Aryl substituted pyridines, pyrimidines, pyrazines and triazines and the use thereof

Abstract

This invention relates aryl substituted pyridines, pyrimidines, pyrazines and triazines of Formula I: or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein A 1 , A 2 , A 3 , R 1 -R 4 , 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.

1 - 58 . (Cancelled)  
     
     
         59 . A method of treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 Y is  
                     
 
       or R 7 , 
 provided that when Y is R 7 , R 1  is aminocarbonyl;  
 A 1  is N and A 2  and A 3  are CR 2 , or A 3  is N and A 1  and A 2  are CR 2 ;  
 R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthio, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
 each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
 R 3 , R 4 , R 5 , and R 6  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;  
 R 7  is an optionally substituted alkyl;  
 R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
 R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
 X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
 X is one of O, S, NH, CH 2  or absent when Y is R 7 .  
 
     
     
         60 . The method of  claim 59 , wherein the method is for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating pain or tinnitus; treating, preventing or ameliorating manic depression; providing local anesthesia; or treating arrhythmias, or treating convulsions, comprising administering to a mammal in need of such treatment an effective amount of a compound formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 Y is  
                     
 or R 7 ,  
 provided that when Y is R 7 , R 1  is aminocarbonyl;  
 A 1  is N and A 2  and A 3  are CR 2 , or A 3  is N and A 1  and A 2  are CR 2 ;  
 R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthio, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
 each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
 R 3 , R 4 , R 5 , and R 6  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;  
 R 7  is an optionally substituted alkyl;  
 R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
 R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
 X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
 X is one of O, S, NH, CH 2  or absent when Y is R 7 .  
 
     
     
         61 . The method of  claim 60 , wherein the method is for treating, preventing or ameliorating pain and said pain is one of neuropathic pain, surgical pain or chronic pain.  
     
     
         62 . The method of  claim 59 , wherein the method is of alleviating or preventing seizure activity in an animal subject, comprising administering to said animal in need of such treatment an effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 Y is  
                     
 or R 7 ,  
 provided that when Y is R 7 , R 1  is aminocarbonyl;  
 A 1  is N and A 2  and A 3  are CR 2 , or A 3  is N and A 1  and A 2  are CR 2 ;  
 R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthio, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
 each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
 R 3 , R 4 , R 5 , and R 6  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;  
 R 7  is an optionally substituted alkyl;  
 R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
 R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
 X is one of O, S, NH, or CH 2  when Y is other than R 7 ; or  
 X is one of O, S, NH, CH 2  or absent when Y is R 7 .  
 
     
     
         63 . The method of  claim 59 , wherein the compound administered is a compound having the Formula II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 A 1  is N and A 2  and A 3  are CR 2 , or A 3  is N and A 1  and A 2  are CR 2 ;  
 R 1  is selected from the group consisting an optionally substituted alkyl, amino, alkylthio, C(O)R 8 , SO 2 R 8 , OC(O)NH 2 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;  
 each R 2  is selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or R 1  and R 2  are taken together with the carbon atoms to which they are attached to form a heterocyclic ring;  
 R 3 , R 4 , R 5 , and R 6  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, and alkylthiol; and  
 R 8  is selected from the group consisting of alkyl, alkenyl, alkynyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino, alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 ; wherein  
 R 9  is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkali metal; and  
 X is one of O, S, NH, or CH 2 .  
 
     
     
         64 . The method of  claim 63 , wherein A 3  is N and A 1  and A 2  are CR 2 .  
     
     
         65 . The method of  claim 63 , wherein R 1  is selected from the group consisting of an alkyl optionally substituted by halogen or hydroxy, C(O)R 8 , SO 2 R 8 , 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, and 5-isoxazolyl, wherein R 8  is as defined in  claim 60 , provided that R 8  is not OR 9  when R 1  is SO 2 R 8 .  
     
     
         66 . The method of  claim 65 , wherein R 8  is selected from the group consisting of alkyl, alkenyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted, and wherein R 9  is as defined in  claim 63 .  
     
     
         67 . The method of  claim 63 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino.  
     
     
         68 . The method of  claim 67 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         69 . The method of  claim 63 , wherein R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         70 . The method of  claim 69 , wherein R 3  and R 4  are both hydrogen and R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro.  
     
     
         71 . The method of  claim 63 , wherein X is O or S.  
     
     
         72 . The method of  claim 71 , wherein X is O.  
     
     
         73 . The method of  claim 63 , wherein R 2  is hydrogen, X is O or S and R 1  is aminocarbonyl.  
     
     
         74 . The method of  claim 63 , wherein A 1  is N, A 2  is CR 2 , wherein R 2  is other than H and A 3  is CH.  
     
     
         75 . The method of  claim 63 , wherein A 3  is N, A 2  is CR 2 , wherein R 2  is other than H and A 1  is CH.  
     
     
         76 . The method of  claim 63 , wherein the compound administered is a compound having the Formula III:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein; 
 A 1 —A 3 , R 2 —R 6 , R 8  and X are as defined in  claim 63 .  
 
     
     
         77 . The method of  claim 76 , wherein A 3  is N and A 1  and A 2  are CR 2 .  
     
     
         78 . The method of  claim 76 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino.  
     
     
         79 . The method of  claim 78 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         80 . The method of  claim 76 , wherein R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         81 . The method of  claim 80 , wherein R 3  and R 4  are both hydrogen and R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro.  
     
     
         82 . The method of  claim 76 , wherein R 8  is selected from the group consisting of alkyl, alkenyl, OR 9 , amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino, all of which can be optionally substituted, provided that R 8  is not OR 9  when R 1  is SO 2 R 8 .  
     
     
         83 . The method of  claim 76 , wherein X is O or S.  
     
     
         84 . The method of  claim 83 , wherein X is O.  
     
     
         85 . The method of  claim 76 , wherein 
 X is O;    A 1  is N and A 2  and A 3  are CR 2 ; or A 3  is N and A 1  and A 2  are CR 2 ; wherein    R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl, and aminocarbonyl;    R 3  and R 4  are both hydrogen;    R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro; and    R 8  is amino.    
     
     
         86 . The method of  claim 76 , wherein A 1  is N, A 2  is CR 2 , wherein R 2  is other than H and A 3  is CH.  
     
     
         87 . The method of  claim 76 , wherein A 3  is N, A 2  is CR 2 , wherein R 2  is other than H and A 1  is CH.  
     
     
         88 . The method of  claim 63 , wherein the compound administered is a compound having Formula IV:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof; wherein: 
 A 1 —A 3 , R 2 —R 6 , and X are as defined in  claim 63  and  
 R 8  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.  
 
     
     
         89 . The method of  claim 88 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino.  
     
     
         90 . The method of  claim 89 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         91 . The method of  claim 88 , wherein R 3 , R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         92 . The method of  claim 91 , wherein R 3  and R 4  are both hydrogen and R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, and nitro.  
     
     
         93 . The method of  claim 88 , wherein R 8  is selected from the group consisting of alkyl, alkenyl, amino, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, and heterocycloalkylamino, all of which can be optionally substituted.  
     
     
         94 . The method of  claim 88 , wherein X is O or S.  
     
     
         95 . The method of  claim 94 , wherein X is O.  
     
     
         96 . The method of  claim 63 , 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 tert-butylamide;    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-flourophenoxy)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-flourophenoxy)phenyl]-4-methyl-pyrimidine;    4-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine-2-carboxamide; or 2-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine-4-carboxamide;    or a pharmaceutically acceptable salt, prodrug or solvate thereof.    
     
     
         97 . The method of  claim 59 , wherein the compound administered is a compound having the Formula V:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein; 
 A 1 -A 3 , R 2 -R 4 , and R 7  are as defined in  claim 59;  and  
 X is one of O, S, NH, CH 2  or absent.  
 
     
     
         98 . The method of  claim 97 , wherein A 3  is N and A 1  and A 2  are CR 2 .  
     
     
         99 . The method of  claim 97 , wherein R 7  is a C 1-6  alkyl optionally substituted with one or more of halogen, hydroxy, nitro, amino, cyano and alkoxy.  
     
     
         100 . The method of  claim 97 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl.  
     
     
         101 . The method of  claim 97 , wherein R 3  and R 4  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, and cyano.  
     
     
         102 . The method of  claim 101 , wherein R 3  and R 4  are both hydrogen.  
     
     
         103 . The method of  claim 97 , wherein X is O or S.  
     
     
         104 . The method of  claim 103 , wherein X is O.  
     
     
         105 . The method of  claim 63 , wherein the compound administered is 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide or a pharmaceutically acceptable salt, prodrug or solvate thereof.  
     
     
         106 . The method of  claim 105 , wherein the compound administered is 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide.  
     
     
         107 . The method of  claim 63 , wherein A 1  is N and A 2  and A 3  are CR 2 .  
     
     
         108 . The method of  claim 76 , wherein A 1  is N and A 2  and A 3  are CR 2 .  
     
     
         109 . The compound of  claim 97 , wherein A 1  is N and A 2  and A 3  are CR 2 .