Aryl substituted pyrisines pyrimidines pyrazines and triazines and the use thereof
This invention is in the field of medicinal chemistry. In particular, the invention relates to aryl substituted pyridines, pyrimidines, pyrazines and triazines, and the discovery that these compounds are anticonvulsants and act as blockers of sodium (Na+) channels. Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na+ channel activity ( Recently, other Na+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials ( The neuroprotective activity of Na+ channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na+ channel blockers prevent hypoxic damage to mammalian white matter ( Another example of clinical use of a Na+ channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS ( It has been established that there are at least five to six sites on the voltage-sensitive Na+ channels which bind neurotoxins specifically ( The present invention is related to the discovery that aryl substituted pyridines, pyrimidines, pyrazines and triazines represented by Formula I are anticonvulsants and act as blockers of sodium (Na+) channels. Described is also treating a disorder responsive to the blockade of sodium channels in a mammal suffering from excess activity of said channels by administering an effective amount of a compound of Formula I as described herein. The present invention is also directed to a compound of Formula I for use in the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), for the treatment of tinnitus, as antimanic depressants, as local anesthetics, as antiarrhythmics, as anticonvulsants and for the treatment or prevention of diabetic neuropathy and for the treatment of pain including both acute and chronic pain and migraine headache. A number of compounds useful in the present invention have not been heretofor reported. Thus, one aspect of the present invention is directed to the aryl substituted pyridines, pyrimidines, pyrazines and triazines of Formula I. Another aspect of the present invention is directed to the compounds of Formula I as blockers of sodium channels. Also, an aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the blockade of sodium ion channels, containing an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents. Additional embodiments and advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. The present invention arises out of the discovery that aryl substituted pyridines, pyrimidines, pyrazines and triazines of Formula I are anticonvulsants and act as blockers of Na+ channels. In view of this discovery compounds of Formula I are useful for treating disorders responsive to the blockade of sodium ion channels. The compounds useful in this aspect of the present invention are aryl substituted pyridines, pyrimidines, pyrazines and triazines represented by Formula I: or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein: Y is or R7, provided that when Y is R7, R1 is aminocarbonyl; A1, A2 and A3 are independently CR2 or N, provided that A1, A2 and A3 are not all N at the same time; R1, is selected from the group consisting of alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, amino, alkylthio, C(O)R8, SO2R8, OC(O)NH2, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl; each R2 is selected from the group consisting of hydrogen, alkyl, alkenyl or alkynyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthio; R7 is alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino; R8 is selected from the group consisting of alkyl, alkenyl, alkynyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenylamino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl; hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, provided that R8 is not OR9 when R1, is SO2R8; wherein R9 is selected from the group consisting of hydrogen, alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, and an alkali metal; and X is one of O, S, NH, or CH2 when Y is other than R7; or X is one of O S, NH, CH2 or absent when Y is R7; with the provisos that: Accordingly, compounds useful in the present invention are aryl substituted pyridines, pyrimidines, pyrazines and triazines represented by Formula II: or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein: Another group of compounds useful in this aspect of the present invention are aryl substituted pyridines, pyrimidines, pyrazines and triazines represented by the general Formula II, wherein A1 A2, A3, R1-R6 and R8-R11 are as described above, with the provisos that Examples of bridges formed by R1, and R2 taken together are -CH2NCH2-, -C(O)NC(O)- and -C(NH2)=NH-CH=CH-. Preferably, A1, A2 and A3 are each CR2 (pyridyl); or A1 is N and A2 and A3 are CR2 (pyrimidinyl); or A3 is N and A1, and A2 are CR2 (pyrimidyl); or A2 is N and A1 and A3 are CR2 (pyrazinyl); or A1, and A3 are N and A2 is CR2 (1,3,5-triazinyl). More preferably, A1, A2 and A3 are each CR2 (pyridyl); or A1, is N and A2 and A3 are CR2 (pyrimidinyl); or A3 is N and A1, and A2 are CR2 (pyrimidyl); or A2 is N and A1 and A3 are CR2 (pyrazinyl). Most preferably, A1, A2 and A3 are each CR2 (pyridyl); or A1, is N and A2 and A3 are CR2 (pyrimidinyl); or A3 is N and A1 and A2 are CR2 (pyrimidyl). Preferably, R1, is selected from the group consisting of an alkyl optionally substituted by halogen or hydroxy, thiomethyl, C(O)R8, SO2R8, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, and 5-isoxazolyl, wherein R8 is selected from the group consisting of alkyl, alkenyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted, provided that R8 is not OR9 when R1 is SO2R8. Preferably, R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino; arylcarbonylamino, and aralkylcarbonylamino, more preferably hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl. Preferably, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano. More preferably, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro. Preferred values of R3-R6 include hydrogen, halo, C1-C6 haloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, nitro, amino, ureido, cyano, C1-C6 acylamido, hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy, or carboxy. The groups R3-R6 each take the place of a hydrogen atom that would otherwise be present in any position on the aryl ring to which the R group is attached. Especially preferred are compounds where R3 and R4 are both hydrogen, R6 is hydrogen and R5 is a fluoro in the para-position. Preferably, R7 is a straight or a branched alkyl group of C1-10 carbon atoms, more preferably C1-6 carbon atoms, optionally substituted with one or more of halogen, hydroxy, nitro, amino, cyano, and alkoxy. Preferably, R8 is selected from the group consisting of alkyl, alkenyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted, wherein R9 is as defined above, provided that R8 is not OR9 when R1 is SO2R8. Preferably X is O or S, more preferably X is O. When X is CH2, R1, is preferably aminocarbonyl. When A1, A2 and A3 are each CR2 and one R2 is other than H, said R2 is preferably in the position of A2. When A1, is N, A2 and A3 both are CR2 and one R2 is other than H, said R2 is preferably in the position of A2. When A3 is N, A1, and A2 both are CR2 and one R2 is other than H, said R2 is preferably in the position of A2. When A2 is N, A1 and A3 both are CR2 and one R2 is other than H, said R2 is preferably in the position of A1. In one aspect of the invention, preferred compounds falling within the scope of Formula II include compounds wherein X is O or S. In this aspect of the invention R1 is preferably aminocarbonyl, and R2 is preferably hydrogen. Preferred R3-R6 groups are as described above. Since the compounds of Formula I are blockers of sodium (Na+ channels, a number of diseases and conditions mediated by sodium ion influx can be treated employing these compounds. Therefore, described is to a method of treating, preventing or ameliorating neuronal loss associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, spinal cord trauma; as well as treating or ameliorating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, treating or ameliorating anxiety, convulsions, glaucoma, migraine headache, and muscle spasm. The compounds of Formula I are also useful as antitinnitus agents, antimanic depressants, as local anesthetics, and as antiarrhythmics; as well as for treating, preventing or ameliorating pain including surgical, chronic and neuropathic pain. In each instance, the methods require administering to an animal in need of such treatment an effective amount of a sodium channel blocker of the present invention, or a pharmaceutically acceptable salt, ester, amide or solvate thereof. The invention also relates to aryl-substituted pyridines, pyrimidines, pyrazines and triazines represented by Formula III: or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein: A1-A3, R2-R6, R8 and X are defined previously with respect to Formulae I-II. Preferred compounds falling within the scope of Formula III include compounds wherein R2 is hydrogen, R8 is amino; and X is O and S. R3 through R6 have preferred values as described above for Formula II. Further, preferably R8 is selected from the group consisting of alkyl, alkenyl, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted. Further, the invention relates to aryl-substituted pyridines, pyrimidines, pyrazines and triazines represented by Formula IV: or a pharmaceutically acceptable salt, ester, amide or solvate thereof; wherein: Preferred compounds falling within the scope of Formula IV include compounds wherein R2 is hydrogen, R8 is amino, and X is O and S. Also, the present invention relates to compounds of Formula V: or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein: A1-A3, R2-R4, and R7 are defined previously with respect to Formula I-IV, and X is one of O, S, NH, CH2 or absent. Preferred compounds falling within the scope of Formulae V include compounds wherein R2 is hydrogen, and X is O and S. Preferably, R7, is a straight or branched chain C1-6, more preferably C1-4, alkyl, optionally substituted with one or more of halogen, especially fluoro or chloro. R3 and R4 have preferred values as described above for Formula II. Exemplary preferred compounds that may be employed in this method of invention include : Additional useful compounds of the present invention include: Further useful compounds of the invention include: Furthermore, useful compounds of the invention include: Useful aryl groups are C6-14 aryl, especially C6-10 aryl. Typical C6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups. Useful cycloalkyl groups are C3-8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Useful halo or halogen groups include fluorine, chlorine, bromine and iodine. Useful alkyl groups include straight-chained and branched C1-10 alkyl groups, more preferably C1-6 alkyl groups. Typical C1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, Useful alkenyl groups are C2-6 alkenyl groups, preferably C2-4 alkenyl. Typical C2-4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl. Useful alkynyl groups are C2-6 alkynyl groups, preferably C2-4 alkynyl. Typical C2-4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups. Useful arylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned C6-14 aryl groups. Useful values include benzyl, phenethyl and naphthylmethyl. Useful arylalkenyl groups include any of the above-mentioned C2-4 alkenyl groups substituted by any of the above-mentioned C6-14 aryl groups. Useful arylalkynyl groups include any of the above-mentioned C2-4 alkynyl groups substituted by any of the above-mentioned C6-14 aryl groups. Useful values include phenylethynyl and phenylpropynyl. Useful cycloalkylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned cycloalkyl groups. Useful haloalkyl groups include C1-10 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups. Useful hydroxyalkyl groups include C1-10 alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups. Useful alkoxy groups include oxygen substituted by one of the C1-10 alkyl groups mentioned above. Useful alkylthio groups include sulfur substituted by one of the C1-10 alkyl groups mentioned above. Useful acylamino groups are any acyl group, particularly C2-6 alkanoyl or C6-10 aryl(C2-6)alkanoyl attached to an amino nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido, and benzoyl. Useful acyloxy groups are any C1-6 acyl (alkanoyl) attached to an oxy (-O-) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like. The term heterocyclic is used herein to mean saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazoline, pyrazolidine, benzodiazepines, and the like. Useful heterocycloalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heterocyclic groups. Useful heterocycloalkylamino groups include any of the above-mentioned heterocycloalkyl groups attached to an amino nitrogen, such as N-piperidinylethylamino. Useful alkylamino and dialkylamino groups are -NHR10 and -NR10R11, wherein R10 and R11 are C1-10 alkyl groups. Useful dialkylaminoalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned dialkylamino groups. Useful dialkylaminoalkylamino groups include any of the above-mentioned dialkylaminoalkyl groups attached to an amino nitrogen, such as dimethylaminoethylamino. Aminocarbonyl group is -C(O)NH2. Useful alkylaminocarbonyl groups are carbonyl groups substituted by -NHR10 and -NR10R11, wherein R10 and R11 are C1-10 alkyl groups. Useful alkylthiol groups include any of the above-mentioned C1-10 alkyl groups substituted by a -SH group. A carboxy group is -COOH. An azido group is -N3. An ureido group is -NH-C(O)-NH2. An amino group is NH2. An amide group is an organic radical having -NHC(O)- as a functional group. Optional substituents on R1, R2, and R7-R1 include any one of halo, halo(C1-6) alkyl, aryl, heterocycle, cycloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, cycloalkyl(C1-6)alkyl, heterocyclo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, carboxy(C1-6)alkyl, alkoxy(C1-6)alkyl, nitro, amino, ureido, cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, aminocarbonyl, and C1-6 alkylthiol groups mentioned above. Preferred optional substituents include: halo, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy and amino. Certain of the compounds of Formulae I-V may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers as well as the individual enantiomers that may be separated according to methods that are well know to those of ordinary skill in the art. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate and oxalate. Examples of prodrugs include esters or amides of Formulae I-V with R2, R3, R4, R5 and R6 as hydroxyalkyl or aminoalkyl, and these may be prepared by reacting such compounds with anhydrides such as succinic anhydride. The invention is also directed to a method for treating disorders responsive to the blockade of sodium channels in animals suffering thereof. Particular preferred embodiments of the aryl substituted heteraryl compounds for use in method of this invention are represented by previously defined Formulae I-V. The compounds of this invention may be prepared using methods known to those skilled in the art. 4-Aryl pyrimidine derivatives of compounds of Formula III can be prepared as illustrated by exemplary reactions in Scheme 1. Formation of the pyrimidine ring was accomplished as described by Pyrazine derivatives of compounds of Formula III can be prepared as illustrated by exemplary reactions in Scheme 2 using the method of 2-Aryl pyrimidine derivatives of compounds of Formula III can be prepared as shown in Scheme 3. The pyrimidine ring was prepared as described by The 2-arylpyrimidine-4-carboxamides can also be prepared by coupling 2-chloropyrimidine-4-carboxamide and a boronic acid or boronate as shown in Scheme 4. 2-Chloropyrimidine-4-carboxamide is prepared from 4-methyl-2-pyrimidinol hydrochloride using the procedure of Pyridine amides of Formula III can be synthesized as shown in Scheme 5: 6-Bromopicolinic acid (commercially available, marketed by, e.g., Aldrich) is converted to the corresponding amide and coupled with aryl boronic acids in the presence of catalytic Pd(PPh3)4. See for example Alternatively, 2-bromo-6-methylpyridine can be coupled with 4-bromoboronic acid and the bromide formed subjected to Ullmann coupling with a phenol in the presence of Cs2CO3 and copper powder ( Pyrazines can be prepared by coupling a suitably substituted 6-halopyrazine with an aryl boronic acid using the method described in the synthesis of the corresponding pyridine as shown in the Scheme 7 below. 1,3,5-Triazines of the present invention can be prepared, for example, using the method of 5-Aryl-1,2,4-triazines of the invention can be prepared using the procedure of 3-Aryl-1,2,4-triazines of the invention can be prepared as shown in Scheme 10. The sodium salt of hydrazine can be added to a benzonitrile using the method of The compounds of Formula V can be prepared by the methods described above using suitable starting compounds. The compounds of the present invention were assessed by electrophysiological assays in dissociated hippocampal neurons for sodium channel blocker activity. These compounds also could be assayed for binding to the neuronal voltage-dependent sodium channel using rat forebrain membranes and [3H]BTX-B. Sodium channels are large transmembrane proteins that are expressed in various tissues. They are voltage sensitive channels and are responsible for the rapid increase of Na+ permeability in response to depolarization associated with the action potential in many excitable cells including muscle, nerve and cardiac cells. One aspect of the present invention is the discovery of the mechanism of action of the compounds herein described as specific Na+ channel blockers. Based upon the discovery of this mechanism, these compounds are contemplated to be useful in treating or preventing neuronal loss due to focal or global ischemia, and in treating or preventing neurodegenerative disorders including ALS, anxiety, and epilepsy. They are also expected to be effective in treating, preventing or ameliorating neuropathic pain, surgical pain, chronic pain and tinnitus. The compounds are also expected to be useful as antiarrhythmics, anesthetics and antimanic depressants. The present invention is directed to compounds of Formulae I-V that are blockers of voltage-sensitive sodium channels. According to the present invention, those compounds having preferred sodium channel blocking properties exhibit an IC50 of about 100 µM or less in the electrophysiological assay described herein. Preferably, the compounds of the present invention exhibit an IC50 of 10 µM or less. Most preferably, the compounds of the present invention exhibit an IC50 of about 1.0 µM or less. Substituted heteroaryl compounds of the present invention may be tested for their Na+ channel blocking activity by the following electrophysiological and binding assays. The following voltage pulse protocols were used to assess the potency and kinetics of inhibition of the Na+ channels by the compounds (Fig. 1). Current-voltage relationship (IV-curve), protocol A, was used to report the voltage at which the maximal inward Na+ current is achieved. This voltage was used throughout the experiment as testing voltage, Vt. The steady-state inactivation (or, availability) curve, protocol C, was used to get the voltage at which almost complete (≥95%) inactivation of Na+ channels occurs; it served as voltage for conditioning prepulse, V Electrophysiological Assay 2 was used to measure potencies of compounds of the present invention rBIIa/beta 1 sodium channels expressed in Two to six ovarian lobes were surgically removed. Oocytes at developmental stages V-VI were dissected from the ovary, oocytes were still surrounded by enveloping ovarian tissues. Oocytes were defolliculated on the day of surgery by treatment with collagenase (0.5 mg/mL Sigma Type I, or Boehringer Mannheim Type A, for 0.5-1 hr). Treated oocytes were vortexed to dislodge epithelia, washed repeatedly and stored in Barth's medium containing 88 mM NaCl, 1 mM KCl, 0.41 mM CaCl2,, 0.33 mM Ca(NO3)2, 0.82 mM MgSO4, 2.4 mM NaHCO3, 5 mM HEPES, pH 7.4 adjusted with 0.1 mg/mL gentamycin sulphate. The purpose was to find compounds that are state dependent modifiers of neuronal sodium channels. Preferably, the compounds have a low affinity for the rested/closed state of the channel, but a high affinity for the inactivated state. The following voltage protocol was used to measure a compounds affinity for the inactivated state. Oocytes were held at a holding potential of -120mV. At this membrane voltage, nearly all of the channels would be in the closed state. Then a 4 second depolarization was made to the voltage where the maximum current was elicited. At the end of this depolarization, nearly all the channels would be in the inactivated state. A 10ms hyperpolarizing step was then made in order to remove some channels from the incativated state. A final depolarizing test pulse was used to assay the sodium current after this prolonged depolarization (see analysis below). Sodium currents were measured at this test pulse before and after the application of the tested compound. Data was acquired using pClamp 8.0 software and analyzed with clampfit software (Axon instruments). The ability of compounds of the present invention to modulate either site 1 or site 2 of the Na+ channel was determined following the procedures fully described in The compounds of the present invention may be tested for The compounds may be tested for their antinociceptive activity in the formalin model as described in The compounds may be tested for their potential for the treatment of chronic pain (antiallodynic and antihyperalgesic activities) in the Chung model of peripheral neuropathy. Male Sprague-Dawley rats weighing between 200-225 g were anesthetized with halothane (1-3 % in a mixture of 70 % air and 30 % oxygen) and their body temperature controlled during anesthesia through use of a homeothermic blanket. A 2-cm dorsal midline incision was then made at the L5 and L6 level and the para-vertibral muscle groups retracted bilaterally. L5 and L6 spinal nerves were then be exposed, isolated, and tightly ligated with 6-0 silk suture. A sham operation was performed exposing the contralateral L5 and L6 spinal nerves as a negative control. The compounds may be tested for their neuroprotective activity after focal and global ischemia produced in rats or gerbils according to the procedures described in The compounds may be tested for their neuroprotective activity after traumatic spinal cord injury according to the procedures described in Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for epilepsy, neurodegenerative diseases, anesthetic, arrhythmia, manic depression, and pain. For intramuscular injection, the dose is generally about one-half of the oral dose. In the method of treatment or prevention of neuronal loss in global and focal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia, status epilepsy and surgery, the compound can be administrated by intravenous injection at a dose of about 0.025 to about 10 mg/kg. The unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates. In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. Preferably, the preparations, particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient. Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the particular heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like. Basic salts are formed by mixing a solution of the heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like. The pharmaceutical compositions of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited. The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses. Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added. Possible pharmaceutical preparations, which can be used rectally, include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, and include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers. The following examples are illustrative of the method and compositions of the present invention. a) 1-[4-(4-Fluorophenoxy)phenyl]ethanone: A mixture of 4-fluorophenol (4.45 g, 39.3 mmol), 4-fluoroacetophenone (4.4 mL, 36 mmol), and potassium carbonate (13 g, 94 mmol) in DMF (40 mL) was refluxed overnight. The mixture was allowed to cool to room temperature, then partitioned between ethyl acetate (200 mL) and water (200 mL). The separated aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate layers were washed with an aqueous sodium hydroxide solution (2N, 200 mL), washed twice with water (200 mL each), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a dark oil. The oil solidified on standing at room temperature overnight. The weight of crude 1-[4-(4-fluorophenoxy)phenyl]ethanone was 6.7 g (80%).1H NMR (CDCl3): 7.96 (d, J = 9.0 Hz, 2H), 7.11-7.06 (m, 4H), 6.98 (d, J = 8.7 Hz, 2H), 2.59 (s, 3H). b) 3-Dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone: A mixture of crude 1-[4-(4-fluorophenoxy)phenyl]ethanone (17.9 mmol) and c) 2-Methyl-4-[4-(4-fluorophenoxy)phenyl]-pyrimidine: Acetamidine hydrochloride (2.00 g, 20.1 mmol) and potassium d) 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid: 4-[4-(4-Fluorophenoxy)phenyl]-2-methyl-pyrimidine (1.70 g, 6.03 mmol) and selenium dioxide (1.16 g, 10.4 mmol) in pyridine (40 mL) were refluxed overnight. The mixture was filtered to remove a solid that had formed. The filtrate was evaporated under reduced pressure. The residue was added to a 2N aqueous sodium hydroxide solution. The resulting solid was collected by filtration and partitioned between aqueous hydrochloric acid (2N) and ethyl acetate. The aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1.5 g (80%) of the acid as a solid.1H NMR (DMSO-d6): δ 8.95 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 8.7 Hz, 2H), 8.18 (d, J = 5.4 Hz, 1H), 7.30 (t, J = 8.7 Hz, 2H), 7.22-7.17 (m, 2H), 7.13 (d, J = 9.3 Hz, 2H). e) 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxarnide: A mixture of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid (1.00 g, 3.23 mmol) and carbonyl diimidazole (1.10 g, 6.78 mmol) in DMF (10 mL) were stirred at room temperature for 2 hours. Solid ammonium acetate (2.10 g, 27.2 mmol) was then added to the reaction. After stirring overnight at room temperature, the reaction was diluted with ethyl acetate, washed several times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography (gradient from 100% ethyl acetate to 95:5 ethyl acetate/methanol) to give 669 mg (67%) of the desired product as yellow solid, mp 180-182 °C.1H NMR (DMSO-d6): δ 8.94 (d, J = 5.1 Hz, 1H), 8.38 (d, J = 8.7 Hz, 2H), 8.34 (bs, 1H), 8.15 (d, J = 5.4 Hz, 1H), 7.83 (bs, 1H), 7.30 (t, J = 8.4 Hz, 2H), 7.22-7.17 (m, 2H), 7.12, (d, J = 8.7 Hz, 2H). The following compounds were prepared similarly: Further, the following compounds can be prepared similarly: a) 2-Thiomethyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine: A mixture of 3-dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone (551 mg, 1.93 mmol) and thiourea (294 mg, 3.86 mmol) suspended in 5 mL of ethanol was treated with 1.6 mL (1.93 mmol) of a stock solution prepared from 382 mg of 85% KOH in 5 mL of ethanol added dropwise via syringe. The resulting solution was heated at reflux for 4 hours. Once at room temperature, the yellow precipitate (348 mg) that formed was isolated by filtration and washed with ethanol (2 mL). The solid (338 mg) was then suspended in 5 mL of water and 0.25 mL (2.6 mmol) of dimethyl sulfate was added. After 5 minutes, 1.6 mL of a 2N aqueous NaOH solution was added. After stirring overnight, the mixture was extracted with ether (3 x 15 mL). The organic layers were pooled, washed with water and brine, dried (Na2SO4) and concentrated. Flash chromatography (silica gel; 3:1 hexane/ethyl acetate) afforded 226 mg of the thiol as an off-white solid.1H NMR (CDCl3) δ 8.51 (d, 1H, J=5.1 Hz), 8.08 (d, 2H, J = 8.8 Hz), 7.31 (d, 1H, J = 5.5 Hz), 7.11-7.00 (m, 6H), 2.64 (s, 3H). b) 2-Methanesulfonyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine: A solution of 205 mg (0.656 mmol) of 2-thiomethyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine in 8 mL of CH2Cl2 was treated with a solution of 321 mg of a) 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid ethyl ester: A mixture of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid (3.15 g, 10.2 mmol), iodoethane (2.0 mL, 25 mmol), and cesium carbonate (7.00 g, 21.5 mmol) in DMF (100 mL) was maintained at 70-80 °C for 16 hours. The mixture was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed 3 times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give an oil. Purification by column chromatography (1:1 hexane/ethyl acetate) afforded the desired product (2.14 g, 62%) as an oil which solidified upon standing at room temperature overnight, mp 61-63 °C.1H NMR (CDCl3): δ 8.88 (d, J = 5.4 Hz, 1H), 8:16 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 5.4 Hz, 1H), 7.12-7.05 (m, 6H), 4.55 (q, J = 7.5 Hz, 2H), 1.49 (t, J = 7.5 Hz, 3H). b) 1-[4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-yl]-ethanone: To a solution of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid ethyl ester (0.66 g, 1.95 mmol) in anhydrous THF (20 mL) at -78 °C under nitrogen was added a 1.4 M solution of methyl magnesium bromide in ether (1.4 mL, 1.96 mmol) in one portion. The reaction was stirred at -78 °C for 30 minutes, quenched with water and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a solid. The crude product was then subjected to column chromatography (6:4 hexane/ethyl acetate) affording 0.36 g (60%) of the desired product as a solid.1H NMR (CDCl3): δ 8.90 (d, J = 4.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 4.8 Hz, 1H), 7.09-7.06 (m, 6H), 2.85 (s, 3H). a) 4-(4-Chloro-2-fluorophenoxy)benzonitrile: A mixture of 4-fluorobenzonitrile (5.0 g, 41.3 mmol), 4-chloro-2-fluorophenol (4.7 mL, 44 mmol), and potassium carbonate (13.8 g, 99.8 mmol) in DMF (100 ml) was refluxed overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed twice with a 2N aqueous sodium hydroxide solution, washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give very light yellow solid. The weight of crude product was 7.56 g (74%).1H NMR (CDCl3): δ 7.61 (d, J = 8.1 Hz, 2H), 7.27 -7.07 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H). b) 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-4-methyl-pyrimidine: Hydrogen chloride gas was bubbled through a solution of 4-(4-chloro-2-fluorophenoxy)benzonitrile (1.64 g, 6.64 mmol) in ethanol (100 mL) under N2 at 0 °C for 15 minutes. The solution was stoppered, and stirred at room temperature for 24 hours and concentrated to dryness. The residue was dissolved in ethanol (100 mL), ammonium carbonate (6.3 g, 65 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a white solid. The crude intermediate was not purified, and was carried on to the next step.1H NMR (DMSO-d6): δ 7.90 (d, J = 8.4, 2H), 7.40 - 7.25 (m, 3H), 7.18 (d, J = 8.4, 2H). A mixture of the crude amidine and potassium c) 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid: A mixture of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-4-methyl-pyrimidine (0.90 g, 2.87 mmol), and selenium dioxide (0.62 g, 5.6 mmol) in pyridine (50 mL) was refluxed overnight. The mixture was allowed to cool to room temperature, then filtered through a bed of Celite. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and washed twice with a 2N aqueous hydrochloric acid solution. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 0.808 g (82%) of a light yellow solid.1H NMR (DMSO-d6): δ 9.11 (d, J = 5.1 Hz, 1H), 8.46 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 4.5 Hz, 1H), 7.38-7.35 (m, 3H), 7.15 (d, J = 9.0 Hz, 2H) d) 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide: A solution of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxylic acid (0.6 g, 1.74 mmol), and carbonyl diimidazole (0.54 g, 3.3 mmol) in DMF (20 mL) was stirred at room temperature under nitrogen for 30 minutes. Solid ammonium acetate (2.0 g, 26 mmol) was added and the reaction was stirred overnight. The reaction was then diluted with ethyl acetate, washed 3 times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a yellow solid. The crude product was purified by column chromatography (4:1 dichloromethane/ethyl acetate) to give 331 mg (55%) of the final product as a white solid, mp 198-200°C.1H NMR (CDCl3): δ 9.01 (d, J = 4.8 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 4.2 Hz, 1H), 7.88 (bs, 1H), 7.26-7.23 (m, 1H), 7.16 - 7.10 (m, 2H), 7.06 (d, J = 8.7 Hz, 2H), 5.75 (bs, 1H). The following compound was prepared similarly: a) 2-Hydroxy-4-pyrimidinecarboxaldehyde, oxime: A solution of 4-methyl-2-pyrimidinol hydrochloride (14.7 g, 0.100 mol) in 100 mL of 50% aqueous HOAc at 12°C was treated with solid NaNO2 (10.47 g, 0.150 mol) added in one portion. Brown gas evolved and a yellow precipitate formed as the reaction temperature rose to 42°C. After stirring at room temperature for 3 hours, the solid precipitate was isolated by filtration and washed with cold water (2 x 50 mL). The resulting solid was recrystallized from 550 mL of boiling water, affording 11.9 g (85%) of the oxime as yellow-brown needles, mp 222-226 °C (decomp.).1H NMR (DMSO-d6): δ 12.4 (br s, 1H), 11.9 (br s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.79 (s, 1H), 6.68 (d, 1H, J = 6.6 Hz). b) 2-Chloro-4-cyanopyrimidine: To neat POCl3 (40 mL, 65.8 g, 0.429 mol) cooled in an ice-water bath was added powdered solid 2-hydroxy-4-pyrimidinecarboxaldehyde, oxime (10.0 g, 71.9 mmol) in portions. The cold bath was removed and the mixture was slowly heated to reflux. When the reaction began to reflux on its own, heating was stopped. Once the reflux had subsided, neat c) 2-Chloropyrimidine-4-carboxamide: To 15 mL of concentrated H2SO4 at 15°C was added finely ground 2-chloro-4-cyanopyrimidine (4.0 g, 28.7 mmol). The mixture that formed was allowed to warm to room temperature and stirred for 5 hours. The resulting light yellow solution was then slowly added to 80 g of crushed ice. The mixture was filtered, washed with cold water (2 x 25 mL) and a saturated aqueous NaHCO3 solution (25 mL), to give 490 mg of the amide as a yellow solid, mp 151-152 °C. The mother liquor was extracted with EtOAc (3 x 50 mL). The pooled organic layers were washed with water (25 mL) and a saturated aqueous NaHCO3 solution (2 x 25 mL). After drying (Na2SO4) the EtOAc was removed in vacuo, affording an additional 2.5 g of the amide as a yellow solid. Total yield of the title compound was 2.99 g (66%).1H NMR (CDCl3): δ 8.88 (d, 1H, J = 4.8 Hz), 8.07 (d, 1H, J = 4.8 Hz), 7.65 (br s, 1H), 5.93 (br s, 1H). a) 6-Bromopyridine-2-carboxamide: Reaction of 6-bromopicolinic acid (Aldrich) with carbonyl diimidazole in DMF followed by the addition of an excess of ammonium acetate was carried out as described above, affording the amide as a white solid, mp 130-135 °C.1H NMR (CDCl3): δ 8.17 (d, 1H, J = 7.5 Hz), 7.73 (t, 1H, J = 7.8 Hz), 7.64 (d, 1H, J= 7.5 Hz), 5.66 (br s, 1H). b) 6-[(4-Trifluoromethoxy)phenyl]pyridine-2-carboxamide: A mixture of 6-bromopyridine-2-carboxamide (110 mg, 0.547 mmol), 4-(trifluoromethoxy)phenylboronic acid (Aldrich; 138 mg, 0.670 mmol), sodium carbonate (185 mg) and Pd(PPh3)4 (32 mg, 5 mol %) in 10 mL of toluene and 2.5 mL each of water and EtOH was heated at reflux overnight. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous layer was washed twice with EtOAc and the pooled organic layers were washed with water (3x), dried (Na2SO4) filtered and concentrated to dryness. Flash chromatography (6:4 hexane/acetone) afforded 122 mg (79%) of the title compound as a white solid, mp 133-135 °C.1H NMR (CDCl3): δ 8.19 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H), 7.96 (t, J = 7.8 Hz, 1H), 7.94 (bs, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.35 (d, J =8.1 Hz, 2H), 5.76 (bs, 1H). A solution of 1-{4-[4-(4-fluorophenoxy)phenyl]pyrimidin-2-yl}ethanone (0.36 g, 1.17 mmol) and To a mixture of 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid (1.03 g, 3.1 mmol), ethanolamine (0.31 mL, 5.08 mmol), and 1-hydroxybenzotriazol hydrate (0.53 g, 3.46 mmol) in DMF (20 mL) under nitrogen at 0 °C was added 4-methylmorpholine (0.76 mL, 6.9 mmol), and 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.68 g, 3.48 mmol). The mixture was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed 3 times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the desired product as an oil.1H NMR (CDCl3): δ 8.82 (d, J = 5.7 Hz, 1H), 8.50 (bs, 1H), 8.10 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 5.1 Hz, 1H), 7.08-7.03 (m, 6H), 3.88 (t, J = 4.2 Hz, 2H), 3.70 (q, J = 4.8 Hz, 2H), 3.25 (bs, 1H). 6-Bromopicolinic acid (Aldrich) was coupled with methyl amine using carbonyl diimidazole (CDI) as coupling reagent to afford 6-bromopyridine-2-carboxylic acid methylamide. The 6-bromopyridine-2-carboxylic acid methylamide underwent Suzuki coupling with 4-phenoxyphenylboronic acid, in the presence of tetrakis(triphenylphosphine)palladium as catalyst to give 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid methylamide as a solid.1H NMR (CDCl3): δ 8.12 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.90 (t, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 8.4 Hz, 2H), 7.18-7.06 (m, 5H), 3.08 (d, J = 5.4 Hz, 3H). a) 2-Methyl-6-(4-bromophenyl)pyridine: To a mixture of 4-bromophenylboronic acid (3.14 g, 15.6 mmol), 2-bromo-6-methylpyridine (1.7 ml, 14.9 mmol), solid sodium carbonate (5.1 g, 31.9 mmol) in toluene (60 mL), water (15 mL), and ethanol (15 mL) was added tetrakis(triphenylphosphine)palladium (0) (890 mg, 0.77 mmol). The mixture was refluxed (100-110 °C) overnight. The reaction was allowed to cool to room temperature, then partitioned between ethyl acetate and water. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. Purification by flash chromatography (silica gel; 4% EtOAc/hexane) afforded 2.5 g (87%) of the product as a white solid.1H NMR (CDCl3): δ 7.88 (d, J = 9.0 Hz, 2H), 7.67-7.56 (m, 3H), 7.48 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 2.61 (s, 3H). b) 2-Methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine: A mixture of 2-methyl-6-(4-bromophenyl)pyridine (3.25 g, 13 mmol), 4-fluorophenol (2.5 g, 22 mmol), cesium carbonate (11.2 g, 34 mmol), and copper powder (4.5 g) in DMF (50 mL) was refluxed overnight. The reaction was allowed to cool to room temperature, filtered and partitioned between ethyl acetate and water. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed three times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a solid that was subjected to flash chromatography (silica gel; 4% EtOAc/hexane) to give 1.8 g (50%) of the product as a white solid.1H NMR (CDCl3,): δ 7.94 (d, J = 9.0 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.08-7.01 (m, 7H), 2.61 (s, 3H). c) 6-[4-(4-Fluorophenoxy)phenyl]pyridine-2-carboxamide: A mixture of 2 methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine (1.8 g, 6.45 mmol), and selenium dioxide (3.6 g, 32.4 mmol) in pyridine (30 mL) was heated at reflux overnight. Once at room temperature, the reaction was filtered through Celite. The filtrate was partitioned between ethyl acetate and an aqueous hydrochloric acid solution (2N). The aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with an aqueous hydrochloric acid solution (2N), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1.8 g (90%) of the crude acid as a yellow solid. The crude acid (1.2 g, 3.88 mmol) was dissolved in DMF (50 mL) and carbonyl diimidazole (1.3 g, 8.0 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. Solid ammonium acetate (3.1 g, 39 mmol) was added and the mixture was stirred overnight. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed three times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. Purification by flash chromatography (silica gel column; 65/35 hexane/acetone) afforded 509 mg (42%) of the title compound, mp 150-152 °C.1H NMR (DMSO-d6): δ 8.32 (d, J = 9.0 Hz, 2H), 8.31 (bs, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.03 (dd, J = 8.1, 7.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.69 (bs, 1H), 7.27 (t, J = 9.0 Hz, 2H), 7.18-7.13 (m, 2H), 7.07 (d, J = 9.0, 2H). The following compounds can be prepared similarly: 6-(4-Phenoxyphenyl)pyridine-2-carboxamide was prepared by the method used for its 4-fluoro analog in Example 10, except 4-phenoxyphenylboronic acid (Aldrich) was used in place of 4-bromophenylboronic acid. a) 2-Methyl-6-(4-phenoxyphenyl)pyridine:1H NMR (CDCl3): δ 7.95 (d, J = 9.0 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.13-7.02 (m, 6H), 2.61 (s, 3H). b) 6-(4-Phenoxyphenyl)pyridine-2-carboxylic acid:1H NMR (DMSO-d6): δ 13.1 (bs, 1H), 8.21 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 7.8 Hz, 1H), 8.04 (t, J = 7.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.11 (dd, J = 8.4, 7.5 Hz, 4H). c) 6-(4-Phenoxyphenyl)pyridine-2-carboxamide:1H NMR (DMSO-d6): δ 8.33 (d, J = 8.7 Hz, 2H), 8.31 (bs, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.03 (t, J = 7.6 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.69 (bs, 1H), 7.43 (dd, J = 8.7, 7.5 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.09 (d, J =8.7 Hz, 4H), mp 178-180 °C, 45% yield from starting materials (3 steps). a) 4-(4-Fluorophenoxy)benzonitrile: A mixture of 4-fluorophenol (5.1 g, 45.5 mmol), 4-fluorobenzonitrile (4.58 g, 37.8 mmol) and potassium carbonate (12 g, 86.8 mmol) in DMF (150 mL) was refluxed overnight. The reaction was allowed to cool to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed three times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 7.5 g (93%) of crude 4-(4-fluorophenoxy)benzonitrile as solid.1H NMR (CDCl3): δ 7.60 (d, J = 9.0 Hz, 2H), 7.10-6.96 (m, 6H). Ref. b) 4-(4-Fluorophenoxy)benzamidine acetate: 4-(4-Fluorophenoxy)benzonitrile (4.7 g, 22.4 mmol) was dissolved in ethanol. The solution was cooled to 0°C and HCl gas was bubbled through the solution for 20 minutes. The reaction was stoppered and stirred at room temperature overnight. The solution was evaporated under reduced pressure and the solid residue that formed was dissolved in ethanol and treated with solid ammonium acetate (6.0 g, 75.5 mol). After stirring overnight, pure amidine was isolated by filtration. Additional product was isolated from the filtrate. The solid obtained after the filtrate was concentrated to dryness was triturated with hexane (4 times) and recrystallized twice from EtOH. The total weight of amidine obtained was 2.92 g (45% yield).1H NMR (DMSO-d6): δ 7.85 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.7 Hz, 2H), 7.21-7.17 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 1.77 (s, 3H). c) 2-[4-(4-Fluorophenoxy)phenyl]-4-methylpyrimidine: A 1M solution of potassium d) 2-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid: A mixture of 2-[4-(4-fluorophenoxy)phenyl]-4-methylpyrimidine (yellow oil from previous step), selenium dioxide (3.0 g, 27 mmol) and pyridine (30 mL) was refluxed overnight. The reaction was allowed to cool to room temperature and filtered to remove selenium metal. The filtrate was evaporated under reduced pressure and the residue was treated with an aqueous 2N HCl solution. The resulting solid was triturated with hexane (3 x) and dried in vacuo, affording 2.72 g (86%) of the acid.1H NMR (DMSO-d6): δ 13.8 (bs, 1H), 9.10 (d, J = 5.0 Hz, 1H), 8.45 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 5.0 Hz, 1H), 7.30 (t, J = 9.0 Hz, 2H), 7.22 - 7.17 (m, 2H), 7.11 (d, J =9.0 Hz, 2H). e) 2-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxamide: To a solution of 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid (2.00 g, 6.45 mmol) in DMF was added carbonyl diimidazole (2.00 g, 12.3 mmol). After stirring at room temperature for 1 hour, solid ammonium acetate (5.00 g, 62.9 mmol) was added. After stirring overnight at room temperature, the reaction was partitioned between water and EtOAc. The aqueous layer was extracted with ethyl acetate and the pooled organic layers were washed with water (3 times), dried (Na2SO4), filtered, and evaporated under reduced pressure to give the crude product as solid. Column chromatography (silica gel) afforded 1.1 g (55%) of the desired product as a light tan solid (99.80% pure by HPLC), mp 195-197 °C.1H NMR (CDCl3): δ 9.01 (d, J = 4.8 Hz, 1H), 8.43 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 4.8 Hz, 1H), 7.89 (bs, 1H), 7.08 - 7.04 (m, 6H), 5.72 (bs, 1H). The following compound can be prepared similarly: To a mixture of 4-phenoxyphenylboronic acid (0.22 g, 1.02 mmol), 3,5-diamino-6-chloropyrazine-2-carboxamide (0.176 g, 0.919 mmol), sodium carbonate (0.33 g, 2.06 mmol) in toluene (14 mL), ethanol (3.5 mL), and water (3.5 mL) was added tetrakis(triphenylphosphine)palladium (60 mg). The mixture was refluxed overnight. The reaction was allowed to cool to room temperature, then partitioned between water and ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product as a solid. Flash chromatography (Silica gel; 6:4 ethyl acetate/dichloromethane to 7:3 ethyl acetate/ dichloromethane) and subsequent recrystalization from chloroform afforded 81 mg (27%) of the desired product as white solid.1H NMR (CDCl3): δ 7.58 (d, J = 9.0 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.38 (bs, 1H), 7.15 (t, J = 8.4 Hz, 1H), 7.10-7.05 (m, 4H), 5.26 (bs, 1H), 4.97 (s, 4H). a) 2-Chloro-6-(4-phenoxyphenyl)pyrazine: A mixture of 4-phenoxyphenylboronic acid (0.54 g, 2.52 mmol), 2,6-dichloropyrazine (1.28 g, 7.73 mmol), sodium carbonate (1.15 g, 7.18 mmol), and tetrakis(triphenylphosphine)palladium (0.15 g, 0.13 mmol) in toluene (50 mL), ethanol (12 mL), and water (12 mL) was heated at reflux overnight. The reaction was allowed to cool to room temperature, then partitioned between water and ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give crude product as a solid. Purification by column chromatography gave 0.49 g (69 %) of 2-chloro-6-(4-phenoxyphenyl)pyrazine as a solid.1H NMR (CDCl3): δ 8.87 (s, 1H), 8.47 (s, 1H), 7.99 (d, J = 9.0 Hz, 2H), 7.38 (t, J = 8.1 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.12-7.06 (m, 4H). b) 6-(4-Phenoxyphenyl)pyrazine-2-carboxamide: A mixture of 2-chloro-6-(4-phenoxyphenyl)pyrazine (0.49 g, 1.73 mmol), potassium cyanide (98%, 0.30 g, 4.51 mmol), and tetrakis(triphenylphosphine)palladium (0.10 g, 0.086 mmol) in DMF was refluxed overnight. Workup as described as above and column chromatography gave 35 mg (7%) of 6-(4-phenoxyphenyl)pyrazine-2-carboxamide as a solid.1H NMR (CDCl3): δ 9.30 (s, 1H), 9.16 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.75 (bs, 1H), 7.40 (t, J = 8.4 Hz, 2H), 7.21-7.08 (m, 5H), 5.84 (bs, 1H). a) N-Dimethylaminomethylene-4-(4-nitrophenoxy)benzamide: A solution of 4-(4-nitrophenoxy)benzonitrile (0.90 g, 3.75 mmol), potassium hydroxide (2.0 g, 30 mmol) in water (10 mL), a 30% aqueous hydrogen peroxide solution (4 mL, 39 mmol) and ethanol (50 mL) was refluxed for several hours. The reaction was allowed to cool to room temperature, then partitioned between water and ethyl acetate. The separated organic layer was washed several times with water, dried over MgSO4, filtered, and evaporated under reduced pressure to give the amide intermediate as a solid. The amide and b) 2-[4-(4-Nitrophenoxy)phenyl]-4-methyl-[1,3,5]triazine: A mixture of a) 6-Bromopyridine-2-carboxylic acid N-piperidinylethylamide (2): To a solution of 6-bromopicolinic acid (5.0 g, 24.8 mmol) (1) and 1-(2-aminoethyl)-piperidine (3.3 g, 26.0 mmol) in DMF was added N-hydroxybenzotriazole (HOBt) (3.4 g, 24.8 mmol) and 5-(3,4-dimethyl-1-triazenyl)-1 b) 6-[4-(fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide (3): 4-(4-fluorophenoxy)phenyl boronic acid (557 mg, 2.4 mmol) was added to a solution of compound 2 (624 mg, 2.0 mmol) in 1,2-dimethoxyethane (DME) (6 mL), followed by water (2 mL) and potassium carbonate (746 mg, 5.4 mmol). Pd(PPh3)4 (92 mg, 0.08 mmol) was added to this mixture, and the reaction was heated at 85 °C for 16 hours under an argon atmosphere. The reaction was allowed to cool to ambient temperature, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate. The solution was filtered, concentrated, and then filtered over a bed of florisil to give crude compound 3. Purification of compound 3 was then carried out by silica gel chromatography.1H NMR (400 MHz, CDCl3): δ 1.48 (bs, 2H), 1.61-1.67 (m, 4H), 2.48 (bs, 2H), 2.59 (t, 2H, J = 6.3 Hz), 7.05-7.07 (m, 5H), 7.64-7.71 (m, 1H), 7.81-7.91 (m, 5H), 8.80 (bs, 1H). a) Compound 6: 20% piperidine in DMF was added to polystyrene-Rink-amide resin having 9-fluorenylmethoxycarbonyl (FMOC) protective group (PS-rink-NH-FMOC resin) (4) (4.45 g, 4.14 mmol) in a solid-phase reaction vessel, and the reaction was shaken for 1.5 hours at ambient temperature. The resin was washed (DMF twice, dichloromethane twice, DMF) and then treated again with 20% piperidine in DMF. It was shaken for an additional 1 hour, and the washing sequence was repeated. DMF was added to the resin, followed by N-hydroxybenzotriazole (HOBt) (3.4 g, 24.8 mmol), 6-bromopicolinic acid (1, 5.0 g, 24.8 mmol), and a solution of 5-(3,4-dimethyl-1-triazenyl)-1 b) Compounds 7a-7f: 1,2-Dimethoxyethane (DME) (2.5 mL) was added to the individual reaction vessels containing compound 6 (0.25 mmol), followed by the addition of the phenyl boronic acid (1.5 mmol). To this mixture was added water (1.0 mL), potassium carbonate (3.8 mmol), and Pd(PPh3)4 (0.043 mmol). The reactions were heated at 85 °C for 16 hours. After returning to ambient temperature, the reactions were drained, and the resin was washed (1:1 DME-water twice, water, 1:1 DME-water twice, DME twice, water twice, THF twice, dichloromethane twice) to yield 7a-7f. c) Compounds 8a-8f: Compounds 7a-7f were shaken in the presence of 1:1 trifluoroacetic acid (TFA)-dichloromethane for 1.5 hours. The reactions were filtered, the resins were washed with dichloromethane, and the solvent was then evaporated. Purification of compounds 8a-8f was carried out by first filtering over a bed of florisil followed by subjection to silica gel chromatography. 6-(4- 6-(4- 6-(4- 6-(4-thiomethylphenyl)pyridine-2-carboxamide (8d):1H NMR (400 MHz, CDCl3): δ 2.56 (s, 3H), 7.38 (d, 2H, J = 8.7 Hz), 7.93-8.09 (m, 5H). 6-(4-ethoxyphenyl)pyridine-2-carboxamide (8e):1H NMR (400 MHz, CDCl3): δ 1.46 (t, 3H, J = 7.0 Hz), 4.11 (q, 2H, J = 6.8 Hz), 7.01 (d, 2H, J = 8.9 Hz), 7.82-7.91 (m, 2H), 7.97 (d, 2H, J = 8.9 Hz), 8.01 (bs, 1H), 8.10 (d, 1, J=8.6 Hz H). 6-(4-methoxyphenyl)pyridine-2-carboxamide (8f):1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 7.05 (d, 2H, J = 8.9 Hz), 7.90-8.05 (m, 5H). Yields of the above reactions were not optimized. MS spectra for all compounds were obtained with LCMS. The reactions were followed by either TLC or/and LCMS or/and1H NMR. a) Compound 10: A solution of 10 g (100 mmol) of 2,4-pentadione (9) and 11.2 g (120 mmol) of aniline in 100 mL toluene and catalytical amount of p-toluenesulfonic acid monohydrate was refluxed in a round bottom flask equipped with azotropic apparatus and condenser for 12 hours. The solution was concentrated to dryness and the product was used without purification.1H NMR (CDCl3): δ 7.35 (t, 2H, J=5.69 Hz), 7.19 (t, 1H, J=6.4 Hz), 7.10 (d, 2H, J=7.5 Hz), 5.19 (s, 1H), 2.10 (s, 3H), 1.99 (s,3H). b) 2-Methyl-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinone (12): 31 mL of 1.6 M n-BuLi (50 mmol) was added dropwise to a solution of 7.21 g (51 mmol) of 2,2,6,6-tetrametylpiperidine in 80 mL THF at -78°C under inert atomosphere. After the addition, the reaction mixture was stirred for 30 minutes at the same temperature. A solution of 3 g (17 mmol) of compound 10 in 10 mL of THF at -78°C was added to this solution dropwise. After the addition, the reaction mixture was stirred for 30 minutes. To the resulting dark red solution was added dropwise a solution of 2.7 g (17 mmol) of compound 11 in 13 mL of THF at -78 °C. After the addition, the mixture was slowly warmed to -50 °C and stirred at that temperature for one hour. The reaction mixture was poured into cold, saturated aqueous solution of NH4Cl and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried with magnesium sulfate, and filtrated. The filtrate was concentrated to dryness. 2-Methyl-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinone was used without purification.1H NMR (CDCl3): δ 7.54 (d, 2H, H=3.8 Hz), 7.31 (m, 2H), 6.90-7.10 (m, 4H), 5.23 (s, 1H), 5.08 (s,1H), 2.03 (s, 3H). c) 4-Chloro-2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine (13): To a flask containing 20 mL of POCl3 at 120 °C oil bath was carefully added a solution of 5 g (17 mmol) of crude compound 12 and 2.6 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (17 mmol) in 20 mL of methylene chloride. After the addition, the reaction mixture was refluxed for one hour. The resulting mixture was concentrated to dryness and diluted with ethyl acetate (EtOAc). Saturated aqueous NaHCO3 was carefully added to the solution to adjust pH to 5-6. The organic phase was separated and the aqueous phase was extracted with the same volume of EtOAc. The combined organic phases were then washed with brine and dried with magnisium sulfate, filtered and concentrated to dryness. The residue was purified with flash chromatography (silica gel, 5% EtOAc/hexane) to get 1.8 g of compound 13 and 850 mg of a mixture of compound 13 and unreacted compound 11.1H NMR (CDCl3): δ 7.93 (d, 2H, J=6.7 Hz), 7.48 (d, 1H, J=1.36 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.00 (m, 6H), 2.59 (s, 3H). MS: 314.1. d) 2-Methyl-4-dimethylamino-6-[4-(4-fluorophenoxy)-phenyl]pyridine (14): e) 2-Methyl-4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyrimidine (15): A sealed tube containing 1.8 g (4.8 mmol) of compound 13 in 10 ml of 25 wt-% NaOMe in methanol was heated in 85 °C for four hours. The cooled reaction mixture was concentrated to dryness and diluted with ethyl acetate. The mixture was washed with saturated aqueous NH4Cl and then brine. The organic phase was dried with magnisium sulfate, filtered, and concentrated to dryness to give 1.5 g of clean compound 15.1H NMR (CDCl3): δ 7.92 (d, 2H, J=6.8 Hz), 7.00 (m, 7H), 6.62 (d, 1H, J=2.1 Hz), 3.88 (s, 3H), 2.57 (s, 3H). MS: 310.2. f) 4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid (16): To a solution of 1.5 g (4.8 mmol) of compound 15 in 36 ml of pyridine was added 2.1 g of SeO2 (19 mmol) and the resulting solution was refluxed for 3 days. The cooled reaction mixture was concentrated to dryness and diluted with methanol, filtered, and concentrated to give 100 % conversion.1H NMR (CDCl3): δ 7.92 (d, 2H, J=8.8 Hz), 7.69 (s, 1H), 7.38 (m, 3H), 7.07 (m, 4H), 3.97 (s, 3H). MS: 320.9. g) 4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid methyl ester (17): To the methanol solution of the crude compound 16 was slowly added 0.701 ml (9.6 mmol) of thionyl chloride carefully. After the addition, the resulting solution was refluxed for 12 hours. The cooled reaction mixture was filtered, and concentrated to dryness. The residue was then filtered through a plug of silica gel with 10 % Et3N in EtOAc. The filtrate was concentrated to dryness to yield 1.6 g of clean compound 17.1H NMR (CDCl3): δ 7.98 (d, 2H, J=8.7 Hz), 7.61 (d, 1H, J=2.2 Hz), 7.33 (d, 1H, J=2.2 Hz), 7.00 (m, 6H), 4.05 (s, 3H), 4.00 (s, 3H). MS: 354.1. h) 4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide (18): 140 mg (0.39 mmol) of compound 17 was added to a solution of 10 ml of 2M NH3 in methanol and the resulting solution was stirred for 12 hours. The mixture was then concentrated to dryness and the resulting solid was recrystalized in methanol to give 67 mg clean 4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide (18).1H NMR (DMSO-d6): δ 8.31 (d, 2H, J=8.9 Hz), 8.27 (bs, 1H, N-H), 7.70 (bs, 1H, N-H), 7.61 (d, 1H, J=2.3 Hz), 7.47 (d, 1H, J=2.3 Hz), 7.26 (t, 2H, 8.7 Hz), 7.13 (m, 2H), 7.03 (d, 2H, J=9.0 Hz), 3.94 (s, 3H). MS: 339.2. i) 4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid dimethylaminoethylamide (19): Excess of N,N-dimethyl ethylene diamine was added to the solution of 200 mg (0.56 mmol) of compound 17 in 10 ml methanol, and the resulting solution was stirred at room temperature for 4 days at which time the conversion was complete. The reaction mixture was concentrated to dryness. HCl in Et2O was added to the residue and the solid was recrystalized to yield clean compound 19.1H NMR (CDCl3): δ 8.97 (bs, 1H, N-H), 8.10 (d, 2H, J=8.8 Hz), 7.61 (d, 1H, J=2.2 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.05 (m, 6H), 4.00 (m, 1H), 3.96 (s, 3H), 3.78 (m, 1H), 3.63 (m, 1H), 3.45 (s, 3H), 3.27 (bs, 1H), 2.85 (s, 3H). MS: 410.2. The ability of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxamide to block maximal electroshock-induced seizures (MES) was determined according to the method above. 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide was administered p.o. to mice 30 minutes before the test procedure. The compound exhibited protection against MES with an ED50 (the dose protecting 50% of animals) of 1.6 mg/kg. The following compounds on Table 1 were tested accordingly after a p.o. administration and also after an i.v. injection. The compounds were injected i.v. 15 minutes before the test procedure. 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide was tested in the electrophysiological assay 1 and binding assay as described above and produced dose-dependent inhibition of voltage-gated sodium currents recorded in HEK-293 cells stably expressing the rBIIA isoform of Na+ channels. The blocking effect of this compound on Na+ currents was highly sensitive to the holding voltage, indicating that 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxamide binds to voltage-sensitive Na+ channels in their inactivated states and has weak potency towards Na+ channels in their resting states ( The Ki (the concentration of a compound that produces half maximal inhibition) value for 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxamide and other tested compounds are presented in Table 2. 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide was tested in the electrophysiological assay 2 as described above. The result of 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide and other compounds are represented in Table 3. The tactile antiallodynia effect of the compounds listed in Table 4 was tested in the Chung model of neuropathic pain in rats as described above and described by This invention relates aryl substituted pyridines, pyrimidines, pyrazines and triazines of Formula I: or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein A1, A2, A3, R1-R4, X and Y are set in the specification. The invention is also directed to the use of compounds of Formula I for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or amelioration of both acute or chronic pain, as antitinnitus agents, as anticonvulsants, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy. A compound having the Formula I:
or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein:
Y is
or R7, provided that when Y is R7, R1 is aminocarbonyl;
A1, A2 and A3 are independently CR2 or N, provided that A1, A2 and A3 are not all N at the same time;
R1, is selected from the group consisting of alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, amino, alkylthio, C(O)R8, SO2R8, OC(O)NH2, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;
each R2 is selected from the group consisting of hydrogen, alkyl, alkenyl or alkynyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino;
R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthio;
R7 is alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino;
R8 is selected from the group consisting of alkyl, alkenyl, alkynyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenylamino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, provided that R8 is not OR9 when R1, is SO2R8; wherein
R9 is selected from the group consisting of hydrogen, alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, and an alkali metal; and
X is one of O, S, NH, or CH2 when Y is other than R7; or
X is one of O, S, NH, CH2 or absent when Y is R7;
with the provisos that:
1) R2 is not methoxy if R5 is trifluoromethyl, R6 is H, X is O and R1 is SO2CH2Ph 2) R2 is not NH2 if R1 is methylthio, X is O and two of A1, A2 and A3 are N; 3) R2 is not methyl if R1, is SO2R8, wherein R8 is methylphenyl, R3 and R4 are methoxy, X is S and two of A1, A2 and A3 are N; or 4) R2 is not CCl3 if R1 is CCl3, X is S and two of A1 , A2 and A3 are N; 5) R1, and R2 are not both NH2 if X is O or S and two of A1, A2 and A3 are N; or 6) the compound of Formula I is not N-[4-amino-6-(4-phenoxyphenyl)-1,3,5-triazin-2-yl]acetamide. A compound having the Formula II:
or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein:
A1, A2 and A3 are independently CR2 or N, provided that A1, A2 and A3 are not all N at the same time; R1 is selected from the group consisting of alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, amino, alkylthio, C(O)R8, SO2R8, OC(O)NH2, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl; each R2 is selected from the group consisting of hydrogen, alkyl, alkenyl or alkynyl optionally substituted with one or more of halogen, halo(C1-6)alkyle, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthio; and R8 is selected from the group consisting of alkyl, alkenyl, alkynyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenylamino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, provided that R8 is not OR9 when R1, is SO2R8; wherein R9 is selected from the group consisting of hydrogen, alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, and an alkali metal; and X is one of O, S, NH, or CH2; with the provisos that:
1) R2 is not methoxy if R5 is trifluoromethyl, R6 is H, X is O and R1, is SO2CH2Ph; 2) R2 is not NH2 if R1, is methylthio, X is O and two of A1, A2 and A3 are N; 3) R2 is not methyl if R1 is SO2R8, wherein R8 is methylphenyl, R3 and R4 are methoxy, X is S and two of A1, A2 and A3 are N; 4) R2 is not CCl3 if R1, is CCl3, X is S and two of A1, A2 and A3 are N; 5) R1, and R2 are not both NH2 if X is O or S and two of A1, A2 and A3 are N; or 6) the compound of Formula II is not N-[4-amino-6-(4-phenoxyphenyl)-1,3,5-triazin-2-yl]acetamide. The compound of claim 2, wherein R1, is selected from the group consisting of an alkyl optionally substituted by halogen or hydroxy, C(O)R8, SO2R8, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, and 5-isoxazolyl, wherein R8 is as defined in claim 2, provided that R8 is not OR9 when R1 is SO2R8. The compound of claim 3, wherein R8 is selected from the group consisting of alkyl, alkenyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, and wherein R9 is as defined in claim 2. The compound of claim 2, wherein R2 is hydrogen, X is O or S and R1, is aminocarbonyl. The compound of claim 2, having the Formula III:
or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein;
A1-A3; R2-Rb, R8 and X are as defined in claim 2. The compound of claim 2 or claim 6, wherein R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino. The compound of claim 6, wherein R8 is selected from the group consisting of alkyl, alkenyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, provided that R8 is not OR9 when R1 is SO2R8, and wherein R9 is as defined in claim 2. The compound of claim 6, wherein
X is O;
A1, A2 and A3 are each CR2; or A1 is N and A2 and A3 are CR2; or A3 is N and A1 and A2 are CR2; or A2 is N and A1 and A3 are CR2; or A1 and A3 are N and A2 is CR2; wherein
R2 is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl, and aminocarbonyl;
R3 and R4 are both hydrogen;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro; and
R8 is amino. The compound of claim 2 or 6, wherein A2 is CR2, wherein R2 is other than H and A1, and A3 are each CH. The compound of claim 2 or 6, wherein A1 is N, A2 is CR2, wherein R2 is other than H and A3 is CH. The compound of claim 2 or 6, wherein A3 is N, A2 is CR2, wherein R2 is other than H and A1 is CH. The compound of claim 2 or 6, wherein A2 is N, A1 is CR2, wherein R2 is other than H, and A3 is CH. The compound of claim 2, having Formula IV:
or a pharmaceutically acceptable salt, ester, amide or solvate thereof;
wherein:
A1-A3, R2-R6, and X are as defined in claim 2 and
R8 is selected from the group consisting of alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino. The compound of claim 14, wherein A1, A2 and A3 are each CR2; or A1, is N and A2 and A3 are CR2; or A3 is N and A1 and A2 are CR2; or A2 is N and A1 and A3 are CR2; or A1 and A3 are N and A2 is CR2, and R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino. The compound of any one of claims 2, 6 or 14 , wherein R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano. The compound of claim 16, wherein R3 and R4 are both hydrogen and R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro. The compound of claim 14, wherein R8 is selected from the group consisting of alkyl, alkenyl, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, and heterocycloalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino. A compound, wherein said compound is:
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxamide; 4-[4-(4-nitrophenoxy)phenyl]pyrimidine-2-carboxamide; 4-[4-(4-methoxyphenoxy)phenyl]pyrimidine-2-carboxamide; 4-[4-(4-trifluoromethylphenoxy)phenyl]pyrimidine-2-carboxamide; 4-[4-(3-chloro-2-cyanophenoxy)phenyl]pyrimidine-2-carboxamide; 4-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-2-carboxamide; 4-[4-(2,4-difluorophenoxy)phenyl]pyrimidine-2-carboxamide; 4-[4-(2-chloro-4-fluorophenoxy)phenyl]pyrimidine-2-carboxamide; 1-[4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-yl]-ethanone; 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; 2-[4-(4-fluorophenoxy)phenyl]-4-methylpyrimidine; 2-methyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine; 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid; 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid sodium salt; 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid methylamide; 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid dimethylamide; 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid; 2-(4-phenoxyphenyl)-6-(dimethylamino)pyrimidine-4-carboxylic acid dimethylamide; 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 2-hydroxyethylamide; 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid hydroxymethyleneamide; 2-(2-hydroxyprop-2-yl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine; 4-[4-(2,4-difluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 2-morpholin-4-yl-ethyl amide; 2-(4,5-dihydro-1H-imidazol-2-yl)-4-[4-(4-fluorophenoxy)phenyl]-pyrimidine; 2-(3-pyrazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine; 2-(5-isoxazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine; 2-(1-methyl-3-pyrazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine; 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid methylamide; 3-dimethylamino-1-{4-[4-(4-fluorophenoxy)phenyl}pyrimidin-2-yl]propenone; 2-thiomethyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine; 2-methanesulfonyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine; 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-4-methyl-pyrimidine; 4-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine-2-carboxamide; 2-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine=4-carboxamide; 2-methyl-6-(4-phenoxyphenyl)pyridine; 6-(4-phenoxyphenyl)pyridine-2-carboxamide; 2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine; 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid; 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid methylamide; 6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide; 6-[4-(2,4-difluorophenoxy)phenyl]pyridine-2-carboxamide; 6-[4-(4-chloro-2-fluorophenoxy)phenyl]pyridine-2-carboxamide; 6-[4-(4-fluorophenoxy)-3-fluorophenyl]pyridine-2-carboxamide; 6-[4-(4-trifluoromethylphenoxy)phenyl]pyridine-2-carboxamide; 6-(4-phenoxyphenyl)pyrazine-2-carboxamide; 3,5-diamino-6-(4-phenoxyphenyl)pyrazine-2-carboxamide; or 2-[4-(4-nitrophenoxy)phenyl]-4-methyl-[1,3,5]-triazine, or a pharmaceutically acceptable salt, ester, amide or solvate thereof. A compound of claim 1, wherein said compound is:
6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid N-piperidinylethylamide; 6-(4- 6-(4- 6-(4- 6-(4-thiomethylphenyl)pyridine-2-carboxamide; 6-(4-ethoxyphenyl)pyridine-2-carboxamide; or 6-(4-methoxyphenyl)pyridine-2-carboxamide, or a pharmaceutically acceptable salt, ester, amide or solvate thereof. The compound of claim 1, having the Formula V:
or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein;
A1-A3, R2-R4, and R7 are as defined in claim 1; and
X is one of O, S, NH, CH2 or absent. The compound of any one of claims 2, 6 or 21, wherein A1, A2 and A3 are each CR2; or A1 is N and A2 and A3 are CR2; or A3 is N and A1 and A2 are CR2; or A2 is N and A1 and A3 are CR2; or A1 and A3 are N and A2 is CR2. The compound of claim 21, wherein R7 is a C1-6 alkyl optionally substituted with one or more of halogen, hydroxy, nitro, amino, cyano and alkoxy. The compound of any one of claims 7, 15 and 21, wherein R2 is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl. The compound of claim 21, wherein R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano. The compound of claim 25, wherein R3 and R4 are both hydrogen. The compound of any one of claims 2, 6, 14 or 21, wherein X is O or S. The compound of claim 27, wherein X is O. The compound of claim 21, wherein said compound is 6-[(4-trifluoromethoxy)phenyl]pyridine-2-carboxamide or a pharmaceutically acceptable salt, ester, amide or solvate thereof. A pharmaceutical composition, comprising the compound of formula:
or a pharmaceutically acceptable salt, ester, amide or solvate thereof, wherein:
Y is
or R7, provided that when Y is R7, R1 is aminocarbonyl;
A1, A2 and A3 are independently CR2 or N, provided that A1, A2 and A3 are not all N at the same time;
R1 is selected from the group consisting of alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, amino, alkylthio, C(O)R8, SO2R8, OC(O)NH2, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;
each R2 is selected from the group consisting of hydrogen, alkyl, alkenyl or alkynyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino;
R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
R7 is alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino;
R8 is selected from the group consisting of alkyl, alkenyl, alkynyl, OR9, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenylamino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, provided that R8 is not OR9 when R1 is SO2R8; wherein
R9 is selected from the group consisting of hydrogen, alkyl optionally substituted with one or more of halogen, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, alkoxy, and amino, and an alkali metal; and
X is one of O, S, NH, or CH2 when Y is other than R7;
X is one of O, S, NH, CH2 or absent when Y is R7; and a pharmaceutically acceptable carrier or diluent;
with the provisos that:
R1 and R2 are not both NH2 if X is O or S and two of A1, A2 and A3 are N; or the compound of Formula I is not N-[4-amino-6-(4-phenoxyphenyl)-1,3,5-triazin-2-yl]acetamide. Use of a compound as defined in claim 30 in the manufacture of a medicament for treating a disorder responsive to the blockade of sodium channels. Use of a compound as defined in claim 30 in the manufacture of a medicament for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing, or ameliorating pain; treating, preventing or ameliorating tinnitus; treating, preventing or ameliorating manic depression; providing local anesthesia; or treating arrhythmias, or treating convulsions. The use of claim 32, wherein the medicament is for treating, preventing or ameliorating pain and said pain is one of neuropathic pain, surgical pain or chronic pain. Use of a compound as defined in claim 30 in the manufacture of a medicament for alleviating or preventing seizure activity. The composition of claim 30, or the use of any one of claims 31 to 34, wherein the compound is as claimed in any one of claims 1-29. The compound of claim 2, wherein said compound is 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof.BACKGROUND OF THE INVENTION
Field of the Invention
Related Art
SUMMARY OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
with the provisos that:
More preferably, R8 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, aryl and amino. R3 through R6 have preferred values as described above for Formula II.Electrophysiological Assay 1:
Electrophysiological Assay 2:
In vitro Binding Assay:
In vivo Pharmacology:
EXAMPLE 1
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide
EXAMPLE 2
2-Methanesulfonyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine
EXAMPLE 3
1-[4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-yl]-ethanone
EXAMPLE 4
2-[4-(4-Chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide
EXAMPLE 5
2-Chloropyrimidine-4-carboxamide
EXAMPLE 6
6-[(4-Trifluoromethoxy)phenyl]pyridine-2-carboxamide
EXAMPLE 7
3-Dimethylamino-1-{4-[4-(4-fluorophenoxy)phenyl]pyrimidin-2-yl}propenone
EXAMPLE 8
4-[4-(4-Fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid, (2-hydroxyethyl)amide
EXAMPLE 9
6-(4-Phenoxyphenyl)pyridine-2-carboxylic acid methylamide
EXAMPLE 10
6-[4-(4-Fluorophenoxy)phenyl]pyridine-2-carboxamide
EXAMPLE 11
6-(4-Phenoxyphenyl)pyridine-2-carboxamide
EXAMPLE 12
2-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxamide
EXAMPLE 13
3,5-Diamino-6-(4-phenoxyphenyl)pyrazine-2-caxboxamide
EXAMPLE 14
6-(4-Phenoxyphenyl)pyrazine-2-carboxamide
EXAMPLE 15
2-[4-(4-Nitrophenoxy)phenyl]-4-methyl-[1,3,5]triazine
EXAMPLE 16
6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide (3)
EXAMPLE 17
EXAMPLE 18
EXAMPLE 19
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide as Anticonvulsant
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxamide 1.6 0.7 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid methylamide 6.1 2.8 4-[4-(4-trifluoromethylphenoxy)phenyl]-pyrimidine-2-carboxamide 2.5 0.5 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide 5.7 2.3 4-[4-(2,4-difluorophenoxy)phenyl]-pyrimidine-2-carboxamide 1.4 0.9 4-[4-(nitrophenoxy)phenyl]pyrimidine-2-carboxamide 10.0 3.1 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid hydroxymethyleneamide 5.0 1.5 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxamide 7.5 2.5 6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide 3.3 1.2 6-(4-phenoxyphenyl)pyridine-2-carboxamide 10.5 3.2 2-(4-phenoxyphenyl)-6-(dimethylamino)-pyrimidine-4-carboxylic acid dimethylamide 2.10 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxylic acid dimethylamino-methyleneamide 4.10 1.50 EXAMPLE 20
Activity of 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide as Sodium Channel Blocker
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxamide 0.49 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid dimethylamide 13.50 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 0.18 4-[4-(4-trifluoromethylphenoxy)phenyl]-pyrimidine-2-carboxamide 0.21 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide 0.22 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 51 4-[4-(2,4-difluorophenoxy)phenyl]-pyrimidine-2-carboxamide 0.36 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxamide 0.10 6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide 0.07 2-[4-(4-fluorophenoxy)phenyl]-4-[3-(1,2,4-triazolyl)]pyrimidine 20.00 3,5-diamino-6-(4-phenoxyphenyl)pyrazine-2-carboxamide 2.20 EXAMPLE 21
Activity of 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide as Sodium Channel Blocker
6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide (3) 0.06 6-(4- 6.13 6-(4- 10.53 6-(4- 41.61 6-(4-thiomethylphenyl)pyridine-2-carboxamide (8d) 52.73 6-(4-ethoxyphenyl)pyridine-2-carboxamide (8e) 58.72 6-(4-methoxyphenyl)pyridine-2-carboxamide (8f) 23.87 2-methyl-4-dimethylamino-6-[4-(4-fluorophenoxy)phenyl]pyridine (14) 0.33 4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide (18) 3.43 4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid dimethylaminoethylamide (19) 0.32 2-dimethylamino-4-[4-(4-fluorophenoxy)phenyl]pyrimidine 27.57 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid ethyl ester 9.86 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carbamate 8.70 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 2-chloroethylamide 2.62 1-[4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-yl]-2,2-dibromoethanone 10.63 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid methylaminomethyleneamide hydrochloride 11.36 2-[3-(1,2,4-triazolyl)]-4-[4-(4-fluorophenoxy)phenyl]pyrimidine 5.91 4-[4-(2,4-difluorophenoxy)phenyl]pyrimidine-2-carboxylic acid methyl ester 139 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid methyl ester 71.53 6-[4-(4-fluorophenoxy)phenyl]pyridine-2,3-dicarboxamide 4.54 2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine-3-carboxamide 8.45 5-cyano-6-(4-phenoxyphenyl)pyridine-2-carboxamide 11.9 5-hydroxy-6-(4-phenoxyphenyl)pyridine-2-carboxamide 99.3 2-(5-isoxazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine 2.63 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid hydroxymethyleneamide 3.53 4-[4-(4-nitrophenoxy)phenyl]pyrimidine-2-carboxamide 1.13 EXAMPLE 22
Activity of 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N-piperidinylethylamide as Sodium Channel Blocker
2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide 1.25 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxamide 2.50 6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide 2.50