MXPA06005298A - Substituted triazoles as sodium channel blockers - Google Patents

Abstract

Substituted triazole compounds represented by Formula I, II or III, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, sodium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, migraine, headache pain, migraine headache, epilepsy, irritable bowel syndrome, diabetic neuropathy, multiple sclerosis, manic depression and bipolar disorder, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds. A method of administering local anesthesia comprises administering an effective amount of a compound of the instant invention, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier (I), (II), (III).

Description

TRIAZOLS REPLACED AS SODIUM CHANNEL BLOCKERS FIELD OF THE INVENTION The present invention is directed to a series of substituted triazole compounds. In particular, this invention is directed to substituted triazoles that are sodium channel blockers, useful for the treatment and prevention of chronic pain and neuropathic pain. The compounds of the present invention are also useful for the treatment of other conditions, including acute pain, inflammatory pain, visceral pain, migraine, headache, migraine headache, and central nervous system (CNS) disorders such as epilepsy. , manic depression, bipolar disorder and diabetic neuropathy.

BACKGROUND OF THE INVENTION Voltage-activated ion channels allow electrically excitable cells to generate and propagate action potentials and are therefore crucial for nerve and muscle function. Sodium channels play a special role in mediating rapid depolarization, which constitutes the growth phase of the action potential and in turn activates voltage-activated calcium and potassium channels. Voltage-activated sodium channels represent a family of multiple genes. Nine subtypes of the sodium channel have been cloned and have been functionally expressed to date. [Clare, J. J., Tate, S. N., Nobbs, M. & Romans, M.A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. These have been differentially expressed in all muscle tissues and nerve tissues and show different biophysical properties. All voltage-activated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent activation. [Catterall, W. A. Structure and function of voltage-gated sodium and calcium channels. Current Opinion in Neurobiology 1, 5-13 (1991)]. In negative or hyperpolarizing membrane potentials, the sodium channels are closed. After depolarization of the membrane, the sodium channels open quickly and then become inactive. Sodium channels only conduct currents in the open state and, once inactivated, they have to return to the resting state, favored by hyperpolarization of the membrane, before they can reopen. The different subtypes of the sodium channel vary in the voltage range in which they are activated and inactivated, as well as in their activation and inactivation kinetics. Sodium channels are the target of a diverse array of pharmacological agents, including neurotoxins, antiarrhythmics, anticonvulsants and local anesthetics. [Clare, J. J., Tate, S. N., Nobbs, M. & Romans, M.A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. Various regions in the secondary structure of the sodium channel are involved in interactions with these blockers and most are highly conserved. In fact, most sodium channel blockers known to date interact with similar potency with all subtypes of the channel. However, it has been possible to produce sodium channel blockers with therapeutic selectivity and a suitable therapeutic window for the treatment of epilepsy (for example lamotrigine, phenytoin and cmazepine) and certain cardiac arrhythmias (for example lignocaine, tocainide and mexiletine). It is well known that voltage-gated Na + channels in the nerves play a critical role in neuropathic pain. Peripheral nervous system injuries often result in neuropathic pain that persists long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgia. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to afferent primary sensory neurons can lead to neuroma formation and spontaneous activity, as well as activity elicited in response to normally innocuous stimuli. [Cárter, G. T. and B. S. Galer, Advances in the management of neuropathic pain. Physical Medicine and Rehabilitation Clinics of North America, 2001. 12 (2): p. 447-459]. It is thought that the ectopic activity of normally silent sensory neurons contributes to the generation and maintenance of neuropathic pain. It is generally assumed that in neuropathic pain it is associated with an increase in the activity of the sodium channel in the nerve injuring. [Baker, M. D. and J. N. Wood, Involvement of Na channels in pain pathways. TRENDS in Pharmacological Sciences, 2001, 22 (1): p. 27-31.]. In fact, in the rat models with peripheral nerve injury, the ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, the intravenous application of the sodium channel blocker and the local anesthetic lidocaine can suppress ectopic activity and reverse tactile allodynia at concentrations that do not affect general behavior and motor function. [Mao, J. and L. L. Chen, Systemic lidocaine for neuropathic pain relief. Pain, 2000. 87: p. 7-17.]. These effective concentrations were similar to the concentrations that are clinically efficient in humans. [Tanelian, D. L. and W. G. Brose, Neuropathic pain can be relieved by drugs that are used-dependent sodium channel blockers: lidocaine, carbamazepine and mexiletine. Anesthesioiogy, 1991.74 (5): p. 949-951.]. In a controlled placebo study, continuous infusion of lidocaine causes reduced pain assessments in patients with peripheral nerve injury, and in a separate study, intravenous lidocaine reduced the intensity of pain associated with postherpetic neuralgia (PHN). [Mao, J. and L. L. Chen, Systemic lidocaine for neuropathic pain relief. Pain, 2000. 87: p. 7-17. Anger, T., et al., Medicinal chemistry of neuronal voltage-gated sodium channel blockers. Journal of Medicinal Chemlstry, 2001. 44 (2): p. 115-137.]. Lidoderm®, lidocaine applied in the form of a skin patch, is currently the only treatment tested by the FDA for PHN. [Devers, A. and B. S. Galer, Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-Iabel study. Clinical Journal of Pain, 2000.16 (3): p. 205-208.]. In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). [Clare, J. J. et. to the. and Anger, T. et. to the.]. International Patent Publication WO 00/57877 discloses pyrazoles, midazoles, oxazoles, thiazoles, and aryl substituted pyrrols and their uses as sodium channel blockers. International Patent Publication WO 01/68612 describes pyridines, pyrimidines, pyrazines and triazines substituted with aryl and their uses as sodium channel blockers. International Patent Publication WO 99/32462 describes triazine compound for the treatment of CNS disorders. However, a need remains for novel compounds and compositions that therapeutically block neuronal sodium channels with less side effects and higher potency than currently known compounds.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to substituted triazole compounds which are sodium channel blockers, useful for the treatment and prevention of chronic pain and neuropathic pain. The compounds of the present invention are also useful for the treatment and prevention of other conditions, including CNS disorders such as epilepsy, manic depression and bipolar disorder. This invention also provides pharmaceutical compositions comprising a compound of the present invention, either alone, or in combination with one or more therapeutically active compounds, and a pharmaceutically acceptable carrier. This invention additionally comprises methods for the treatment and prevention of acute pain, visceral pain, migraine, headache, migraine headache, inflammatory pain, and CNS disorders including, but not limited to, epilepsy, manic depression and bipolar disorder comprising the administration of the compounds and pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention comprises compounds represented by the formula (I) or (II): 0) or pharmaceutically acceptable salts thereof, wherein R 1 is (a) H, (b) C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, any of which is optionally substituted with one or more of the following substituents: NRaRb, COOH, CONRaRb, or (c) -C (= 0) Ra, COORa, CONRaRb; Ra is (a) H, (b) CrC6 alkyl, optionally substituted with one or more of halogen or CF3, or (c) CF3; Rb is (a) H, or (b) C 1 -C 2 alkyl, optionally substituted with one or more of halogen or CF 3, or (c) CF 3; R2 is H or CrC alkyl; R3 and R4 each independently is (a) H, (b) -Cal-C-perfluoroalkyl of C? -C4 or -O-C-C-perfluoroalkyl alkyl of CrC4, or (c) halogen, or ( d) - CrC6l alkyl optionally substituted with one or more of halogen or CF3; and R5, R6 and R7 each independently is (a) H, (b) -O-C6-C6 alkyl, -O-C6-C6 alkenyl, C-C6-O-alkynyl, any of which is optionally substituted with one or more of halogen or CF3I (c) -C0-C4 alkyl-perfluoroalkyl of C C4, or -O-alkyl of Co-C-perfluoroalkyl of CrC4, (d) -O-phenyl, or -O-alkyl of CrC4-phenyl, wherein the phenyl is optionally substituted with 1-3 substituents selected from i) halogen, ii) -CN, iii) -N02, iv) CF3, v) -ORa, vi) -NRaRb, vii ) - C0-C4 alkyl-CO-ORa, viii) - (C0-4 alkyl) -CO-N (Ra) (Rb), ix) and x) -CMO alkyl, wherein one or more of the carbons of the alkyl can be replaced by a -NRa, C (0) -0-, or -N (Ra) -C (0) -N (Ra) -, or (e) halogen, -0Ra, or phenyl wherein the phenyl is optionally substituted with 1-3 substituents selected from i) halogen, ii) -CN, ii) -N02, iv) CF3, v) pyrazolyl, vi) -ORa, vii) -NRaRb, viii) -alkyl of C0-4-CO-ORa, ix) - (C0- alkyl) - CO-N (Ra) (Rb), and x) -alkyl of d. or, wherein one or more of the alkyl carbons can be replaced by a -NRa, C (0) -0-, or -N (Ra) -C (0) -N (Ra) -. The present invention additionally comprises compounds described by formula III: (ffl) or pharmaceutical salts thereof, wherein each R1-R7 is as defined above.

In a first aspect, the present invention provides a compound described by the chemical formula (I), or a pharmaceutically acceptable salt thereof, wherein R5 is different from H and is attached in the ortho position. In one embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted phenyl. In a second embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is -O-CrC6 alkyl optionally substituted. In a third embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is -O-C4 alkyl-phenyl, wherein the phenyl is optionally substituted. In another embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R6 is halogen.

In a further embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 is halogen. In a further embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are halogen. In even a further embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3, R4 and R6 are halogen. In yet another embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 is -O-alkyl of H ^ rperfluoroalkyl of CrC4. In even an additional embodiment of this first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is -O-alkenyl of CrC6 optionally substituted. In a second aspect, the present invention provides a compound described by the chemical formula (II), or a pharmaceutically acceptable salt thereof, wherein R5 is different from H and is attached in the ortho position. In one embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted phenyl. In a second embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is -O-C-? -C4 alkyl-phenol, wherein the phenyl is optionally substituted . In a third embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted-C-C-O-alkenyl. In a fourth embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is -O-C6 alkyl optionally substituted. In another embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein Rd is halogen.

In a further embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 is halogen. In a further embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are halogen. In even a further embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3, R4 and R6 are halogen. In yet another embodiment of this second aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 is -0-C4-C-C-perfluoroalkyl alkylamide. In a third aspect, the present invention provides a compound described by the chemical formula (III), or a pharmaceutically acceptable salt thereof, wherein R5 is different from H and is attached at the ortho position. In one embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted phenyl. In a second embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted -O-d-Cß alkyl. In a third embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is -O-CrC4-phenyl alkyl, wherein the phenyl is optionally substituted. In a fourth embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R5 is -O-alkenyl of CrC6 optionally substituted. In another embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 is halogen. In a further embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R6 is halogen.

In even a further embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are halogen. In even a further embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3, R4 and R6 are halogen. In still another embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R3 is -O-aikyl of Co-C4-perfluoroalkyl of C1-C4. As used in the present invention, "alkyl" as well as other groups having the prefix "ale" such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl means carbon chains which may be linear or branched or combinations of the same. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl. "Alkenyl", "alkynyl" and other similar terms include carbon chains containing at least one unsaturated C-C bond. The terms "Co- alkyl" and "C0-C4 alkyl" include alkyls containing 4, 3, 2, 1, or no carbon atom. An alkyl without carbon atoms is a substituent of the hydrogen atom when the alkyl is a terminal group and is a direct bond when the alkyl is a bridging group. The term "amine", unless specifically stated otherwise, includes primary, secondary and tertiary amines substituted with C0-6 alkyl- The term "carbonyl", unless specifically stated otherwise, includes a group Co-6 alkyl substituent when the carbonyl is terminal. The term "halogen" includes fluorine, chlorine, bromine and iodine atoms. The term "optionally substituted" is intended to include both substituted and unsubstituted forms. Thus, for example, optionally substituted phenyl could represent a pentafluorophenyl ring or a phenyl ring. In addition, multiple optionally substituted moieties such as, for example, alkyl phenyl are intended to mean that the alkyl and phenyl groups are optionally substituted. If only one of the multiple portions is optionally substituted then it will be specifically mentioned such as "an -O-CrC4-phenyl alkyl, wherein the phenyl is optionally substituted with halogen." The compounds described in the present invention may contain one or more double bonds and therefore may give rise to cis / trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers unless specifically stated otherwise. When the indicated site has only a single bond, the presence of the required hydrogens is meant. When the site is a double bond, the cis / trans isomers are formed and encompassed by this invention. The compounds described in the present invention may contain one or more asymmetric centers and therefore may give rise to diastereomers and optical isomers. The present invention includes all those possible diastereoisomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The aforementioned chemical formulas are shown without a definitive stereochemistry in certain positions. The present invention includes all stereoisomers of the chemical formulas and pharmaceutically acceptable salts thereof. Additionally, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare said compounds, or in the use of racemization or epimerization procedures known to those skilled in the art, the products of said processes can be a mixture of stereoisomers. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acid, its corresponding salt can be conveniently prepared from non-toxic pharmaceutically acceptable bases, including inorganic bases and organic bases. Salts derived from said inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganese and manganose), potassium, sodium, zinc and the like salts. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring substituted amines and substituted amines synthesized. Other non-toxic, pharmaceutically acceptable organic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol. , ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pam, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Particularly preferred acids are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric. The present invention includes within its scope prodrugs of the compounds of this invention. In general, said prodrugs will be functional derivatives of the compounds of this invention which are readily converted in vivo to the required compounds. Therefore, in the methods of treatment of the present invention, the term "administration" should encompass the treatment of the various conditions described with the specifically described compound or with a compound which may not be specifically described, but which becomes to the specified compound in vivo after administration to the 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. The metabolites of these compounds include active species produced after the introduction of the compounds of this invention into the biological environment. The pharmaceutical compositions of the present invention comprise a compound represented by formula I, II or III (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. Such additional therapeutic agents may include, for example, i) opioid agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or iv) sodium channel antagonists, v) receptor agonists NMDA or antagonists, vi) selective inhibitors to COX-2, vii) antagonists to NK1, viii) non-steroidal anti-inflammatory drugs ("NSAID"), ix) selective serotonin reuptake inhibitors ("SSRI") and / or inhibitors of selective serotonin and norepinephrine reuptake ("SSNRI"), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontine (gabapentin). The present compositions include compositions suitable for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous), although the most appropriate route in any given case will depend on the particular host, and the nature and severity of the conditions for which the active ingredient is administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and are prepared by any of the methods well known in the pharmacy art. The present compounds and compositions are useful for the treatment and prevention of syndromes of chronic, visceral, inflammatory and neuropathic pain. The present compounds and compositions are also useful for the treatment and prevention of other conditions, including acute pain, migraine, headache, and migraine headache. These are useful for the treatment and prevention of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, and diabetic neuropathy. The present compounds and compositions are also useful for the treatment and prevention of chronic low back pain, phantom limb pain, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and related neuralgia, and associated pain with cancer, chemotherapy, neuropathy induced by HIV and by HIV treatment. The compounds of this invention can also be used as local anesthetics. The compounds of this invention are useful for the treatment and prevention of irritable bowel syndrome and related disorders, as well as Crohn's disease. The present compounds have clinical uses for the treatment and prevention of epilepsy and partial and generalized tonic seizures. These are also useful for neuroprotection under ischemic conditions caused by stroke or neural trauma and for the treatment of multiple sclerosis. The present compounds are useful for the treatment and prevention of bipolar disorder and tachyarrhythmias. It is understood that the compounds of this invention can be administered at a prophylactically effective dose level to prevent the aforementioned conditions, as well as to prevent other conditions associated with the activity of the sodium channel. Creams, ointments, jellies, solutions, or suspensions containing the present compounds can be used for topical use. Mouthwashes and / or gargle solutions are included within the scope of topical use for the purposes of this invention. Dose levels of about 0.01 mg / kg to about 140 mg / kg of body weight per day are useful in the treatment of inflammatory pain and neuropathic pain, or alternatively from about 0.5 mg to about 7 g per patient per day. For example, inflammatory pain can be effectively treated by administering from about 0.01 mg to about 75 mg of the compound per kilogram of body weight per day, or alternatively from about 0.5 mg to about 3.5 g per patient per day. Neuropathic pain can effectively be treated by administering from about 0.01 mg to about 125 mg of the compound per kilogram of body weight per day, or alternatively from about 0.5 mg to about 5.5 g per patient per day. The amount of the active ingredient that can be combined with the carrier materials to produce a particular dosage form will vary depending on the host treated and the particular mode of administration. For example, a formulation that is intended for oral administration to humans can conveniently contain from about 0.5 mg to about 5 g of the active agent, compounded with an appropriate and convenient amount of the carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain from about 1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg. However, it is understood that the dose level is specific for any particular patient will depend on a variety of factors. Such factors related to the patient include age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, combination of the drug, and the severity of the particular disease that undergoes therapy. In practice, the compounds represented by the formula I, II and III or pharmaceutically acceptable salts thereof can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier in accordance with the techniques for the formation of conventional pharmaceutical compounds. The vehicle can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration administration such as capsules, seals or tablets each containing a predetermined amount of the active ingredient. In addition, the compositions may be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a liquid water-in-water emulsion. -oil. In addition to the common dosage forms set forth above, the compounds represented by formula I, II and III or pharmaceutically acceptable salts thereof may also be administered by controlled release means and / or devices for administration. The compositions can be prepared by any of the pharmacy methods. In general, said methods include a step of bringing the active ingredient into association with the vehicle which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniform and intimate mixing of the active ingredient with liquid carriers or finely divided solid carriers or both. The product can be conveniently shaped to the desired presentation. Therefore, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and the pharmaceutically acceptable compounds or salts of Formula I, II and / or III. The compounds of formula I, II and III, or pharmaceutically acceptable salts thereof, may also be included in the pharmaceutical compositions in combination with one or more therapeutically active compounds. The pharmaceutical vehicles used can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of funny vehicles include carbon dioxide and nitrogen.

In the preparation of the compositions for oral dosage form, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dose units that are employed for solid pharmaceutical vehicles. Occasionally, the tablets may be reversed by standard aqueous or non-aqueous techniques. A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powders or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. The molded tablets can be made by molding in a suitable machine, a mixture of the wetted powder compound with an inert liquid diluent.

Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each seal or capsule preferably contains from about 0.1 mg to about 500 mg of the active ingredient. Therefore, a tablet, seal, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient taking one or two tablets, seals, or capsules, once, twice or three times a day. The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant may be included such as, for example, hydroxypropylcellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, a preservative may be included to prevent the detrimental growth of microorganisms. The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Additionally, the compositions may be in the form of sterile powders for the extemporaneous preparation of said sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively a fluid for ease of application by syringe. The pharmaceutical compositions must be stable under the conditions of processing and storage; therefore, they should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The vehicle can be a solvent medium or a dispersion medium containing, for example, water, ethanol, polio! (for example glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. The pharmaceutical compositions of the present invention may be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, and fine powder. In addition, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared, using a compound represented by formula I, II or III, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5% by weight to about 10% by weight of the compound, to produce a cream or ointment having a desired consistency. The pharmaceutical compositions of this invention may be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by the initial mixing of the composition with the smoothed or melted carrier (s) followed by cooling and molding in molds. In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, pH regulators, flavoring agents, binders, surface active agents, thickeners, lubricants, and preservatives. (including anti-oxidants). In addition, other adjuvants may be included to return to the isotonic formulation with the blood of the intended recipient. Compositions containing a compound described by formula I, II or III, or a pharmaceutically acceptable salt thereof, can also be prepared in the form of a powder or liquid concentrate. It has been found that the compounds and pharmaceutical compositions of this invention block the sodium channels. Accordingly, one aspect of the invention is the treatment in mammals of diseases that can be ameliorated by blocking neuronal sodium channels, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, and neuropathic pain by the administration of an effective amount of a compound of this invention. The term "mammals" includes humans, as well as other animals, such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans refers to the treatment of clinical conditions in non-human mammals that correlate with the aforementioned conditions. In addition, as described above, the present compounds can be used in combination with one or more therapeutically active compounds. In particular, the compounds of the invention can be used advantageously in combination with i) opioid agonists 0 antagonists, ii) calcium channel blockers, iii) 5HT receptor agonists or antagonists, iv) sodium channel blockers, v) N-methyl-D-aspartate (NMDA) receptor agonists or antagonists, vi) inhibitors selective to COX-2, vii) neurokinin receptor antagonists 1 (NK1), viii) non-steroidal anti-inflammatory drugs (SAID), ix) selective serotonin reuptake inhibitors (SSRI) and / or inhibitors of serotonin and norepinephrine selective reuptake (SSNRI), x) tricyclic antidepressant drugs , xi) modulators of norepinephrine, xii) lithium, xiii) valproate, and xiv) neurontine (gabapentin). The abbreviations used in the present invention have the following tabulated meanings. The abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.

Abbreviation of alkyl groups The following in vitro and in vivo assays were used in the evaluation of the biological activity of the present compounds.

Compound evaluation (in vitro assay): The identification of sodium channel inhibitors is based on the ability of sodium channels to cause cellular depolarization with sodium ions permean through the channels modified by the agonist. In the absence of inhibitors, exposure of a channel modified by the agonist to sodium ions will cause cellular depolarization. Sodium channel inhibitors will prevent cellular depolarization caused by the movement of sodium ions through the sodium channels modified by the agonist. Changes in membrane potential can be determined with the dye-pair transfer of the voltage-dependent fluorescence resonance energy (FRET) used by both components, a coumarin during (CC2DMPE) and an acceptor oxanol (DiSBAC2 (3)) . Oxanol is a lipophilic anion and is distributed through the membrane in accordance with the membrane potential. In the presence of a sodium channel agonist, but in the absence of sodium, the interior of the cell is negative with respect to the outside, the oxanol accumulates in the outer membrane sheet and the excitation of coumarin will cause it to appear the FRET. The addition of sodium will cause depolarization of the membrane leading to the redistribution of oxanol inside the cell, and, as a consequence, to the decrease in FRET. Therefore, the rate of change (donor / acceptor) increases after depolarization of the membrane. In the presence of a sodium channel inhibitor, cell depolarization will not occur, and therefore the distribution of oxanol and FRET will remain unchanged. Cells stably transfected with the sodium channel PN1 (HEK-PN1) were grown in 96-well plates coated with polylysine at a density of almost 140,000 cells / well. The medium was aspirated, and the cells were washed with pH PBS buffer, and incubated with 100 uL of 10 μM CC2-DMPE in 0.02% pluronic acid. After incubation at 25 ° C for 45 minutes, the medium was removed and the cells washed 2x with pH regulator. The cells were incubated with 100 uL of DiSBAC2 (3) in a TMA pH regulator containing 20 μM veratridine, 20 nM brevetoxin-3, and the sample tested. After incubation at 25 ° C for 45 minutes in the dark, the plates were placed in the VI PR apparatus, and the fluorescence emission of both CC2-DMPE and DiSBAC2 (3) was recorded for 10 seconds. At this point, 100 μL of pH buffer with saline was added to the wells to determine the degree of depolarization of the sodium-dependent cell, and the fluorescence emission of both quadrants recorded for an additional period of 20 s. The CC2-DMPE / DiSBAC2 (3) ratio, before the addition of the pH regulator with saline equal to 1. In the absence of the inhibitors, the ratio after the addition of the pH regulator with saline is > 1.5. When the sodium channel has been completely inhibited either by a known standard compound or a compound test, this ratio remains as 1. Therefore, it is possible, titrating the activity of a sodium channel inhibitor by monitoring the load dependent on concentration in the fluorescence ratio.

Electrophysiological assays (in vitro assays): Cell preparation: a HEK-293 cell line stably expressing the sodium channel subtype PN1 was established in the laboratory. The cells were cultured in medium for growth MEM (Gibco) with 0.5 mg / mL of G418, 50 units / mL of penicillin / streptomycin and 1 mL of fetal bovine serum inactivated by heat at 37 ° C and 10% C02. For the electrophysiological recordings, the cells were seeded on 35 mm discs coated with poly-D-lysine. Total cell counts: HEK-293 cells stably expressing the PN1 sodium channel subtype were examined by total cell voltage fixation (Hamill et al., Pfluegers Archives 391: 85-100 (1981)) using a EPC-9 amplifier and with Pulse software (HEKA Electronics, Lamprecht, Germany). The experiments were carried out at room temperature. The electrodes were polished by heat at the 2-4 MQ resistances. Voltage errors were minimized by series of compensatory resistances, and the capacitance of the device was canceled using the circuit made by EPC-9. The data was acquired at 50 kHz and filtered at 7-10 kHz. The bath solution consisted of 40 mM NaCl, 120 mM NMDG Cl, 1 mM KCI, 2.7 mM CaCl 2, 0.5 mM MgCl 2, 7-10 mM NMDG HEPES, pH 7.4, and the internal solution (pipette) containing Cs-methanesulfonate 110 mM, 5 mM NaCl, 20 mM CsCI, 10 mM CsF, 10 mM BAPTA (tetra Cs salt), 10 mM C HEPES, pH 7.4. The following protocols were used to estimate the steady-state activity of the compounds for the resting and inactivating states of the channel (Kr and K, respectively): 1) the test pulses of 8 ms for the depolarization of the voltages of - 60 mV to +50 mV from a maintenance potential of -90 mV were used to prepare the current-voltage relationships (curves IV). A voltage near the peak of curve IV (typically at 10 or 0 mV) was used as the voltage pulse test throughout the experiment. 2) Steady state inactivation curves (availability) were constructed by measuring the activated current during a test pulse of 8 ms followed by conditioning pulses of 10s for the potentials that ranged from -120 mV to -10 mV . 3) the compounds were applied at a maintenance potential in which 20-50% of the channels were inactivated and the sodium channel blockade was monitored during pulses of 8 ms test at intervals in 2s. 4) after the compounds were equilibrated, the inactivation of the steady state voltage dependent in the presence of the compound was determined in accordance with the aforementioned protocol 2). Compounds blocking the steady state of the channel decrease the induced current during the test pulses from all maintenance potentials, while the compounds that block mainly the inactivated state changed the midpoint of the stationary state inactivation curve. The maximum current in the negative holding potentials (lmax) and the difference in the midpoints of the steady-state inactivation curves (? V) in control and in the presence of a compound were used to calculate Kr and K¡ using the following equations: [Drug l * / Mj)? F? F > ? ttC0 K * / M < ? < tX.mztrpt ~ / iMíur, FariTiíiCC * In cases where the compound did not affect the steady state, K, was calculated using the following equation: jy ~ i Drug] Rat leg formalin test (in vivo assay): The compounds were tested for their ability to inhibit the behavioral response induced by an injection of 50 μL of formalin (5%).

A metal fence was fixed to the left rear leg of male rats Sprague-Dawley (Charles River, 200-250 g) and each rat was conditioned to the band for 60 minutes inside a plastic cylinder (15 cm in diameter).

The rats were dosed with either the vehicle or a compound test either before (local) or after (systemic) testing of the formalin. For local administration, the compounds were prepared in a 1: 4: 5 vehicle of ethanol, PEG400 and saline (EPEGS) and injected subcutaneously into the dorsal surface of the left hind paw 5 minutes before formalin. For systemic administration, the compounds were prepared in either an EPEGS vehicle or a Tween 80 vehicle (10%) / sterile water (90%) and injected i. v. (via the lateral vein of the tail 15 minutes after the formallna) or p. or. (60 minutes before the formalin). The number of vacillations was counted continuously for 60 minutes using an automated nociception analyzer (UCSD Anesthesiology Research, San Diego, CA). Statistical significance was determined by comparing the total hesitations detected in the early (0-10 minutes) and delayed (11-60 minutes) phase with an unpaired t-test.

In vivo assay using the rat CFA model: Unilateral inflammation was induced with 0.2 ml injection of Freund's complete adjuvant (CFA: Mycobacterium tuberculosis, Sigma, suspended in an oil / saline emulsion (1: 1); Mycobacterium mg / mL) on the plantar surface of the left posterior part.

This dose of CFA produced significant swelling of the hind paw but the animals exhibited normal grooming and weight gain behavior during the course of the experiment. Mechanical hyperalgesia was evaluated 3 days after tissue injury using a Randall-Selitto test. Repeated ANOVA measures, followed by Dunnett's test Post Hoc.

SNL: Mechanical allodynia (in vivo test): The tactile allodynia was evaluated with von Frey calibrated filaments using an up-down paradigm before and two weeks after the nerve injury. The animals were placed in plastic cages with a wire mesh floor and allowed to acclimate for 15 minutes before each test session. To determine the 50% threshold response, the von Frey filaments (during a range of intensities of 0.4 to 28.8 g) were applied to the average plant surface for 8 seconds, or until a paw withdrawal response appeared. After a positive response, an incrementally weaker stimulus was evaluated. If there was no response to a stimulus, then an incrementally stronger stimulus was presented. After the initial crossing of the threshold, this procedure was repeated for four stimulus presentations per animal per test session. Mechanical sensitivity was evaluated 1 and 2 hours after oral administration of the test compound. The compounds described in this invention exhibited sodium channel blocking activity of about < 0.1 μM to about < 50 μM in the in vitro tests described above. It is advantageous that the compounds exhibit sodium channel blocking activity < 5 μM in the in vitro tests. It is more advantageous that the compounds exhibit sodium channel blocking activity of < 1 μM in the in vitro tests. It is even more advantageous that the compounds exhibit sodium channel blocking activity of < 0.5 μM in the in vitro tests. It is even more advantageous that the compounds exhibit sodium channel blocking activity of < 0.1 μM in the in vitro tests. The present compounds can be prepared according to the general schemes provided below as well as the procedures provided in the examples. The following schemes and examples further describe, but do not limit, the scope of the invention. Unless specifically stated otherwise, the experimental procedures were carried out under the following conditions: all operations were carried out at room temperature or at room temperature; that is, at a temperature range of 18-25 ° C. The evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 passages: 4.5-30 mm Hg) with a bath temperature of up to 60 ° C. The course of the reactions was followed by thin layer chromatography (TLC) and the reaction times are given only for illustration. The melting points are not corrected and 'd' indicates decomposition. The melting points provided are those obtained for the materials prepared as described. The polymorphism can result in the isolation of materials with different melting points in some preparations. The structure and purity of all final products was ensured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. When they are provided, the productions are for illustration only. When provided, the NMR data in the form of delta (d) values for the main diagnostic protons are given in parts per million (ppm) relative to tetramethylsilane (TMS) as the internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. The conventional abbreviations used for the signal form are: s. singlet; d. doublet; t. triplet; m. multiplet; br. Large; etc. In addition, "Ar" means an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations are used: v (volume), p (weight), p. and. (boiling point), p. F. (melting point), L (liter (s)), mL (milliliters), g (gram (s)), mg (milligram (s)), mol (moles), millimole (millimoles), eq (equivalent (s)) )).

Synthesis Methods The compounds of the present invention can be prepared according to the schemes provided below as well as the methods provided in the reference examples and the examples. The substituents are the same as in the aforementioned formulas except when defined otherwise or are otherwise evident to one skilled in the art. The novel compounds of the present invention can be easily synthesized using techniques known to those skilled in the art, such as those described, for example, in Advanced Organic Chemistry, March, 4th Ed., John Wiley and Sons, New York, NY, 1992; Advanced Organic Chemistry, Carey and Sundberg, Vol. A and B, 3rd Ed., Plenum Press, Inc., New York, NY, 1990; Protective groups in Organic Synthesis, Green and Wuts, 2nd Ed., John Wiley and Sons, New York, NY, 1991; Comprehensive Organic Transformations, Larock, VCH Publishers, Inc., New York, NY, 1988; Handbook of Heterocyclic Chemistry, Katritzky and Pozharskii, 2nd Ed., Pergamon, New York, NY, 2000 and references cited therein. The raw materials for the present compounds can be prepared using standard synthetic transformations of chemical precursors which are readily available from commercial sources, including Aldrich Chemical Co. (Milwaukee, Wl); Sigma Chemical Co. (St. Louis, MO); Lancaster Synthesis (Windham, N. H.); Ryan Scientific (Columbia, S.C.); Maybridge (Comwall, UK); Matrix Scientific (Columbia, S.C.); Arcos, (Pittsburgh, PA) and Trans World Chemicals (Rockville, MD). The methods described in the present invention for the synthesis of the compounds may include one or more steps of manipulations of protecting and purification groups, such as, recrystallization, distillation, column chromatography, flash chromatography, thin layer chromatography (TLC), radial chromatography and high pressure chromatography (HPLC). The products can be characterized using various techniques well known in the chemical arts, including proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis and CLAR and mass spectrometry (LC-MS). Methods for protective group manipulation, purification, structure identification and quantification are well known to one skilled in the art of chemical synthesis. Suitable solvents are those which will at least partially dissolve one or all of the reagents and will not interact adversely with any of the reagents or with the product. Suitable solvents are aromatic hydrocarbons (e.g., toluene, xylenes), halogenated solvents (e.g., methylene chloride, chloroform, carbon tetrachloride, chlorobenzenes), ethers (e.g., diethyl ether, diisopropyl ether, tert-butyl methyl ether, diglyme, tetrahydrofuran, dioxane, anisole), nitriles (e.g., acetonitrile, propionitrile), ketones (e.g., 2-butanone, dltyl ketone, tert-butyl methyl ketone), alcohols (e.g., methanol, ethanol, n-propanol , iso-propanol, n-butanol, t-butanol), dimethyl formamide (DMF), dimethylsulfoxide (DMSO) and water. Mixtures of two or more solvents can also be used. Suitable bases are generally alkali metal hydroxide, alkaline earth metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide; alkali metal hydrides and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; the alkali metal amides such as lithium amide, sodium amide and potassium amide; alkali metal carbonates and alkaline earth metal carbonate such as lithium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, and cesium carbonate acid; Alkali metal alkoxides and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metal alkali methyl lithium, n-butyl lithium, sec-butyl lithium, t-bultyl lithium, phenyl-lithium, alkyl magnesium halides, organic bases such as trimethylamine, triethylamine, triisopropylamine, N, N-diisopropylethylamine , piperidine, N-methyl piperidine, morpholine, N-methyl morpholine, pyridine, collidines, lutidines, and 4-dimethylaminopyridine; and bicyclic amines such as DBU and DABCO. As previously described in, in the preparation of the compositions for oral dosage form, any of the usual pharmaceutical media can be employed. For example, in the case of oral liquid preparations such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used; or in the case of solid oral preparations such as powders, capsules, and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be included. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which solid pharmaceutical carriers are employed. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. In addition to the common dosage forms set forth above, controlled release media and / or devices for administration in the administration of the present compounds and compositions can also be used. It is understood that the functional groups present in the compounds described in the schemes below can be further manipulated, where appropriate, using the standard techniques for functional group transformation available to those skilled in the art, to provide the desired compounds described herein. invention. Other variants or modifications, which will be obvious to those skilled in the art, are within the scope and teachings of this invention. This invention should not be limited except as set forth in the following claims.

SCHEME 1 According to the scheme 1,3-bromobenzoic acid 1 is coupled with t-butyl carbazate by activation with HOBt (hydroxybenzotriazole) in the presence of a suitable carbodiimide such as EDC [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and diisopropylethylamine (DIEA) in dichloromethane or THF to produce the protected hydrazide 2. There are many other suitable methods for activating the carboxylic acids for coupling formation (see March J., Advanced Organic Chemistry, 5th ed., John Wiley & Sons, New York, pp. 506-512 (2001)). Compound 2 can be converted to a variety of non-symmetrical biphenyl intermediates 3 by means of a variety of coupling reactions. One type is the Suzuki reaction wherein the bromine, iodine, or triflate 2 compound is reacted with an aryl boronic acid in the presence of a palladium catalyst such as palladium acetate with triphenyl phosphine and aqueous sodium carbonate in a solvent such as toluene and a co-solvent such as n-propanol. (See Suzuki et al., Chem. Rev., 95, 2457, 1995). A variety of aryl boronic acids is commercially available or can conveniently be prepared from the corresponding aryl bromide or iodide by converting it to an organolithium derivative [Baldwin, J. E. et al., Tetrahedron Lett. 39, 707-710 (1998)], or a Grignard reagent followed by treatment with trialkylborate [Li, J. J. et al, J. Med. Chem, 38: 4570-4578 (1995) and Piettre, S. R. et al. J. Med Chem. 40, 4208-4221 (1997)]. Aryl boronates can also be used as an alternative to aryl boronic acids in these coupling reactions catalyzed by Pd [Giroux, A. et. al., Tetrahedron Lett., 38, 3841 (1997)]. Boronates can be easily prepared from the aryl bromides, iodides and trifluoromethane sulfonates using the methods described by [Murata, M. et. al., J. Org. Chem. 65: 164-168 (2000)]. The Boc protecting group of compound 3 is removed under standard conditions - trifluoroacetic acid in dichloromethane - to produce the TFA salt of hydrazide 4 which can be desalted with an aqueous solution of NaOH.

SCHEME 2 In scheme 2, a method for the preparation of substituted 1, 2,4-triazole 5-biphenyl-3 derivatives (Francis et al., Tetrahedron Lett., 28 (43), 5133-5136, 1987) is described. . The reaction of hydrazide 4 with an amidine substituted with a base such as sodium methoxide in methanol provides the intermediate 5 in which, in the pure state by heating (without co-solvent), provides the triazole 6.

SCHEME 3 A &J * In Scheme 3, a method is described for the preparation of 1, 2,4-triazole-5-biphenyl-3-substituted derivatives wherein the substitution may be esters, acids, amides, etc. (Catarzi et al., J. Med. Chem., 38, 2196-2201, (1995)). The reaction of hydrazide 4 with carbetoxy-5-methyl-thioformimide tetrafluoroborate and triethylamine in dichloromethane yields oxamid, ratiate 7 which is cycled to triazole ester 8. The reagent tetrabluoroborate of carbetoxy-5-methyl-thioformimide is prepared by the reaction of ethyl-2-thiooxamate with trimethyl oxonium tetrafluoroborate (see Catarzi et al., supra) mentioned in dichloromethane. Ester 8 can be converted to a variety of amides simply by heating it with the corresponding amine, in this case ammonium, in a solvent such as methanol.

SCHEME 4 13 12 1. MH2 HS 2. HOAc In scheme 4, a method for the preparation of an unsubstituted 3-triazole ring system is described (Lin et al, J. Org Chem., 44 (23), 4160-4165, 1979). Ethyl-3-bromobenzoate 10 is reacted with an aryl boronic acid, described in scheme 1 to produce biphenylester 11. Ester 11 provides a preformed biphenyl intermediate that can be further processed to compound 4 and related derivatives as described in the previous schemes 1-3. In this scheme 4. , ester 11 is converted to amide 12 under standard conditions. Specifically, ester 11 is hydrolyzed to the corresponding acid which is subsequently activated with carbonyldiimidazole (CDI) in DMF, followed by the addition of ammonia in the form of ammonium acetate to produce amide 12. Amide 12 in dimethylformamide dimethylacetal is it is heated to produce intermediate 13 which, when heated with hydrazine in acetic acid, produces triazole 14.

SCHEME 5 In scheme 5, the alkylation of triazole 6 by the use of a base such as sodium methoxide in a solvent such as methanol with an alkyl halide or triflate produces a mixture of tautomeric products 15 and 15 '.

SCHEME 6 CD!. DMF R »Prf H In scheme 6, the triazole ester 8 can be hydrolyzed to acid 16 under standard conditions (sodium hydroxide, methanol). Acid 16 can be converted to amide 17 under a variety of conditions described in scheme 1. In this variation, activation of acid 16 with carbonyldiimidazole (CDI) in dimethylformamide (DMF) followed by the addition of an amine produces the amide 17 SCHEME 7 NaSH ,. Oj In Scheme 7, the triazole ester 8 can be converted to a secondary alcohol 18 as the main product by reaction with a mixture of lithium borohydride and a Grignard reagent in an aprotic solvent such as THF. Alternatively, the ester 8 can be reduced to a primary alcohol 20 by any of various reducing agents, which include lithium aluminum hydride (LAH), diisobutylaluminum hydride (DIBAL-H) and sodium borohydride (NaBH4). Any alcohol 18 or 20 can be further derivatized by any number of methods. In one example, alcohol 18 can be oxidized to acetone 19 by a variety of reagents for oxidation which includes chromium-based reagents, and Swem type reagents (DMSO and oxalyl chloride).

SCHEME 8 The alcohol 18 can also be converted to fluoride derivatives 21 by reaction with diethylaminosulfur trifluoride (DAST) in dichloromethane at reduced temperatures, as described in Scheme 8.

SCHEME 9 According to scheme 9, bromoaniline 22, wherein the amino group is protected with a Boc group, and an arylboronic acid is converted to a variety of non-symmetrical biphenyl intermediates 23 as described in scheme 1. The protecting group Boc of compound 23 is removed as previously described and converted to its diazonium salt 24 by standard reaction with sodium nitrite and HCl in water. Addition of compound 24 to a mixture of methyl isocyanoacetate and sodium acetate in methanol and water yields the triazole ester 25. The key intermediate 25 can then be converted to a variety of useful derivatives using the methods described in schemes 1-7 .

SCHEME 10 In scheme 10, which is a variation of the protocols described in the aforementioned schemes 1, 4 and 9, the protected Boc aniline 26 containing a boronic acid or boronate ester group and an aryl, iodide or triflate bromide is converts to a variety of non-symmetrical biphenyl intermediates 23 as described in scheme 1.

The following reference examples provide methods for the preparation of certain compounds of the invention: REFERENCE EXAMPLE 1 3- [3- (2-Trifluoromethoxyphenyl) -phenyl] -1,4, -triazole Step A: 2-trifluoromethoxyphenylboronic acid to B (OH) 2 00, to a stirring solution of 2 g (9.5 mmol) of 1 -bromo-2- trifluoromethoxy benzene in 28 mL of tetrahydrofuran (THF) at -78 ° C, 5.9 mL of a solution of 1.7 M t-butyl lithium in hexanes (9.5 mmol) was carefully added. This reaction mixture was stirred at -78 ° C for 45 minutes. To this reaction mixture at -78 ° C was added 2.58 mL (11.1 mmol) of tri-isopropyl borate, followed by slow heating of the mixture at room temperature (RT) for a period of 16 hours. The reaction mixture was diluted with water and made basic with a 2N NaOH solution. Subsequently, the mixture was washed with EtOAc. The aqueous fraction was acidified with a 2N HCl solution and stirred for 1 hour at room temperature. The reaction mixture was extracted with EtOAc and the organic fractions were washed with water and saturated NaCl solution (brine), dried over Na2SO and filtered. The filtrate was concentrated to yield the title compound as a white solid. 1 H NMR (CDCl 3) (d, ppm): 7.96 (dd, J = 7.2, 1.6 Hz, 1 H), 7.53 (ddd, J = 9.1, 7.3, 1.8 Hz, 1 H), 7.38 (td, J = 7.3 , 0.7 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 5.25 (br s, 2 H). MS (M + H): 206.9.

Step B: Ethyl-3- (2-trifluoromethoxyphenyl) -benzoate To a solution of 0.94 g (4.58 mmol) of ethyl-3-bromobenzoate in 14.5 mL of toluene at room temperature was added 0.25 g (0.218 mmol) of tetrakis (triphenylphosphine) palladium (0), 0.94 g (4.58 mmol) of 2-trifluoromethoxyphenylboronic acid, 2.22 mL (4.45 mmol) of 2M aqueous sodium carbonate solution and 7 mL of ethanol. The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled and diluted with ethyl acetate and water. The organic fraction was separated and washed with a saturated NaCl solution (brine), dried over MgSO4, and filtered. The filtrate was concentrated to an oil which was purified by chromatography (silica, 1%, 5%, 30% successively ethyl acetate: hexanes) to yield the title compound. 1 H NMR (CD 3 OD) (d, ppm): 8.02 (s, 1 H), 7.97 (dd, J = 7.8, 1.2 Hz, 1 H), 7.60 (dd, J = 7.7, 1.3 Hz, 1 H), 7.50 -7.33 (m, 5H), 4.31 (q, 2H), 1.31 (t, 3H). Mass spectrum (ESI) m / e (M + 1): 311.2.

Step C: 3- (2-trifluoromethoxyphenyl) -benzoic acid A solution of 0.3 g (4.19 mmol) of ethyl-3- (2-trifluoromethoxyphenyl) -benzoate and 8.3 mL (8.3 mmol) of a 1 N solution of NaOH in 12.5 mL of methanol was stirred 18 hours at room temperature. The reaction mixture was concentrated and the pH was adjusted to a pH of 2 with a 1 N HCl solution. The mixture was extracted with ethyl acetate (EtOAc) and the organic fraction was dried over MgSO 4 and filtered. The filtrate was concentrated to yield the title compound as a white solid which was used without further purification.

Step D: 3- (2-Trifluoromethoxyphenyl) -benzamide To a solution of 0.94 g (3.36 mmol) of 3- (2-trifluoromethoxyphenyl) -benzoic acid in 17 mL of DMF was added 0.55 g (3.36 mmol) of carbonyldiimidazole (CDI) and the reaction was stirred at room temperature for 4 hours. To the reaction mixture was added 2.6 g (33.6 millimoles) of ammonium acetate and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water and the organic fraction was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30%, 50% successively EtOAc: hexanes) to yield the title compound. Mass spectrum (ESI) m / e (M + 1): 282.2.

Step E: 3- [3- (2-Trifluoromethoxyphenyl) -fenp-1, 2,4-triazole A solution of 0.137 g (0.48 mmol) of 3- (2-trifluoromethoxyphenyl) -benzamide in 1 mL of N, N-dimethylformamide dimethyl acetal was heated at 120 ° C for 2 hours, after which time the reaction was concentrated in vacuo. . To this material in 2.3 mL of acetic acid was added 0.028 g (0.55 millimoles) of hydrazine hydrate and the reaction mixture was heated at 90 ° C for 2 hours. Subsequently, the reaction mixture was concentrated and partitioned between EtOAc and a saturated solution of NaHCO 3. The organic fraction was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30: 1, 9: 1, 3: 1 successively CH2Cl2: acetone) to yield the title compound. 1 H NMR (CD 3 OD) (d, ppm): 8.32 (s, 1 H), 8.06 (s, 1 H), 7.98 (m, 1 H), 7.50 (m, 3 H), 7.39 (m, 3 H). Mass spectrum (ESI) m / e (M + 1): 306.1.

REFERENCE EXAMPLE 2 -Methyl-3- [3 - ((2-trifluoromethoxy) phenyl) -phenyl] -1, 2,4-triazole Step A: 3-Bromophenylcarbonyl- (N-t-butoxycarbonylphidrazide A solution of 1 g (4.97 mmol) of 3-bromobenzoic acid, 0. 59 g (4.52 millimoles) of t-butylcarbazate, 0.95 g (4.97 millimoles) of EDC [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), 0.67 g (4.97 millimoles) of hydroxybenzotriazole (HOBt) and 3.15 mL (18.1 millimoles) ) of diisopropylethylamine in 23 mL of CH2Cl2 was stirred at room temperature for 18 hours. The reaction mixture was diluted with CH2Cl2 and washed with a solution of 1N HCl, a saturated solution of NaHCO3 and brine. The solution was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30: 1, 9: 1, 3: 1 successively CH2Cl2: acetone) to yield the title compound. Mass Spectrum (ESI) m / e (M): 314.0, (M + 2): 316.0 Step B: 3 - ((2-Trifluoromethoxy) phenyl) -phenylhydrazide A solution of 0.22 g (1.07 mmol) of 2-trifluoromethoxyphenylboronic acid and 0.32 g (1.02 mmol) of 3-bromophenylcarbonyl-N-t-butoxycarbonylhydrazide in 5 mL of toluene and 2.5 mL of n-propanol was stirred for 30 minutes. To this reaction mixture were added 0.0007 g (0.003 millimoles) of palladium acetate, 0.0024 g (0.009 millimoles) of triphenylphosphine and 0.61 mL (1.2 millimoles) of a 2M aqueous sodium carbonate solution and the reaction mixture was heated reflux for 18 hours. The reaction mixture was cooled and diluted with EtOAc and water. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30: 1, 9: 1 successively, CH2Cl2: acetone) to yield the protected hydrazide which was subsequently dissolved in a mixture of 2.1 mL of TFA and 2.1 mL of CH2CI2. The reaction mixture was stirred for 2 hours after which it was concentrated, dissolved in CH 2 Cl 2 and washed with a 1 N NaOH solution. The organic fraction was dried over MgSO 4, filtered and the filtrate was concentrated to yield the compound of the title as a white solid. Mass spectrum (ESI) m / e (M + 1): 297.1.

Step C: 5-Methyl-3-r3 - ((2-trifluoromethoxy) phenyl enin-1, 2,4-triazole To a solution of 0.093 g (0.98 mmol) of acetamidine hydrochloride in 1.1 mL of ethanol was added 0.22 mL (0.98 mmol) of a 25% solution of sodium methoxide in methanol and the reaction mixture was stirred for 30 minutes . After which it was filtered. To the filtrate was added 0.19 g (0.66 mmol) of 3 - ((2-trifluoromethoxy) phenyl) -bromophenylhydrazide and the reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by chromatography (silica, 3%, 10%, 30% successively, methanol: CH 2 Cl 2) to give a white solid. The white solid was heated (pure) to its melting temperature for 30 minutes. The reaction was cooled to room temperature, dissolved in CH2Cl2 and concentrated. The residue was purified by chromatography (silica, 3%, 10%, successively, methanol: CH 2 Cl 2) to give the title compound as a white solid. 1 H NMR (CD 3 OD) (d, ppm): 8.00 (s, 1H), 7.93 (m, 1 H), 7.49-7.34 (m, 6H), 2.41 (s, 3H). Mass spectrum (ESI) m / e (M + 1): 320.5.

REFERENCE EXAMPLE 3 3- [3 - ((2-Trifluoromethoxy) -phenyl] -phenyl] -1, 2,4-triazole-5-carboxamide Step A. Ethyl-N1-3- (2-trifluoromethoxy) -benzoyl-N2-oxamidrazonate To a solution of 0.45 g (1.54 mmol) of 3- (2-trifluoromethoxyphenyl) bromophenyl hydrazide (Example 9, Step B) in 20 mL of CH2Cl2 was added 0.54 g (2.3 mmol) of carbetoxy-S-methylthioformimide tetrafluoroborate and 0.43 mL (3.08 mmol) of triethylamine and the reaction was stirred at reflux temperatures for 4 hours. The reaction mixture was cooled to room temperature, washed with water, dried over Na 2 SO 4, filtered and the filtrate was concentrated to a solid. Two mL of CH2Cl2 was added and the resulting solid product was recovered by filtration. Mass spectrum (ESI) m / e (M + 1): 396.1.

Step B. 5-Ethyl-3-r3 - ((2-trifluoromethoxy) -phenyl) -phenn-1, 2,4-triazole-5-carboxylate The solid etiI-N -3- (2-trifluoromethoxy) ) -benzoyl-N2-oxamidrazonate (0.25 g, 0.616 mmol) was heated in an oil bath above its melting point for 20 minutes. After cooling to room temperature, the residue was dissolved in CH2Cl2 and concentrated to yield a yellow solid. This was purified by chromatography (silica, 10%, 30%, 50% successively, EtOAc: hexanes) to give a white solid. Mass spectrum (ESI) m / e (M + 1): 378.1.

Step C. 3-r3 - ((2-Tr, fluoromethoxy) -phenyD-phenyl1-1, 2,4-triazole-5-carboxamide A solution of 0.13 g (0.34 mmol) of 5-ethyl-3- [3- ((2-trifluoromethoxy) phenyl) -phenyl-1,4-triazole-5-carboxylate in 2 mL of methanol in a tube was saturated with ammonia, the tube was sealed and the reaction mixture was heated to 60 ° C. overnight the reaction mixture was concentrated and the residue was purified by chromatography (silica, 3%, 10%, 20% successively methanol: CH2Cl2) to yield the title compound.1H NMR (CD3OD) (d, ppm): 8.10 (s, 1 H), 8.02 (m, 1 H), 7.54-7.36 (m, 6H) Mass Spectrum (ESI) m / e (M + 1): 349.2.

REFERENCE EXAMPLE 4 1 - . 1 - [3 - ((2- (2,2,2-Trifluoroethoxy) -phenyl) -phenyl] -1, 2,4-triazole-3-carboxamide Step A. 3 - ((2- (2,2,2-Trifluoroethoxy) -phenyl) -aniline To a solution of 1.0 g (3.93 mmol) of 2-trifluoroethoxyphenyl bromide (Example 2, Step A) in 39 mL of toluene was added 0.136 g (0.118 mmol) of tetrakis (triphenylphosphine) palladium (0), 0.56 g ( 4.31 moles) of 3-aminophenylboronic acid, 47 mL (94.1 mmol) of a 2M sodium carbonate solution and 8 mL of ethanol and the reaction mixture was heated at 90 ° C for 22 hours. The reaction mixture was cooled to room temperature, and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc and the combined organic fractions were washed with water and brine and dried over Na 2 SO 4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4: 1 hexanes: EtOAc) to yield the title compound. Mass spectrum (ESI) m / e M + 1 268.1.

Step B. Methyl-1- [3 - ((2- (2,2,2-Trifluoroethoxy) -phenyl) -phenn-1, 2,4-triazole-3-carboxylate To a solution of 0.923 g (3.45 mmol) of 3- ((2-trifluoroethoxy) -phenyl) aniline in 6 mL of a 1 N solution of HCl at 0 ° C was added 0.238 g (3.45 mmol) of sodium nitrite. and 1 mL of water and the reaction mixture was stirred for 20 minutes to yield the diazonium salt solution. To a solution of 0.27 g (2.76 mmol) of methyl isocyanoacetate in 15 mL of methanol and 2 mL of water at 0 ° C was added 1.8 g (22.08 mmol) of sodium acetate. To this reaction mixture was added dropwise the diazonium salt solution and the reaction mixture was stirred at 0 ° C for 1 hour. Then the reaction mixture was diluted with methanol and concentrated. The residue was diluted with EtOAc and 0.5N HCl solution. The aqueous layer was extracted with EtOAc and the combined organic fractions were washed with a 5% NaHC03 solution, brine, dried over Na2SO4, filtered and the filtrate was concentrated . The residue was purified by chromatography (silica, 1: 1 EtOAc: hexanes) to yield the title compound. Mass spectrum (ESI) m / e M + 1 378.1.

Step C. 1- [3 - ((2- (2,2,2-Trifluoroethoxy) phenyl) -phenyl] -1,2,4-triazole-3-carboxylic acid A solution of 0.29 g (0.769 millimoles) of methyl-1 - [3 - ((2-trifluoroethoxy) -phenyl) -phenyl] -1,4-triazole-3-carboxylate and 2.2 mL (2.2 mmol) of a 1 M NaOH solution in water was stirred for 18 hours at room temperature. The reaction mixture was concentrated. The residue was diluted with water and the pH was adjusted to 2-4 with a 1 N HCl solution. The mixture was extracted with EtOAc and the combined organic fractions were washed with brine, dried over Na 2 SO 4, filtered and the filtrate was filtered. concentrated to produce the title compound. Mass spectrum (ESI) m / e M + 1 363.9.

Step D. 1-r3 - ((2- (2,2,2-Trifluoroethoxy) -phenyl) -fenip-1, 2,4-triazole-3-carboxamide To a solution of 0.225 g (0.619 mmol) of 1- [3 - ((2-trifluoroethoxy) phenyl) -phenyl] -1,2,4-triazole-3-carboxylic acid in 3.1 mL of DMF was added 0.1 g (0.19 mmol) of CDI and the reaction mixture The mixture was stirred at room temperature for 4 hours, 0.477 g (6.19 mmol) of ammonium acetate was added to the reaction mixture and the reaction mixture was stirred for 19 hours.The reaction mixture was diluted with water and EtOAc and the The aqueous layer was extracted with EtOAc The combined organic fractions were washed with brine, dried over Na 2 SO 4, filtered and the filtrate was concentrated The residue was purified by chromatography (silica, 1: 1 EtOAc: hexanes, 1% strength). methanol: CH 2 Cl 2, 10% methanol: CH 2 Cl 2) to give the title compound: Mass spectrum (ESI) m / e M + 1 363.1.

REFERENCE EXAMPLE 5 i k 1- [3 - ((2-Trifluoromethoxy) -phenyl) -phenyl] -1, 2,4-triazole-3-carboxamide Step A. 1-N-t-butoxycarbonylamino-3-bromobenzene A solution of 10 g (58.13 mmoles) of 3-bromoaniline and 15.2 g (69.75 mmoles) of Boc20 in 300 mL of toluene was heated overnight at 70 ° C. The reaction mixture was concentrated and diluted with EtOAc and a 0.5 N HCl solution. The organic fraction was washed with a 0.5 N HCl solution and brine. This was dried over Na2SO, filtered and the filtrate was concentrated. The residue was purified by chromatography (hexanes, 9: 1 hexanes: EtOAc successively) to yield the title compound.

Step B. 1-N-t-Butoxycarbonyl-3 - ((2-trifluoromethoxy) -phenyl) aniline 1-N-t-butoxycarbonylamino-3-bromobenzene was coupled with acid 2-trifluoromethoxyphenylboronic acid in accordance with the procedures described in reference example 4, Step A.

Step C. 3 - ((2-trifluoromethoxy-phenyl) aniline A solution of 0.977 g (2.77 mmol) of 1-N-t-butoxycarbonyl-3 - ((2-trifluoromethoxy) -phenyl) aniline in 7 mL of TFA and 7 mL of CH2CI2 was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was diluted with a solution of 1 N NaOH and EtOAc. The organic fraction was washed with a 1N NaOH solution and brine, dried over Na2SO4, filtered and the filtrate was concentrated to yield the title compound. Mass spectrum (ESI) m / e M + 1 254.1.

Step D. 1-r 3 - ((2-Trifluoromethoxy) phenyl) -phenyl-1, 2,4-triazole-3-carboxamide The title compound was prepared from 3 - ((2-trifluoromethoxy) phenyl) aniline of Conformity with the procedures described in reference example 4. Mass spectrum (ESI) m / e M + 1 349.1. The following examples were prepared in accordance with the previously described procedures and are provided to illustrate the present invention and are not to be construed as limiting the scope of the invention in any way.

EXAMPLE 1 - [6-Fluoro-2 '- (2,2,3,3,3-pentafluoropropyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 431.1.

EXAMPLE 2 - [5-Fluoro-2-trifluoromethoxy) biphenyl-3-yl] -2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 367.0.

EXAMPLE 3 - [5-Fluoro-2, - (2,2,3,3,3-pentafluoropropyloxy) bipheni-3-yl] 2 H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 431.0.

EXAMPLE 4 d-μ-Fluoro ^ '^^. S.S.S-pentafluoropropyloxyJ ifenyl-S -yl ^ H -l ^^ - triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 431.0.

EXAMPLE 5 - [5, -FluorO-2, - (2,2l3,3,3-pentafluoropropyloxy) bffBnil-3-ll] 2H-1 I2l4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 431.1.

EXAMPLE 6 - [2-Fluoro-2 '- (trifluoromethoxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 367.0.

EXAMPLE 7 - [6-Fluoro-2 '- (ethoxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 381.1.

EXAMPLE 8 d - ^. e-Difluoro ^ '- ítrifluorometox biphenyl-S-il ^ H-l ^^ - triazole-S-carboxamide Mass spectrum (ESI) m / e (M + 1): 385.0.

EXAMPLE 9 d- [2 \ 6-B¡s (trifluoromethoxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 432.9. d-rd'.e-Difluoro ^ trifluoromethoxy-phenyl-S-i ^ H-I ^ -triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 384.9. EXAMPLE 11 d- [2 '- (2,2,3,3,3-pentafluoropropyloxy) biphenyl-3-yl] 2 H-1,2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 413.2.

EXAMPLE 12 d- [2,6-Difluoro-2 '- (2,2,3,3,3-pentafluoropropyloxy) biphenyl-3-yl] 2 H-, 2,4-triazole-3-carboxamide EXAMPLE 13 d- [2, d, 6-Trifluoro-2, - (2,2,3,3,3-pentafluoropropyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide EXAMPLE 14 d- [d, 6-D] -fluoro-2 '- (trifluoromethoxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1) : 386.0.

EXAMPLE 15 d- [d, 6-Difluoro-2 '- (2, 2,3, 3,3-pentafluoropropyloxy) biphenyl-3-yl] 2H-, 2,4-triazole-3-carboxamide EXAMPLE 16 - [d, d ', 6-Trifluoro-2' - (2,2,3,3,3-pentafluoropropyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide EXAMPLE 17 d- [6-Fluoro-2, - (allyloxy) biphenyl-3-yl] 2 H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 339.1.

EXAMPLE 18 d-td'-Fluoro ^ '- alkylox biphenyl-S-ip ^ H -l ^^ - triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 339.2.

EXAMPLE 19 - [6-Fluoro-2, - (n-propyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 341.1 .

EXAMPLE 20 d- [d-Fluoro-2 '- (n-propyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide 1- [6-Fluoro-2, - (2,2,3,3,3-pentafluoropropyloxy) b-phenyl-3-yl] -1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) ) m / e (M + 1): 430.9.

EXAMPLE 22 1- [2, - (2,2,3) 3,3-Pentafluoropropyloxy) biphenyl-3-yl] -1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1 ): 413.0.

EXAMPLE 23 l-td'Fluoro ^ '^^^. S.S-pentafluoropropilox biphenyl-S-ilj-l ^^ - triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 431.0.

EXAMPLE 24 d- [2 '- (phenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Step A. Ethyl-d-f3-bromophenyl-12H-1, 2,4-triazole-3 -carboxylate The compound from ethyl-3-bromobenzoate according to the procedures described in reference example 3.

Step B. Ethyl-2-trimethylsilylethoxymethyl-d- [3-bromophenyl] -1, 2,4-triazole-3-carboxylate To a mixture of 0.79 g (19.8 mmol) of sodium hydride (60% in oil) in 1 d mL of THF at 0 ° C was added dropwise a solution of d.31 g (18 mmol) of ethyl-5 - [3-bromophenyl] 2H-1, 2,4-triazole-3-carboxylate in 80 ml of THF. After stirring for 20 minutes at RT, the reaction mixture was cooled to 0 ° C and to this was added dropwise 3 g (18 mmol) of tri-methyl chloride I if methyl ethoxy (SEM-CI) . After stirring for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO 4), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate: hexanes, gradient of 10-2d%) to yield the title compound as a mixture of two regioisomers.

Step C. 2-Trimethylsilyl-ethoxymethyl-5- [3-bromophenip-1, 2,4-triazole-3-carboxamide A solution of 4.39 g (10.3 mmol) of ethyl-2-trimethylsilylethyloxymethyl-d- [3-bromophenyl] -1,2,4-triazole-3-carboxylate in 10 mL of a solution of ammonia in 2N methanol was stirred throughout the night to 60 ° C. Then the reaction mixture was concentrated to yield the title compound.

Step D. 2-Tritymethylsilylethoxymethyl-d- [3- (pyricolboranyl) phenyl] -1,2,4-triazole-3-carboxamide To a mixture of 7.1 g (17.9 mmol) of 2-trimethylsilyl ethoxymethyl-d- [3-bromofenyl] -1, 2,4-triazole-3-carboxamide and 9.1 g (3d.8 mmol) of pinicolboro (4 , 4,6, d-tetramethyl-1,3,2-dioxaborolane) in 150 mL of DMSO at RT was added 7 g (71.5 mmol) of potassium acetate and the reaction was stirred at 40 ° C for 1 d minutes in an atmosphere of nitrogen. To the reaction mixture was added 2.92 g (3.58 mmol) of PdCl2 (dppf) and the reaction mixture was stirred for 18 hours at 96-100 ° C. The reaction mixture was cooled and partitioned between EtOAc and water. The organic fraction was washed with water and brine, dried (MgSO), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate: hexanes, gradient of 0-26%) to yield the title compound.

Step E. 2-Trimethylsilyloxymethyl-d- [2 '- (pheny!) Biphenyl-3-p-1,2,4-triazole-3-carboxamide To a mixture of 0.0386 g (0.082 millimoles) of 2-trimethylsilyl ethoxymethyl-d- [3-phenyl-colboranyl) phenyl] -1, 2,4-triazole-3-carboxamide, 0.0297 g (0.128 mmol) of 2 -bromobiphenyl, 0.128 mL. (0.2dd millimoles) of a 2M sodium carbonate solution in 1.6 mL of toluene and Od mL of ethanol was added 0.013 g (0.011 mmol) of Pd (PPh3) 4 and the reaction mixture was stirred at 100 ° C by 6 hours. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic fraction was washed with brine, dried (MgSO 4), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: EtOAc, gradient 0-60%) to yield the title compound.

Step F. d-f2 '- (phenyl) b-phenyl-3-in2H-1, 2,4-triazole-3-carboxamide A mixture of 0.036 g of 2-Trimethylsilylethoxymethyl-d- [2'- (phenyl) biphenyl-3-yl] -1,4-triazole-3-carboxamide in 3 mL of acetonitrile and 9 mL of a HF solution 60% in water was stirred at room temperature for 6 hours. Then the reaction mixture was concentrated and the residue was purified by chromatography (silica, CH 3 OH: CH 2 Cl 2 0-6% gradient) to yield the title compound. Mass spectrum (ESI) m / e (M + 1): 341.2.

EXAMPLE 25 d- [2, - (2-Fluorophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide The title compound was prepared according to the procedures described in Example 24. 2'- Fluoro-2-bromobiphenyl was prepared from 2-fluorophenolboronic acid and 2-bromophenyl iodide in accordance with the procedure described in Example 24, Step D. Mass Spectrum (ESI) m / e (M + 1): 369.2 .

The following examples 26 to 33 were prepared according to the procedures described in examples 24 and 25.

EXAMPLE 26 d- [2 3-Fluorophenl] b-phenyl-3-yl] 2 H -1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 369.2.

EXAMPLE 27 d- [2 '- (4-Fluorophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 369.2.

EXAMPLE 28 d- [6-Fluoro-2 * - (3-fluorophenyl) biphenyl-3-yl] 2 H-1,2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 377.2 . EXAMPLE 29 - [5, -FluorO-2, - (3-fluorophenyl) biphenyl-3-yl] 2H-1 I2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 377.2 . d-fS'.d'-Difluoro ^ '- ÍS-fluorophenylJbiphenyl-S -yl ^ H -l ^^ -triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 396.03.

EXAMPLE 31 - [6-FluorO-5, -fluoro-2, - (3-fluorophenyl) b-phenyl-3-yl] 2H-1, 2I4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M +1): 396.23.

EXAMPLE 32 d- [6-Fluoro-3,, d-difluoro-2, - (3-fluorophenyl) b-phenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 413.16.

EXAMPLE 33 d-1-Fluoro ^ '-fluoro ^' - IS-fluoropheni biphenyl-S -yl ^ H -l ^ -triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 396.23.

EXAMPLE 34 d- [2, - (2-trifluoromethylphenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Step A. 2-Trimethylsilyl-ethoxymethyl-5-r2 '- (bromo) biphenyl-3-in-1, 2,4-triazole-3-carboxamide The title compound was prepared from 2-trimethylsilyl ethoxymethyl-d- [3- (pyricolboranyl) phenyl] -1,4-triazole-3-carboxamide (example 24, Step D) and 2-bromophenyl iodide from in accordance with the procedures described in Example 24, Step E.

Step B. 2-Trimethylsilylethoxymethyl-d- [2 '- (2-trifluoromethyl-phenyl) biphenyl-3-yl] -1,4-triazole-3-carboxamide The title compound was prepared from 2-trimethylsilylethoxymethyl-5- [2- (bromo) biphenyl-3-yl] -1,4-triazole-3-carboxamide and 2-trifluoromethylphenylboronic acid in accordance with Suzuki conditions described in the preceding examples.

Step C. d-r2 '- (Trifluoromethylphenyl) bifenii-3-ill-1, 2,4-triazole-3-carboxamide The title compound was prepared from 2-trimethylsilyl ethoxymethyl-d- ^' ^ - trifluoromethylpheni biphenyl-S-yl-1-triazole-S-carboxamide according to the procedure described in Example 24, Step F. Mass Spectrum (ESI) m / e (M + 1): 408.98. The following examples 36 to 42 were prepared according to the procedures described in examples 24 and 34.

EXAMPLE 35 d-p'-IS-Trifluoromethylpheni-biphenyl-S -yl ^ H -l ^ -triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 408.98.

EXAMPLE 36 d-p '^ - Trifluoromethylphen-O-biphenyl-S -yl ^ H -l ^ -triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 408.98.

EXAMPLE 37 d- [2 '- (2-Trifluoromethoxyphenyl) b-phenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 424.9.

EXAMPLE 38 - [2 '- (3-Trifluoromethoxyfhenyl) b-phenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 426.2.

EXAMPLE 39 d - ^ '^ - Trifluoromethoxypheni biphenyl-S-i ^ H-l ^^ -triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 426.3.

EXAMPLE 40 d - ^ '- ÍS-Carbomethoxyphene biphenyl-S-i ^ H-l ^^ - triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 367.2 (M-OCH3) EXAMPLE 41 d- [2 '- (4-Carbomethoxyphenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 367.2 (M-OCH3 ) EXAMPLE 42 d- [2, - (2-Fluoro-4-trifluoromethylphenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1) : 427.1.

EXAMPLE 43 d- [2 '- (3, d-Difluorophenyl) b-phenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 377.2.

EXAMPLE 44 - [2, - (2, d-Difluorophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 377.18 .

EXAMPLE 45 d- [2 '- (2,4-Difluorophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 377.18.

EXAMPLE 46 d- [2 '- (3,4-Difluorophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 377.0. EXAMPLE 47 - [243.4, d-Trifluorophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 396.15.

EXAMPLE 48 d-P '^. S ^ -TrifluorophenylJbiphenyl-S-ii H-l ^^ -triazole-S-carboxamide Mass spectrum (ESI) m / e (M + 1): 396.2.

EXAMPLE 49 d- [2 '- (3-Dimethylaminophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 384.3.

EXAMPLE 50 - [2 '- (4-Dimethylaminophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1): 383.9.

EXAMPLE 51 - [2 3-Cyanophenyl] biphenl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 366.18.

EXAMPLE 52 - [2 '- (3- (Pyrazol-1-yl) phenyl) biphenyl-3-yl] 2 H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1 ): 408.17.

EXAMPLE 53 - [6-Fluoro-2 '- (4-dimethylaminophenyl) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Step A. 2-Trimethylsilyl-ethoxymethyl-5- [3-bromo-6-fluorophenyl] -1,2,4-triazole-3-carboxamide The title compound was prepared according to the procedures described in Example 24. Step B. 2-Trimethylsilyl-ethoxymethyl-5-r2 '- (hydroxy) biphenyl-3-p-1, 2,4-triazole-3 carboxamide The title compound was prepared from 2-trimethylsilyl ethoxymethyl-5- [3- (pyricolboranyl) phenyl] -1,4-triazole-3-carboxamide (example 24, step D) and 2-bromophenyl iodide from according to the procedures described in example 24, step E.

Step C. Trimethylsilylethoxymethyl-5- [2'- (trifluoromethylsulfonyloxypropyl) biphenyl-3-yl] -1.2.4-triazole-3-carboxamide To a solution of 0.2 g (0.467 millimoles) of 2-trimethylsilyl ethoxymethyl-5- [2 '- (hydroxy) biphenyl-3-yl] -1, 2,4-triazole-3-carboxamide and 0.106 mL (0.61 millimoles) of diisopropylethylamine in 10 mL of acetonitrile at 0 ° C was added 0.217 g (0.61 mmol) of N-phenyltrifluoromethanesulfonamide and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, CH 3 OH: CH 2 Cl 2, gradient of 0-6% after 6% CH 3 OH: CH 2 Cl 2) Step D. 5-r6-Fluoro-2 '- (4-dimethylaminophenyl) biphenyl-3-y2H-1, 2,4-triazole-3-carboxamide The title compound was prepared by initial coupling with trimethylsilylethoxymethyl-5- [2, - (trifluoromethylphenyl) b-phenyl-3-yl] -1, 2,4-triazole-3-carboxamide with 4-dimethylaminophenylboronic acid under standard conditions of Suzuki coupling. Subsequently the trimethylsilylethoxymethyl protecting group was removed as described in Example 24, Step F. Mass Spectrum (ESI) m / e (M + 1): 402 The following Examples 54 to 56 were prepared in accordance with the procedures described in example 53 EXAMPLE 54 - [6-Fluoro-2 '- (4-trifluoromethoxy-phenyl) -biphenyl-3-yl] -2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1) : 443.0.

EXAMPLE 55 d - ^ - Fluoro ^ '- ÍS ^ -difluoropheni biphenyl-S -yl ^ H -l ^^ - triazole-S-carboxamide Mass spectrum (ESI) m / e (M + 1): 395.18.

EXAMPLE 56 d-te-Fluoro ^ HS .d-trifluorophenylJbiphenyl-S -yl ^ H -l ^^ - triazole-S-carboxamide Mass Spectrum (ESI) m / e (M + 1): 412.8.

EXAMPLE 57 d- [6-Fluoro-d, -2, - (2,2,3,3,4,4,4-heptafluorobutyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Spectrum mass (ESI) m / e (M + 1): 481.2.

EXAMPLE 58 - [d-Fluoro-2 '- (2,2,3,3,4,4,4-heptafluorobutyloxy) biphenyl-3-yl] 2 H-1, 2,4-triazole-3-carboxamide Spectrum of mass (ESI) m / e (M + 1): 481.4.

EXAMPLE 59 - [6-Fluoro-2 '- (n-butyloxy) biphenyl-3-yl] 2 H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1) : 3dd.3.

EXAMPLE 60 D- [d-Fluoro-2 '- (2,2,3,3,4,4,4-heptafluorobutyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxylic acid To a solution of 0.1 g (0.196 mmol) of ethyl 5- [5'-fluoro-2'- (2,2,3,3,4,4,4 heptafluorobutyloxy) biphenyl-3-yl] 2H-1,2,4-triazole-3-carboxylate (prepared according to the procedures described in reference example 3, Step B) in 1.4 mL of methanol was added 0.69 mL (0.69 mmol) of an aqueous solution of 1 N NaOH and the reaction mixture was stirred at room temperature for 23 hours. The pH of the reaction mixture was adjusted to pH = 4-d with 1N HCl solution and the mixture was extracted with EtOAc. The organic fractions were dried (Na 2 SO), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, CH 2 Cl 2: acetone 9: 1, then CH 3 OH: CH 2 Cl 2 linear gradient from 1 to 10%) to yield the title compound. Mass spectrum (ESI) m / e (M + 1): 482.1. The following examples 61-63 were prepared in accordance with the procedures described in reference example 3, Step B.

EXAMPLE 61 d- [d-Fluoro-2, - (2,2,3,3,3-pentafluoropropyloxy) b-phenyl] 3-yl] 2H-1, 2,4-triazole-3-carboxylate Spectrum mass (ESI) m / e (M + 1): 432.1.

EXAMPLE 62 d- [d-Fluoro-2 '- (2,2,3,3,4,4,4-heptafluorobutyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxylate Spectrum mass (ESI) m / e (M + 1): 482.3.

EXAMPLE 63 d- [6-Fluoro-2 '- (n-butyloxy) b-phenyl-3-yl] 2H-1, 2,4-triazole-3-carboxylate Mass Spectrum (ESI) m / e ( M + 1): 366.2.

The following Examples 64 to 65 were prepared according to the procedures described in Example 53.

EXAMPLE 64 - [2, - (4-Fluorobenzyloxy) biphenl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Step A. 2-Tritymethylsilylethoxymethyl-d-f2 '- (4-fluorobenzyloxy) biphenyl-3-yl-1-, 2,4-triazole-3-carboxamide To a solution of 0.05 g (0.122 mmol) of 2-tritymethylsilylethyloxymethyl-d- [2 '- (hydroxy) biphenyl-3-yl] -1,2,4-triazole-3-carboxamide (prepared in accordance with procedures described in Example 63) in 4 mL of DMSO was added 0.16 g (0.488 mmol) of cesium carbonate and the reaction mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 0.025 mL (0.244 mmol) of 4-fluorobenzyl bromide and the reaction mixture was heated at 80 ° C for 18 hours. The reaction mixture was partitioned between water and EtOAc. The organic fraction was washed with water and brine, dried (MgSO 4) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica, EtOAc: hexanes, 3:10) to yield the title compound.

Step B. d-r2 '- (4-Fluorobenzyloxy) biphenyl-3-in2H-1, 2,4-triazole-3-carboxamide The title compound was prepared from 2-trimethylsilylethoxymethyl-d- ^' ^ -fluorobenzyloxy. biphenyl-Si-1 ^ -triazole-S-carboxamide in accordance with the procedures described above. Mass spectrum (ESI) m / e (M + 1): 389.21. The following Examples 65 to 72 were prepared according to the procedures described in Example 64.

EXAMPLE 65 d-fe-Fluoro ^ '^^. d -trifluorobenzyloxybiphenyl-S-i ^ H -l ^^ -triazole- -carboxamide Mass Spectrum (ESI) m / e (M + 1): 443.31.

EXAMPLE 66 d- [6-Fluoro-2 '- (2,4-difluorobenzyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 42d.3d.

EXAMPLE 67 d- [6-Fluoro-2, - (2, d-difluorobenzyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M +1): 42d.3d.

EXAMPLE 68 d- [2, - (2,4, d-Trifluorobenzyloxy) biphenl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1) : 424.91.

EXAMPLE 69 d - ^ '^. d-Difluorobenzyloxy biphenyl-S-i ^ H-l ^^ - triazole-S-carboxamide Mass spectrum (ESI) m / e (M + 1): 406.99.

EXAMPLE 70 d- [2, - (2,4-Difluorobenzyloxy) biphenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 407.16.

EXAMPLE 71 l i! VCONH,; or d- [2, - (2-Fluorobenzyloxy) biphenyl-3-yl] 2 H-1, 2,4-triazole-3-carboxamide Mass Spectrum (ESI) m / e (M + 1 ): 389.21.

EXAMPLE 72 d- [2 '- (Benzyloxy) b-phenyl-3-yl] 2H-1, 2,4-triazole-3-carboxamide Mass spectrum (ESI) m / e (M + 1): 371.0.

Claims (4)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound represented by the formula (I) or (II): (I) (H) or a pharmaceutically acceptable salt thereof, wherein R1 is (a) H, (b) CrC6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, any of which is optionally substituted with one or more of the following substituents: NRaRb, COOH, CONRaRb, or (c) -C (= 0) Ra, COORa, CONRaRb; Ra is (a) H, (b) CrC6 alkyl, optionally substituted with one or more of halogen or CF3, or (c) CF3; Rb is (a) H, or (b) CrC6 alkyl, optionally substituted with one or more of halogen or CF3, or (c) CF3; R2 is H or CrC alkyl; R3 and R4 each independently is (a) H, (b) -C0-C4 alkyl- perfluoroalkyl of C C4 or -O-alkyl of C0-C -perfluoroalkyl of dC, or (c) halogen, or (d) - CI-CT alkyl, optionally substituted with one or more of halogen or CF3; and R5, R6 and R7 each independently is (a) H, (b) -O- CrC6 alkyl, -O-alkenyl of CrC6, -O-alkynyl of CrC6, any of which is optionally substituted with one or more of halogen or CF3, (c) -C0-C4-perfluoroalkyl of dd, or -O-C0-C-alkyl-C1-C4-perfluoroalkyl, (d) -O-phenyl, or -O-C-alkyl ? -C-phenyl, wherein the phenyl is optionally substituted with 1-3 substituents selected from i) halogen, i) -CN, iii) -N02, iv) CF3, v) -ORa, vi) -NRaRb, vii) -alkyl of C0-C4-CO-ORa, vlii) - (alkyl of Co-) -CO-N (Ra) (Rb), ix) and x) -alkyl of d-10, wherein one or more of the alkyl carbons can be replaced by a -NRa, C (0) -0-, or -N (Ra) -C (0) -N (Ra) -, or (e) halogen, -ORa, or phenyl wherein the phenyl is optionally substituted with 1-3 substituents selected from i) halogen, ii) -CN, ii) -N02, iv) CF3, v) pyrazolyl, vi) -ORa, vii) -NRaRb , viii) -alkyl of C0-4-CO-ORa, ix) - (C0.4 alkyl) -CO-N ( Ra) (Rb), and x) -alkyl of C-MO, wherein one or more of the alkyl carbons may be replaced by a -NRa, C (0) -0-, or -N (Ra) -C ( 0) -N (Ra) -.
2. 2. The compound according to claim 1, as described by the chemical formula (I), or a pharmaceutically acceptable salt thereof, further characterized in that R5 is different from H and is attached in the ortho position.
3. 3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is -O-C6-C6 alkyl optionally substituted.
4. 4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is optionally substituted phenyl. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is -O-d-d-phenyl alkyl, wherein phenyl is optionally substituted. 6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is -O-C-C6 alkenyl optionally substituted. 7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R6 is halogen. 8. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R3 is halogen. 9. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R3 and R4 are halogen. 10. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R3, R4 and R6 are halogen. 11. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that R3 is -O-C0-C4-perfluoroalkyl of CrC4. 12. The compound according to claim 1 described by the chemical formula (II), or a pharmaceutically acceptable salt thereof, further characterized in that R5 is different from H and is attached in the ortho position. 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is -O-dC6 alkyl optionally substituted. 14. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is optionally substituted phenyl. 1d.- The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that Rd is -O-C4-alkyl-phenyl, wherein the phenyl is optionally substituted. 16. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is -O-C6 alkenyl optionally substituted. 17. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R6 is halogen. 18. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R3 It is halogen. 19. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R3 and R4 are halogen. 20. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R3, R4 and R6 are halogen 21. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, further characterized in that R3 is -O-C0-C4 alkyl-perfluoroalkyl of C1-C4-. 22. A compound represented by the formula (III) (? H) or a pharmaceutically acceptable salt thereof, wherein each R1-R7 is as defined in claim 1. 23. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is different from H and is attached in the ortho position. 24. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is -O-C1-C6 alkyl optionally substituted. 26. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is optionally substituted phenyl. 26. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is -O-d-d-phenyl alkyl, wherein the phenyl is optionally substituted. 27. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R5 is optionally substituted -O-alkenyl of d-C6. 28. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R6 is halogen. 29. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R3 is halogen. 30. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R3 and R4 are halogen. 31. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R3, R4 and R6 are halogen. 32. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, further characterized in that R3 is -O-Co-d-perfluoroalkyl alkyl of d-d. 33.- A compound represented by 34. - A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 3d.- The pharmaceutical composition according to claim 34, further characterized in that it additionally comprises a second therapeutic agent selected from the group consisting of: i) opioid agonists, i) opioid antagonists, iii) calcium channel blockers, V) dHT receptor agonists, v) dHT receptor antagonists, vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2 selective inhibitors, x) NK1 antagonists, xi) non-steroidal anti-inflammatory drugs, xii) selective serotonin reuptake inhibitors, xiii) selective serotonin and norepinephrine reuptake inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate , and xviii) neurontine. 36. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of pain. 37. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of syndromes of chronic, visceral, inflammatory and / or neuropathic pain. 38.- The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment or prevention of pain resulting from, or associated with, traumatic nerve injury, nerve compression or entrapment , postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and / or chemotherapy. 39.- The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of chronic low back pain. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of phantom limb pain. 41.- The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of HIV-induced neuropathy or treatment of HIV, chronic pelvic pain, neuroma pain, syndrome of complex regional pain, chronic arthritic pain and / or related neuralgia. 42. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for administering local anesthesia. 43.- The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of irritable bowel syndrome and / or Crohn's disease. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of epilepsy and / or partial and generalized tonic seizures. 46. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for neuroprotection under ischemic conditions caused by cerebrovascular accident or neural trauma. 46. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of multiple sclerosis. 47. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of bipolar disorder. 48. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of tachyarrhythmias. 49.- The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of migraine, headache and / or migraine headache. 60.- A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 61.- The pharmaceutical composition according to claim 49, further characterized in that it additionally comprises a second therapeutic agent selected from the group consisting of: i) opioid agonists, ii) opioid antagonists, iii) calcium channel blockers, iv ) dHT receptor agonists, v) dHT receptor antagonists vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, x) selective inhibitors COX-2, x) NK1 antagonists, xl) non-steroidal anti-inflammatory drugs, xii) selective serotonin reuptake inhibitors, xiii) inhibitors of serotonin and norepinephrine selective reuptake, xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate, and xviii) neurontine. 62.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of pain. 63.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of syndromes of chronic, visceral, inflammatory and / or neuropathic pain. 64.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia , trigeminal neuralgia, diabetic neuropathy, cancer and / or chemotherapy. The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of chronic low back pain. The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of phantom limb pain. 57. The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of HIV-induced neuropathy or treatment of HIV, chronic pelvic pain, pain due to neuroma, complex regional pain, chronic arthritic pain and / or related neuralgia. 58.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for administering local anesthesia. 59. The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of irritable bowel syndrome and / or Crohn's disease. The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of epilepsy and / or partial and generalized tonic seizures. 61.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for neuroprotection under ischemic conditions caused by cerebrovascular accident or neural trauma. 62.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of multiple sclerosis. 63.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of bipolar disorder. 64.- The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of tachyarrhythmias. The use of a compound according to claim 22, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment or prevention of migraine, headache and / or migraine headache.