Amide compounds, compositions and uses thereof

Abstract

Compounds are provided according to formula (I), where A, B, W, X′, L, R 1 , R 3 , R 4b , and m′ are as defined herein. Provided compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, cognitive disorders, anxiety, depression, and others.

1 . A compound having a formula 1: 
       
         
           
           
               
               
           
         
         wherein
 each of A, B, and W are independently selected from CR 4  and N; provided that not all A, B, and W are N at the same time; 
 X′ is selected from CR 4a  and N; 
 L is substituted or unsubstituted C 1 -C 9  alkylene or C 1 -C 9  heteroalkylene; 
 R 1  is selected from substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 R 3  is substituted or unsubstituted 6-10 membered aryl, or substituted or unsubstituted 6-10 membered heteroaryl; or
 R 3  is substituted or unsubstituted N containing heterocycloalkyl; and the heterocycloalkyl is attached to the core group via the N; 
 
 each R 4  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol; 
 each R 4a , and R 4b  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and subscript m′ is selected from 0-4; 
 
         or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A compound according to  claim 1 , wherein the compound is according to formula 2: 
       
         
           
           
               
               
           
         
         wherein 
         X′, L, R 1 , R 3 , R 4a ; R 4b , and m′ are as in  claim 1 ; 
         or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof. 
       
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A compound according formula 2a: 
       
         
           
           
               
               
           
         
         wherein
 X′ is selected from CR 4a  and N; 
 R 1  is selected from substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 each of R 2a  and R 2b  is independently selected from hydrogen, C 1 -C 4  alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, and halo; or R 2a  and R 2b  join together to form a cycloalkyl or heterocycloalkyl ring of 3-7 atoms; 
 R 3  is substituted or unsubstituted 6-10 membered aryl, or substituted or unsubstituted 6-10 membered heteroaryl; and when R 3  is 6,5 fused bicyclic heteroaryl then R 3  is joined to the core group via the 6 membered ring;
 R 3  is N containing heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo; and the heterocycloalkyl is attached to the core group via the N; 
 
 each R 4a , and R 4b  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and subscript m′ is selected from 0-4; and the subscript n2 is 0 or 1; 
 
         or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof; 
         provided that 
         a) when n2 is 0, R 1  is other than Me; or 
         b) the compound is other than 
         i) 3,5-di(4-fluorophenyl)benzoic acid N-[1-methyl-2-[4-(pyrimidin-2-yl)piperazin-1-yl]ethyl]amide; 
         ii) 3,5-di(4-fluorophenyl)benzoic acid N-[1-methyl-2-(4-acetylpiperazin-1-yl)ethyl]amide; 
         iii) 3-(3-fluoro-2-pyridinyl)-N-[2-hydroxy-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]-5-(5-methyl-2-pyridinyl)-benzamide; 
         iv) 3-(5-methyl-2-pyridinyl)-5-(1-piperidinyl)-N-[(1S)-1-(1H-1,2,4-triazol-5-yl)ethyl]-benzamide; 
         v) N-[(1R)-1-(3-fluoro-2-pyridinyl)ethyl]-3-(5-methyl-2-pyridinyl)-5-(1-piperidinyl)-benzamide; 
         vii) 5-(2,4-dioxo-1-imidazolidinyl)-2′-fluoro-4′-methyl-N-(1-methylethyl)-[1,1′-biphenyl]-3-carboxamide; 
         viii) N-(3,3-dimethylbutyl)-γ-hydroxy-α-methyl-δ-[[[5-(2-oxo-1-pyrrolidinyl) [1,1′-biphenyl]-3-yl]carbonyl]amino]-,(αR,δS,γS)-benzenehexanamide; 
         ix) 2-[[3′-[(2R)-2-[(dimethylamino)carbonyl]-1-pyrrolidinyl]-5′-[[[(1S)-1-[(dimethylamino)methyl]-2-phenylethyl]amino]carbonyl]-2-methoxy[1,1′-biphenyl]-3-yl]methyl]-4-[(1S)-1-hydroxyethyl]-5-(hydroxymethyl)-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-, (3S,4R,5R)-3-isoxazolidinecarboxamide; or 
         x) N-(3,3-dimethylbutyl)-γ-hydroxy-α-methyl-δ-[[[5-(2-oxo-1-pyrrolidinyl)[1,1′-biphenyl]-3-yl]carbonyl]amino]-(αR,δS,γS)-benzenehexanamide. 
       
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A compound according to  claim 1 , wherein R 3  is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, pyrazinyl or unsubstituted pyrimidinyl, substituted or unsubstituted quinolinol, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . A compound according to  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
         and wherein subscript n1 is selected from 1-5 and each R 5a  is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol. 
       
     
     
         16 . A compound according to  claim 1 , of formula 3, 4, or 5: 
       
         
           
           
               
               
           
         
         wherein
 X′ is selected from CR 4a  and N; 
 
         R 1  is selected from substituted or unsubstituted aryl, and heteroaryl; or
 R 1  is substituted or unsubstituted cycloalkyl; or
 R 1  is selected from alkyl, and hydroxyalkyl; or
 R 1  is heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo; 
 
 
 each of R 2a  and R 2b  is independently selected from hydrogen, C 1 -C 4  alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, and halo; or R 2a  and R 2b  join together to form a cycloalkyl or heterocycloalkyl ring of 3-7 atoms; 
 each R 4a , and R 4b  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and subscript m′ is selected from 0-4; 
 each R 5a  is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; the subscript n1 is selected from 1-5; and the subscript n2 is 0 or 1; 
 
         or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof; 
         provided that 
         a) when n2 is 0, R 1  is other than Me; or 
         b) the compound is other than 
         i) 3-(3-fluoro-2-pyridinyl)-N-[2-hydroxy-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]-5-(5-methyl-2-pyridinyl)-benzamide. 
       
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A compound according to  claim 16 , wherein the compound is according to formula 6, 7, 8, 9, 10, or 11: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2a , R 2b , R 4a , R 4b , R 5a , n1 and n2 are as in  claim 16 ; 
         or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof. 
       
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A compound according to  claim 1 , of formula 2a: 
       
         
           
           
               
               
           
         
         wherein
 X′ is selected from CR 4a  and N; 
 R 1  is selected from substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 each of R 2a  and R 2b  is independently selected from hydrogen, C 1 -C 4  alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, and halo; or R 2a  and R 2b  join together to form a cycloalkyl or heterocycloalkyl ring of 3-7 atoms; 
 R 3  is N containing heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo; and the heterocycloalkyl is attached to the core group via the N; 
 each R 4a , and R 4b  is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; subscript m′ is selected from 0-4; and the subscript n2 is 0 or 1; 
 
         or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof; 
         provided that the compound is other than 
         i) 3-(5-methyl-2-pyridinyl)-5-(1-piperidinyl)-N-[(1S)-1-(1H-1,2,4-triazol-5-yl)ethyl]-benzamide; 
         ii) N-[(1R)-1-(3-fluoro-2-pyridinyl)ethyl]-3-(5-methyl-2-pyridinyl)-5-(1-piperidinyl)-benzamide; 
         iii) 5-(2,4-dioxo-1-imidazolidinyl)-2′-fluoro-4′-methyl-N-(1-methylethyl)-[1,1′-biphenyl]-3-carboxamide; 
         iv) N-(3,3-dimethylbutyl)-γ-hydroxy-α-methyl-δ-[[[5-(2-oxo-1-pyrrolidinyl)[1,1′-biphenyl]-3-yl]carbonyl]amino]-,(αR,δS,γS)-benzenehexanamide; 
         v) 2-[[3′-[(2R)-2-[(dimethylamino)carbonyl]-1-pyrrolidinyl]-5′-[[[(1S)-1-[(dimethylamino)methyl]-2-phenylethyl]amino]carbonyl]-2-methoxy[1,1′-biphenyl]-3-yl]methyl]-4-[(1S)-1-hydroxyethyl]-5-(hydroxymethyl)-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-,(3S,4R,5R)-3-isoxazolidinecarboxamide; or 
         vi) N-(3,3-dimethylbutyl)-γ-hydroxy-α-methyl-δ-[[[5-(2-oxo-1-pyrrolidinyl)[1,1′-biphenyl]-3-yl]carbonyl]amino]-(αR,δS,γS)-benzenehexanamide. 
       
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . A compound according to  claim 26 , wherein the compound is according to formula 18, 19, 20, 21, 22, or 23: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         X′, R 1 , R 2a , R 2b , R 4b ; and n2 are as in  claim 26 ; and R 3a  is hydrogen, or substituted or unsubstituted alkyl; 
         or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof. 
       
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . A compound according to  claim 16 , wherein
 each of R 2a  and R 2b  is hydrogen; or   one of R 2a  and R 2b  is methyl, hydroxymethyl or hydroxyethyl; or   each of R 2a  and R 2b  is methyl; or   R 2a  and R 2b  join together to form a cycloalkyl ring.   
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . A compound according to  claim 1 , wherein R 1  is selected from unsubstituted pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, and azepinyl. 
     
     
         52 . A compound according to  claim 1 , wherein R 1  is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo. 
     
     
         53 . A compound according to  claim 1 , wherein R 1  is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, substituted with oxo. 
     
     
         54 . A compound according to  claim 1 , wherein R 1  is selected from morpholinyl, and 1,1-dioxo-thiomorpholinyl. 
     
     
         55 . A compound according to  claim 1 , wherein R 1  is Et, i-Pr, or t-Bu. 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . A compound according to  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
         and wherein subscript n3 is selected from 1-5 and each R 5b  is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol. 
       
     
     
         62 . (canceled) 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . A compound according to  claim 1 , selected from compounds exemplified in Table 1; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof. 
     
     
         69 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of  claim 1 . 
     
     
         70 . (canceled) 
     
     
         71 . (canceled) 
     
     
         72 . (canceled) 
     
     
         73 . A method for preventing or treating in a mammal in need thereof a disease or condition which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to  claim 1 . 
     
     
         74 . (canceled) 
     
     
         75 . (canceled) 
     
     
         76 . (canceled) 
     
     
         77 . (canceled) 
     
     
         78 . (canceled) 
     
     
         79 . (canceled) 
     
     
         80 . (canceled) 
     
     
         81 . (canceled) 
     
     
         82 . (canceled) 
     
     
         83 . A method of treating a mammal suffering from at least one symptom selected from the group consisting of symptoms of exposure to capsaicin, symptoms of burns or irritation due to exposure to heat, symptoms of burns or irritation due to exposure to light, symptoms of burns, bronchoconstriction or irritation due to exposure to tear gas, and symptoms of burns or irritation due to exposure to acid, which comprises administering to the mammal an effective symptom-treating amount of a compound according to  claim 1 . 
     
     
         84 . (canceled) 
     
     
         85 . The method of  claim 73 , wherein the disease or condition is selected from: pain including acute, inflammatory and neuropathic pain, chronic pain, dental pain and headache including migraine, cluster headache and tension headache, Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation, encephalitis; centrally-mediated neuropsychiatric diseases and disorders, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; neurological and neurodegenerative diseases and disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis, myocardial infarction, autoimmune diseases and disorders, itch/pruritus, psoriasis; obesity; lipid disorders; cancer; and renal disorders.