SULFAMIDES AS TRPM8 MODULATORS
This application claims priority to U.S. Provisional Patent Application No. 61/138,598, filed Dec. 18, 2008, which is hereby incorporated by reference in its entirety. The present invention relates to sulfamides that act as modulators of the TRPM8 receptor. The present invention also relates to processes for the preparation of sulfamides and to their use in treating various diseases, syndromes, and disorders, including those that cause inflammatory or neuropathic pain, cold intolerance or cold allodynia, peripheral vascular pain, itch, urinary incontinence, chronic obstructive pulmonary disease (COPD), pulmonary hypertension and anxiety, including other stress-related disorders, and combinations thereof. Transient receptor potential (TRP) channels are non-selective cation channels that are activated by a variety of stimuli. Numerous members of the ion channel family have been identified to date, including the cold-menthol receptor, also called TRPM8 (McKemy D. D., et al., TRPM8 is located on primary nociceptive neurons (A-delta and C-fibers) and is also modulated by inflammation-mediated second messenger signals (Abe, J., et al., International patent application WO 2006/040136 A1 from Bayer Healthcare AG purportedly describes substituted 4-benzyloxy-phenylmethylamide derivatives as cold menthol receptor-1 (CMR-1) antagonists for the treatment of urological disorders. International patent application WO 2006/040103 A1 from Bayer Healthcare AG purportedly describes methods and pharmaceutical compositions for treatment and/or prophylaxis of respiratory diseases or disorders. International patent applications WO 2007/017092A1, WO 2007/017093A1 and WO 2007/017094A1, from Bayer Healthcare AG, purportedly describe benzyloxyphenylmethyl carbamate, substituted 2-benzyloxybenzoic acid amide and substituted 4-benzyloxybenzoic acid amide derivatives for the treatment of diseases associated with the cold menthol receptor (CMR), a.k.a. TRPM8. There is a need in the art for TRPM8 antagonists that can be used to treat a disease, syndrome, or condition in a mammal in which the disease, syndrome, or condition is affected by the modulation of TRPM8 receptors, such as pain, the diseases that lead to such pain, and pulmonary or vascular dysfunction. The present invention provides, inter alia, compounds of Formula (I) wherein Y is
R1is
R2is
R3is
R4is
RAis C1-6alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-4alkoxycarbonyl, C1-3alkoxy, and hydroxy; RBis hydrogen or C1-6alkyl; or, RAand RBare taken together with the nitrogen atom to which they are attached to form a 6 membered ring containing one heteroatom selected from the group consisting of O, S, and S(O2); or, RAand RBare taken together with the nitrogen atom to which they are attached to form a 5 or 6 membered ring, optionally containing one additional N atom, to form
RCis
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. The present invention also provides, inter alia, a pharmaceutical composition comprising, consisting of and/or consisting essentially of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent and a compound of Formula (I) or a pharmaceutically acceptable salt form thereof. Also provided are processes for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I) and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent. The present invention further provides, inter alia, methods for treating or ameliorating a TRPM8-modulated disorder in a subject, including a mammal and/or human in which the disease, syndrome, or condition is affected by the modulation of TRPM8 receptors, such as pain, the diseases that lead to such pain, and pulmonary or vascular dysfunction using a compound of Formula (I). In particular, the methods of the present invention are directed to treating or ameliorating a TRPM8 receptor-modulated disorder including inflammatory pain, cold-intolerance or cold allodynia, peripheral vascular pain, itch, urinary incontinence, chronic obstructive pulmonary disease, pulmonary hypertension and anxiety, including other stress-related disorders, using a compound of Formula (I). The present invention also provides, inter alia, methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof. The term “independently” means that when more than one of such substituent is possible, such substituents may be the same or different from each other. The term “alkyl” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range. Therefore, designated numbers of carbon atoms (e.g., C1-8) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups such as (C1-6alkyl)2-amino—the C1-6alkyl groups of the dialkylamino may be the same or different. The term “alkoxy” refers to an O-alkyl substituent group, wherein alkyl is as defined supra. To the extent substituted, an alkyl and alkoxy chain may be substituted on a carbon atom. The terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains having 2 or more carbon atoms, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. The term “cycloalkyl” refers to saturated or partially unsaturated, monocyclic or polycyclic hydrocarbon rings of from 3 to 14 carbon atom members. Examples of such rings include, and are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. Similarly, “cycloalkenyl” refers to a cycloalkyl that contains at least one double bond in the ring. Additionally, a “benzofused cycloalkyl” is a cycloalkyl ring that is fused to a benzene ring. A “heteroaryl-fused cycloalkyl” is a cycloalkyl ring that is fused to a 5 or 6-membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen). The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members are nitrogen, or a nonaromatic cyclic ring of 5 to 7 members in which zero, one or two members are nitrogen and up to two members are oxygen or sulfur; wherein, optionally, the ring contains zero to one unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it contains up to two unsaturated bonds. As used herein, “benzofused heterocyclyl” includes a 5 to 7 membered monocyclic heterocyclic ring fused to a benzene ring. As used herein, “heteroaryl-fused heterocyclyl” refers to 5 to 7 membered monocyclic heterocyclic ring fused to a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen). As used herein, “cycloalkyl-fused heterocyclyl” refers to a 5 to 7 membered monocyclic heterocyclic ring fused to a 5 to 7 membered cycloalkyl or cycloalkenyl ring. Furthermore, as used herein, “heterocyclyl-fused heterocycyl” refers to a 5 to 7 membered monocyclic heterocyclic ring fused to a 5 to 7 membered heterocyclyl ring (of the same definition as above but absent the option of a further fused ring). For instant compounds of the invention, the carbon atom ring members that form the heterocyclyl ring are fully saturated. Other compounds of the invention may have a partially saturated heterocyclyl ring. As used herein, “heterocyclyl” also includes a 5 to 7 membered monocyclic heterocycle bridged to form bicyclic rings. Such compounds are not considered to be fully aromatic and are not referred to as heteroaryl compounds. Examples of heterocyclyl groups include, and are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl or anthracenyl. Preferred aryl groups for the practice of this invention are phenyl and naphthalenyl. The term “heteroaryl” refers to an aromatic ring of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include N, O, or S. In the case of 5 membered rings, the heteroaryl ring contains one member of N, O, or S and, in addition, may contain up to three additional nitrogen atoms In the case of 6 membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the 6 membered ring has three nitrogen atoms, at most two nitrogen atoms are adjacent. Optionally, the heteroaryl ring is fused to a benzene ring to form a “benzo fused heteroaryl”; similarly, the heteroaryl ring is optionally fused to a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen atom) to form a “heteroaryl-fused heteroaryl”; similarly, the heteroaryl ring is optionally fused to a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo ring (as defined supra but absent the option of a further fused ring) to form a “cycloalkyl-fused heteroaryl”. Examples of heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; examples of heteroaryl groups with the optionally fused benzene rings include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolizinyl, quinolinyl, isoquinolinyl or quinazolinyl. The term “arylalkyl” means an alkyl group substituted with an aryl group (e.g., benzyl, phenethyl). Similarly, “arylalkoxy” indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy). The term “halogen” refers to fluorine, chlorine, bromine and iodine. Substituents that are substituted with multiple halogens are substituted in a manner that provides compounds that are stable. Whenever the terms “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C1-C6) refer independently to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl and alkoxy substituents, the designated number of carbon atoms includes all of the independent members included within a given range specified. For example C1-6alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g. C1-2, C1-3, C1-4, C1-5, C2-6, C3-6, C4-6, C5-6, C2-5, etc.). In general, under standard nomenclature rules used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylC1-C6alkylamidoC1-C6alkyl” substituent refers to a group of the formula: Unless otherwise noted, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term “therapeutically effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated. The term “composition” is intended to encompass a product comprising the specified ingredients in therapeutically effective amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. The term “antagonist” is used to refer to a compound capable of producing, depending on the circumstance, a functional antagonism of the TRPM8 ion channel, including, but not limited to, competitive antagonists, non-competitive antagonists, desensitizing agonists, and partial agonists. As used herein, “inflammatory hypersensitivity” is used to refer to a condition that is characterized by one or more hallmarks of inflammation, including edema, erythema, hyperthermia and pain, and/or by an exaggerated physiologic or pathophysiologic response to one or more than one type of stimulation, including thermal, mechanical, and/or chemical stimulation. The term “TRPM8-modulated” is used to refer to the condition of being affected by the modulation of the TRPM8 receptor, including the state of being mediated by the TRPM8 receptor. An embodiment of the invention is a method of treating or preventing at least one of the following diseases, syndromes, and conditions selected from the group consisting of migraine, post herpetic neuralgia, post traumatic neuralgia, post chemotherapy neuralgia, complex regional pain syndrome I and II (CRPS I/II), fibromyalgia, inflammatory bowel disease, pruritis, asthma, chronic obstructive pulmonary disease, toothache, bone pain and pyresis in a subject, which method comprises, consists of, and/or consists essentially of administering to the subject, including an animal, a mammal, and a human in need of such treatment or prevention, a therapeutically effective amount of a TRPM8 antagonist that is a compound of Formula (I). Another embodiment of the invention is a method of treating or preventing at least one of the following diseases, syndromes, and conditions selected from hypertension, peripheral vascular disease, Raynaud's disease, reperfusion injury or frostbite in a subject, which method comprises administering to the subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a TRPM8 antagonist that is a compound of Formula (I). A further embodiment of the invention is a method of accelerating post-anesthetic recovery or post-hypothermia recovery in a subject, including an animal, a mammal, and a human, which method comprises administering to the subject, including an animal, a mammal, and a human in need of such accelerated recovery, a therapeutically effective amount of a TRPM8 antagonist that is a compound of Formula (I). An embodiment of the present invention is directed to compounds of Formula (I) wherein
and any combination of embodiments a) through j) above, provided that it is understood that combinations in which different embodiments of the same substituent would be combined are excluded; and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. A further embodiment of the present invention is directed to a compound of Formula (I) wherein Y is hydrogen; bromo; chloro; fluoro; iodo; C3-6cycloalkyl; or C1-4alkyl; R1is
R2is
R3is
R4is
RAis C1-4alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-3alkoxy, and hydroxy; RBis hydrogen or C1-4alkyl;
RCis
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. A further embodiment of the present invention is directed to a compound of Formula (I) wherein Y is hydrogen; methyl; isopropyl; chloro; cyclopropyl; cyclobutyl; cyclopentyl; or bromo; R1is
R2is
R3is
R4is
RAis C1-4alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-3alkoxy, and hydroxy; RBis hydrogen or C1-4alkyl;
RCis
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. A further embodiment of the present invention is directed to a compound of Formula (I) wherein Y is hydrogen; methyl; isopropyl; chloro; cyclopropyl; or bromo; R1is
R2is
R3is
R4is
RAis C1-4alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-3alkoxy, and hydroxy; RBis hydrogen or C1-4alkyl;
RCis
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. A further embodiment of the present invention is directed to compounds of Formula (I) selected from the group consisting of
and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof. For use in medicine, salts of compounds of Formula (I) refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of Formula (I) or of their pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of compounds of Formula (I) include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of Formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Representative acids and bases that may be used in the preparation of pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide. Embodiments of the present invention include prodrugs of compounds of Formula (I). In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treating or preventing embodiments of the present invention, the term “administering” encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. Where the compounds according to embodiments of this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula I. Where the processes for the preparation of the compounds according to certain embodiments of the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. One embodiment of the present invention is directed to a composition, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+)-enantiomer of a compound of Formula (I) wherein said composition is substantially free from the (−)-isomer of said compound. In the present context, substantially free means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2% and even more preferably less than about 1% of the (−)-isomer calculated as Another embodiment of the present invention is a composition, including a pharmaceutical composition, comprising, consisting of, and consisting essentially of the (−)-enantiomer of a compound of Formula (I) wherein said composition is substantially free from the (+)-isomer of said compound. In the present context, substantially free from means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2% and even more preferably less than about 1% of the (+)-isomer calculated as During any of the processes for preparation of the compounds of the various embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in By way of example, in the pharmaceutical compositions of embodiments of the present invention, the compounds of Formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof. Solid oral dosage forms, such as tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations. Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents. Alternatively, compounds of Formula (I) can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between about 1% and about 10% by weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a white wax or white soft paraffin base together with any stabilizers and preservatives as may be required. An alternative means of administration includes transdermal administration by using a skin or transdermal patch. The pharmaceutical compositions of the present invention (as well as the compounds of the present invention alone) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent. For parenteral administration, the pharmaceutical compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration, the pharmaceutical compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner. By way of further example, pharmaceutical compositions containing at least one of the compounds of Formula (I) as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques. The carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.). Thus for liquid oral preparations, such as suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be optionally coated with substances, such as sugars, or be enterically-coated so as to modulate the major site of absorption and disintegration. For parenteral administration, the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives, such as solubilizers and preservatives. A therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or, more particularly, from about 10 mg to about 500 mg of active ingredient in a regimen of about 1 to 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the diseases, syndromes, conditions, and disorders being treated. For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of the inventive compound as the active ingredient. Advantageously, a compound of Formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily. Optimal dosages of a compound of Formula (I) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease, syndrome, condition, or disorder. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention. Compounds of Formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) is required for a subject in need thereof. As antagonists of the TRPM8 ion channel, the compounds of Formula (I) are useful in methods for treating and preventing a disease, a syndrome, a condition, or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, the condition, or the disorder is affected by the modulation of TRPM8 receptors. Such methods comprise, consist of, and consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a compound, salt, or solvate of Formula (I). In particular, the compounds of Formula (I) are useful for preventing or treating pain, or diseases, syndromes, conditions, or disorders causing such pain, or pulmonary or vascular dysfunction. More particularly, the compounds of Formula (I) are useful for preventing or treating inflammatory pain, inflammatory hypersensitivity conditions, neuropathic pain, anxiety, depression, and cardiovascular disease aggravated by cold, including peripheral vascular disease, vascular hypertension, pulmonary hypertension, Raynaud's disease, and coronary artery disease, by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I). Examples of inflammatory pain include pain due to a disease, condition, syndrome, disorder, or a pain state including inflammatory bowel disease, visceral pain, migraine, post-operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, sinus headache, tension headache, or arachnoiditis. One type of inflammatory pain is inflammatory hyperalgesia, which can be further distinguished as inflammatory somatic hyperalgesia or inflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesia can be characterized by the presence of an inflammatory hyperalgesic state in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists. Inflammatory visceral hyperalgesia can also be characterized by the presence of an inflammatory hyperalgesic state, in which an enhanced visceral irritability exists. Examples of inflammatory hyperalgesia include a disease, syndrome, condition, disorder, or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases including Crohn's Disease or ulcerative colitis. One embodiment of the present invention is directed to a method for treating inflammatory somatic hyperalgesia in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists, comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I). A further embodiment of the present invention is directed to a method for treating inflammatory visceral hyperalgesia in which a enhanced visceral irritability exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I). A further embodiment of the present invention is directed to a method for treating neuropathic cold allodynia in which a hypersensitivity to a cooling stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I). Examples of an inflammatory hypersensitivity condition include urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis and nasal hypersensitivity, itch, contact dermatitis and/or dermal allergy, and chronic obstructive pulmonary disease. Examples of a neuropathic pain include pain due to a disease, syndrome, condition, disorder, or pain state including cancer, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, neuralgias (trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia and causalgia), lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vulvodynia, or vidian neuralgia. One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-associated allodynic state in which a hypersensitivity to cooling stimuli exists. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, syndrome, disorder or pain state including neuropathic pain (neuralgia), pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy. Examples of anxiety include social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder. Examples of depression include major depression, bipolar disorder, seasonal affective disorder, post-natal depression, manic depression, and bipolar depression. Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions described in the schemes. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein. Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:
LC-MS/HPLC Methods: Method 1 (HPLC):
Method 2 (LC-MS):
Method 3 (RP-HPLC):
Scheme A illustrates a route for the synthesis of certain intermediates of the present invention, wherein YAis hydrogen or alkyl; and R2, R3and R4are as defined herein. A compound of the formula A1 is either commercially available or may be prepared by known methods described in the scientific literature. A compound of the formula A1, wherein XAis chloro or fluoro and YAis hydrogen or alkyl, may be reacted with an R-substituted thioglycolate (wherein R is C1-6alkyl) in the presence of base to afford a compound of the formula A2, which may be saponified to afford a compound of the formula A3 using conventional chemistry known to one skilled in the art. A compound of the formula A3 may be converted to a compound of the formula A4 using diphenylphosphoryl azide, tert-butanol and an organic base. A compound of the formula A4 may be converted to the corresponding amine, a compound of the formula A5, by the action of HCl or another mineral acid, or by the action of an organic acid, such as trifluoroacetic acid. Scheme B illustrates a route for the synthesis of compounds of formula (I)-B wherein RAand RBare taken together to form an optionally substituted pyrrolidinyl or piperidinyl ring. A compound B1 may be converted to a compound B2 using sulfuryl chloride in an aprotic organic solvent. A compound B2 may be methylated in the presence of methyl triflate to form a compound B3. A compound B3 may be treated with a cyclic amine of the formula B4 to form a compound of the formula B5. Subsequent treatment with methyl triflate forms a methylated product of the formula B6, which may be reacted with a compound of the formula A5 to form a compound of the formula B7. A compound of the formula B7 may be treated with a base such as sodium hydride, lithium bis(trimethylsilyl)amide, n-butyllithium, potassium carbonate, or potassium tert-butoxide followed by alkylation with a compound of the formula, R1X, where X is a leaving group such as bromo, chloro, iodo, tosylate, mesylate, and the like, to afford a compound of the formula (I)-B. Alternatively, a compound of the formula B7 may be treated with a triarylphosphine such as triphenylphosphine, tri-o-tolylphosphine, tri-2-furylphosphine and the like; a C1-6dialkyl azodicarboxylate such as diethyl-, diisopropyl-, or di-t-butyl-azodicarboxylate, and the like; and an appropriately substituted alcohol, R′OH, to afford a compound of the formula (I)-B. Scheme C illustrates a route for the synthesis of compounds of formula (I)-C1 and formula (I)-C2 wherein RAand RBare taken together to form an optionally substituted ring containing an additional heteroatom G (G is selected from the group consisting of O, S, S(O2), N(PG), and N(RC), wherein PG is a conventional amino protecting group. A compound B3 may be treated with a cyclic amine of the formula C1 to form a compound of the formula C2. Methylation of a compound of the formula C2 with methyl triflate affords a compound of the formula C3. Treatment with a compound of the formula A5 affords a compound of the formula C4, which may be alkylated according to the methods described in scheme B to form a compound of the formula (I)-C1 (wherein G is O, S, or S(O2)). Alternatively, G may be a protected amino group, N(PG). When G is N(PG), the protecting group may be removed using conventional chemistry to afford an amine of the formula C5, which may be alkylated or acylated using conventional reductive amination, alkylation, or acylation chemistry with an appropriate RC-substituted reagent to form a compound of the formula (I)-C2 wherein RCis as defined herein. Scheme D illustrates a route for the synthesis of compounds of formula (I)-D wherein RAand RBare taken together to form a piperidinyl ring substituted at the 4-position with NRDRE. A compound of the formula D1 may be prepared according to the methods described in scheme B, substituting 1,4-dioxa-8-aza-spiro[4,5]decane for a compound of the formula B4. Treatment with ceric ammonium nitrate (CAN) affords a ketone of the formula D2. Reductive amination with an amine of the formula D3 in the presence of a hydride source such as triacetoxysodiumborohydride affords a compound of the formula (I)-D. Scheme E illustrates a route for the synthesis of compounds of formula (I)-E wherein piperidin-1-yl is substituted with 4-C(O)NRYRZ, wherein RYand RZare as defined herein, and are optionally taken together to form a 5 or 6-membered ring, wherein said 6-membered ring optionally contains an O or N-methyl. A compound of the formula E1 may be prepared according to the methods described in scheme B, by substituting a 4-ethoxycarbonyl-piperidine for a compound of the formula B4. Conventional saponification of a compound of the formula E1 affords a carboxylic acid of the formula E2. Coupling of the acid with an amine of the formula E3 in the presence of a coupling agent such as HBTU, DCC, HATU, EDC, and the like; in an aprotic solvent, affords an amide of the formula (I)-E. Scheme F illustrates a route for the synthesis of compounds of formula (I)-F wherein RAis C1-6alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy and C1-4alkoxycarbonyl. A compound of the formula F1 is either commercially available or may be prepared by known methods described in the scientific literature. A compound of the formula F1 may be treated with diphenylphosphorylazide in the presence of a base and t-butyl alcohol to form a Boc-protected amine of the formula F2, which may then be alkylated according to the methods described in scheme B to form an R1-substituted compound of the formula F3. The Boc protecting group may be removed using conventional chemistry, such as by the action of HCl or another mineral acid, or by the action of an organic acid, such as trifluoroacetic acid to form a compound of the formula F4. Treatment of an amine of the formula F4 with chlorosulfonyl isocyanate, in the presence of t-butyl alcohol, affords a sulfamide of the formula F5. A compound of the formula F5 may be alkylated by the action of a base in the presence of an RA-substituted alkylating agent of the formula F6, wherein LG is a leaving group such as a bromide, iodide, tosylate, and the like. Final removal of the Boc amino protecting group affords a compound of the formula (I)-F. Scheme G illustrates a route for the synthesis of certain intermediates of formula G5 wherein Y is fluoro. A compound of the formula G1, where XGis fluoro, chloro or bromo, may be treated with methyl thioglycolate in the presence of a suitable inorganic or organic amine base to form a compound of the formula G2. Diazotization and fluorination of a compound of the formula G2 with sodium nitrite and hydrogen tetrafluoroborate affords a compound of the formula G3. Basic hydrolysis of a compound of formula G3 affords a compound of formula G4, which can subsequently be converted to a compound of formula G5 as per chemistries outlined in Scheme A. Reagents were purchased from commercial sources. Nuclear magnetic resonance (NMR) spectra for hydrogen atoms were measured in the indicated solvent with (TMS) as the internal standard on a Bruker Avance 400 MHz spectrometer. The values are expressed in parts per million downfield from TMS. The mass spectra (MS) were determined on an Agilent spectrometer as (ESI) m/z (M+H+) using an electrospray technique. Unless otherwise noted, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to one skilled in the art of chemical synthesis. The substituent groups, which vary between examples, are hydrogen unless otherwise noted. Where reactions were carried out in a microwave reactor, a Personal Chemistry Smith Synthesizer™ was used. All reverse-phase semi-prep HPLC purifications were performed on a Gemini C-18 column (100×30 mm I.D.; 5μ), eluting with a MeCN—H2O gradient, with or without TFA additive. A 5-L 4-neck flask equipped with an overhead mechanical stirrer, N2inlet/outlet adapter, reflux condenser, heating mantle and thermocouple was charged with t-butyl alcohol (2.11 L), compound 1-A (225.0 g, 1.17 mol), and diisopropylethylamine (225 mL, 1.29 mol). Diphenylphosphorylazide (304 mL, 1.4 mol) was premixed with toluene (300 mL) and then added drop-wise over 10 min. The reaction mixture was refluxed with stirring for 21 h, cooled to 22° C. and then evaporated in vacuo. The residue was dissolved in CH2Cl2(1 L), washed with 1N NaOH (500 mL), brine (500 mL), the organic layer separated, dried over MgSO4, filtered, and evaporated in vacuo to afford a dark orange oil (557 g). The crude residue was purified by the flash column chromatography (SiO2) eluting with heptane-EtOAc to afford 265 g of compound 1-B as a pale yellow solid.1H-NMR (CDCl3): δ 7.71 (d, 1H), 7.54 (d, 1H), 7.36-7.31 (m, 1H), 7.30-7.20 (m, 1H), 6.75 (br s, 1H), 2.23 (s, 3H), 1.55 (s, 9H). A 5-L 3-neck flask equipped with an overhead mechanical stirrer, N2inlet/outlet adapter, and thermocouple was charged with 4M HCl in dioxane (3.1 L), compound 1-B (265 g, 1.0 mol) and stirred for 18 h at 22° C. The white precipitate was collected by filtration, washed with diethyl ether (3×500 mL), and dried under house vacuum at 40° C. for 48 h to afford 174 g of compound 1-C as a white solid.1H-NMR (DMSO-d6): δ 8.7 (br s, 3H), 7.71 (d, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 7.14 (t, 1H), 2.184 (s, 3H). To a solution of compound 1-D (20.0 g, 294 mmol) in anhydrous CH2Cl2(210 mL), cooled to 0° C., was added a solution of sulfuryl chloride (5.0 mL, 61.6 mmol) in CH2Cl2(28 mL), drop-wise. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was filtered, the solvent evaporated under reduced pressure, and the resulting solid crystallized from isopropyl alcohol (100 mL). The white needles were filtered, washed with cold isopropyl alcohol and dried under reduced pressure to afford 7.81 g (64%) of compound 1-E as a white solid.1H-NMR (DMSO-d6, 400 MHz): δ 8.50-8.51 (d, 2H), 7.92 (s, 2H), 7.24-7.23 (d, 2H); MS (method 2) m/z 198.9 (M+1). To a solution of compound 1-E (1.26 g, 6.36 mmol) in CH2Cl2(10 mL), cooled to 0° C., was added methyl triflate (0.719 mL, 6.36 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The solvent was evaporated under reduced pressure to afford compound 1-F as a white solid. To compound 1-F (0.375 g, 1.03 mmol) dissolved in MeCN (1 mL) was added piperidine (1-G) (0.123 mL, 1.24 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 30% to 50% gradient (no TFA additive) to afford 79.6 mg (36%) of compound 1-H as a white solid. MS (method 2): m/z 216.0 (M+1). To a solution of compound 1-H (79.6 mg, 0.37 mmol) in CH2Cl2(2 mL), cooled to 0° C., was added methyl triflate (46 μL, 0.407 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The solvent was evaporated under reduced pressure to afford compound 1-I as a white solid. MS (method 2): m/z 229.9 (MH+). To a solution of compound 1-I (85.2 mg, 0.37 mmol) in MeCN (1.0 mL) was added a solution of compound 1-C (120.8 mg, 0.74 mmol) in MeCN (1.0 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 10 minutes. The reaction mixture was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 45% MeCN—H2O (0.1% TFA) to 65% MeCN—H2O (0.1% TFA) gradient to afford 46 mg of compound 1-J as a film.1H-NMR (CDCl3, 400 MHz): δ 7.71-7.73 (t, 1H), 7.63-7.66 (t, 1H), 7.34-7.40 (m, 2H), 6.28 (s, 1H), 3.27-3.29 (m, 4H), 2.39 (s, 3H), 1.53-1.73 (m, 6H); MS (method 2): m/z 311.0 (M+1). To a solution of compound 14 (46 mg, 0.148 mmol) in DMF (1.5 mL) was added potassium carbonate (30.7 mg; 0.222 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. 4-Trifluoromethoxy benzyl bromide (1-K) (45.3 mg, 0.178 mmol) was added drop-wise and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between H2O and EtOAc, the organic phase washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a yellow oil. The crude residue was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 65% MeCN—H2O (0.1% TFA) to 85% MeCN—H2O (0.1% TFA) gradient to afford 40.6 mg of compound 1 as a semi-solid.1H-NMR (CDCl3, 400 MHz): δ 7.71-7.73 (m, 1H), 7.52-7.58 (m, 1H), 7.34-7.37 (m, 2H), 7.27-7.31 (m, 2H), 6.99-7.21 (m, 2H), 4.72 (s, 2H), 3.24-3.27 (m, 4H), 1.97 (s, 3H), 1.52-1.62 (m, 6H); MS (method 2): m/z 485.0 (M+1). Following the procedure described above for Example 1 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared: Compound 2 was prepared substituting morpholine for piperidine in Example 1, step E, to afford 32.6 mg as a semi-solid.1H-NMR (CDCl3, 400 MHz): δ 7.71-7.75 (m, 1H), 7.54-7.64 (m, 1H), 7.34-7.40 (m, 2H), 7.27-7.29 (m, 2H), 6.99-7.16 (m, 2H), 4.76 (s, 2H), 3.68-3.70 (m, 4H), 3.11-3.30 (m, 4H), 1.97 (s, 3H); MS (method 2): m/z 487.0 (M+1). Compound 2-A (159.9 mg (80%), white foam) was prepared substituting N-boc piperazine for piperidine in Example 1, step E, and using the chemistry outlined in steps F to H.1H-NMR (DMSO-d6, 400 MHz): δ 7.86-7.88 (m, 1H), 7.64-7.66 (m, 1H), 7.35-7.41 (m, 4H), 7.27-7.29 (m, 2H), 4.77 (s, 2H), 3.38-3.40 (m, 4H), 3.25-3.27 (m, 4H), 1.99 (s, 3H), 1.40 (s, 9H); MS (method 2): m/z 485.9 (M-Boc+); HPLC (method 1): Rt=7.76 minutes. To a solution of compound 2-A (159.9 mg, 0.273 mmol) was added 4N hydrochloride solution in dioxane (4 mL) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the crude reaction mixture purified by reverse-phase semi-prep HPLC (method 3) eluting with a 40% MeCN—H2O (0.1% TFA) to 60% MeCN—H2O (0.1% TFA) gradient to afford 129.2 mg (79%) of compound 3 as a waxy white solid. MS (method 2): m/z 485.9 (MH+); HPLC (method 1): Rt5.18 minutes. To a solution of compound 3 (38.4 mg, 0.066 mmol) in dichloromethane (0.8 mL) was added triethylamine (10 μL, 0.073 mmol) and acetone (2-B) (24 μL, 0.33 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (21 mg, 0.099 mmol) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with dichloromethane, washed with H2O, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude reaction mixture purified by reverse-phase semi-prep HPLC (method 3) eluting with a 40% MeCN—H2O (0.1% TFA) to 60% MeCN—H2O (0.1% TFA) gradient to afford 28.2 mg of compound 4 as a clear semi-solid.1H-NMR (CD3OD, 400 MHz): δ 7.72-7.84 (m, 1H), 7.57-7.70 (m, 1H), 7.29-7.46 (m, 4H), 7.17 (d, 2H), 4.76 (s, 2H), 3.98 (s, 1H), 3.43-3.64 (m, 4H), 3.32-3.39 (m, 4H), 1.98 (s, 3H), 1.35 (d, 6H); MS (method 2): m/z 528.0 (M+1); HPLC (method 1): Rt4.94 minutes. Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared: Compound 5 was prepared by substituting valeraldehyde for acetone in Example 2, step B, to afford 34.2 mg as a clear semi-solid.1H-NMR (CD3OD, 400 MHz): δ 7.73-7.86 (m, 1H), 7.54-7.69 (m, 1H), 7.28-7.45 (m, 4H), 7.17 (d, 2H), 4.76 (s, 2H), 3.98 (s, 1H), 3.43-3.64 (m, 4H), 3.32-3.39 (m, 4H), 3.06-3.25 (m, 3H), 1.98 (s, 3H), 1.53-1.74 (m, 3H), 0.98 (d, 6H); MS (method 2): m/z 556.0 (M+1); HPLC (method 1): Rt5.33 minutes. Compound 6 was prepared by substituting formaldehyde for acetone in Example 2, step B, to afford 3.6 mg as a clear semi-solid.1H-NMR (CD3OD, 400 MHz): δ 7.75-7.79 (m, 1H), 7.61-7.63 (m, 1H), 7.34-7.41 (m, 4H), 7.16-7.18 (d, 2H), 4.76 (s, 2H), 3.43-3.64 (m, 4H), 3.32-3.39 (m, 4H), 2.92 (s, 3H), 1.98 (s, 3H); MS (method 2): m/z 500.0 (M+1); HPLC (method 1): Rt5.29 minutes. To a solution of compound 3 (38.4 mg, 0.066 mmol) in toluene (1.0 mL) was added diisopropylamine (14 μL, 0.083 mmol) followed by trifluoromethanesulfonic acid 2,2,2-trifluoromethyl (30 mg, 0.128 mmol) and the reaction mixture was heated at 82° C. for 18 hours. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The crude reaction mixture purified by reverse-phase semi-prep HPLC (method 3) eluting with a 50% MeCN—H2O (0.1% TFA) to 70% MeCN—H2O (0.1% TFA) gradient to afford 21.8 mg of compound 7 as a white solid.1H-NMR (CD3OD, 400 MHz): δ 7.70-7.86 (m, 1H), 7.60 (m, 1H), 7.26-7.43 (m, 4H), 7.15 (d, 2H), 4.79 (s, 2H), 3.32-3.43 (m, 4H), 3.10 (m, 2H), 2.65-2.81 (m, 4H), 1.96 (s, 3H); MS (method 2): m/z 567.9 (MH+); HPLC (method 1): Rt7.29 minutes. Compound 4-A was prepared substituting 1,4-dioxa-8-aza-spiro[4,5]decane for piperidine in Example 1, step E, and using the chemistry outlined in steps F to H, to afford 204.1 mg (54%) as a white foam.1H-NMR (CD3OD, 400 MHz): δ 7.74-7.76 (m, 1H), 7.54-7.60 (m, 1H), 7.28-7.37 (m, 4H), 7.13-7.15 (m, 2H), 4.76 (s, 2H), 3.93 (m, 4H), 3.41-3.42 (m, 4H), 1.96 (s, 3H), 1.70-1.73 (m, 4H); MS (method 2): m/z 542.8 (MH+); HPLC (method 1): Rt6.77 minutes. To a solution of compound 4-A (204.1 mg, 0.376 mmol) in acetonitrile (3.0 mL), heated to 70° C., was added a solution of ceric ammonium nitrate (515.5 mg, 0.94 mmol) in H2O (2.0 mL) and the reaction mixture was heated at 70° C. for 1 hour. The reaction mixture was cooled, diluted with EtOAc, the organic phase washed with H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude reaction mixture purified by flash column chromatography (SiO2) eluting with 100% heptane to 50% heptane-50% EtOAc to afford 67.9 mg (36%) of compound 4-B as a clear oil.1H-NMR (CDCl3, 400 MHz): δ 7.71-7.75 (m, 1H), 7.57-7.66 (m, 1H), 7.35-7.40 (m, 2H), 7.21-7.27 (m, 2H), 7.04-7.16 (m, 2H), 4.77 (s, 2H), 3.58-3.64 (m, 4H), 2.50-2.53 (m, 4H), 1.99 (s, 3H); MS (method 2): m/z 499.0 (M+1); HPLC (method 1): Rt6.82 minutes. To a solution of compound 4-B (33.9 mg, 0.068 mmol) in dichloromethane (1.0 mL) was added a 2M solution of dimethylamine in THF (4-C) (170 μL, 0.34 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (22 mg, 0.102 mmol) was added and the reaction mixture was stirred for 18 hours. An additional portion of dimethylamine-THF (0.5 mL) and sodium triacetoxyborohydride (22 mg) were added and the reaction mixture stirred at room temperature for an additional 18 hours. The reaction mixture was diluted with dichloromethane, washed with H2O, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude reaction mixture purified by reverse-phase semi-prep HPLC (method 3) eluting with a 40% MeCN—H2O (0.1% TFA) to 60% MeCN—H2O (0.1% TFA) gradient to afford 19.2 mg of compound 8 as a clear semi-solid.1H-NMR (CD3OD, 400 MHz): δ 7.73-7.78 (m, 1H), 7.59-7.63 (m, 1H), 7.32-7.39 (m, 4H), 7.15-7.17 (d, 2H), 4.79 (s, 2H), 3.95-3.98 (m, 2H), 2.91-3.13 (m, 2H), 2.84 (m, 7H), 2.07-2.10 (m, 2H), 1.98 (s, 3H), 1.66-1.77 (m, 2H); MS (method 2): m/z 528.0 (M+1); HPLC (method 1): Rt5.29 minutes. Following the procedure described above for Example 4 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared: Compound 9 was prepared by substituting pyrrolidine for dimethylamine in Example 4, step B, to afford 13.2 mg as a clear semi-solid. Only one treatment with pyrrolidine was necessary to complete this reaction.1H-NMR (CD3OD, 400 MHz): δ 7.73-7.77 (m, 1H), 7.59-7.62 (m, 1H), 7.32-7.39 (m, 4H), 7.15-7.17 (d, 2H), 4.79 (s, 2H), 3.91-3.94 (m, 3H), 3.42-3.48 (m, 2H), 3.10-3.12 (m, 2H), 2.93-2.96 (t, 2H), 2.14-2.20 (m, 4H), 1.98 (s, 3H), 1.65-1.72 (m, 2H); MS (method 2): m/z 554.0 (M+1); HPLC (method 1): Rt5.38 minutes. Compound 5-A was prepared by substituting piperidine-4-carboxylic acid ethyl ester for piperidine in Example 1, step E, and using the chemistry outlined in steps F to H, to afford 27 mg (60%) as an oil.1H-NMR (CD3OD, 400 MHz): δ 7.71-7.86 (m, 1H), 7.54-7.61 (m, 1H), 7.29-7.42 (m, 4H), 7.10-7.23 (m, 2H), 4.72-4.85 (br s, 2H), 4.07-4.23 (q, 2H), 3.63-3.79 (m, 2H), 2.95-3.11 (m, 2H), 2.44-2.61 (m, 1H), 1.99 (s, 3H), 1.87-1.96 (m, 2H), 1.60-1.81 (m, 2H), 1.15-1.31 (t, 4H); MS m/z 557.0 (M+1); HPLC (method 1): Rt7.60 minutes. To a solution of compound 5-A (27 mg, 0.049 mmol), dissolved in MeOH (1.0 mL), was added 3N NaOH (24 μL, 0.073 mmol) and the reaction mixture was refluxed for 18 hours. The reaction was cooled and the solvent evaporated under reduced pressure. The residual solid was partitioned between H2O and EtOAc, the organic layer collected, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude material was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 50% MeCN—H2O (0.1% TFA) to 70% MeCN—H2O (0.1% TFA) gradient to afford 11.2 mg of compound 10 as a white solid.1H-NMR (CD3OD, 400 MHz): δ 7.71-7.86 (m, 1H), 7.54-7.61 (m, 1H), 7.29-7.42 (m, 4H), 7.10-7.23 (m, 2H), 4.72-4.85 (br s, 2H), 3.63-3.79 (m, 2H), 2.95-3.11 (m, 2H), 2.44-2.61 (m, 1H), 1.99 (s, 3H), 1.87-1.96 (m, 2H), 1.60-1.81 (m, 2H); MS (method 2): m/z 528.9 (MH+); HPLC (method 1): Rt6.68 minutes. To a solution of compound 10 (49 mg, 0.093 mmol), dissolved in dichloromethane (2.0 mL), was added EDC (27 mg, 0.139 mmol) and N-methyl-piperazine (5-B) (12 μL, 0.111 mmol) and the reaction mixture stirred for 18 hours. The reaction mixture was diluted with dichloromethane, washed with H2O, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 38% MeCN—H2O (0.1% TFA) to 58% MeCN—H2O (0.1% TFA) gradient to afford 17.6 mg of compound 11 as an oil.1H-NMR (CD3OD, 400 MHz): δ 7.70-7.82 (m, 1H), 7.53-7.67 (m, 1H), 7.27-7.43 (m, 4H), 7.10-7.23 (m, 2H), 4.70-4.84 (br s, 2H), 3.82-3.90 (m, 2H), 3.40-3.65 (m, 3H), 2.89-3.07 (m, 3H), 2.92 (s, 3H), 2.76-2.89 (m, 1H), 1.87-2.00 (m, 4H), 1.63-1.85 (m, 5H); MS (method 2): m/z 611.0 (M+1); HPLC (method 1): Rt5.24 minutes. Following the procedure described above for Example 5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared: Compound 12 was prepared by substituting dimethylamino-ethylamine for n-methyl-piperazine in Example 5, step B, to afford 25.0 mg as an oil.1H-NMR (CD3OD, 400 MHz): δ 7.69-7.86 (m, 1H), 7.53-7.67 (m, 1H), 7.28-7.45 (m, 4H), 7.08-7.23 (m, 2H), 4.69-4.83 (br s, 2H), 3.83-3.91 (m, 2H), 3.74-3.83 (m, 2H), 3.46-3.61 (m, 2H), 3.18-3.27 (m, 8H), 2.25-2.45 (m, 1H), 1.90-2.00 (m, 4H), 1.80-1.90 (m, 2H), 1.60-1.80 (m, 2H); MS (method 2): m/z 599.1 (M+1); HPLC (method 1): Rt5.31 minutes. A 5-L 4-neck flask equipped with an overhead mechanical stirrer, N2inlet/outlet adapter, reflux condenser, heating mantle and thermocouple was charged with t-butyl alcohol (2.11 L), compound 6-A (225.0 g, 1.17 mol), and diisopropylethylamine (225 mL, 1.29 mol). Diphenylphosphorylazide (304 mL, 1.4 mol) was premixed with toluene (300 mL) and then added drop-wise over 10 min. The reaction mixture was refluxed with stirring for 21 hours, cooled to 22° C. and then evaporated under reduced pressure. The residue was dissolved in CH2Cl2(1 L), washed with 1N NaOH (500 mL), brine (500 mL), the organic layer separated, dried over MgSO4, filtered, and evaporated under reduced pressure to afford a dark orange oil (557 g). The crude residue was purified by the flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford 265 g of compound 6-B as a pale yellow solid.1H-NMR (CDCl3): δ 7.71 (d, 1H), 7.54 (d, 1H), 7.36-7.31 (m, 1H), 7.30-7.20 (m, 1H), 6.75 (br s, 1H), 2.23 (s, 3H), 1.55 (s, 9H). To a solution of compound 6-B (2.0 g, 7.59 mmol) in DMF (20 mL), cooled to 0° C., was added 60% NaH (0.334 g, 8.35 mmol) and the reaction mixture was stirred for 15 minutes. 4-Fluoro-3-trifluoromethyl benzyl bromide (1.26 mL, 8.35 mmol) was added drop-wise at 0° C. and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, the organic phase washed with H2O, brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude oil was purified by flash column chromatography (SiO2) eluting with a 0% EtOAc-heptane to 25% EtOAc-heptane gradient to afford compound 6-C as a clear oil. Compound 6-C was used without further purification in the next step. To compound 6-C was added a solution of 4N HCl in dioxane (20 mL) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with ether, the solid filtered, washed with ether, and dried under vacuo to afford 1.86 g of compound 6-D as a white solid.1H NMR (CD3OD, 300 MHz): δ 7.61-7.83 (m, 3H), 7.52 (d, 1H), 7.26-7.39 (m, 2H), 7.10-7.26 (m, 1H), 4.57 (s, 2H), 2.22 (s, 3H); MS (method 2): m/z 340.0 (MH+); HPLC (method 1): Rt6.78 minutes. To a solution of chlorosulfonyl isocyante (0.720 mL, 3.91 mmol) in CH2Cl2(7.0 mL), at 0° C., was added t-butanol (0.793 mL, 3.91 mmol) in CH2Cl2(4.0 mL) and the reaction was allowed to stir at 0° C. for 30 min. (reaction exotherms upon addition of t-butanol). The prepared solution was then added to a cold (0° C.) solution of compound 6-D (1.47 g, 3.91 mmol) in CH2Cl2(7.0 mL) and TEA (1.63 mL, 11.73 mmol), drop-wise, and the reaction mixture was allowed to warm to ambient temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with 1N HCl, H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford 813 mg of compound 6-E as a white foam.1H-NMR (DMSO-d6, 400 MHz): δ 11.65 (s, 1H), 7.91-7.93 (m, 1H), 7.68-7.62 (m, 2H), 7.61-7.65 (m, 4H), 7.37-7.48 (m, 3H), 5.00 (br s, 2H), 2.01 (s, 3H), 1.52 (s, 9H); MS (method 2): m/z 541.0 (M+Na); HPLC (method 1): Rt6.79 minutes. To a solution of compound 6-E (200 mg, 0.386 mmol) in DMF (2.0 mL), at room temperature, was added a solution of 1.0M KOtBu in THF (0.579 mL, 0.579 mmol), and the suspension was allowed to stir at room temperature for 30 minutes. Ethyl 4-bromobutryate (0.221 mL, 1.54 mmol) was added drop-wise to the reaction mixture and it was allowed to stir for 18 hours. The reaction mixture was incomplete, and K2CO3(53 mg) followed by ethyl 4-bromobutyrate (0.1 mL) were added and the reaction mixture was stirred at 65° C. for 18 hours. The reaction mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford 186.6 mg of compound 6-F as a viscous oil. MS (method 2): m/z 533.1 ((M-Boc)+1)/655.2 (M+Na); HPLC (method 1): Rt7.36 minutes. To compound 6-F (186 mg, 0.296 mmol) was added a solution of 4N HCl in dioxane (4.0 mL) and the reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, the residue azeotroped with CH2Cl2(2×), and the residue dried under vacuo to afford 164.4 mg of compound 6-G as a yellow oil. HPLC (method 1): Rt6.49 minutes. To a solution of compound 6-G (164.4 mg, 0.309 mmol) in MeOH (3.0 mL) was added 3N NaOH (0.206 mL, 0.617 mmol) and the reaction mixture was refluxed for 18 hours. The reaction mixture was cooled and the crude residue purified by reverse-phase semi-prep HPLC (method 3) eluting with a 60% MeCN—H2O (0.1% TFA) to 80% MeCN—H2O (0.1% TFA) gradient to afford 44.8 mg of compound 13 as a clear oil.1H-NMR (DMSO-d6, 400 MHz): δ 12.09 (s, 1H), 7.99 (m, 1H), 7.83-7.88 (m, 1H), 7.62-7.69 (m, 2H), 7.34-7.45 (m, 3H), 4.76 (s, 2H), 3.07-3.17 (m, 2H), 2.06-2.07 (m, 4H), 1.23-1.77 (t, 2H); MS (method 2): m/z 505.0 (M+1); HPLC (method 1): Rt6.31 minutes. Compound 7-A was prepared substituting benzo[b]thiophene-2-carboxylic acid for compound 6-A in Example 6, step A, and using the chemistry outlined in steps B to D, to afford 654 mg as an orange oil.1H-NMR (DMSO-d6, 400 MHz): δ 11.76 (s, 1H), 7.87-7.91 (m, 1H), 7.69-7.80 (m, 3H), 7.46-7.51 (t, 1H), 7.33-7.38 (m, 2H), 7.29 (s, 1H), 5.13 (s, 2H), 1.48 (s, 9H); HPLC (method 1): Rt6.71 minutes. To a solution of compound 7-A (654 mg, 1.29 mmol) in DCE (6.0 mL), at room temperature, was added NBS (254 mg, 1.42 mmol), and the reaction was allowed to stir at room temperature for 18 hours. Additional NBS (100 mg) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford 565 mg of compound 7-B as a brown solid.1H-NMR (DMSO-d6, 400 MHz): δ 11.80 (s, 1H), 8.00-8.03 (m, 1H), 7.70-7.77 (m, 2H), 7.62-7.66 (m, 1H), 7.49-7.54 (m, 2H), 7.41-7.45 (t, 1H), 5.06 (s, 2H), 1.51 (s, 9H); HPLC (method 1): Rt6.87 minutes. To a solution of compound 7-A (654 mg, 1.29 mmol) in DCE (6.0 mL), at room temperature, was added NBS (254 mg, 1.42 mmol), and the reaction was allowed to stir at room temperature for 18 hours. Additional NBS (100 mg) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford 565 mg of compound 7-B as a brown solid.1H-NMR (DMSO-d6, 400 MHz): δ 11.80 (s, 1H), 8.00-8.03 (m, 1H), 7.70-7.77 (m, 2H), 7.62-7.66 (m, 1H), 7.49-7.54 (m, 2H), 7.41-7.45 (t, 1H), 5.06 (s, 2H), 1.51 (s, 9H); HPLC (method 1): Rt6.87 minutes. To a solution of compound 7-B (92 mg, 0.158 mmol) in DMF (0.5 mL), at room temperature, was added 60% NaH (8.0 mg, 0.205 mmol), and the suspension was allowed to stir at room temperature for 30 minutes. Bromo acetoacetate (7-C) (21 μL, 0.190 mmol) was added drop-wise to the reaction mixture and it was allowed to stir for 18 hours. The reaction mixture was treated with additional 60% NaH (8 mg) followed by bromo acetoacetate (21 μL) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford 34.6 mg of compound 7-D as a yellow oil.1H-NMR (CD3OD, 400 MHz): δ 7.73-7.82 (m, 2H), 7.67-7.69 (m, 1H), 7.45-7.55 (m, 3H), 7.16-7.21 (t, 1H), 5.15 (s, 2H), 4.23 (s, 2H), 4.12-4.21 (m, 2H), 1.57 (s, 9H), 1.15-1.29 (m, 3H); MS (method 2): m/z 570.6 ((M-Boc)+1); HPLC (method 1): Rt7.79 minutes. To compound 7-D (34.6 mg, 0.052 mmol) was CH2Cl2(2 mL) followed by TFA (2 mL) and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and dried. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford 23.9 mg of compound 7-E as an oil. MS (method 2): m/z 570.6 (M+1); HPLC (method 1): Rt6.58 minutes. To a solution of compound 7-E (23.9 mg, 0.042 mmol) in MeOH (0.5 mL) was added 3N NaOH (21 μL, 0.062 mmol) and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled and the crude residue purified by reverse-phase semi-prep HPLC (Gemini, C-18 column; 100×30 mm I.D.; 5μ) eluting with a 55 to 75% MeCN—H2O (0.1% TFA) gradient to afford 9.8 mg of compound 14 as a clear oil.1H-NMR (CD3OD, 400 MHz): δ 7.68-7.79 (m, 3H), 7.54-7.56 (m, 1H), 7.40-7.45 (m, 2H), 7.12-7.17 (m, 1H), 4.00 (s, 2H); MS (method 2): m/z 543.0 (M+1); HPLC (method 1): Rt5.81 minutes. Following the procedure described above for Example 7 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared: Compound 15 was prepared by substituting ethyl 4-bromobutyrate for bromo acetoacetate in Example 7, step B, to afford 17.6 mg as an oil.1H-NMR (CD3OD, 400 MHz): δ 7.38-7.79 (m, 6H), 7.11-7.23 (m, 1H), 5.45 (s, 2H), 2.32-2.41 (m, 2H), 1.75-1.88 (m, 2H); MS (method 2): m/z 570.9 (M+1); HPLC (method 1): Rt5.91 minutes. Compound 16 was prepared by substituting ethyl 5-bromovalerate for bromo acetoacetate in Example 7, step B, to afford 17.6 mg as an oil.1H-NMR (DMSO-d6, 400 MHz): δ 12.06 (s, 1H), 8.15-8.18 (m, 1H), 7.94-7.98 (m, 1H), 7.64-7.75 (m, 3H), 7.40-7.51 (m, 3H), 4.81 (s, 2H), 3.02-3.16 (m, 2H), 2.21-2.34 (m, 2H), 1.54-1.55 (m, 4H); MS (method 2): m/z 585.0 (M+2); HPLC (method 1): Rt6.54 minutes. Compounds 1 through 16 of Formula (I), shown in Table 1, were prepared according to the Schemes and Examples described herein. The functional activity of compounds of the formula (I) was determined by measuring changes in intracellular calcium concentration using a Ca2+-sensitive fluorescent dye. The changes in fluorescent signal were monitored by a fluorescence plate reader, either a FLIPR™ (Molecular Devices) or FDSS (Hamamatsu). Increases in intracellular Ca2+ concentration were readily detected upon activation with icilin. At 24 hrs prior to assay, HEK293 cells stably expressing canine TRPM8 were seeded in culture medium in black wall, clear-base poly-D-lysine coated 384-well plates (BD Biosciences, NJ, USA) and grown overnight in 5% CO2at 37° C. On assay day, growth media was removed and cells were loaded with Calcium 3 Dye (Molecular Devices) for 35 min at 37° C., under 5% CO2and then for 25 min at room temperature and atmosphere. Subsequently, cells were tested for agonist-induced increases in intracellular Ca2+ levels using FLIPR™ or FDSS. Cells were challenged with a compound of the Formula (I) (at varying concentrations) and intracellular Ca2+ was measured for 5 min prior to the addition of icilin to all wells to achieve a final concentration that produces approximately an 80% maximal response. EC50or IC50values for compounds of the present invention were determined from eight-point dose-response studies. Curves were generated using the average of quadruplicate wells for each data point. The resultant data are displayed in Table 2. Icilin was initially developed as a “super-cooling” compound by Delmar Chemicals Ltd. Subsequently it was shown to be one of the most potent known agonists of TRPM8 (McKemy D D, et al. Nature 2002, 416(6876): 52-8), having an EC50=0.2 μM in stimulating calcium ion influx into TRPM8 transfected cells (Behrendt H J et al. Brit J Pharmacol 2004, 141(4): 737-45). Initial in vivo testing of icilin showed it to cause “wet-dog” shakes in rats. Similar shaking or jumping behavior was also evident in mice, rabbits, cats, dogs and monkeys. In humans, icilin produced a sensation of coolness on contact with mucous membranes, cold prickling when 0.1 mg was dropped on the tongue and coldness in the mouth, pharynx and chest lasting 30-60 minutes when 5-10 mg was ingested orally (Wei E T, Seid D A, J Pharm Pharmacol. 1983, 35, 110). The inhibition or reversal of icilin-induced shaking behaviors in rodents provides evidence for the utility of TRPM8 antagonists of the formula (I) in treating or preventing a disease, syndrome, disorder, or condition in a subject in which the disease, syndrome, disorder or condition is affected by the modulation of TRPM8 receptors. Male Sprague Dawley rats (220-450 g, Charles River Labs, n=6-9/treatment) may be used to evaluate the ability of selected compounds of the formula (I) to block icilin-induced “wet-dog” shakes (WDS). Compounds of the formula (I) may be administered in an appropriate vehicle, such as hydroxypropyl-β-cyclodextrin (HPβCD), methocellulose, 10% Solutol, or H2O, or the like, by the appropriate route, i.p. or p.o., 30-120 minutes before icilin. Icilin may be administered in PEG-400 or 10% solutol/H2O, at 1.0 or 3.0 mg/kg, i.p. and spontaneous “wet-dog” shakes may be counted 10-20 minutes post-icilin. Compounds of the present invention capable of inhibiting the onset of icilin-induced “wet-dog” shaking behavior may also be assessed for their ability to reverse an existing icilin-induced “wet-dog” shaking behavior. In this paradigm, icilin-induced shaking is counted for 10 minutes followed by administration of a compound of the present invention in a suitable vehicle such as hydroxypropyl methylcellulose, hydroxypropyl-β-cyclodextrin or 10% Solutol in water. The diminution of shaking behavior is represented as a percent inhibition relative to icilin-induced shakes in the absence of test compound administration, as described by the following formula: % Inhibition=[1−(WDS count following test compound dose/WDS count prior to test compound dose)]×100. The resultant data are shown in Table 3. Intraplantar injection of carrageenan into the hind paw of rats causes a robust acute inflammatory response characterized by reddening, swelling and hypersensitivity of the paw to thermal and mechanical stimuli typically peaking 3-6 hours following application and subsiding over the 12-24 hours. To assess the effect of test compounds of the formula (I) on inflammatory hyperalgesia, radiant heat response latencies may be evaluated 3 hours following intraplantar carrageenan (Lambda, Type IV, 200 uL) injection into a single hind paw in male Sprague-Dawley rats. The test compound may be administered either 2 hours prior to or 1 hour following carrageenan injection. The intent is to determine whether the compound may prevent or retard the hypersensitivity associated with this inflammogen. Baseline thermal response latencies may be determined prior to any treatment and again 3 hours after carrageenan injection. Percent reversal of hyperalgesia relative to vehicle treatment (% R) may be calculated for both compound treatment paradigms according to the following formula: Intraplantar injection of complete Freund's adjuvant (CFA) in rodents results in a long-lasting inflammatory reaction, characterized by a pronounced hypersensitivity to both thermal and mechanical stimuli. This hypersensitivity peaks between 24-72 hours following injection and can last for several weeks. To assess whether test compounds of the formula (I) reverse established hypersensitivity, a 100 μL intraplantar injection of CFA (suspended in a 1:1 emulsion of saline and heat-killed Each rat may be placed in a test chamber on a warm glass surface and allowed to acclimate for approximately 10 minutes. A radiant thermal stimulus (beam of light) may then be focused through the glass onto the plantar surface of each hind paw in turn. The thermal stimulus may be automatically shut off by a photoelectric relay when the paw is moved or when the cut-off time is reached (20 seconds for radiant heat at ˜5 Amps). An initial (baseline) response latency to the thermal stimulus may be recorded for each animal prior to the injection of CFA. Twenty-four hours following intraplantar CFA injection, the response latency of the animal to the thermal stimulus may be re-evaluated and compared to the animal's baseline response time. Only rats that exhibit at least a 25% reduction in response latency (i.e., hyperalgesia) are included in further analysis. Immediately following the post-CFA latency assessment, test compound or vehicle (usually Solutol, hydroxypropyl methylcellulose, hydroxypropyl beta-cyclodextrin or PEG-400) may be administered i.p. or p.o. to rats. Post-compound treatment withdrawal latencies may be assessed at fixed time intervals, typically 30, 60 and 120 minutes. The percent reversal (% R) of hypersenstivitiy is calculated according to the following formula: Prior to intraplantar CFA injection, mice or rats may be placed individually in elevated observation chambers having wire mesh floors. Through the mesh floor a series of three applications of acetone (0.04-0.10 mL/application) may be sprayed onto the bottom of the paw using a multidose syringe device. A positive response can take the form of an abrupt withdrawal and licking of the paw. The cumulative duration of licking may be recorded for each of the three trials which are then averaged to give the individual's response. Twenty-four hours following CFA injection acetone licking durations may be markedly elevated implying a hypersensitivity to cooling. Test compounds of the formula (I) can be assessed for its ability to return acetone-evoked paw licking durations to pre-CFA levels (typically near zero) following systemic administration. Percent inhibition is calculated as follows A chemical irritant (such as acetic acid, kaolin, bradykinin, phenyl-p-(benzo) quinine, bromo-acetylcholine, or zymosan) may be injected in mice intraperitoneally, causing a contraction of the abdominal musculature, which is characterized by an elongation of the body extending through to the hind limbs The number of such responses may be quantitated and may be reduced by pretreatment of analgesic agents, thus forming the basis for a screening test (Collier H O et al. Br J Pharmacol Chemother 1968, 32(2): 295-310). This type of abdominal irritant test has been used to predict the analgesic effect of numerous clinically effective agents, the potency of which in the abdominal irritant test parallels the magnitude of the dose needed in the relief of clinical pain. Such agents include acetaminophen, NSAIDS such as aspirin and ibuprofen, opioids, such as morphine and codeine, and other centrally acting analgesics, such as tramadol. One modification of the chemically-induced abdominal irritant model of visceral pain is to pretreat animals with agents known to induce inflammatory responses following intraperitoneal injection (such as LPS, zymosan, or thioglycolate). A small intraperitoneal dose of such an inflammogen, administered hours or days before the acute chemical irritant challenge, has been shown to increase the number of abdominal contractions observed (Ribeiro R A, et al. Eur J Pharmacol 2000, 387(1): 111-8). While some analgesic agents are effective at mitigating acute viscerochemical nociception, others, particularly those dependent upon receptor induction are more effective at preventing or reversing the enhancement of behavioral responses caused by a preconditioning inflammatory stimulus. Because of the up-regulation of the TRPM8 receptor in inflammation, TRPM8 antagonists that are effective at reducing the mean number of contractions are predicted to provide analgesic action in human clinical use. The ability of compounds of the formula (I) to mitigate chemical irritant-induced abdominal contractions following a pre-conditioning inflammatory stimulus may be studied as follows. Thioglycolate (3%, w/v, 2-3 mL i.p.) may be injected into male CD1 mice (20-40 g, Charles River Labs), at a maximum dosage volume of 80 mL/kg, to induce peritoneal inflammation. Following a twenty-four hour pre-inflammation period these mice may be dosed orally with compounds of the formula (I) (30 mg/kg; n=10) or vehicle (HPMC with 2% Tween80; n=9) and then one hour later subjected to an abdominal irritant challenge of acetic acid (1%, 10 mL/kg, i.p.). Immediately following injection of acetic acid, mice may be placed individually in glass bell jars (approximately 15 cm in diameter) for counting of abdominal contractions over the next 15 minutes. The total number of abdominal contractions may be summed for each treatment group and employed in the following formula to calculate Percent Inhibition (% I): The sciatic nerve is the major sensorimotor innervation of the (hind) leg and foot. Injury to the sciatic nerve or its constituent spinal nerves often results in pain-related behaviors. In rats and mice, tight ligation of the L5 spinal nerve with silk suture, partial tight ligation of the sciatic nerve with silk suture or loose ligation of the sciatic nerve with chromic gut suture each result in behaviors reminiscent of neuropathic pain in humans. These lesions (one per animal) may be performed surgically in anesthetized rodents. Both the spinal nerve and sciatic nerve lesions result in allodynia, a painful response to normally innocuous stimuli, and hyperalgesia, an exaggerated response to normally noxious stimuli. It is important to note that both of these pain-related behaviors may be evoked by the testing procedures and that normal use of the paw (e.g., walking) is relatively uncompromised, apart from occasional “guarding” of the paw. Subsequent to the surgery, the subjects' behaviors, such as grooming, feeding, and weight gain, are normal, except for hypersensitivity (as defined above) of the affected paw. In addition to induction by nerve damage resulting from accidental trauma or surgical procedures, neuropathic pain can also be induced by diabetes (Fox, A et al., Agents that attenuate neuropathic pain in the clinic also are effective in rodent neuropathic pain models. These agents include the recently approved Cymbalta (Duloxetine, Iyengar, S., et al., Male Sprague Dawley rats (225-450 g; n=5-8/treatment) may be used to evaluate the ability of selected compounds of the formula (I) to reverse CCI-induced cold hypersensitivity. Four loose ligatures of 4-0 chromic gut may be surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennett et al (Bennett G J, Xie Y K. In male SD rats (175-325 g), four loose ligatures of 4-0 chromic gut may be surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennet et al (Bennett G J, Xie Y K. In male SD rats (175-325 g), four loose ligatures of 4-0 chromic gut may be surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennet et al (Bennett G J, Xie Y K. Compounds of the formula (I) can be tested in animal models of pyresis, according to previously documented and validated methods, such as those described by Kozak et al (Kozak W, Fraifeld V. To assess the effect of potential antipyretic compounds on basal rectal temperature study animals can have their TR measured for 4 h, and after the fourth TR measurement they can be subcutaneously (s.c.) injected with vehicle (such as 10% Solutol in sterile water 5 ml/kg) or compounds of the formula (I) prepared in vehicle. TR can then be recorded every hour up to 8 h after the compound injections. To assess the effect of compounds of the formula (I) on baker yeast-induced hyperthermia, study animals can have their basal TR measured and then be injected with a pyrogenic dose of baker yeast (for example, 0.135 g/kg). TR changes can be recorded every hour up to 4 h, when potential antipyretics agents such as those compounds of the formula (I) are administered. Rectal temperature can then be monitored over the following 8 h. Basal rectal temperature and changes in rectal temperature can be expressed as means±S.E.M. of the differences from TR at 07:00 h. Data can be analyzed by two-way analysis of variance (ANOVA), with time of measures treated as within subject factor, depending on the experimental design. Post hoc analysis can be carried out by the F-test for simple effect and the Student-Newman-Keuls test, when appropriate. A value of P<0.05 would be considered statistically significant. The modification of the subsequent pyretic response by therapeutic agents can also be monitored by rectal telemetry or other measurements of body temperature. Several clinically relevant agents such as acetaminophen, aspirin and ibuprofen, reduce fever in these models. The antipyretic effect of TRPM8 antagonists, such as compounds of the formula (I), in these tests would also be predictive of their clinical effect. Compounds of the formula (I) can be tested in animal models of rheumatoid arthritis, according to previously documented and validated methods, such as those described by Nagakura et al (Nagakura Y, et al. The scoring of mobility can be performed by modifying the evaluation scale reported by Butler et al. (Butler S H et al Compounds of the formula (I) can be assessed for antihyperalgesic efficacy as follows: thirty-two rats (8 rats per dose and four doses per compound) that are be treated with the CFA and another eight rats as naive controls can be used for each drug evaluation. The analgesic effects can be evaluated on post-inoculation day 9, when mechanical allodynia, thermal hyperalgesia, joint hyperalgesia, and joint stiffness in the ipsilateral paw reached almost the maximum, although those parameters in the contralateral paw changed only slightly and the systemic disturbance shown by the change of mobility score is small. On the day before evaluation, body weight, mechanical allodynia, thermal hyperalgesia, and joint hyperalgesia can be measured for the 32 rats that are to be used for compound evaluation. The rats are allocated to four groups (eight rats per group) such that the differences in the averages of those parameters among the groups became small. All the analgesic effect evaluations and behavioral observations can be carried out by the observer who is blind to the drug treatment. Data can be expressed as the mean+/−S.E.M. The time-course curves for mechanical allodynia, thermal hyperalgesia, joint hyperalgesia, body weight, and paw volume can be subjected to two-way repeated measures analysis of variance with post hoc t test. In experiments for evaluation of compounds of formula (I), the difference in scores between the vehicle-treated and naive control groups can be analyzed by Student's t test to confirm significant changes in the pain parameters in the ipsilateral paw. The analgesic effects can be analyzed by Dunnett's t test, and in each case the drug-treated groups can be compared with the vehicle-treated group. In each statistical analysis, the comparison can be conducted for paws on the corresponding side. P<0.05 is considered statistically significant. In this model, the centrally acting analgesics morphine and tramadol fully relieved pain, whereas the NSAIDs, indomethacin and diclofenac are partially effective, evidencing the model's clinical predictability. The analgesic effect of compounds of the formula (I) in this test would predict their clinical usefulness in treating arthritis. Compounds of the formula (I) can be tested in animal models of osteoarthritis, according to previously documented and validated methods, such as those described by Sluka et al (Sluka K A, Westlund K N. The Kruskal-Wallis test, a nonparametric test, can be used to analyze the effects for frequency, intensity, and group for response to mechanical stimuli at baseline, 4 hours after inflammation, and after compound treatment (5 hours, 8 hours, 12 hours, and 24 hours after inflammation). Further post hoc testing between groups can be executed by using the Mann-Whitney signed rank test. The data can be presented as median with 25th and 75th percentiles. Significance is P<0.05. Additionally, the gait of the animal or other pain-related behavior can be scored as the dependent measure of the painful effect of the arthritis on the animal's activity (Hallas B, Lehman S, Bosak A, et al. Compounds of the formula (I) can be tested in animal models of bone cancer pain, according to previously documented and validated methods, such as those described in the scientific literature (El Mouedden M, Meert T F. Pain behaviors can be evaluated in separate groups (n=6) of sham and bone tumor mice with confirmed hyperalgesia as assessed by spontaneous lifting behavior. Animals can be behaviorally tested during a 3-week period prior to and after tumor inoculation. Body weight of the mice can be recorded throughout the experimental period to help monitor general health status. To measure the spontaneous lifting, the animals can be habituated in a transparent acrylic cylinder of 20 cm diameter put on an horizontal surface and thereafter observed during 4 min for spontaneous lifting behavior of the left hind paw. After spontaneous lifting behavior assessment, animals can be immediately placed on a mouse rotarod (e.g. ENV-575M\, Med Associates Inc., GA, USA) at a speed of 16 rpm for 2 min wherein limb-use during forced ambulation is scored: 4=normal; 3=limping; 2=partial non-use of left hind paw; 1=substantial non-use of left hind paw; 0=non-use of left hind paw. Assessment of cold allodynia may be made by exposing the ipsilateral hind paw of the mouse to 5 repeated applications of acetone (20 μL) and quantifying the lift/licking frequency and/or duration. Post-mortem evaluation of bone destruction can be assessed by ACT processing followed by scanning using a system such as the Skyscan 1076 microtomograph system for small animal imaging (Skyscan 1076\, Skyscan, Aartselaar, Belgium). Measured histomorphometry parameters of bone destruction can be subsequently correlated with behavioral endpoints. The antihyperalgesic, antiallodynic and disease modifying effects of compounds of the formula (I) can be tested in this murine model of bone cancer pain in separate groups (n=6 per dose group). Animals with confirmed hyperalgesia, as assessed by spontaneous or acetone-evoked lifting, can be behaviorally tested, for example, on days 15 and 22 after distal femur tumor inoculation before and 1 h after systemic administration of vehicle (e.g. 20% HPbCD in sterile water) or compounds of the formula (I). The statistical analysis can be performed by one-way ANOVA to compare behavioral measurements and bone parameters among the experimental groups. To compare behavioral measurements and bone parameters between sham and tumor-bearing animals, a Mann-Whitney U test can be used. Results are considered statistically significant at P<0.05 (two-tailed). Data are expressed as mean+/−S.E.M. Bone cancer causes intense pain in humans, mimicked in animal models of bone cancer pain in rodents such as that described above. Analgesic treatments that are effective in this model include COX-2 inhibitors (Sabino M A, Ghilardi J R, Jongen J L, et al. Compounds of the formula (I) can be tested in animal models of antitussive activity, according to previously documented and validated methods, such as those described by: Tanaka, M. and Maruyama, K. Compounds of the formula (I) can be tested in animal models of contact dermatitis or itch, according to previously documented and validated methods, such as those described in the scientific literature (Saint-Mezard P et al. Compounds of the formula (I) can be tested in animal models of rhinitis, according to previously documented and validated methods, such as those described in the scientific literature (Hirayama Y, et al. Compounds of the formula (I) can be tested in animal models of anxiety, panic disorders and other non-adaptive responses, according to previously documented and validated methods, such as those described by Cryan and Holmes (Cryan J F, Holmes A. Open-field and plus-maze measures can be grouped into two behavioral classes, namely ‘anxiety-like behaviors’ and ‘activity’. Open-field behavioral measures may include 1) Anxiety measures: % time in center square, % number of entries to center square (from total squares entered), % time freezing, latency to first freezing (freezing is scored when the subject is in an immobile state for at least 3 seconds; and 2) Activity measures: Total squares entered, number of rearings (standing on two hind legs), latency for first rearing. Plus-maze measures may include 1) Anxiety: % time in open arms, % number of entries to open arms (from total entries), number of unprotected head dips, latency to enter open arm; and 2) Activity: Total entries to all arms. Anxiety-like behaviors and activity can be analyzed by one-way ANOVA's on each of the measures, for each the between-subject comparisons. Plus-maze analyses can be conducted in a similar fashion. Testing may also be conducted in mouse or rat in this fashion in order to measure avoidance of other aversive environmental stimuli such as Geller or Vogel anticonflict tests, the light/dark test and the hole-board test (see Cryan J F, Holmes A. Compounds of the formula (I) can be tested in animal models of urinary incontinence according to previously documented and validated methods, such as those described by in the scientific literature (Kaiser S, Plath T, (Metagen Pharmaceuticals GmbH, Germany DE Patent 10215321; McMurray G, et al. Compounds of the formula (I) can also be evaluated under conditions of bladder hypertrophy and instability. Under anesthesia, a silk ligature is tied around the proximal urethra of rodents producing a partial outlet obstruction and subsequent hypertrophied bladder development within 6-9 weeks (Woods M. et al., Injury to the brain or spinal cord, such as that caused by trauma, interrupted blood flow or neurodegenerative diseases, often precipitates a central pain condition. Examples of such injuries characterized, in part by, a hypersensitivity to cold stimuli include multiple sclerosis (Morin C, et al. SCI rats can be routinely tested for the presence of pain-like behaviors from 3-4 weeks after surgery. The fur of the animals can be shaved at least a day prior to examination of the cutaneous pain threshold to avoid sensitization of the skin receptors. During testing, the rats can be gently held in a standing position by the experimenter and the flank area and hindlimbs can be examined for hypersensitivity to sensory stimulation. On the day of drug testing, SCI rats can be administered drug according to the experimental schedule and the time course of pain-like behaviors can be measured. To test for the presence of cold allodynia, ethyl chloride or acetone can be sprayed onto the skin of the animals, often that which has been previously determined to be sensitive to mechanical stimulation by von Frey filament testing. The subsequent response to cold stimulation can be observed and classified according to the following scale: 0, no visible response; 1, localized response (skin twitch) without vocalization; 2, transient vocalization; 3, sustained vocalization. Kruskal Wallis ANOVA on ranks can be used to analyze the overall effects of non-parametric data obtained in response to cold stimulation following pretreatment with either compounds of the formula (I) or vehicle. Spontaneous post-anesthetic tremor that resembles shivering is common during recovery from anesthesia. Risks to postoperative patients include an increase in metabolic rate of up to 400%, hypoxemia, wound dehiscence, dental damage, and disruption of delicate surgical repairs. The etiology of spontaneous post-anesthetic tremor is most commonly attributed to normal thermoregulatory shivering in response to intraoperative hypothermia. In most operating and recovery rooms, shivering is controlled by the use of humidifiers, warming blankets, and inhalation of humidified heated oxygen. However, pharmacological control is an effective alternate treatment modality (Bhatnagar S, et al. Compounds of the formula (I) can be tested in animals and humans for their ability to mitigate cardiovascular pressor responses evoked by cold exposure. Seasonal environmental cooling is directly associated with elevated blood pressure and an increased incidence of coronary events in human populations worldwide (Barnett, A G et al. Damage may occur to a bodily tissue when blood flow is compromised or interrupted. Reasons for vascular compromise include peripheral vascular disease (Lamah M et al, European journal of vascular and endovascular surgery (1999), 18(1), 48-51), prior traumatic or frostbite injury, Raynaud's syndrome (Lutolf, O et al Microvascular research (1993), 46(3), 374-82), diabetic neuropathy (Forst T et al, Clinical science (London, England: 1979) (1998), 94(3), 255-61.), surgical intervention and autonomic dysregulation (Gherghel D et al, Investigative ophthalmology & visual science (2004), 45(10), 3546-54). In the case of marginal resting perfusion, vasoconstriction as enhanced by cool temperature may aggravate symptoms and potentiate tissue injury (Cankar K et al, The Journal of hand surgery (2000), 25(3), 552-8; Lutolf O et al Microvascular research (1993), 46(3), 374-82.). Several of these conditions may be readily modeled in animals to assess of the ability of TRPM8 antagonists such as compounds of the formula (I) to preserve tissue perfusion in the face of local cooling. For example, laser Doppler assessment of skin blood flow may be studied in the paws of anesthetized rats (Hord A H et al, Anesthesia and analgesia (1999), 88(1), 103-8), wherein the paw is subject to a series of decreasing temperatures steps as applied by physical contact with a Peltier cooling element under computer control. The laser Doppler measures skin perfusion in the face of cooling-induced vasoconstriction thereby generating a temperature×perfusion relationship. Systemic administratin of a TRPM8 antagonist is anticipated to shift this curve toward preserving perfusion at reduced temperatures relative to vehicle pretreatment. This activity is envisioned to be therapeutic in protecting tissue from hypo-perfusion and ischemia thereby minimizing the associated symptoms (e.g. pain) and potential tissue damage. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: wherein Y, R1, R2, R3, R4, RA, and RB are defined herein. 1-19. (canceled) 20. A method for treating neuropathic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) wherein Y is
(i) H; (ii) bromo; (iii) chloro; (iv) fluoro; (v) iodo; (vi) C3-6cycloalkyl; or (vii) C1-6alkyl; R1is
(i) C3-6cycloalkyl; (ii) C1-6alkyl substituted with one C6-10aryl group and optionally one additional substituent selected from the group consisting of hydroxy and oxo, wherein said C6-10aryl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy optionally substituted with 1 to 3 fluoro substituents, hydroxy, C1-4alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, aminocarbonyl, C1-3alkylaminocarbonyl, di(C1-3)alkylaminocarbonyl, C1-3alkylsulfonyl optionally substituted with 1 to 3 fluoro substituents, nitro, amino, C1-3alkylamino, di(C1-3)alkylamino, and C1-3alkylcarbonyl; with the proviso that not more than two of the substituents are selected from the group consisting of C1-4alkoxy substituted with 1 to 3 fluoro substituents, C1-4alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, aminocarbonyl, C1-3alkylaminocarbonyl, di(C1-3)alkylaminocarbonyl, C1-3alkylsulfonyl optionally substituted with 1 to 3 fluoro substituents, nitro, amino, C1-3alkylamino, di(C1-3)alkylamino, and C1-3alkylcarbonyl; (iii) C1-6alkyl substituted with phenyl, wherein phenyl is substituted with 4 or 5 fluoro substituents; or phenyl is substituted with methoxy and 3 to 4 fluoro substituents; (iv) C1-6alkyl optionally substituted with C3-6cycloalkyl or trifluoromethyl; or (v) methylene substituted with benzo[1,3]dioxol-5-yl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, or 2,3-dihydro-benzo[1,4]dioxin-6-yl; R2is
(i) hydrogen, (ii) fluoro, (iii) chloro, (iv) methoxy, or (v) methyl; R3is
(i) hydrogen, (ii) fluoro, (iii) chloro, or (iv) methyl; R4is
(i) hydrogen, (ii) C1-6alkyl, (iii) trifluoromethyl, (iv) C1-4alkoxy, (v) bromo, (vi) chloro, (vii) fluoro, or (viii) hydroxy; RAis C1-6alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-4alkoxycarbonyl, C1-3alkoxy, and hydroxy; RBis hydrogen or C1-6alkyl; or, RAand RBare taken together with the nitrogen atom to which they are attached to form a 6 membered ring containing one heteroatom selected from the group consisting of O, S, and S(O2); or, RAand RBare taken together with the nitrogen atom to which they are attached to form a 5 or 6 membered ring, optionally containing one additional N atom, to form
(i) piperizin-1-yl wherein the piperizinyl nitrogen is substituted with RC; (ii) pyrrolidin 1 yl optionally substituted at the 3-position with NRDRE; wherein RDand REare independently selected from the group consisting of hydrogen and C1-4alkyl; or, RDand REare taken together with the nitrogen atom to which they are both attached to form a 5 or 6 membered ring; or (iii) piperidin-1-yl optionally substituted with carboxy; C1-3alkoxycarbonyl; or C1-4alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-3alkoxy, and hydroxy;
or piperidinyl is optionally substituted at the 4-position with (i) C(O)NRYRZ; wherein RYis hydrogen or C1-6alkyl; and RZis hydrogen or C1-6alkyl optionally substituted with amino, C1-2alkylamino, or di(C1-2alkyl)amino; or, RYand RZare taken together with the nitrogen atom to which they are both attached to form a 5 or 6 membered ring, and said 6 membered ring is optionally containing 0 or 4-N(methyl); (ii) NRHRJ; wherein RHand RJare independently selected from the group consisting of hydrogen and C1-4alkyl; or, RHand RJare taken together with the nitrogen atom to which they are both attached to form a 5 or 6 membered ring; or (iii) a spirofused pyrrolidinyl ring bound via a carbon atom of said ring, wherein the pyrrolidinyl nitrogen atom is optionally substituted with C1-4alkyl, C3-6cycloalkyl(C1-3)alkyl, or CH2CF3; and wherein a piperidinyl ring is optionally benzofused to form a 1,2,3,4-tetrahydro-isoquinolin-1-yl, wherein said 1,2,3,4-tetrahydro-isoquinolin-1-yl is optionally substituted on the heterocyclyl portion of said ring with one to two substituents independently selected from the group consisting of methyl and fluoro; or, the heterocyclyl portion of said 1,2,3,4-tetrahydro-isoquinolin-1-yl is unsubstituted and the benzo portion of said ring is optionally substituted with one to two substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, cyano, ethoxycarbonyl, carboxy, and methoxy; provided that no more than one of the substituents is carboxy or ethoxycarbonyl; RCis
(i) hydrogen; (ii) C1-8alkyl; (iii) C3-6cycloalkyl; (iv) C3-6cycloalkyl(C1-4)alkyl; (v) CH2CF3; or (vi) phenyl optionally independently substituted with one to two substituents selected from the group consisting of methyl, methoxy, chloro, fluoro, and trifluoromethyl; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof. 21. The method of 22. The method of 23. The method of 24. A method for treating neuropathic cold allodynia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I) wherein Y is
(i) H; (ii) bromo; (iii) chloro; (iv) fluoro; (v) iodo; (vi) C3-6cycloalkyl; or (vii) C1-6alkyl; R1is
(i) C3-6cycloalkyl; (ii) C1-6alkyl substituted with one C6-10aryl group and optionally one additional substituent selected from the group consisting of hydroxy and oxo, wherein said C6-10aryl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy optionally substituted with 1 to 3 fluoro substituents, hydroxy, C1-4alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, aminocarbonyl, C1-3alkylaminocarbonyl, di(C1-3)alkylaminocarbonyl, C1-3alkylsulfonyl optionally substituted with 1 to 3 fluoro substituents, nitro, amino, C1-3alkylamino, di(C1-3)alkylamino, and C1-3alkylcarbonyl; with the proviso that not more than two of the substituents are selected from the group consisting of C1-4alkoxy substituted with 1 to 3 fluoro substituents, C1-4alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, aminocarbonyl, C1-3alkylaminocarbonyl, di(C1-3)alkylaminocarbonyl, C1-3alkylsulfonyl optionally substituted with 1 to 3 fluoro substituents, nitro, amino, C1-3alkylamino, di(C1-3)alkylamino, and C1-3alkylcarbonyl; (iii) C1-6alkyl substituted with phenyl, wherein phenyl is substituted with 4 or 5 fluoro substituents; or phenyl is substituted with methoxy and 3 to 4 fluoro substituents; (iv) C1-6alkyl optionally substituted with C3-6cycloalkyl or trifluoromethyl; or (v) methylene substituted with benzo[1,3]dioxol-5-yl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, or 2,3-dihydro-benzo[1,4]dioxin-6-yl; R2is
(i) hydrogen, (ii) fluoro, (iii) chloro, (iv) methoxy, or (v) methyl; R3is
(i) hydrogen, (ii) fluoro, (iii) chloro, or (iv) methyl; R4is
(i) hydrogen, (ii) C1-6alkyl, (iii) trifluoromethyl, (iv) C1-4alkoxy, (v) bromo, (vi) chloro, (vii) fluoro, or (viii) hydroxy; RAis C1-6alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-4alkoxycarbonyl, C1-3alkoxy, and hydroxy; RBis hydrogen or C1-6alkyl; or, RAand RBare taken together with the nitrogen atom to which they are attached to form a 6 membered ring containing one heteroatom selected from the group consisting of O, S, and S(O2); or, RAand RBare taken together with the nitrogen atom to which they are attached to form a 5 or 6 membered ring, optionally containing one additional N atom, to form
(i) piperizin-1-yl wherein the piperizinyl nitrogen is substituted with RC; (ii) pyrrolidin 1 yl optionally substituted at the 3-position with NRDRE; wherein RDand REare independently selected from the group consisting of hydrogen and RDand REare taken together with the nitrogen atom to which they are both attached to form a 5 or 6 membered ring; or (iii) piperidin 1 yl optionally substituted with carboxy; C1-3alkoxycarbonyl; or C1-4alkyl substituted at a terminal carbon atom with a substituent selected from the group consisting of carboxy, C1-3alkoxy, and hydroxy;
or piperidinyl is optionally substituted at the 4-position with (i) C(O)NRYRZ; wherein RYis hydrogen or C1-6alkyl; and RZis hydrogen optionally C1-2alkylamino, or di(C1-2alkyl)amino; or, RYand RZare taken together with the nitrogen atom to which they are both attached to form a 5 or 6 membered ring, and said 6 membered ring is optionally containing 0 or 4-N(methyl); (ii) NRHRJ; wherein RHand RJare independently selected from the group consisting of hydrogen and C1-4alkyl; or, RHand RJare taken together with the nitrogen atom to which they are both attached to form a 5 or 6 membered ring; or (iii) a spirofused pyrrolidinyl ring bound via a carbon atom of said ring, wherein the pyrrolidinyl nitrogen atom is optionally substituted with C1-4alkyl, C3-6cycloalkyl(C1-3)alkyl, or CH2CF3; and wherein a piperidinyl ring is optionally benzofused to form a 1,2,3,4-tetrahydro-isoquinolin-1-yl, wherein said 1,2,3,4-tetrahydro-isoquinolin-1-yl is optionally substituted on the heterocyclyl portion of said ring with one to two substituents independently selected from the group consisting of methyl and fluoro; or, the heterocyclyl portion of said 1,2,3,4-tetrahydro-isoquinolin-1-yl is unsubstituted and the benzo portion of said ring is optionally substituted with one to two substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, cyano, ethoxycarbonyl, carboxy, and methoxy; provided that no more than one of the substituents is carboxy or ethoxycarbonyl; RCis
(i) C(O)R1awherein R1ais C1-6alkyl, C3-6cycloalkyl, or phenyl; or (ii) SO2R2a, wherein R2ais methyl or phenyl; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof. 25. (canceled)CROSS-REFERENCE TO RELATED APPLICATIONS
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
SUMMARY OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
General Synthetic Methods
SPECIFIC EXAMPLES
Example 1
A. tert-Butyl-3-methylbenzo[b]thiophen-2-ylcarbamate (1-B)
B. 3-Methylbenzo[b]thiophen-2-amine hydrochloride (1-C)
C. 1,1′-Bis-imidazole-1-sulfonyl (1-E)
D. 1,1′-Bis-(3-methyl-imidazole)-1-sulfonyl triflate salt (1-F)
E. 1-(Imidazole-1-sulfonyl)-piperidine (1-H)
F. 1-Methyl-3-(piperidine-1-sulfonyl)-3H-imidazol-1-ium triflate salt (1-I)
G. Piperidine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-amide (1-J)
H. Piperidine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-amide, Compound 1
Morpholine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-amide, Compound 2
Example 2
A. 4-[(3-Methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-piperazine-1-carboxylic acid tert butyl ester (2-A)
B. piperazine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide, Compound 3
C. 4-Isopropyl-piperazine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide, Compound 4
4-(3-Methyl-butyl)-piperazine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide, Compound 5
4-Methyl-piperazine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide, Compound 6
Example 3
4-(2,2,2-Trifluoro-ethyl)-piperazine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide, Compound 7
Example 4
A. 1,4-Dioxa-8-aza-spiro[4,5]decane-8-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-amide (4-A)
B. 4-Oxo-piperidine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide (4-B)
C. 4-Dimethylamino-piperidine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide, Compound 8
4-Pyrrolidin-1-yl-piperazine-1-sulfonic acid (3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-amide, Compound 9
Example 5
A. 1-[(3-Methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-piperidine-4-carboxylic acid ethyl ester (5-A)
B. 1-[(3-Methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-piperidine-4-carboxylic acid, Compound 10
C. 4-(4-Methyl-piperazine-1-carbonyl)-piperidine-1-sulfonic acid 3-methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-amide, Compound 11
1-[(3-Methyl-benzo[b]thiophen-2-yl)-(4-trifluoromethoxy-benzyl)-sulfamoyl]-piperidine-4-carboxylic acid (2-dimethylamino-ethyl)-amide, Compound 12
Example 6
A. (3-Methyl-benzo[b]thiophen-2-yl)-carbamic acid tert-butyl ester (6-B)
B. (4-Fluoro-3-trifluoromethyl-benzyl)-(3-methyl-benzo[b]thiophen-2-yl)-carbamic acid tert-butyl ester (6-C)
C. (4-Fluoro-3-trifluoromethyl-benzyl)-(3-methyl-benzo[b]thiophen-2-yl)-amine hydrochloride (6-D)
D. N-(4-Fluoro-3-trifluorobenzyl)-N-(3-methyl-benzo[b]thiophen-2-yl)-[N′-tert-butyloxycarbonyl]-sulfonamide (6-E)
E. N-(4-Fluoro-3-trifluoromethyl-benzyl)-N-(3-methyl-benzo[b]-thiophen-2-yl)-N′-(butyric acid ethyl ester)-N-(tert-butyloxycarbonyl)-sulfonamide (6-F)
F. N-(4-Fluoro-3-trifluoromethyl-benzyl)-N-(3-methyl-benzo[b]-thiophen-2-yl)-N′-(butyric acid ethyl ester)-sulfonamide (6-G)
G. N-(4-Fluoro-3-trifluoromethyl-benzyl)-N-(3-methyl-benzo[b]-thiophen-2-yl)-N′-(butyric acid)-sulfonamide, Compound 13
Example 7
A. N-(4-Fluoro-3-trifluorobenzyl)-N-(benzo[b]thiophen-2-yl)-[N′-tert-butyloxycarbonyl]-sulfonamide (7-A)
B. N-(3-Bromo-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluorobenzyl)-[N′-tert-butyloxycarbonyl]-sulfonamide (7-B)
C. N-(3-Bromo-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluorobenzyl)-[N′-tert-butyloxycarbonyl]-sulfonamide (7-B)
D. N-(3-Bromo-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluorobenzyl)-(N-acetic acid ethyl ester)-[N′-tert-butyloxycarbonyl]-sulfonamide (7-D)
E. N-(3-Bromo-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluorobenzyl)-(N-acetic acid ethyl ester)-sulfonamide (7-E)
F. N-(3-Bromo-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluorobenzyl)-(N-acetic acid)-sulfonamide, Compound 14
N-(3-Bromo-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluorobenzyl)-(N-butyric acid)-sulfonamide, Compound 15
N-(3-Bromo-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluorobenzyl)-(N-hexanoic acid)-sulfonamide, Compound 16
1 methyl 4- piperidin-1-yl trifluoromethoxy phenylmethyl 2 methyl 4- morpholin-4-yl trifluoromethoxy phenylmethyl 3 methyl 4- piperazin-1-yl trifluoromethoxy phenylmethyl 4 methyl 4- 4-isopropyl- trifluoromethoxy piperazin-1-yl phenylmethyl 5 methyl 4- 4-(3-methyl-butyl)- trifluoromethoxy piperazin-1-yl phenylmethyl 6 methyl 4- 4-methyl trifluoromethoxy piperazin-1-yl phenylmethyl 7 methyl 4- 4-(2,2,2- trifluoromethoxy trifluoroethyl)- phenylmethyl piperazin-1-yl 8 methyl 4- 4-(dimethylamino)piperidin- trifluoromethoxy 1-yl phenylmethyl 9 methyl 4- 4-(pyrrolidin-1-yl)piperidin- trifluoromethoxy 1-yl phenylmethyl 10 methyl 4- 4-carboxy trifluoromethoxy piperidin-1-yl phenylmethyl 11 methyl 4- 4-(4-methylpiperazin- trifluoromethoxy 1-ylcarbonyl)piperidin- phenylmethyl 1-yl 12 methyl 4- 4-(2-dimethylamino- trifluoromethoxy ethylaminocarbonyl)piperidin- phenylmethyl 1-yl 13 methyl 4-fluoro-3- H 3-carboxypropyl trifluoromethyl phenylmethyl 14 bromo 4-fluoro-3- H carboxymethyl trifluoromethyl phenylmethyl 15 bromo 4-fluoro-3- H 3-carboxypropyl trifluoromethyl phenylmethyl 16 bromo 4-fluoro-3- H 4-carboxybutyl trifluoromethyl phenylmethyl BIOLOGICAL EXAMPLES
Example 1
In Vitro Canine TRPM8 Functional Assay
1 0.0036 99 2 0.0057 100 3 19 4 0.060 5 0.071 6 0.046 90 7 0.013 100 8 36 9 9 10 0.0046 101 11 30 12 0.061 70 13 0.062 72 14 33 15 0.018 101 16 0.0085 101 *IC50values are based on single determinations In Vivo Models
Example 2
Inhibition of Icilin-Induced Behaviors in Rodents
Example 2a
Inhibition of Icilin-Induced “Wet-Dog” Shakes in Rats
Example 2b
Reversal of Icilin-Induced Behaviors in Rats
10 10 p.o. 1 h 57 Example 3
In Vivo Model of Subacute Inflammatory Pain
Carrageenan-Induced Hyperalgesia
Example 3a
Rat Carrageenan-Induced Radiant Heat Hypersensitivity
% Example 4
In Vivo Model for of Chronic Inflammatory Pain
Complete Freund's Adjuvant (CFA)-Induced Hyperalgesia
Example 4a
CFA-Induced Paw Radiant Heat Hypersensitivity
% Reversal=(Treatment Response−CFA Response)/(Baseline Response−CFA Response)×100.Example 4b
CFA-Induced Paw Cold Hypersensitivity
% Inhibition=[1−(treatment licking duration/vehicle licking duration)]×100.Example 5
Chemically-Induced Abdominal Irritant Models of Visceral Pain
% Example 6
In Vivo Models of Neuropathic Pain
Example 6a
Chronic Constriction Injury (CCI)-Induced Model of Neuropathic Pain
Acetone-Induced Hypersensitivity
Example 6b
Chronic Constriction Injury (CCI)-Induced Model of Neuropathic Pain
Cold Plate-Induced Hypersensitivity
Example 6c
Chronic Constriction Injury (CCI)-Induced Model of Neuropathic Pain
Mechanical Allodynia (von Frey Test)
Example 7
Inflammatory Agent-Induced Models of Pyresis/Antipyresis
Example 8
CFA-Induced Model of Rheumatoid Arthritis
Example 9
In Vivo Model for Arthritis
Inflammogen-Induced Hyperalgesia of the Knee Joint
Example 10
Sarcoma Cell-Induced Models of Bone Cancer Pain
Example 11
Respiratory Irritant-Induced Models of Cough
Example 12
Chemical Irritant-Induced Models of Itch, Contact Dermatitis, Eczema and Other Manifestations of Dermal Allergy, Hypersensitivity and/or Inflammation
Example 13
Chemical Irritant-Induced Models of Rhinitis and Other Manifestations of Nasal Hypersensitivity and/or Inflammation
Example 14
Conflict-Induced Models of Anxiety, Panic Disorder and Other Non-Adaptive Stressful or Phobic Responses
Example 15
Bladder Pressure- and Hypertrophy-Induced Models of Urinary Incontinence
Example 16
In Vivo Model for Cold-Enhanced Central Pain States
Example 17
In Vivo Model for Post-Anesthetic Shivering
Example 18
Cold-Evoked Cardiovascular Pressor Responses
Example 19
Cold-Induced Vasoconstriction
Ramifications for Tissue Perfusion