 1 ,2,3]triazol- 1 -ylmethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-benzo[ 7]thiophene-2-carbonitrile; the title compounds were resolved by preparative HPLC. The stationary phase was a ChiralPak® AD column and the mobile phase was hexane/IPA 25:75 with a flow rate of 8 mL/min. Fractions were collected, combined and the solvent removed using a rotary evaporator to afford the first eluting enantiomer, Enantiomer 1, and the second eluting enantiomer, Enantiomer 2. Mass spectrometric data: [M+H] = 542 (Compound 3-14) and 542 (Compound 3-15).

Example 30: Synthesis of 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)- [l,2,3]triazol-l-ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carbonitrile (Compound 3-16)

Step 1: 3-Bromo-6-[4-(l-cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l- ylmethyl] -benzo [b] thiophene-2-carbonitrile

[00452] Prepared according to the procedure described in Example 26, Step 3, using the following starting materials: 6-azidomethyl-3-bromo-benzo[ ?]thiophene-2-carbonitrile and 2- cyclopropyl- 1,1,1 -trifluoro-4-triisopropylsilanyl-but-3-yn-2-ol.

Step 2: 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3- (6-methoxy-pyridin-3-yl)-benzo [b] thiophene-2-carbonitrile

[00453] Prepared according to the procedure described in Example 16, Step 10, using the following starting materials: 3-bromo-6-[4-(l-cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)- [ 1 ,2,3]triazol- 1 -ylmethyl]-benzo[ ?]thiophene-2-carbonitrile and 2-methoxypyridine-5-boronic acid. Mass spectrometric data: [M+H] = 486.

Example 31: Synthesis of 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)- [l,2,3]triazol-l-ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 1) (Compound 3-17) and 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l- hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2- carboxylic acid amide (Enantiomer 2) (Compound 3-18)

ntiomer 1 and 2

Step 1: 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3- (6-methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 1) and 6-[4-(l-Cyclopropyl-2,2,2-trifluoro-l-hydroxy-ethyl)-[l,2,3]triazol-l-ylmethyl]-3-(6- methoxy-pyridin-3-yl)-benzo[6]thiophene-2-carboxylic acid amide (Enantiomer 2)

[00454] Prepared according to the procedure described in Example 4, Step 1, using the following starting material: 6-[4-(l -cyclopropyl-2,2,2-trifluoro- 1 -hydroxy-ethyl)-[ 1 ,2,3]triazol- l-ylmethyl]-3-(6-methoxy-pyridin-3-yl)-benzo[ ?]thiophene-2-carbonitrile; the title compounds were resolved by preparative HPLC. The stationary phase was a ChiralPak® AD column and the mobile phase was hexane/IPA 50:50 with a flow rate of 8 mL/min. The racemate was dissolved at a concentration of lOmg/mL in the mobile phase. Fractions were collected, combined and the solvent removed using a rotary evaporator to afford the first eluting enantiomer, Enantiomer 1, and the second eluting enantiomer, Enantiomer 2. Mass

spectrometric data: [M+H] = 504 (Compound 3-17) and 504 (Compound 3-18).

Example 32: Synthesis of l,l,l-Trifluoro-2-(l-((3-(6-methoxypyridin-3- yl)benzo[d]isothiazol-6-yl)methyl)-l -l,2,3-triazol-4-yl)butan-2-ol (Compound 4-3)

Step 1: 2-(Benzylthio)-4-methylbenzonitrile

[00455] To a stirred solution of 2-fluoro-4-methylbenzonitrile (3.0 g, 22.2 mmol) and benzyl mercaptan (2.47 mL, 21.1 mmol) in dioxane (100 mL) at 0°C was added NaH (1.16 g of a 60% dispersion in mineral oil, 28.9 mmol) in 2 equal portions. The cold bath was removed, and the mixture was stirred for 3 hours at room temperature, then warmed further to 80°C and left to stir for an additional 30 min, after which time the reaction was determined to be complete by analytical LCMS. The mixture was then cooled to 0°C, quenched with 2 mL H 0, and neutralized with 1 N HC1 (28 mL). The solvent was removed by rotary evaporation, and the crude residue was dissolved in EtOAc (300 mL) then dried over MgS0₄. Filtration and concentration gave the title compound which was used in the next step without further purification.

Step 2: 2-Mercapto-4-methylbenzonitrile

[00456] To a stirred suspension of AICI₃ (4.39 g, 33.0 mmol) in benzene (20 mL) at room temperature was added dropwise a solution of 2-(benzylthio)-4-methylbenzonitrile (4.88 g, 20.0 mmol) in benzene (60 mL). After complete addition, the reaction mixture was left to stir for an additional 20 minutes, at which time analytical TLC analysis showed disappearance of starting material. The reaction was then cooled to 0°C and quenched by addition of ice chips. The resulting mixture was diluted with EtOAc (300 mL) and washed with H₂0 (2 x 100 mL) and brine (50 mL). The combined aqueous layers were back extracted with EtOAc (100 mL). The organic layers were combined, dried over MgS0₄, filtered and concentrated to give the title compound which was used in the next step without further purification.

Step 3: 3-Bromo-6-methylbenzo[d]isothiazole

[00457] To a stirred solution of 2-mercapto-4-methylbenzonitrile (2.98 g, 20.0 mmol) in EtOAc (150 mL) at 0°C was added Br₂ (1.54 mL, 30 mmol) neat via syringe. After 5 min, the cold bath was removed and the mixture was warmed to reflux, where stirring continued for 20 minutes, at which time analytical TLC analysis showed full conversion to higher Rf spot. The mixture was cooled to room temperature, diluted with EtOAc (400 mL) and washed with saturated aqueous sodium thiosulfate (2 x 100 mL), H₂0 (100 mL), and brine (100 mL). The resulting organic layer was dried over MgS0₄, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-15% EtOAc in hexanes) to give the title compound.

Step 4: 3-(6-Methoxypyridin-3-yl)-6-methylbenzo[d]isothiazole

[00458] 3-Bromo-6-methylbenzo[d]isothiazole (456 mg, 2.0 mmol), 2-methoxy-5- pyridineboronic acid (459 mg, 3.0 mmol), and sodium bicarbonate (430 mg, 5.0 mmol) were dissolved in 2: 1 DME:H₂0 (20 mL). The resulting solution was bubbled with N₂ for 5 min, followed by addition of (l ,l'-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) (146 mg, 0.2 mmol). The resulting suspension was warmed to 80°C and stirred for 4 hours then cooled to room temperature, diluted with EtOAc (100 mL) and partitioned with H 0 (50 mL). The EtOAc layer was washed with H₂0 (50 mL) and brine (50 mL), then dried over MgS0₄, filtered, and concentrated. The crude material was purified by silica gel chromatography (0- 100% EtOAc in hexanes) to give the title com ound.

Step 5 : 6-(Bromomethyl)-3-(6-methoxypyridin-3-yl)benzo [d] isothiazole

[00459] 3-(6-Methoxypyridin-3-yl)-6-methylbenzo[d]isothiazole (256 mg, 1.0 mmol), N- bromosuccinimide (178 mg, 1.0 mmol), and dibenzoyl peroxide (24 mg, 0.1 mmol) were combined at room temperature in carbon tetrachloride (20 mL). The resulting mixture was heated to reflux and stirred for 2 hours, then cooled to room temperature, diluted with EtOAc (100 mL), and partitioned with H 0 (50 mL). The EtOAc layer was further washed with saturated NaHC0₃ (50 mL) and H₂0 (50 mL), then dried over MgS0₄, filtered, and

concentrated. The crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.

Step 6: 6-(Azidomethyl)-3-(6-methoxypyridin-3-yl)benzo[d]isothiazole

[00460] Sodium azide (140 mg, 2.15 mmol) was added to a stirred solution of 6- (bromomethyl)-3-(6-methoxypyridin-3-yl)benzo[d]isothiazole (175 mg, 0.52 mmol) in DMF (10 mL) at room temperature. After 10 minutes, the reaction was determined to be complete by analytical TLC. The mixture was then diluted with 1 : 1 hexanes:EtOAc (50 mL), washed with dilute brine (4 x 25 mL), dried over MgS0₄, filtered, and concentrated to give the title compound which was used in the next step without further purification.

Step 7: l,l,l-Trifluoro-2-(l-((3-(6-methoxypyridin-3-yl)benzo[d]isothiazol-6-yl)methyl)- lH-l,2,3-triazol-4-yl)butan-2-yl 4-nitrobenzoate

[00461] Prepared according to the procedure described in Example 5, step 11 using the following starting materials: 6-(azidomethyl)-3-(6-methoxypyridin-3-yl)benzo[d]isothiazole and 4-nitro-benzoic acid 1 -ethyl- 1 -trifluorometh l-prop-2-ynyl ester (Enantiomer B).

Step 8: l,l,l-Trifluoro-2-(l-((3-(6-methoxypyridin-3-yl)benzo[d]isothiazol-6-yl)methyl)- lH-l,2,3-triazol-4-yl)butan-2-ol [00462] Prepared according to the procedure described in Example 5, Step 12, using the following starting material: l ,l ,l-trifluoro-2-(l-((3-(6-methoxypyridin-3-yl)benzo[d]isothiazol- 6-yl)methyl)-lH-l ,2,3-triazol-4-yl)butan-2-yl 4-nitrobenzoate.

Example 32: Human 5-lipoxygenase activity inhibition assay

[00463] A non-limiting example of a 5-lipoxygenase activity inhibition assay is as follows: Human polymorphonuclear leukocytes are prepared from blood by Ficoll-Hypaque separation, lysed and centrifuged at 100,000xg. The 100,000xg supernatant containing 5-lipoxygenase is added to tubes, containing 100 mM TrisCl pH 8.0, 2 mM ATP, 2 mM calcium and incubated with 20-200 μΜ arachidonic acid in a final volume of 100 μΐ_^ for 1-10 minutes at 37 °C.

Reaction is terminated by the addition of an equal volume of ice cold methanol, centrifuged at 10,000xg for 10 minutes and supernatant analyzed by reverse phase HPLC for formation of 5- HETE/5HPETE monitoring absorbance at 235 nm.

Example 33: Human leukocyte LTB₄ inhibition assay

[00464] A non- limiting example of a human leukocyte inhibition assay is as follows;

Blood was drawn from consenting human volunteers into heparanized tubes and 3% dextran 0.9% saline 1/3 rd volume added. After sedimentation of red blood cells a hypotonic lysis of remaining red blood cells was performed and leukocytes sedimented at 1200 rpm. The pellet was resuspended at 1.25 x 10⁵ cells /ml and aliquoted into wells containing 1 μΕ 100% DMSO (vehicle) or 2.5 μΐ_^ drug in 100% DMSO. Samples were incubated for 5 minutes at 37 °C and 2 μΐ_^ calcium ionophore A23817 (from a 50 mM DMSO stock diluted just prior to the assay in Hanks balanced salt solution (Invitrogen)) to 1.25 mM) was added, solutions mixed and incubated for 30 minutes at 37°C. Samples were centrifuged at 1 ,200 rpm (-200 x g) for 10 minutes at 4°C, plasma removed and a 1 :4 dilution assayed for LTB₄ concentration using ELISA (Assay Designs). Drug concentrations to achieve 50%) inhibition (ICso's) of vehicle LTB₄ were determined by nonlinear regression (Graphpad Prism) of % inhibition versus log drug concentration.

[00465] Representative data for illustrative compounds is provided in the Table below:

Compound LTB₄ HLA LTB₄ HWB

# ICso ICso

1-12 A B

1-13 A B

1-14 A A

1-18 A A

1-20 A A

l-20a A B

1-21 A A

1-22 A A

1-24 A B

1-31 A A

1-35 A A

1-38 A A

1-47 A A

1-48 A B

2-3 A A

2-7 A A

2-18a A B

2- 18b A B

3-1 A A

3-2 A A

3-9 A A

3-10 A A

3-11 A A

3-12 A B

3-13 A B

3-14 A B

3-15 C C

3-16 A A

3-17 A A

3-18 A A

4-3 nd A

A = less than 300nM

B = greater than 300nM but less than 1 μηι

C = greater than 1 μηι but less than 50 μηι

Example 34: Human Blood LTB₄ inhibition Assay

[00466] A non-limiting example of such a human blood LTB₄ inhibition assay is as follows: Blood was drawn from consenting human volunteers into heparinized tubes and 148 μΐ_^ aliquots added to wells containing 1.5 μΐ. 100% DMSO (vehicle) or 1.5 μΐ. drug in 100% DMSO.

Samples were incubated for 15 minutes at 37°C then 2 μΐ_^ calcium ionophore A23817 (from a 50 mM DMSO stock diluted just prior to the assay in Hanks balanced salt solution (Invitrogen)) to 1.25 mM) was added, solutions mixed and incubated for 30 minutes at 37°C. Samples were centrifuged at 1,500 rpm (-300 x g) for 10 minutes at 4°C, plasma removed and a 1 : 100 dilution assayed for LTB₄ concentration using ELISA (Assay Designs). Drug concentrations to achieve 50% inhibition (IC₅₀'s) of vehicle LTB₄ were determined by nonlinear regression (Graphpad Prism) of % inhibition versus log drug concentration.

Example 35: Rat peritoneal Inflammation and Edema Assay

[00467] A non- limiting example of such a rat peritoneal inflammation and edema assay is as follows: The in vivo efficacy of leukotriene biosynthesis inhibitors against inflammation and vascular edema was assessed using a rat model of peritoneal inflammation. Male Sprague- Dawley rats (weighing 200 - 300 grams) received a single intraperitoneal (i.p.) injection of 3 ml saline containing zymosan (5 mg/mL) followed immediately by an intravenous (i.v.) injection of Evans blue dye (2 mL of 1.5% solution). Compounds were administered orally (3 mL/kg in 0.5%) methylcellulose vehicle) 2 to 4 hours prior to zymosan injection. One to two hours after zymosan injection, rats were euthanized, and the peritoneal cavity was flushed with 10 mL phosphate buffered saline solution (PBS). The resulting fluid was centrifuged at 1,200 rpm for 10 minutes. Vascular edema was assesses by quantifying the amount of Evans blue dye in the supernatant using a spectrophotometer (Absorbance 610 nm). LTB₄ and cysteinyl leukotriene concentrations in the supernatant were determined by ELISA. Drug concentrations to achieve 50%) inhibition of plasma leakage (Evans blue dye) and inhibition of peritoneal LTB₄ and cysteinyl leukotrienes could be calculated by nonlinear regression (Graphpad Prism) of %> inhibition versus log drug concentration.

Example 36: Rat Ionophore Lung Lavage

[00468] A non-limiting example of such a rat ionophore lung lavage assay is as follows:

A rat ionophore lung lavage model (see Smith et al., J.P.E.T., 1995, 275, 1332-1338) was utilized to determine efficacy of leukotriene biosynthesis inhibitors in the target tissue for respiratory therapy. Male Sprague-Dawley rats (weighing 200 - 300 grams) were administered compound orally (3 ml/kg in 0.5%> methylcellulose vehicle) 2 to 4 hours prior to lung lavage. LTB₄ and cysteinyl leukotrienes were stimulated within the lung via an intra-tracheal instillation of 10ml PBS containing 20μg/mL calcium ionophore. After a 3-min period the fluid was withdrawn from the lung and was centrifuged at 1,200 rpm for 10 minutes. LTB₄ and cysteinyl leukotriene concentrations in the supernatant were determined by ELISA. Drug concentrations to achieve 50%> inhibition of lung LTB₄ and cysteinyl leukotrienes could be calculated by nonlinear regression (Graphpad Prism) of %> inhibition versus log drug concentration.

Example 37: Pharmacokinetic Analysis

[00469] A non-limiting example of such a pharmacokinetic analysis is as follows:

Catheterized rats (SD-JVC from Charles River) were fasted over night (n = 2/group) and then dosed with compound either at 2 mg/kg IV or 10 mg/kg PO. For IV dosing, compounds were given in solution using 10%> EtOH/40%o PEG/50%> H₂0 as vehicle and blood samples were drawn at 5, 15 and 30 mins, 1, 2, 4, 6, 8 hours. For PO dosing, compounds were given in solution using 25% Hydroxypropyl-beta-cyclodextrin in water as vehicle and blood samples were drawn at 30 mins, 1, 2, 4, 6, 8 hours PO. Samples were then analyzed by HPLC-MS/MS. Example 38: Induction of joint inflammation

[00470] Animals were treated systemically with either vehicle or active compound and then subject to joint inflammation 30 min to 5 hours following dose. Joint inflammation was induced by intra articular (i.a.) injection of zymosan (500 μg/cavity in 25 μΐ sterile saline), by the insertion of a 27-G needle through the suprapatellar ligament into the knee joint cavity. Control animals received an i.a. injection of an equal volume of sterile saline. Knee-joint swelling was evaluated by measurement of the transverse diameters of injected knee joints using a digital caliper. Animals were then euthanized by an excess of CO₂ at specific time points after i.a. inject of zymosan (1 hr to 24 hr). Knee synovial cavities were washed with 300 μΐ PBS containing EDTA (10 mM) by the insertion of a 21-G needle into mouse knee joints, and the synovial fluid recovered by aspiration. Total leukocyte counts were recorded as well as cell differentials. Synovial fluid was centrifuged at 1,200 rpm for 10 minutes. LTB₄ and cysteinyl leukotriene concentrations in the supernatant were determined by ELISA.

Example 39: Mouse arachidonic acid-induced ear inflammation model

Procedures

[00471] A mouse arachidonic acid (AA) -induced ear inflammation model was utilized to determine the extent of inhibition of ear swelling and leukotriene (LT) production by oral application of a 5-LO inhibitor. Methods were adapted from Byrum et ah, J Exp Med. 1997 Mar 17;185(6): 1065-75).

[00472] Female CD-I mice (weighing 18 - 20 grams) were administered compound orally (30 mg/kg in 10 ml/kg of 0.5% methylcellulose vehicle). Four hours following compound administration a 40 μΐ aliquot of a 4 mg/ml solution of AA in ethanol was applied to the experimental (right) ear and vehicle (ethanol) was applied to the control (left) ear. Thirty minutes later mice were placed into an enclosed Plexiglas chamber and exposed to CO₂ for a period of 1 -2 minutes or until breathing ceased. Ear biopsies were then taken for assessment of inflammation and leukotriene levels.

Ear inflammation

[00473] An eight mm ear punch was taken from a similar location of each experimental ear and each control ear and weighed. The extent of inflammation was determined by the difference in weight between the experimental ear and control ear [experimental ear (mg) - control ear (mg)]. A typical response for this assay is in the range of 4 and 12 mg increase in weight. Ear punches were then frozen for later assessment of leukotrienes. Leukotriene analysis

[00474] The ear punch was placed into a tris buffer containing 0.01 % triton x and homogenized using a polytron probe homogenizer. The sample was then centrifuged at 10,000 X g for 10 minutes at 4^°C. Leukotriene B₄ (LTB₄) and cysteinyl leukotriene (CysLT) concentrations in the supernatant were determined by enzyme-immunoassay (EIA).

Example 40: Rat Model of Allergic Conjunctivitis

[00475] A rat model of allergic conjunctivitis is used to test the effect of administration of a 5- LO inhibitor compound on the development of allergic conjunctivitis. Male wistar rats (250 - 350 g) are sensitized by injection with 0.6 mL saline containing ovalbumin (OVA, 1 mg), alum (2mg) and 10¹⁰ killed B. pertussis cells into all four footpads on day 1. Five days later they are boosted by subcutaneous injection with 1 ml of saline containing OVA (0.5 mg) in 10 sites on the back. Local sensitization is performed daily from days 14 to day 42 by instilling OVA in saline (10 mg/ml, 5μ1) into the bilateral eyes using a micropipette. Rats are treated with 5-LO inhibitor on days 14 to 42 (as appropriate). The frequency of eye scratching behavior is counted for 20 min post OVA on selected days. Twenty- four hours following OVA challenge on days 14, 21, 28, 35 and 42 rats are anesthetized and the conjunctiva removed and fixed with 10% neutral buffered formalin. 4-μηι thick frontal sections are stained and eosinophils counted. The inhibition of eye scratching behavior and conjunctiva eosinophils following treatment with a 5- LO inhibitor compound is recorded and plotted using Graphpad Prizm.

Pharmaceutical Compositions

Example 41: Parenteral Composition

[00476] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in sterile water 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 42: Oral Composition

[00477] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein 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 43: Sublingual (Hard Lozenge) Composition

[00478] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound described herein, 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 44: Inhalation Composition

[00479] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound described herein 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 45: Rectal Gel Composition

[00480] To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound described herein is mixed with 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen, 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 46: Topical Gel Composition

[00481] To prepare a pharmaceutical topical gel composition, 100 mg of a compound described herein 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 47: Ophthalmic Solution Composition

[00482] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound described herein 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.

[00483] 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.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I) or a pharmaceutically acceptable salt thereof:

Formula (I)

R¹ is Ci-C₆alkyl, Ci-C₆fiuoroalkyl, C3-C₆cycloalkyl, substituted or unsubstituted

monocyclic heteroaryl, or substituted or unsubstituted bicyclic heteroaryl; X is C(R²) or N;

R² is H, Ci-C₆alkyl, Ci-C₆fluoroalkyl, C₃-C₆cycloalkyl, -Ci-C₄alkylene-R³, -CN,

halogen, -C0₂R¹⁰, -CON(R⁹)₂, -CHO, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, or - S0₂N(R⁹)₂;

R³ is -C0₂H, -C0₂R¹⁰, -C(0)R¹⁰, -C(OH)(R⁹)₂, -CON(R⁹)₂, -C(0)NHS0₂R¹⁰,

tetrazolyl, -OH, C C₄alkoxy, halide, -CN, -SR⁹, -S(0)R¹⁰, -S(0)₂R¹⁰, - S0₂NHC(0)R¹⁰, -N(R⁹)₂, or -NHC(0)R¹⁰;

ring A is a triazolyl,oxadiazolyl or thiazolyl;

L¹ is -0-, -NR⁸-, -S-, C C₃alkylene, -NR⁸C C₃alkylene -, or C C₃heteroalkylene; R⁴ is H, Ci-C₄alkyl, or -C(=0)R⁷;

R⁵ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkyl- Ci-C₄alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl;

R⁶ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl or C₃-

C₆cycloalkyl-Ci-C₄alkyl;

R⁷ is H, Ci-C₄alkyl, Ci-C₄fluoroalkyl, or C₃-C₆cycloalkyl, substituted or unsubstituted phenyl;

R⁸ is H or C C₄alkyl;

each R⁹ is independently selected from H, Ci-C₆alkyl, Ci-C₆fluoroalkyl, C₃-

C₈cycloalkyl, substituted or unsubstituted phenyl, and a substituted or unsubstituted heteroaryl; or two R⁹ can be joined to form a heterocycloalkyl;

R¹⁰ is selected from Ci-C₆alkyl, Ci-C₆fiuoroalkyl, C₃-Cscycloalkyl, substituted or

unsubstituted phenyl, and a substituted or unsubstituted heteroaryl;

where each substituted phenyl or substituted heteroaryl is substituted with 1 or 2 R¹¹, where each R¹¹ is independently selected from halogen, -OH, Ci-C₄alkyl, Ci- C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄alkoxy, Ci-C₄heteroalkyl, C₃-C₆cycloalkyl, - CN, -C0₂H, -C0₂R¹⁰, -CON(R⁹)₂, tetrazolyl, -C(=0)R¹⁰, -C(OH)(R⁹)₂, -S0₂R¹⁰, - S0₂N(R⁹)₂, and -N(R⁹)₂.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

L¹ is -S-, -CH₂-, -NHCH₂-;

R⁴ is H;

R⁵ is Ci-C₄alkyl, C₃-C₆cycloalkyl or Ci-C₄fluoroalkyl;

R⁶ is Ci-C₄alkyl, C₃-C₆cycloalkyl or Ci-C₄fluoroalkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: ring A is oxadiazolyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure of Formula II):

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: ring A is triazolyl.

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure of Formula III):

Formula (III).

The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein:

R² is -H, -CN, CHO, halide, -C0₂R¹⁰, COR¹⁰, -CON(R⁹)₂, -S0₂R¹⁰, or -S0₂N(R⁹)₂;

R⁵ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃;

R⁶ is -CH₃, -CH₂CH₃, -CF₃, or -CH₂CF₃;

each R⁹ is independently selected from H and Ci-C₆alkyl;

R¹⁰ is C C₆alkyl.

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein: R⁵ is -CH₂CH₃;

R⁶ is -CF₃.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is Ci-C₆alkyl, Ci-C₆fiuoroalkyl, or C3-C₆cycloalkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -CH₃, -CH₂CH₃, -CH(CH₃)₂, -C(=CH₂)CH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -CH(CH₃)₂, or -C(=CH₂)CH₃;

R² is -CN, -C0₂R¹⁰, -CON(R⁹)₂, -S0₂R¹⁰, or -S0₂N(R⁹)₂;

each R⁹ is independently selected from H and Ci-C₄alkyl;

R¹⁰ is Ci-C₄alkyl.

12. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt

thereof, wherein:

R¹ is a substituted or unsubstituted monocyclic heteroaryl or a substituted or

unsubstituted bicyclic heteroaryl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a substituted or unsubstituted monocyclic heteroaryl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a substituted or unsubstituted furanyl, substituted or unsubstituted thienyl,

substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted 1,3,4- thiadiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyrazinyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl or substituted or unsubstituted pyrazinyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is substituted or unsubstituted pyridinyl;

R² is -CN, -C0₂R¹⁰, -CON(R⁹)₂, -S0₂R¹⁰, or -S0₂N(R⁹)₂;

each R⁹ is independently selected from H and Ci-C₄alkyl;

R¹⁰ is C C₄alkyl.

17. The compound of of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R⁵ is C3-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or

unsubstituted monocyclic heteroaryl;

R⁶ is Ci-C₄alkyl, Ci-C₄fluoroalkyl, or C₃-C₆cycloalkyl.

18. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-17.

19. A method of treating a leukotriene dependent or leukotriene-mediated disease or

condition in a mammal, or a 5-lipoxygenase dependent or 5-lipoxygenase-mediated disease or condition in a mammal comprising administering to the mammal a therapeutically effective amount of the compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-17.

20. The method of claim 19, wherein the disease or condition is a respiratory disease or condition or cardiovascular disease or condition.

21. The method of claim 19, wherein the disease or condition is asthma, atherosclerosis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, aortic aneurysm, myocardial infarction, stroke, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or pain.

22. A method of treating ocular disease in a mammal comprising administering to the mammal a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-17.

23. A method of treating skin disease in a mammal comprising administering to the

mammal a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-17.

24. A method of treating inflammation in a mammal comprising administering to the

mammal a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-17.

25. The method of claim 24, wherein the inflammation is ocular inflammation, skin

inflammation, or lung inflammation.