TRIARYL SUBSTITUTED IMIDAZOLE DERIVATIVES AND TASTE-
`
`INHIBITING USES THEREOF
`
`CROSS—REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`This application claims the benefit of the filing date of US. Patent Appl. No.
`
`60/796,235, filed April 28, 2006, which is incorporated by reference herein in its entirety.
`
`BACKGROUND OF THE INVENTION
`
`Field of the Invention
`
`[0002]
`
`The present invention relates to the use of compounds of Formula I for inhibiting
`
`certain taste functions and perceptions and related uses. The invention is also directed to,
`
`among other things, compositions comprising a compound of Formula I that can be used
`
`in pharmaceutical, food, and other compositions to inhibit certain taste functions and
`
`perceptions.
`
`Background
`
`[0003]
`
`Taste perception plays a critical role in the nutritional status and survival of both
`
`lower and higher animals (Margolskee, R.F., J. Biol. Chem. 277:1-4 (2002); Avenet, P.
`
`and Lindemann, B.
`
`J., Membrane Biol. 11221-8 (1989)). The ability to taste has
`
`significance beyond providing people with pleasurable culinary experiences.
`
`For
`
`example, the ability to taste allows us to identify tainted or spoiled foods, and provides
`
`satisfying responses that can be proportionate to caloric or nutritive value.
`
`[0004]
`
`Although taste perception is a Vital function, sometimes it is useful to modify
`
`certain tastes.
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`For example, many active pham‘raceutical
`
`ingredients of medicines
`
`produce an undesirable taste, such as a bitter taste. The same holds true for some
`
`compounds that are ingredients or additives in nutriceuticals, foods, dental hygiene
`
`products and cosmetics. Masking or inhibiting the production of an undesirable taste by
`
`these products can lead to improved acceptance by the patient or consumer.
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`Atty. Dkt No. 2305.0330001/TJS/A-L
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`[0005]
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`Traditionally, sweeteners and. flavorants have been used to mask the bitter taste of
`
`pharmaceuticals. The sweetener or flavorant is known to activate taste pathways (other
`
`than the pathway producing the undesirable taste), and at sufficiently high concentration,
`
`can mask the bitter taste of the pharmaceutical. However, this approach has proved
`
`ineffective at masking the taste of very bitter compounds. Microencapsulation in a
`
`cellulose derivative has also been used to mask the bitter taste of some compounds.
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`However, this approach prevents rapid oral absorption of the pharmaceutical.
`
`[0006]
`
`Thus the presently available methods for inhibiting, altering, or masking unwanted
`
`tastes are insufficient. There exists a need for compounds that can effectively inhibit an
`
`unwanted taste.
`
`[0007]
`
`Taste also plays a role the appetite for food. Studies have shown increased food
`
`intake as palatability increased. Sorensen, et (1]., Int. J. Obes. Relat. Metab. Disord.
`
`27(10):1152—66 (2003).
`
`Conversely, certain drugs, such as antihypertensives and
`
`antihyperlipidemics, have been reported to produce untoward alterations in taste and can
`
`result in decreased food intake. Doty, et al., J Hypertens. 21(10):1805-13 (2003). Taste
`
`impairment associated with radiation treatments for head and neck cancer has been
`
`considered to be one of the factors associated with reduced appetite and altered patterns
`
`of food intake in these patients. Vissink, et al., Crit. Rev. Oral Biol. Med. 14(3):213—25
`
`(2003). Decreased food consumption has also been correlated with loss of taste
`
`sensations in the elderly. Shiffman, 8.8., J. Am. Med. Ass’n 278(16):1357—1362 (1997).
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`[0008]
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`Much research has been done in an attempt to find safe and effective means for
`
`decreasing food intake in people in need of weight reduction. A number of agents have
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`been developed and marketed to reduce appetite and food intake, such as amphetamine
`
`derivatives and fenfluramine. However, many have dangerous side effects. More
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`selective approaches, e.g., neuro-regulation via peptide mimetics/antagonists, are still in
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`developmental phases.
`
`[0009]
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`Therefore,
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`there exists a need for compounds that can effectively decrease
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`palatability of food, without dangerous adverse effects, to reduce food intake.
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`BRIEF SUMMARY OF THE INVENTION
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`[0010]
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`The present invention provides methods and compositions for inhibiting, altering,
`
`or masking unwanted tastes.
`
`The present
`
`invention also provides methods and
`
`compositions for inhibiting, masking or altering tastes to decrease palatability of food and
`
`lead to reduced food intake
`
`[0011]
`
`The compositions and methods of the invention use a triaryl substituted imidazole
`
`of Formula 1:
`
`Ar1
`
`Ar2
`
`|
`
`R1
`N/
`/>——Ar3
`N
`
`1
`
`or a pharmaceutically acceptable salt thereof; wherein R1 is hydrogen, unsubstitued alkyl,
`
`or unsubstituted arylalkyl; Ar1 and AI2 are independently phenyl or a heteroaryl, either of
`
`which is optionally substituted as described herein below; and AI3 is phenyl or a
`
`heteroaryl, either of which is optionally substituted as described herein below.
`
`[0012]
`
`In some embodiments of the present invention, Ar1 and Ar2 are independently
`
`selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl,
`
`pyrimidinyl, pyrazinyl, and triazinyl, and N-oxides thereof, each of which is optionally
`
`substituted as described herein below.
`
`[0013]
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`In some embodiments of the present invention, Ar1 and A12 are independently
`
`selected
`
`from the
`
`group
`
`consisting of unsubstituted
`
`phenyl, methylphenyl,
`
`methoxyphenyl,
`
`halophenyl,
`
`cyanophenyl,
`
`carboxyphenyl,
`
`aminophenyl,
`
`and
`
`hydroxyphenyl, wherein the phenyl substitution can be at any one or more of the ortho—,
`
`meta-, and para-positions.
`
`[0014]
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`In some embodiments of the present invention, Ar1 and Ar2 are both unsubstituted
`
`phenyl, or alternatively, Ar1 and Ar2 are both unsubstituted: C-attached pyridyl,
`
`C—attached pyridazinyl, C-attached pyrimidinyl, C—attached pyrazinyl, C—attached
`
`triazinyl, and N-oxides thereof.
`
`[0015]
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`In some embodiments of the present invention, Ar3 is selected from the group
`
`consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and
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`-4-
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`triazinyl, and N-oxides thereof, each of which can be optionally substituted as described
`
`herein below.
`
`[0016]
`
`In some embodiments of the present invention, Ar3 is phenyl, pyrid-2-yl, pyrid-3-
`
`yl, pyrid—4-yl, pyridazin-3-yl, pyridazin-4-y1, pyrimidin—Z-yl, pyrimidin-4-yl, pyrimidin-
`
`5-y1, pyrazin-2-y1, 1,2,3-triazin—4-y1, 1,2,3-triazin-5-yl, or 1,3,5—triazin—2—yl, any of which
`
`is optionally substituted as described herein below.
`
`[0017]
`
`In some embodiments of the present
`
`invention, Ar3 is a C-attached pyridyl,
`
`C attached pyridazinyl, C-attached pyrimidinyl, C-attached pyrazinyl, C—attached
`
`triazinyl, and N-oxides thereof, any of which is optionally substituted as described herein
`
`below.
`
`[0018]
`
`In some embodiments, R1
`
`is hydrogen, an unsubstituted C14 alkyl, or an
`
`unsubstituted aryl(C1.4)alkyl; Ar1 and Ar2 are both unsubstituted phenyl; and A? is
`
`phenyl, substituted by one to three substituents independently selected from the group
`
`consisting
`
`of
`
`carboxy,
`
`alkoxycarbonyl,
`
`hydroxy,
`
`hydroxyalkyl,
`
`amino,
`
`.alkoxycarbonylamino, cyano, alkylsulfonylaminoalkyl, and nitro.
`
`[0019]
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`In some embodiments, Ar3 is selected from the group consisting of phenyl,
`
`'C-attached pyridyl, C-attached pyrimidyl,
`
`and C-attached pyridazinyl, optionally
`
`- substituted with one or more nitro, halo, cyano, carboxyl, amino, hydroxyl, alkyl, and
`
`cyanoalkyl substituents in any one or more of the ortho—, meta-, and para-positions.
`
`[0020]
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`In some embodiments, A13 is phenyl, substituted in the para—position by a
`
`carboxy, alkoxycarbonyl, hydroxyalkyl, hydroxy, amino, alkoxycarbonylamino, cyano,
`
`alkylsulfonylaminoalkyl, or nitro.
`
`[0021]
`
`In some embodiments, the compound of Formula I is one of:
`
`methyl4-(4,5 -diphenyl-1H—imidazol—Z-yl)benzoate;
`
`[4—(4,5-diphenyl-lH—imidazol-Z-yl)phenyl]methanol;
`
`4—(4,5—diphenyl-1H-imidazol—Z—yl)aniline;
`
`4-(4,5-diphenyl-1H-imidazol-2—yl)phenol;
`
`methy14-(4,5 —diphenyl-1H-imidazol-Z-yl)phenylcarbamate;
`
`N—[4—(4,5—dipheny1-1H-imidazol—Z—yl)phenyl]acetamide;
`
`4—(4,5—diphenyl-1H—imidazol-Z-yl)benzonitrile;
`
`N-[4-(4,5-diphenyl-1H-imidazo1-2—yl)benzyl]methanesulfonamide;
`
`4-(4,5-diphenyl—1H-imidazol—2—yl)benzoic acid; and
`
`Atty. Dkt. N0. 2305.0330001/TJS/A—L
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`-5-
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`2-(4—nitro—pheny1)-4,5-diphenyl—lH-imidazole;
`
`and pharmaceutically acceptable salts thereof.
`
`[0022]
`
`The present invention is directed to a method of inhibiting a taste modulating
`
`protein, the method comprising contacting the taste modulating protein with a compound
`
`of Formula I, or a pharmaceutically acceptable salt thereof.
`
`[0023]
`
`In some embodiments,
`
`the taste modulating protein is a non-human TRPMS
`
`protein. Such proteins suitable for inhibiting with a compound of Formula I include, but
`
`are not limited to, those from a cow, horse, sheep, pig, cat, dog, rabbit, or monkey.
`
`In
`
`some embodiments, the species is human.
`
`In some embodiments, the taste modulating
`
`protein is in vitro.
`
`[0024]
`
`The present invention is also directed to a method of masking a taste, the method
`
`comprising administering to a subject in need of taste masking one or more compounds of
`Formula I or a pharmaceutically acceptable salt thereof. A subject in need of taste
`
`masking can be a human. A taste in need of masking can be a bitter taste.
`
`[0025]
`
`The present invention is also directed to a method of inhibiting the depolarization
`
`of a taste receptor cell, the method comprising contacting the taste receptor cell with a
`
`compound of Formulal or a pharmaceutically acceptable salt thereof.
`
`[0026]
`
`In some embodiments of the present invention, the compound of Formula I is
`
`administered in an amount sufficient to inhibit a taste-modulating protein, mask a taste, or
`
`inhibit the depolarization of a taste—receptor cell by about 10% to about 95%.
`
`[0027]
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`The present invention is also directed to a method of decreasing the palatability of
`
`food in a subject, comprising administering to a subject in need thereof one or more
`
`compounds of Formula I, or a pharmaceutically acceptable salt thereof.
`
`[0028]
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`In some embodiments, the palatability of food can be reduced in a subject by
`
`administering a compound of Formula I using a solid dosage form, an orally
`
`disintegrating dosage form, a liquid dosage form, a suspension, an aerosol composition, a
`
`buccal patch, a surgical
`
`implant, a depot
`
`injection, or
`
`intravenously.
`
`In some
`
`embodiments, a compound of Formula I can be administered to a subject immediately
`
`prior to a meal. A subject
`
`in need of such treatment can suffer from compulsive
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`overeating disorder, bulimia, binge eating disorder, obesity, over-eating, or eating without
`
`care for stopping.
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`[0029]
`
`In some embodiments, a reduction in the palatability of food in a subject can
`
`result in a decreased caloric intake in a subject. A subject in need of such treatment can
`
`suffer from, type-II diabetes, or other diabetes related disorders, or alternatively, have a
`
`body mass index of at least 30.
`
`In some embodiments, administering a compound of
`
`Formula I to a subject in need thereof can decrease the caloric intake of the subject by at
`
`least about 10%.
`
`[0030]
`
`In some embodiments, a taste in need of masking arises from a component of a
`
`pharmaceutical, veterinary, food, cosmetic, or dental hygienic composition. The method
`
`of taste masking can comprise adding a compound of Formula I to the pharmaceutical,
`
`veterinary, food, cosmetic, or dental hygienic composition in need of taste masking, or
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`alternatively, administering a compound of Formula] as a separate composition to a
`
`subject in need of such treatment.
`
`[0031]
`
`Compositions having a taste in need of masking can contain biologically active
`
`agents in addition to compounds of Formula I. Biologically active agent suitable for use
`
`with the present
`
`invention include, but are not
`
`limited to, analgesics, anesthetics,
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`anorexiants,
`
`appetite depressants, antacids, antiasthmatics, antidiuretics, antipyretics,
`
`antihistamines,
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`anticholinergics,
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`antidiarrheals,
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`antitussives,
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`antinauseants,
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`antiarrhythmics, antimicrobials, antibacterials, antifungals, antivirals, anti-inflammatory
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`agents, agents active against flatulence, antimigraine agents, beta-receptor blockers,
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`bronchodilators,
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`psychopharrnacological
`
`agents,
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`spasmolytics,
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`sedatives,
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`antihyperkinetics,
`
`tranquilizers,
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`decongestants,
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`demulcents,
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`agents
`
`for
`
`alcohol
`
`withdrawal, antitussives, fluorine supplements, laxatives, local antibiotics, corticosteroid
`
`supplements, agents against goiter formation, antiepileptics, agents against dehydration,
`
`antiseptics, NSAIDs, Hz-receptor antagonists, nutritional supplements, gastrointestinal
`
`active agents, alkaloids, supplements for trace elements, ion-exchange resins, cholesterol-
`
`depressant agents, lipid-lowering agents, expectorants, and combinations thereof.
`
`[0032]
`
`In some embodiments of the present invention, a compound of Formula I can be
`
`administered as a pharmaceutical, veterinary,
`
`food, cosmetic, or dental hygienic
`
`composition to a subject in need thereof. A compound of Formula I can be present in a
`
`pharmaceutical, veterinary, food, cosmetic, or dental hygienic composition of the present
`
`invention in an amount of about 0.01 mg to about 100 mg.
`
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`-7-
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`[0033]
`
`The present invention is also directed to a pharmaceutical composition comprising
`
`one or more pharmaceutically acceptable carriers, and one or more compounds of
`
`Formula I or a pharmaceutically acceptable salt thereof.
`
`[0034]
`
`The present invention is also directed to a method of preparing an improved
`
`pharmaceutical
`
`composition, wherein the
`
`improvement
`
`comprises
`
`adding to
`
`a
`
`pharmaceutical composition one or more compounds of Formula I, or a pharmaceutically
`
`acceptable salt thereof.
`
`In some embodiments, the pharmaceutical composition of the
`
`present invention is a solid dosage form, an orally disintegrating dosage form, a liquid
`
`dosage form, a suspension, an aerosol composition, a buccal patch, a surgical implant, a
`
`depot injection, or an intravenous solution.
`The present invention is also directed to a food composition comprising one or
`
`[0035]
`
`more food ingredients and one or more compounds of Formula I, or a pharmaceutically
`
`acceptable salt thereof.
`
`[0036]
`
`The present invention is also directed to a method of preparing an improved food
`
`composition, wherein the improvement comprises adding to a food composition one or
`
`more compounds of Formula I, or a pharmaceutically acceptable salt thereof.
`
`[0037]
`
`In some embodiments, the food composition of the present invention is suitable
`
`for human consumption, or alternatively, for animal consumption.
`
`[0038]
`
`In some embodiments, the food composition of the present invention is a liquid, or
`
`alternatively, a solid. Food compositions of or for use with the present invention include,
`
`but are not limited to, citrus fruits, vegetables, seasoning or flavoring materials, soybean
`
`compositions,
`
`fish, meats
`
`and processed meats, dairy, breads
`
`and cakes,
`
`and
`
`confectioneries.
`
`[0039]
`
`The present invention is also directed to a cosmetic composition comprising one
`
`or more dental cosmetic ingredients and a compound of Formula I, or a pharmaceutically
`
`acceptable salt thereof.
`
`[0040].
`
`The present invention is also directed to a method of preparing an improved
`
`cosmetic composition, wherein the improvement compriSes adding to a cosmetic
`
`composition one or more compounds of Formula I, or a pharmaceutically acceptable salt
`
`thereof. Cosmetic compositions of or for use with the present invention include, but are
`
`not limited to, face cream, lipstick, lip gloss, and lip balm.
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`[0041]
`
`The present invention is also directed to a dental hygienic composition comprising
`
`one or more dental hygienic ingredients 'and a compound of Formula I, or a
`
`pharmaceutically acceptable salt thereof.
`
`[0042]
`
`The present invention is also directed to a method of preparing an improved dental
`
`hygienic composition, wherein the improvement comprises adding to a dental hygienic
`
`composition one or more compounds of Formula I, or a pharrnaceutically acceptable salt
`
`thereof. Dental hygienic compositions of or for use with the present invention include,
`
`but are not
`
`limited to,
`
`toothpaste, mouthwash, plaque rinse,
`
`a teeth-whitening
`
`composition, and mouth spray.
`
`[0043]
`
`In some embodiments, a compound of Formula I is present in a pharmaceutical,
`
`veterinary, food, cosmetic, or dental hygienic composition of the present invention in a
`
`concentration of about 10'7 to about 10'3 by mole, or about 10'6 to about 10'4 by mole of
`
`the unit dose of the pharmaceutical, veterinary,
`
`food, cosmetic, or dental hygienic
`
`composition.
`
`In some embodiments, a compound of Formula I
`
`is present
`
`in a
`
`pharmaceutical, veterinary, food, cosmetic, or dental hygienic composition of the present
`
`invention in a concentration of about 10'6 to about 102, or about 10'5 to about 10'3 by
`
`weight, of the pharmaceutical, veterinary, food, cosmetic, or dental hygienic composition.
`
`[0044]
`
`These and additional aspects of the present
`
`invention are described in detail
`
`below.
`
`BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES
`
`[0045]
`
`The accompanying drawings, which are incorporated herein and form a part of the
`
`specification, serve to explain the principles of the invention and to enable a person
`
`skilled in the pertinent art to make and use the invention.
`
`[0046]
`
`FIG. 1 illustrates the generation of a response in the taste modulating protein
`
`TRPMS. The response changes cell membrane potential, which can be detected, e.g.,
`
`using fluorescent dyes and a fluorescent imaging plate reader (FLIPR).
`
`[0047]
`
`FIG. 2(A) and 2(B)
`
`illustrate the TRPMS-dependent
`
`fluorescent signal
`
`in
`
`HEK293 cells. The experimental details are explained in EXAMPLE 11.
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`-9-
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`DETAILED DESCRIPTION OF THE INVENTION
`
`[0048]
`
`The present invention provides compounds and compositions that are useful, for
`
`example, for inhibiting the activity of a taste modulating protein. Other aspects of the
`
`present invention are described in detail herein.
`
`[0049]
`
`The methods and composition of the present
`
`invention can also include a
`
`pharmaceutically acceptable
`
`salt of a
`
`compound of Formula
`
`I.
`
`The
`
`term
`
`pharmaceutically acceptable salt refers to an acid— and/or base-addition salt of a
`
`compound of Formula I. Acid—addition salts can be formed by adding an appropriate acid
`
`to the compound of Formula I. Base-addition salts can be formed by adding an
`
`appropriate base to the compound of Formula I. The acid or base does not substantially
`
`degrade, decompose, or destroy the compound of Formula 1. Examples of suitable
`
`pharmaceutically acceptable salts include hydrochloride, hydrobromide, acetate, furmate,
`
`maleate, oxalate, and succinate salts. Other suitable salts include sodium, potassium,
`
`carbonate, and tromethamine salts.
`
`[0050]
`
`The present invention is considered to encompass the use of stereoisomers as well
`
`as optical isomers, e.g., mixtures of enantiomers as well as individual enantiomers and
`
`diastereomers, which arise as a consequence of structural asymmetry in selected
`
`compounds of the present series.
`
`It
`
`is further understood that the present invention
`
`encompasses the use of tautomers of a compound of Formula I. Tautomers are well-
`
`known in the art and include keto—enol tautomers.
`
`[0051]
`
`The compounds of Formula I can also be solvated, including hydrated. Hydration
`
`can occur during manufacturing of the compounds or compositions comprising the
`
`compounds, or the hydration can occur over time due to the hygroscopic nature of the
`
`compounds.
`
`[0052]
`
`Certain compounds within the scope of Formula I can be derivatives referred to as
`
`"prodrugs." The expression "prodrug" denotes a derivative of a known direct acting
`
`agent, wherein the derivative has therapeutic value that can be similar to, greater than, or
`
`less than that of the agent. Generally, the prodrug is transformed into the active agent by
`
`an enzymatic or chemical process when delivered to the subject, cell, or test media.
`
`In
`
`I certain instances, prodrugs are derivatives of the compounds of the invention which have
`
`metabolically cleavable groups and become by solvolysis or under physiological
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`Atty. Dkt. N0. 2305.0330001/TJS/A-L
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`-10-
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`conditions the compounds of the invention which are pharmaceutically active in viva. For
`
`example, ester derivatives of compounds of this invention are often active in vivo, but not
`
`in vitro. Other derivatives of the compounds of this invention have activity in both their
`
`acid and acid derivative forms, but the acid derivative fonn often offers advantages of
`
`solubility,
`
`tissue compatibility, or delayed release in the mammalian organism (see,
`
`Bundgard, H., Design of Prodrugs, pp.
`
`7—9, 21—24, Elsevier, Amsterdam (1985)).
`
`Prodrugs include acid derivatives well known to practitioners of the art, such as, for
`
`example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides
`
`prepared by reaction of the parent acid compound with an amine. Simple aliphatic or
`
`aromatic esters derived from acidic groups pendent on the compounds of this invention
`
`are preferred prodrugs.
`
`In some cases,
`
`it
`
`is desirable to prepare double ester type
`
`prodrugs such as (acyloxy) alkyl esters or [(alkoxycarbony1)oxy]alkyl esters.
`
`[0053]
`
`When any variable occurs more than one time in any constituent or in Formula I,
`
`its definition on each occurrence is independent of its definition at every other
`
`occurrence, unless otherwise indicated. Also, combinations of substituents and/or
`
`variables are permissible only if such combinations result in stable compounds.
`
`[0054]
`
`Unless otherwise indicated, the term "alkyl" or "alk" as used herein alone or as
`
`part of another group includes both straight and branched chain hydrocarbons, containing
`
`1
`
`to 20 carbons, preferably 1 to 10 carbons, more preferably 1
`
`to 8 carbons, such as
`
`methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,
`
`4,4-dimethy1pentyl, octyl, 2,2,4-trimethylpenty1, nonyl, decyl, undecyl, dodecyl, and the
`like. Lower alkyl refers to such groups containing? 1-6 carbon atoms. Unless specified
`
`otherwise, an alkyl group may be optionally substituted with 1 or more 'alkyl substituents'
`
`which may be the same or different at each occurrence. These substituents may occur at
`
`any place and in any combination that provides a stable compound.
`
`[0055]
`
`As used herein, "optionally substituted" refers to substitution with one or more of
`
`the following substituents, which may be the same or different at each occurrence, and
`
`which can occur at any place and in any combination that provides a stable compound.
`
`These 'optional substituents' can be:
`
`halogen;
`
`nitro;
`
`cyano; '
`
`Atty. Dkt. No. 2305.0330001/TJS/A—L
`
`

`

`-11-
`
`0R22;
`
`alkyl which may be substituted with one or more occurrences of R23;
`
`alkenyl which may be substituted with one or more occurrences of R23;
`
`alkynyl which may be substituted with one or more occurrences of R23;
`
`cycloalkyl which may be substituted with one or more occurrences of R23;
`
`aryl which may be substituted with one or more occurrences of R23;
`
`heterocyclo which may be substituted with one or more occurrences of R23;
`
`SR22;
`
`SOszz;
`
`COORZZ;
`
`C(O)R22;
`
`CONR24R25;
`
`302NR24R25;
`
`$02N(H)C(O)R22;
`
`S02N(H)C02R22, wherein R22 is not H;
`
`NR24R25;
`
`N(R24)302R25;
`
`N(R24)C(O)mR25 (wherein m = 1,2);
`
`N(R24)C(O)NR25R26;
`
`N(R24)SOzNR25R26;
`
`OC(O)R22;
`
`OC(O)OR22;
`
`OC(O)NR25R26;
`
`C(O)N(H)SOzNR25R26;
`
`C(O)N(H)502R25;
`
`0x0 (or keto, i.e., =0);
`
`thioxo (i.e., =S);
`
`imino (i.e., =NR27);
`
`NR27—C(=NR28)R29;
`
`NR27—C(=NR28)NR29R30;
`
`C(=NR27)NR28R29;
`
`OC(=NR27)NR28R29;
`
`Atty. Dkt. No. 2305.0330001/TJS/A-L
`
`

`

`-12-
`
`OC(=NR27)R28;
`
`C(=NR27)R28;
`
`C(=NRz7)ORzz;
`
`wherein R22 is selected from H, C1-C8 alkyl, C2-C3 alkenyl, C2—C3 alkynyl, C3-C3
`
`cycloalkyl, C6—C10 aryl, or C1—C9 heterocyclo each of which may be substituted with 1 to
`
`3 independent occurrences of R23; and
`
`wherein R24, R25, and R26 are selected from C1—C8 alkyl, C2-C8 alkenyl, C2-C8
`
`alkynyl, C3-C3 cycloalkyl, C6-C10 aryl, or C1-C9 heterocyclo each of which may be
`
`substituted with 1 to 3 independent occurrences of R23, or R24 and R25, or R24 and R26 or
`
`R25 and R25 may be joined by an alkylene or an alkenylene chain to form a 5- to 8-
`
`membered heterocyclo ring which is defined as for heterocyclo wherein the substituents
`
`may be one or more occurrences of R23.
`
`[0056]
`
`R27, R23, R29, or R30 are independently selected from H, nitro, cyano, OH, O(C1-C6
`
`alkyl), C(O)R22, C(O)NR24R25, CO2R22 (with the proviso that R22 is not H), SO2R22,
`
`SO2NR24R25, C1-C3 alkyl, C2-C3 alkenyl, C2-C8 alkynyl, C3-C3 cycloalkyl, C6-C10 aryl, or
`
`C1—C9 heterocyclo or R27 and R23 or R27 and R29 or R27 and R30 or R23 and R29 or R28 and
`
`R30 or R29 and R30 may be joined by an alkylene or alkenylene chain to form a 5— to
`
`8-membered ring that may be optionally substituted with one or more occurrences of R23.
`
`[0057]
`
`R23 is selected from:
`
`halogen;
`
`nitro;
`
`cyano;
`
`OR31;
`
`alkyl optionally substituted with halogen;
`
`cycloalkyl optionally substituted with halogen;
`
`aryl optionally substituted with halogen, hydroxy, nitro, methoxy, trifluoromethyl,
`
`cyano, carbomethoxy, CONH2, and CHO;
`
`heterocyclo optionally substituted with halogen, hydroxy, nitro, methoxy,
`
`trifluoromethyl, cyano, carbomethoxy, CONH2, and CHO,
`
`SR31;
`
`C02R31;
`
`C(O)Rsl;
`
`Atty. Dkt. No. 2305.0330001/TJS/A—L
`
`

`

`-13-
`
`CONR32R33;
`
`SOzNR32R33;
`
`NR32R33;
`
`N(R32)302R33;
`
`N(R32)C(O)mR33 (m = 1,2);
`
`N(R32)C(O)NR33R34;
`
`N(R32)SOZNR33R34;
`
`OC(O)R31;
`
`OC(O)OR31;
`
`502R31;
`
`SOzN(H)C(O)R31 ;
`
`SOzN(H)C02R31 wherein R3] is not H;
`
`C(O)N(H)SOZNR32R33;
`
`C(0)N(H)302R31 ;
`
`OC(O)NR32R33;
`
`NRss-C(=NR36)R37;
`
`NRss-C(=NR36)OR31;
`
`NRss-C(=NR36)NR37R38;
`
`C(=NR35)NR36R37;
`
`OC(=NR35)R36;
`
`OC(=NR35)NR36R37; and
`
`C(=NR35)OR31 ;
`
`wherein R31 is selected from unsubstituted alkyl, alkenyl, unsubstituted alkynyl,
`
`unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heterocyclo;
`
`wherein R32, R33 and R34 are selected from unsubstituted alkyl, unsubstituted
`
`alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted
`
`heterocyclo, or R3; and R33 or R32 and R3; or R33 and R34 may be joined by an
`
`unsubstituted alkylene or unsubstituted alkenylene chain to form a 5- to 8-membered
`
`unsubstituted heterocyclo ring; and
`
`wherein R35, R36, R37, R38 are selected from nitro, cyano, unsubstituted alkyl,
`
`unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted aryl,
`
`unsubstituted heterocyclo, or R35 and R35, or R35 and R37 or R35 and R33 or R36 and R37 or
`
`Atty. Dkt. No. 2305.0330001/TJS/A—L
`
`

`

`-14-
`
`R36 and R33 or R37 and R38 may be joined by an unsubstituted alkylene chain or
`
`unsubstituted alkenylene chain to form a 5- to 8-membered unsubstituted heterocyclo
`ring.
`‘
`
`[0058]
`
`Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as
`
`part of another group includes saturated or partially unsaturated (i.e., containing one or
`
`more carbon-carbon double bonds) cyclic hydrocarbon groups containing 1
`
`to 3 rings,
`
`containing a total of 3 to 20 carbons forming the ring(s), preferably 3 to 10 carbons,
`
`forming the ring. Polycyclic systems may contain fused or bridged rings or both.
`
`In
`
`addition, the cycloalkyl group may be fused to 1 or 2 aryl rings. Examples include
`
`cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and
`
`cyclododecyl, cyclohexenyl,
`
`ER eh 9% co
`®®®
`
`[0059]
`
`CycloalkyI groups may be optionally substituted with 1 or more "cycloalkyl
`
`substituents" which may be the same or different at each occurrence. These optional
`
`substituents may occur at any place in any combination that provides a stable compound.
`
`These substituents may be any of the optional substituents as defined above.
`
`[0060]
`
`The term "alkanoy " as used herein alone or as part of another group refers to
`
`alkyl linked to a carbonyl group.
`
`[0061]
`
`Unless otherwise indicated, the term "alkenyl" as used herein by itself or as part of
`
`another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2
`
`to 12 carbons, and more preferably 2 to 8 such as Vinyl, 2-propenyl, 3-buteny1, 2-butenyl,
`
`4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexeny1, 2-hepteny1, 3-heptenyl,
`4—heptenyl,
`3-octenyl, 3-nonenyl, 4-decenyl, 3-undeceny1, 4—dodecenyl, 4,8,12-tetradecatrienyl, and
`the like. Lower alkenyl refers to such groups containing 2-6 carbon atoms. Alkenyl
`
`groups may be optionally substituted with 1 or more 'alkenyl substituents' which may be
`
`the same or different at each occurrence. These optional substituents may occur at any
`
`place in any combination that provides a stable compound. These substituents may be
`
`any of the optional substituents as defined above.
`
`Atty. Dkt. No. 2305.0330001/TJS/A—L
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`

`

`-15-
`
`[0062]
`
`Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" as used herein
`
`by itself or as part of another group refers to straight or branched chain radicals of 2 to 20
`
`carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons such as
`
`2-propynyl, 3-butynyl,
`
`2—butynyl,
`
`4—pentynyl,
`
`3—pentynyl, 2-hexynyl, 3-hexynyl,
`
`2-heptyny1,
`
`3-heptyny1, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl,
`
`4-dodecynyl and the like. Lower alkynyl refers to such groups containing 1—6 carbon
`
`atoms.
`
`Alkynyl groups may be optionally substituted with l or more 'alkynyl
`
`substituents' which may be the same or different at each occurrence. These substituents
`
`may occur at any place in any combination that provides a stable compound. These
`
`substituents may be any of those as defined above.
`
`[0063]
`
`Where alkyl groups as defined above have single bonds for attachment to other
`
`groups at
`
`two different carbon atoms,
`
`they are termed "alkylene" groups and may
`
`optionally be substituted as defined above for "alkyl".
`
`[0064]
`
`Where alkenyl groups as defined above and alkynyl groups as defined above,
`
`respectively, have single bonds for attachment at two different carbon atoms, they are
`
`termed "alkenylene groups" and "alkynylene groups", respectively, and may optionally be
`
`substituted as defined above for "alkenyl" and "alkynyl".
`
`[0065]
`
`Unless otherwise indicated, the term "aryl" as employed herein alone or as part of
`
`another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10
`
`carbons in the ring portion (such, as phenyl or naphthyl
`
`including l-naphthyl and
`
`2—naphthyl) and may optionally include one to three additional
`
`rings fused to a
`
`carbocyclic ring. Aryl groups may be substituted with 1 or more 'aryl substituents' which
`
`may be the same or different at each occurrence. These substituents may occur at any
`
`place in any combination that provides a stable compound. These substituents may be
`
`any of the substituents as defined above.
`
`[0066]
`
`Unless otherwise indicated, the term "alkylaryl" as employed herein alone or as
`
`part of another group, refers to an aryl group, as defined above, having an alkyl
`
`substituent, as defined above. Similarly, unless otherwise indicated, the terms "aralkyl"
`
`and "arylalkyl" as employed herein alone or as part of another group, refer to an alkyl
`
`group as defined above having an aryl substituent.
`
`[0067]
`
`Unless otherwise indicated,
`
`the term "lower alkoxy",
`
`"alkoxy",
`
`"aryloxy",
`
`"aralkoxy" or “heterocycloalkoxy” as employed herein alone or as part of another group
`
`Atty. Dkt. No. 2305 .0330001/TJS/A—L
`
`

`

`—16-
`
`includes any of the above alkyl, aralkyl, aryl, or heterocyclo groups linked to an oxygen
`
`atom.
`
`[0068]
`
`Unless otherwise indicated, the term "acyl" as employed herein by itself or part of
`
`9
`( C )
`another group, as defined herein, refers to an organic radical linked to a carbonyl
`group; examples of acyl groups include any of the R1 groups attached to a carbonyl, such
`
`as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, heterocycloalkanoyl
`
`and the like.
`
`[0069]
`
`Unless otherwise indicated, the term "heterocyclo" as used herein alone or as part
`
`of another group refers to a monocyclic or multicyclic ring system wherein one or more
`
`of the ring atoms are elements other than carbon. Preferred systems have 1 to 4 of the
`
`atoms independently selected from N, O or S. The ring system may be unsaturated,
`
`partially saturated, fully saturated or aromatic. Heterocyclo groups containing more than
`
`one ring may be f