2-cyanophenyl fused heterocyclic compounds, and compostions and uses thereof

Abstract

Fused heterocyclic compounds are provided according to formula 1: where R 1 , R 2 , R 3 , 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 . (canceled) 
     
     
         2 . The method according to  claim 33 , wherein the compound is according to formula 2: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 4  are as in  claim 33 ; and R 3  is halo, substituted or unsubstituted C 1 -C 6  alkyl or cycloalkyl; or a pharmaceutically acceptable salt, tautomer or isotopic variant thereof. 
       
     
     
         3 . The method according to  claim 33 , wherein the compound is an enantiomerically pure compound according to formula 3a or 3b: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 4  are as in  claim 33 ; and R 3  is halo, substituted or unsubstituted C 1 -C 6  alkyl or cycloalkyl; or a pharmaceutically acceptable salt, solvate, prodrug, tautomer or isotopic variant thereof. 
       
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method according to  claim 33 , wherein R 1  is selected from unsubstituted phenyl, pyridyl, pyrimidinyl quinolinyl, isoquinolinyl, quinoxaline, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl. 
     
     
         8 . The method according to  claim 33 , wherein R 1  is selected from quinolinyl, isoquinolinyl, quinoxaline, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl, substituted with one or more groups selected from Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO 2 Me, CH 2 —N-morpholino, CH 2 —N-(4-Me-piperidino), NH 2 , CONH 2 , CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SMe, CH═CH—CO 2 H, SOMe, SO 2 Me, SO 2 CF 3 , SO 2 NH 2 , SO 3 H, SO 3 Me, and cyclopropyl. 
     
     
         9 . The method according to  claim 33 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       and wherein subscript n′ is selected from 1-5 and each R 5  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, —SO 3 H, —SO 3 R 61b , wherein R 61b  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —S(O 2 )R 61 , wherein R 61  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —SOR 61a , wherein R 61a  is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, —SR, wherein R is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and SH. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method according to  claim 9 , wherein the subscript n′ is 1 or 2; and each R 5  is independently selected from H, Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO 2 Me, CH 2 —N-morpholino, CH 2 —N-(4-Me-piperidino), NH 2 , CONH 2 , CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SMe, CH═CH—CO 2 H, SOMe, SO 2 Me, SO 2 CF 3 , SO 2 NH 2 , SO 3 H, SO 3 Me, cyclopropyl, triazolyl, morpholinyl, and pyridyl. 
     
     
         13 . The method according to  claim 33 , wherein the compound is according to formula 4a, 4b, or 4c: 
       
         
           
           
               
               
           
         
       
       and wherein R 2  is as in  claim 33 ; R 3  is halo, substituted or unsubstituted C 1 -C 6  alkyl or cycloalkyl; and each R 5  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, —SO 3 H, —SO 3 R 61b , wherein R 61b  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —S(O 2 )R 61 , wherein R 61  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —SOR 61a , wherein R 61a  is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, —SR, wherein R is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and SH. 
     
     
         14 . The method according to  claim 9 , wherein each R 5  is independently selected from H, Me, Et, Pr, iso-Pr, Ph, Cl, F, CN, OH, OMe, OEt, OPh, CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SO 2 Me, SO 2 CF 3 , and SO 3 Me. 
     
     
         15 . A compound according to  claim 9 , wherein R 5  is H, Cl, F, Me, CF 3 , or OMe. 
     
     
         16 . The method according to  claim 33 , wherein R 2  is selected from H, Me, Et, n-Pr, t-Bu, CF 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 (CH 2 ) 2 OH, CH 2 CH 2 NHMe, CH 2 NMe 2 , CH 2 CH 2 NMe 2 , CH 2 CONH 2 , CH 2 CONMe 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 (CH 2 ) 2 COOH, CH 2 OMe, and CH 2 CH 2 OMe. 
     
     
         17 . The method according to  claim 33 , wherein R 2  is selected from CH 2 NR 2′ R 2″ , CH 2 CH 2 NR 2′ R 2″ , and CH 2 CH 2 CH 2 NR 2′ R 2″ ; and wherein R 2′  and R 2″  can join together to form a heterocyclic ring. 
     
     
         18 . The method according to  claim 33 , wherein R 2  is selected from cyclopropyl, cyclobutyl or cyclohexyl. 
     
     
         19 . The method according to  claim 33 , wherein R 2  is Me. 
     
     
         20 . The method according to  claim 33 , R 2  is CH 2 OH or CH 2 CH 2 OH. 
     
     
         21 . The method according to  claim 33 , wherein R 3  is substituted or unsubstituted alkyl. 
     
     
         22 . The method according to  claim 33 , wherein R 3  is Me or CF 3 . 
     
     
         23 . (canceled) 
     
     
         24 . The method according to  claim 33 , R 3  is Cl. 
     
     
         25 . The method according to  claim 33 , wherein the compound is according to formula 5a, 5b, or 5c: 
       
         
           
           
               
               
           
         
       
       and wherein R 2  is as in  claim 33 ; and R 5  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, —SO 3 H, —SO 3 R 61b , wherein R 61b  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —S(O 2 )R 61 , wherein R 61  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —SOR 61a , wherein R 61a  is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, —SR, wherein R is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and SH. 
     
     
         26 . The method according to  claim 25 , wherein R 2  is H, Me, Et, CH 2 OH, or CH 2 CH 2 OH. 
     
     
         27 . The method according to  claim 25 , wherein R 5  is H, Cl, F, Me, CF 3 , or OMe. 
     
     
         28 . The method according to  claim 33 , selected from the group consisting of:
 5-Methyl-2-{4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Bromo-2-{4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Cyclopropyl-2-{4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Trifluoromethyl-2-{4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Bromo-2-{4-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Methyl-2-{4-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Fluoro-2-{4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(2-methyl-6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(6-dimethylamino-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(6-methoxy-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Bromo-2-{4-[(6-methoxy-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Chloro-2-{4-[(3-chloro-5-trifluoromethyl-pyridin-2-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(5-trifluoromethyl-pyridin-2-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   (R)-3-[6-(4-Chloro-2-cyano-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3-(6-methoxy-pyridin-3-yl)-propionic acid tert-butyl ester;   (R)-3-[6-(4-Chloro-2-cyano-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3-(6-methoxy-pyridin-3-yl)-propionic acid;   5-Chloro-2-{4-[(R)-3-hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(R)-3-Hydroxy-1-(6-methyl-pyridin-3-yl)-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(R)-1-(6-Difluoromethyl-pyridin-3-yl)-3-hydroxy-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(S)-2-Hydroxy-1-(6-methoxy-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(R)-3-Hydroxy-1-(6-methoxy-pyridin-3-yl)-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[3-Hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(S)-2-Methoxy-1-(6-methoxy-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(6-Chloro-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(5-Chloro-pyridin-2-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Methyl-2-{4-[(pyridin-2-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(5-Cyclopropyl-pyridin-2-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(4-Amino-2-methyl-pyrimidin-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(3,5-Dichloro-pyridin-2-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(6-Ethyl-pyridin-3-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Chloro-2-{4-[(R)-3-hydroxy-1-(6-methoxy-pyridin-3-yl)-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(S)-2-hydroxy-1-(6-methoxy-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-[4-(3-Cyano-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   2-{4-[(Imidazo[1,2-a]pyridin-7-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(Benzooxazol-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Methyl-2-{4-[(2-methyl-pyrimidin-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Methyl-2-[4-(4-methyl-3-[1,2,4]triazol-1-yl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   (R)-3-[6-(2-Cyano-4-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3-(6-methoxy-pyridin-3-yl)-propionic acid;   (R)-3-[6-(2-Cyano-4-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3-(6-methoxy-pyridin-3-yl)-propionamide;   (R)-3-[6-(2-Cyano-4-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3-(6-methoxy-pyridin-3-yl)-N,N-dimethyl-propionamide;   5-Chloro-2-{4-[(imidazo[1,2-a]pyridin-7-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(2-methyl-pyrimidin-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(S)-2-Hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Chloro-2-{4-[(S)-2-hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-[4-(3-Fluoro-4-methyl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   5-Methyl-2-[4-(4-methyl-3-methylsulfanyl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   2-[4-(4-Chloro-3-[1,2,4]triazol-4-yl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   5-Chloro-2-[4-(3-[1,2,4]triazol-4-yl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   5-Chloro-2-[4-(4-chloro-3-[1,2,4]triazol-4-yl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   5-Methyl-2-[4-(3-[1,2,4]triazol-4-yl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   2-{4-[(4-Amino-2-methoxy-pyrimidin-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-[4-(3-Iodo-4-methyl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   5-Chloro-2-{4-[(R)-1-(2-methoxy-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(R)-1-(2-Methoxy-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-[4-(3-Methanesulfonyl-4-methyl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   2-{4-[(S)-2-Hydroxy-1-(2-methoxy-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(2-Isopropyl-pyrimidin-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Chloro-2-{4-[(R)-1-(6-difluoromethyl-pyridin-3-yl)-3-hydroxy-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Methyl-2-[4-(4-methyl-3-morpholin-4-yl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   2-{4-[(R)-3-Hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(S)-3-Hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-propylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Methyl-2-{4-[(R)-1-(2-methyl-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Methyl-2-{4-[(S)-1-(2-methyl-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(2-Methoxy-pyrimidin-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Chloro-2-{4-[(2-methoxy-pyrimidin-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(S)-1-(6-Difluoromethyl-pyridin-3-yl)-2-hydroxy-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-[4-(4-Chloro-3-methanesulfonyl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   5-Chloro-2-{4-[(S)-1-(6-difluoromethyl-pyridin-3-yl)-2-hydroxy-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-{4-[(S)-2-hydroxy-1-(2-methyl-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(S)-2-Hydroxy-1-(2-methyl-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Chloro-2-{4-[(R)-1-(2-methyl-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Chloro-2-[4-(3-methanesulfonyl-4-methyl-benzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   Acetic acid (R)-3-[6-(2-cyano-4-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3-(6-trifluoromethyl-pyridin-3-yl)-propyl ester;   5-Chloro-2-{4-[(S)-2-hydroxy-1-(2-methoxy-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Methyl-2-{4-[(quinoxalin-6-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Methyl-2-{4-[(quinolin-2-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(1H-Indol-6-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-[4-(1-Benzo[1,3]dioxol-5-yl-ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   5-Chloro-2-{4-[(quinoxalin-6-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   5-Methyl-2-[4-(1-pyrazin-2-yl-ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   5-Methyl-2-[4-(1-quinoxalin-6-yl-ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   2-{4-[(S)-1-(2-Methoxy-pyrimidin-5-yl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[1-(4-Chloro-3-methanesulfonyl-phenyl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-[4-((R)-1-Benzo[1,3]dioxol-5-yl-ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   2-[4-((S)-1-Benzo[1,3]dioxol-5-yl-ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   2-{4-[1-(3-Methanesulfonyl-4-methyl-phenyl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Methyl-2-{4-[(quinolin-7-ylmethyl)-amino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-benzonitrile;   2-{4-[(R)-1-(4-Chloro-3-methanesulfonyl-phenyl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   2-{4-[(S)-1-(4-Chloro-3-methanesulfonyl-phenyl)-ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-5-methyl-benzonitrile;   5-Methyl-2-[4-((R)-1-quinoxalin-6-yl-ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile; and   5-Methyl-2-[4-((S)-1-quinoxalin-6-yl-ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-benzonitrile;   2-[4-(3-cyano-4-methylbenzylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-methyl-benzonitrile;   or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.   
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . 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 pharmaceutical composition,
 said pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to formula 1:   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is aryl or heteroaryl unsubstituted or substituted with one or more R 4  groups; 
 R 2  is H, substituted or unsubstituted C 1 -C 6  alkyl or cycloalkyl; 
 each R 3  and R 4  is independently selected from the group consisting of H, alkyl, acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, arylalkyloxy, amino, aryl, —SO 3 H, —SO 3 R 61b , wherein R 61b  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —S(O 2 )R 61 , wherein R 61  is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, —SOR 61a , wherein R 61a  is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, —SR, wherein R is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, azido, carbamoyl, carboxyl, cyano, cycloalkyl, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro, and SH; and 
 
       m is 1, 2, 3, or 4; 
       or a pharmaceutically acceptable salt, tautomer or isotopic variant thereof. 
     
     
         34 . The method of  claim 33 , 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. 
     
     
         35 . The method of  claim 34 , wherein the disease or condition is Parkinson's disease. 
     
     
         36 . The method of  claim 34 , wherein the disease or condition is Alzheimer's disease. 
     
     
         37 . The method of  claim 34 , wherein the disease or condition is pain. 
     
     
         38 . The method of  claim 37 , wherein the pain is associated with a condition selected from the group consisting of postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, Charcot's pain, toothache, venomous snake bite, spider bite, insect sting, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgis, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, sciatic neuritis, peripheral neuritis, polyneuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, egniculate neuralgia, glossopharyngial neuralgia, migranous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache, tension headache, labor, childbirth, intestinal gas, menstruation, cancer, and trauma. 
     
     
         39 . The method of  claim 38 , wherein the disease or condition is neuropathic pain. 
     
     
         40 . The method of  claim 38 , wherein the disease or condition is an autoimmune disease. 
     
     
         41 . The method of  claim 38 , wherein the disease or condition is an inflammatory disease or condition. 
     
     
         42 . The method of  claim 38 , wherein the disease or condition is a neurological or neurodegenerative disease or condition. 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled)