Synthetic Compounds and Derivatives as Modulators of Smoking or Nicotine Ingestion and Lung Cancer

Abstract

Disclosed are nicotine-related compounds that selectively inhibit cytochrome P-450 2A6 (CYP2A6), selectively inhibit cytochrome P-450 2A13 (CYP2A13), and/or selectively modulate a nicotinic acetylcholine receptor (nAChR). Also disclosed are pharmaceutical compositions comprising a compound of the invention, as well as methods of using the pharmaceutical compositions for treating or preventing a disease or disorder associated with nicotine-ingestion, or a disease or disorder amenable to treatment by selective modulation of nAChRs.

1 . A compound having Formula I: 
       
         
           
           
               
               
           
         
         wherein A, B, C, D, E and F constitute part of a 3-, 4-, 5- or 6-member ring system of unsaturated, partially unsaturated or saturated heterocyclic and carbocyclic rings, wherein the A, B, C, D, E and F ring system is optionally substituted with hydrido, acyl, halo, lower acyl, lower haloakyl, oxo, cyano, nitro, carboxyl, amino, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, alkylamino, arylamino, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, alkylthio, alkylsulfinyl, aryl, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, and lower N-alkyl-N-arylaminosulfonyl; wherein aryl of the A, B, C, D, E and F ring system is selected from phenyl, biphenyl, and naphthyl, 5-membered heteroaryl, and 6-membered heteroaryl, and is optionally substituted with one or two substituents selected from the group consisting of halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, and lower carbonylalkoxy; and wherein the acyl group is optionally substituted with a substituent selected from hydrido, alkyl, halo, and alkoxy; 
         wherein G, H, I, J, K, L M, N, O and P are independently selected from the group consisting of aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heteroaralkyloxy, aroyl, aroylalkyl, aryloxy, aryloxyalkyl, hydrido, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, acylalkyl, acyloxy, acyloxyalkyl, halo, haloalkyl, cyano, cyanoalkyl, nitro, nitroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carbamoylalkyl, carbamoylalkoxy, iminoalkyl, imidoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, arylamino, arylaminoalkyl, hydroxy, hydroxyalkyl, isocyano, isocyanoalkyl, isothiocyano, isothiocyanoalkyl, oximinoalkoxy, morpholino, morpholinoalkyl, azido, azidoalkyl, formyl, formylalkyl, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; wherein the aryl of G, H, I, J, K, L M, N, O and/or P is optionally substituted and is selected from the group consisting of phenyl, biphenyl, naphthyl, 5-membered heteroaryl, and 6-membered heteroaryl. 
       
     
     
         2 . The compound of  claim 1 , wherein the heterocycles which make up the central ring systems of formula I comprising the A, B, C, D, E and F atoms are selected from the group consisting of pyrrolidine, piperidine, piperazine, heptamethyleneimine, hexamethyleneimine, homopiperazine, perhydroindole, azetidine, 4-piperidinopiperidine, 1-azacycloheptane, imidazoyl, perhydroisoquioline, decahydroquinoline, 1-phenylpiperazine. 4-phenylpiperidine, 1-(fluorophenyl)piperazine, 1,3,5-hexa-hydrotriazine, morpholine, phenylmorpholine, thiomorpholine, tetrahydrothiophene, thiazolidine, ω-thiocaprolactam, 1,4-thioxane, 1,3-dithiane, 1,4,7-trithiacyclononane, 1,3,5-trithiane, tetrahydrofuran, tetramethyleneoxide, tetrahydropyran, 1,3,5-trioxane, and oxepane,
 wherein the heterocycles optionally have one or two ring hydrogens substituted with substituents selected from the group consisting of Cl, Br, I, —OR 4 , —R 5 , —OC(O)R 6 , OC(O)NR 7 R 8 , —C(O)R 9 , —CN, —NR 10 R 11 , —SR 12 , —S(O)R 11 , —S(O) 2 R 14 , —C(O)OR 15 , —S(O) 2 NR 16 R 17 ; and —R 18 NR 19 R 20 , wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms or hydrogen radicals.   
     
     
         3 . The compound of  claim 1 , wherein the A B, C, D, E and F ring system is a radical selected from pyranyl, furyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, oxazolyl, pyrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and pyridyl. 
     
     
         4 . The compound of  claim 1 , wherein two adjacent groups selected from G, H, I, J, K, L M, N, O and P are joined together to form a part of a fused carbocyclic or heterocyclic ring system. 
     
     
         5 . The compound of  claim 4 , wherein L and M are part of a second ring that is fused to the C, D, E, F ring. 
     
     
         6 . The compound of  claim 1  having Formula II: 
       
         
           
           
               
               
           
         
         wherein C, D, E and F constitute a 5-membered ring containing carbon, oxygen, sulfur, nitrogen, or phosphorus; X is the A, B ring system defined as in  claim 1 ; and L, M, N, and O are defined as in  claim 1 . 
       
     
     
         7 . The compound of  claim 6 , wherein C is a carbon; D is an oxygen, sulfur, or nitrogen; E is a carbon; and L, M, N, O and X are independently selected from aminoalkyl, alkylaminoalkyl, arylaminoalkyl, dialkylaminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, haloalkyl, cyanoalkyl, iminoalkyl, imidoalkyl, isothiocyanoalkyl, morpholinoalkyl, azidoalkyl, and formylalkyl. 
     
     
         8 . The compound of  claim 7  which is C-(5-pyridin-3-yl-tetrahydro-furan-2-yl)-methylamine, 3-(5-bromomethyl-tetrahydro-furan-2-yl)-pyridine, 3-(5-ethyl-tetrahydro-furan-2-yl)-pyridine, or (5-pyridin-3-yl-tetrahydro-furan-2-yl)-methanol. 
     
     
         9 . The compound of  claim 1  having Formula III: 
       
         
           
           
               
               
           
         
         wherein A, B, G, H, N, O and P are defined as in  claim 1 . 
       
     
     
         10 . The compound of  claim 9 , wherein A is a nitrogen, B is a carbon, and Q is a 5- or 6-member unsaturated, partially unsaturated or saturated heterocyclic and carbocyclic ring,
 wherein the ring system is optionally substituted with a group selected from the group consisting of hydrido, acyl, halo, lower acyl, lower haloakyl, oxo, cyano, nitro, carboxyl, amino, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, alkylamino, arylamino, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, alkylthio, alkylsulfinyl, aryl, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, and lower N-alkyl-N-arylaminosulfonyl;   wherein aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, 5-membered heteroaryl, and 6-membered heteroaryl, and wherein aryl is optionally substituted with one or two substituents selected from the group consisting of halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, lower carbonylalkoxy; and   wherein the acyl group is optionally substituted with a substituent selected from the group consisting of hydrido, alkyl, halo, and alkoxy.   
     
     
         11 . The compound of  claim 9 , wherein the Q ring is a substituted or unsubstituted radical selected from the group consisting of pyrrolyl, N-methylpyrrolyl, pyranyl, furyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, oxazolyl, pyrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and pyridyl; and optionally has one or two ring hydrogens substituted with substituents selected from the group consisting of Cl, Br, I, —OR 4 , —R 5 , —OC(O)R 6 , OC(O)NR 7 R 8 , —C(O)R 9 , —CN, —NR 10 R 11 , —SR 12 , —S(O)R 11 , —S(O) 2 R 14 , —C(O)OR 15 , —S(O) 2 NR 16 R 17 ; and —R 18 NR 19 R 20 , wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms or hydrogen radicals. 
     
     
         12 . The compound of  claim 10  which is 3-(4-methyl-thiophen-3-yl)-pyridine, 3-(1H-imidazol-4-yl)-pyridine, 3-pyrazol-1-yl-pyridine, 3-thiophen-2-yl-pyridine, [3,3′]bipyridinyl, or 3-thiazol-2-yl-pyridine. 
     
     
         13 . The compound of  claim 1  having Formula IV: 
       
         
           
           
               
               
           
         
         wherein G is the A, B ring system defined as in  claim 1 ; X is a saturated carbon chain from C 2 -C 8 ; Y is a carbon, oxygen, sulfur, nitrogen or phosphorus atom; and R is alkyl, akenyl, alkynyl, optionally substituted aryl, or aralkyl. 
       
     
     
         14 . The compound of  claim 13 , wherein X is ethylene; Y is oxygen, sulfur, or nitrogen; R is hydrogen; and G is 3-pyridyl. 
     
     
         15 . The compound of  claim 13 , which is bis-[2-(5-pyridin-3-yl-tetrahydro-furan-2-yl)-ethyl]-amine. 
     
     
         16 . The compound of  claim 1  having Formula V: 
       
         
           
           
               
               
           
         
         wherein G is the A, B ring system defined as in  claim 1 , X is a saturated carbon chain from C 2 -C 8 ; R is hydrogen, alkyl, akenyl, alkynyl, optionally substituted aryl, or aralkyl; and S and T are independently selected from the group consisting of hydrogen, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heteroaralkyloxy, aroyl, aroylalkyl, aryloxy, aryloxyalkyl, hydrido, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, acylalkyl, acyloxy, acyloxyalkyl, halo, haloalkyl, cyano, cyanoalkyl, nitro, nitroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carbamoylalkyl, carbamoylalkoxy, iminoalkyl, imidoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, arylamino, arylaminoalkyl, hydroxy, hydroxyalkyl, isocyano, isocyanoalkyl, isothiocyano, isothiocyanoalkyl, oximinoalkoxy, morpholino, morpholinoalkyl, azido, azidoalkyl, formyl, formylalkyl, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; 
         wherein the aryl of S and/or T is optionally substituted and is selected from the group consisting of phenyl, biphenyl, naphthyl, 5-membered heteroaryl, and 6-membered heteroaryl. 
       
     
     
         17 . The compound of  claim 16 , wherein the heterocycles which make up the Y ring system of Formula V including the S and T substituents are independently selected from the group consisting of pyrrolidine, piperidine, piperazine, heptamethyleneimine, hexamethyleneimine, homopiperazine, perhydroindole, azetidine, 4-piperidinopiperidine, 1-azacycloheptane, imidazoyl, perhydroisoquioline, decahydroquinoline, 1-phenylpiperazine. 4-phenylpiperidine, 1-(fluorophenyl)piperazine, 1,3,5-hexa-hydrotriazine, morpholine, phenylmorpholine, thiomorpholine, tetrahydrothiophene, thiazolidine, co-thiocaprolactam, 1,4-thioxane, 1,3-dithiane, 1,4,7-trithiacyclononane, 1,3,5-trithiane, tetrahydrofuran, tetramethyleneoxide, tetrahydropyran, 1,3,5-trioxane, and oxepane, and optionally have one or two ring hydrogens substituted with substituents selected from the group consisting of Cl, Br, I, —OR 4 , —R 5 , —OC(O)R 6 , OC(O)NR 7 R 8 , —C(O)R 9 , —CN, —NR 10 R 11 , —SR 12 , —S(O)R 11 , —S(O) 2 R 14 , —C(O)OR 15 , —S(O) 2 NR 16 R 17 ; and —R 18 NR 19 R 20 , wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms or hydrogen radicals. 
     
     
         18 . The compound of  claim 16 , wherein the Y ring system is a radical selected from the group consisting of pyranyl, furyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, oxazolyl, pyrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and pyridyl. 
     
     
         19 . The compound of  claim 16 , wherein X is ethylene; the Y ring is a furan; R, S, and T are hydrogen; and G is 3-pyridyl. 
     
     
         20 . The compound of  claim 19 , which is bis-[2-(5-pyridin-3-yl-furan-2-yl)-ethyl]-amine or bis-[2-(5-pyridin-3-yl-thiophen-2-yl)-ethyl]-amine. 
     
     
         21 . The compound of  claim 1  having Formula VI: 
       
         
           
           
               
               
           
         
         wherein G is the A, B ring system defined as in  claim 1 ; X is a saturated carbon chain from C 2 -C 8 ; and Y is a carbon, oxygen, sulfur, nitrogen or phosphorus atom. 
       
     
     
         22 . The compound of  claim 21 , wherein X is ethylene; Y is oxygen, sulfur, or nitrogen; and G is 3-pyridyl. 
     
     
         23 . The compound of  claim 1  having Formula VII: 
       
         
           
           
               
               
           
         
         wherein G is the A, B ring system defined as in  claim 1 ; X is a saturated carbon chain from C 2 -C 8 ; R is alkyl, akenyl, alkynyl, optionally substituted aryl, or aralkyl; and S and T are independently selected from the group consisting of hydrogen, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heteroaralkyloxy, aroyl, aroylalkyl, aryloxy, aryloxyalkyl, hydrido, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, acylalkyl, acyloxy, acyloxyalkyl, halo, haloalkyl, cyano, cyanoalkyl, nitro, nitroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carbamoylalkyl, carbamoylalkoxy, iminoalkyl, imidoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, arylamino, arylaminoalkyl, hydroxy, hydroxyalkyl, isocyano, isocyanoalkyl, isothiocyano, isothiocyanoalkyl, oximinoalkoxy, morpholino, morpholinoalkyl, azido, azidoalkyl, formyl, formylalkyl, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; 
         wherein the aryl of S and/or T is optionally substituted and is selected from the group consisting of phenyl, biphenyl, naphthyl, 5-membered heteroaryl, and 6-membered heteroaryl. 
       
     
     
         24 . The compound of  claim 23 , wherein the heterocycles which make up the Y ring system of Formula VII including the S and T substituents are selected from the group consisting of pyrrolidine, piperidine, piperazine, heptamethyleneimine, hexamethyleneimine, homopiperazine, perhydroindole, azetidine, 4-piperidinopiperidine, 1-azacycloheptane, imidazoyl, perhydroisoquioline, decahydroquinoline, 1-phenylpiperazine. 4-phenylpiperidine, 1-(fluorophenyl)piperazine, 1,3,5-hexa-hydrotriazine, morpholine, phenylmorpholine, thiomorpholine, tetrahydrothiophene, thiazolidine, ω-thiocaprolactam, 1,4-thioxane, 1,3-dithiane, 1,4,7-trithiacyclononane, 1,3,5-trithiane, tetrahydrofuran, tetramethyleneoxide, tetrahydropyran, 1,3,5-trioxane, and oxepane, and optionally have one or two ring hydrogens substituted with substituents selected from the group consisting of Cl, Br, I, —OR 4 , —R 5 , —OC(O)R 6 , OC(O)NR 7 R 8 , —C(O)R 9 , —CN, —NR 10 R 11 , —SR 12 , —S(O)R 11 , —S(O) 2 R 14 , —C(O)OR 15 , —S(O) 2 NR 16 R 17 ; and —R 18 NR 19 R 20 , wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms or hydrogen radicals. 
     
     
         25 . The compound of  claim 23 , wherein the Y ring system is a radical selected from the group consisting of pyranyl, furyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, oxazolyl, pyrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and pyridyl. 
     
     
         26 . The compound of  claim 23 , wherein X is ethylene; the Y ring is a furan; S and T are hydrogen; and G is 3-pyridyl. 
     
     
         27 . The compound of  claim 26 , which is tris-[2-(5-pyridin-3-yl-furan-2-yl)-ethyl]-amine or tris-[2-(5-pyridin-3-yl-thiophen-2-yl)-ethyl]-amine. 
     
     
         28 . The compound of  claim 1  having Formula VIII: 
       
         
           
           
               
               
           
         
         wherein G is the A, B ring system defined as in  claim 1 ; R is alkyl, akenyl, alkynyl, optionally substituted aryl, or aralkyl; and X is selected from the group consisting of aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heteroaralkyloxy, aroyl, aroylalkyl, aryloxy, aryloxyalkyl, hydrido, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, acylalkyl, acyloxy, acyloxyalkyl, halo, haloalkyl, cyano, cyanoalkyl, nitro, nitroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carbamoylalkyl, carbamoylalkoxy, iminoalkyl, imidoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, arylamino, arylaminoalkyl, hydroxy, hydroxyalkyl, isocyano, isocyanoalkyl, isothiocyano, isothiocyanoalkyl, oximinoalkoxy, morpholino, morpholinoalkyl, azido, azidoalkyl, formyl, formylalkyl, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; wherein the aryl of X is selected from phenyl, biphenyl, naphthyl, 5-membered heteroaryl, and 6-membered heteroaryl and is optionally substituted. 
       
     
     
         29 . The compound of  claim 28 , wherein X is prop-2-ynyl, R is hydrogen, and G is 3-pyridyl. 
     
     
         30 . The compound of  claim 29 , which is 3-pyridin-3-yl-prop-2-ynylamine. 
     
     
         31 . The compound of  claim 1  having Formula IX: 
       
         
           
           
               
               
           
         
         wherein G is the A, B ring system defined as in  claim 1 ; X is a saturated carbon chain from C 2 -C 8 , alkyl, akenyl, alkynyl, optionally substituted aryl, or aralkyl; R is alkyl, akenyl, alkynyl, optionally substituted aryl, or aralkyl; and S, T and U are independently selected from the group consisting of hydrogen, aminoalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heteroaralkyloxy, aroyl, aroylalkyl, aryloxy, aryloxyalkyl, hydrido, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, acylalkyl, acyloxy, acyloxyalkyl, halo, haloalkyl, cyano, cyanoalkyl, nitro, nitroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carbamoylalkyl, carbamoylalkoxy, iminoalkyl, imidoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, arylamino, arylaminoalkyl, hydroxy, hydroxyalkyl, isocyano, isocyanoalkyl, isothiocyano, isothiocyanoalkyl, oximinoalkoxy, morpholino, morpholinoalkyl, azido, azidoalkyl, formyl, formylalkyl, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; 
         wherein the aryl of S, T and/or U is optionally substituted and is selected from the group consisting of phenyl, biphenyl, naphthyl, 5-membered heteroaryl, and 6-membered heteroaryl. 
       
     
     
         32 . The compound of  claim 31 , wherein the heterocycle which makes up the Y ring system including the S, T and U substituents is selected from the group consisting of pyrrolidine, piperidine, piperazine, heptamethyleneimine, hexamethyleneimine, homopiperazine, perhydroindole, azetidine, 4-piperidinopiperidine, 1-azacycloheptane, imidazoyl, perhydroisoquioline, decahydroquinoline, 1-phenylpiperazine. 4-phenylpiperidine, 1-(fluorophenyl)piperazine, 1,3,5-hexa-hydrotriazine, morpholine, phenylmorpholine, thiomorpholine, tetrahydrothiophene, thiazolidine, co-thiocaprolactam, 1,4-thioxane, 1,3-dithiane, 1,4,7-trithiacyclononane, 1,3,5-trithiane, tetrahydrofuran, tetramethyleneoxide, tetrahydropyran, 1,3,5-trioxane, and oxepane, and optionally has one or two ring hydrogens substituted with substituents selected from the group consisting of Cl, Br, I, —OR 4 , —R 5 , —OC(O)R 6 , OC(O)NR 7 R 8 , —C(O)R 9 , —CN, —NR 10 R 11 , —SR 12 , —S(O)R 11 , —S(O) 2 R 14 , —C(O)OR 15 , —S(O) 2 NR 16 R 17 ; and —R 18 NR 19 R 20 , wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms or hydrogen radicals. 
     
     
         33 . The compound of  claim 31 , wherein the Y ring system is a radical selected from the group consisting of pyranyl, furyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, oxazolyl, pyrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and pyridyl. 
     
     
         34 . The compound of  claim 31 , wherein X is ethynyl; the Y ring is a substituted or unsubstituted thiophene; S, T and U are hydrogen; and G is 3-pyridyl. 
     
     
         35 . The compound of  claim 34 , which is 3-thiophen-2-ylethynyl-pyridine or 3-(3-methyl-thiophen-2-ylethynyl)-pyridine. 
     
     
         36 . The compound of  claim 34 , which is 3-thiophen-2-ylethenyl-pyridine or 3-[2-(3-methyl-thiophen-2-yl)-vinyl]-pyridine. 
     
     
         37 . The compound of  claim 1  having Formula X: 
       
         
           
           
               
               
           
         
         wherein C, D and E constitute a 3-membered ring containing carbon, oxygen, sulfur, nitrogen, or phosphorus; X is the A, B ring system defined as in  claim 1 ; and I and J are defined as in  claim 1 . 
       
     
     
         38 . The compound of  claim 37 , wherein C, D and E are each carbon and I, J and X are independently selected from the group consisting of aminoalkyl, alkylaminoalkyl, arylaminoalkyl, dialkylaminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, haloalkyl, cyanoalkyl, iminoalkyl, imidoalkyl, isothiocyanoalkyl, morpholinoalkyl, azidoalkyl, and formylalkyl. 
     
     
         39 . The compound of  claim 38 , which is 2-pyridin-3-yl-cyclopropylamine. 
     
     
         40 . The compound of  claim 37 , wherein C and D are each carbon; E is oxygen, sulfur, or nitrogen; and I, J and X are independently selected from the group consisting of aminoalkyl, alkylaminoalkyl, arylaminoalkyl, dialkylaminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, haloalkyl, cyanoalkyl, iminoalkyl, imidoalkyl, isothiocyanoalkyl, morpholinoalkyl, azidoalkyl, and formylalkyl. 
     
     
         41 . A pharmaceutical composition comprising:
 (a) the compound of  claim 1 , or a pharmaceutically acceptable salt, ester, or amide thereof, and   (b) a pharmaceutically acceptable carrier.   
     
     
         42 . A method for treating nicotine addiction in a subject comprising:
 administering to a subject suffering from nicotine addiction an effective amount of a compound having the formula set forth in  claim 1 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein said compound selectively inhibits CYP2A6.   
     
     
         43 . The method of  claim 42 , wherein the compound is a dual inhibitor of CYP2A6 and CYP2A 13. 
     
     
         44 . The method of  claim 42 , wherein the agent selectively modulates α- and/or α/β-nicotinic acetylcholine receptors (nAChR). 
     
     
         45 . (canceled) 
     
     
         46 . A method for reducing the risk of developing cancer in a subject comprising:
 administering to the subject an effective amount of a compound having the formula set forth in  claim 1 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein the compound selectively inhibits CYP2A6 and thereby inhibits mutagenic activation of a promutagen metabolized by CYP2A6.   
     
     
         47 - 48 . (canceled) 
     
     
         49 . A method for treating or preventing a neurodegenerative disease in a subject comprising:
 administering to a subject an effective amount of a compound having the formula set forth in  claim 1 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein said compound selectively modulates α7 nicotinic acetylcholine receptor (nAChR), and wherein said subject is suffering from or is at risk of developing the neurodegenerative disease.   
     
     
         50 - 51 . (canceled) 
     
     
         52 . A method for enhancing cognition is a subject comprising:
 administering to a subject in need of cognition enhancement an effective amount of a compound having the formula set forth in  claim 1 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein said compound selectively stimulates nicotinic acetylcholine receptor (nAChR).   
     
     
         53 . (canceled) 
     
     
         54 . A method for treating or preventing a psychiatric disorder in a subject comprising:
 administering to a subject an effective amount of a compound having the formula set forth in  claim 1 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein said compound selectively modulates nicotinic acetylcholine receptor (nAChR), and wherein said subject is suffering from or is a risk of developing the psychiatric disorder.   
     
     
         55 - 56 . (canceled) 
     
     
         57 . A method for inducing a neuroprotective effect in a subject comprising:
 administering to the subject an effective amount of an agent that selectively binds nicotinic acetylcholine receptor (nAChR), said agent comprising a compound having the formula set forth in  claim 1 , wherein said compound selectively modulates nicotinic acetylcholine receptor (nAChR), and wherein said subject is in need of the neuroprotective effect.   
     
     
         58 . (canceled) 
     
     
         59 . A compound selected from the group consisting of
 (A) a compound having Formula XI:   
       
         
           
           
               
               
           
         
         wherein a 1 , a 2 , a 3 , a 4 , a 5  and a 6  are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, or is absent; 
         b n  is a substituent selected from the group consisting of hydrogen, methyl, lower alkyl, aminomethyl, N-methylaminomethyl, benzyl, oximino, amino, nitro, ethyl, formyl, bromomethyl, heteroarylaminomethyl, heteroaryl, 3-(3-methylthienyl)pyridyl, 2-(3-methyl)thienyl, 3-thienyl, CH 3 (C═O)—, N,N-dimethylaminomethyl, aminopropyl, hydroxymethyl, pyridyl and oxo; or alternatively, any two substituents adjacent to each other on the 5- or 6-membered ring may be taken together with the atoms to which they are attached to form a 5- or 6-membered aryl or heteroaryl ring system; 
         n is an integer from 0 to 10; 
         c is hydrogen or amino; 
         d is selected from the group consisting of hydrogen, fluoro, methoxy, amino and chloro; and 
         e is a substituent selected from the group consisting of hydrogen, methyl, 2-(3-methyl)thienyl, CH 3 O(C═O)—, bromo, ethynyl, 3-thienyl and hydroxymethyl; and 
         (B) a compound having Formula (XII): 
       
       
         
           
           
               
               
           
         
         wherein f and g are each carbon or nitrogen atom; and wherein f and g are connected to each other by a single, double or triple bond; 
         h and i are each independently hydrogen, lower alkyl group, or is absent; wherein h and i together with the atoms to which they attached may optionally be combined to form a 3- to 5-membered ring; 
         j is selected from the group consisting of aminomethyl, N-methylaminomethyl, amino, 2-(3-methyl)thienyl, 3-thienyl, N,N-dimethylaminomethyl, heteroaryl and 3-(3-methylthienyl)pyridyl; 
         c is hydrogen or amino; 
         d is selected from the group consisting of hydrogen, fluoro, methoxy, amino and chloro; and 
         e is a substituent selected from the group consisting of hydrogen, methyl, 2-(3-methylthienyl), CH 3 O(C═O)—, bromo, ethynyl, 3-thienyl and hydroxymethyl. 
       
     
     
         60 . The compound of  claim 59 , wherein a 1 , a 2 , a 3 , a 4 , a 5  and a 6  are part of a 5- or 6-membered, unsaturated or partially unsaturated, ring system. 
     
     
         61 . The compound of  claim 59 , wherein a 1  and a 2  are carbon and a 3 , a 4 , a 5  and a 6  are absent. 
     
     
         62 . The compound of  claim 59  wherein, a 1 , a 2 , a 3 , a 4 , a 5  and a 6  form a 5- or 6-member ring system selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         63 . (canceled) 
     
     
         64 . The compound of  claim 63 , wherein the fragment 
       
         
           
           
               
               
           
         
       
       of Formula XII is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         65 . A pharmaceutical composition comprising:
 (a) the compound of  claim 59 , or a pharmaceutically acceptable salt, ester, or amide thereof, and   (b) a pharmaceutically acceptable carrier.   
     
     
         66 . A method for treating nicotine addiction in a subject comprising:
 administering to a subject suffering from nicotine addiction an effective amount of a compound having the formula set forth in  claim 59 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein said compound selectively inhibits CYP2A6.   
     
     
         67 - 68 . (canceled) 
     
     
         69 . A method for reducing the risk of developing cancer in a subject comprising:
 administering to the subject an effective amount of a compound having the formula set forth in  claim 59 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein the compound selectively inhibits CYP2A6 and thereby inhibits mutagenic activation of a promutagen metabolized by CYP2A6.   
     
     
         70 - 71 . (canceled) 
     
     
         72 . A compound having Formula XIII: 
       
         
           
           
               
               
           
         
         wherein R a , R c , and R e  are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, heteroalkyl, halo, (C1-C6)alkoxy, amino, (C1-C6)alkylamino, hydroxy, cyano, and nitro; 
         R b  is a 5- or 6-member unsaturated, partially unsaturated or saturated heterocyclic and carbocyclic ring system; wherein the R b  ring system is optionally substituted with hydrido, acyl, halo, lower acyl, lower haloakyl, oxo, cyano, nitro, carboxyl, amino, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, alkylamino, arylamino, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, alkylthio, alkyl sulfinyl and aryl, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, lower N-alkyl-N-arylaminosulfonyl; in which the above aryl member is selected from phenyl, biphenyl, naphthyl, or 5- or 6-membered heteroaryl; wherein the above aryl member is optionally substituted with one, two, or three substituents selected from halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, and lower carbonylalkoxy; and wherein the above acyl group is optionally substituted with a substituent selected from hydrido, alkyl, halo, and alkoxy; and 
         R d  is independently selected from a group as defined for R a  and R b . 
       
     
     
         73 . The compound of  claim 72 , wherein the R b  radical has one or two ring hydrogens substituted with substituents selected from Cl, Br, I, —OR 4 , —R 5 , —OC(O)R 6 , OC(O)NR 7 R 8 , —C(O)R 9 , —CN, —NR 10 R 11 , —SR 12 , —S(O)R 11 , —S(O) 2 R 14 , —C(O)OR 15 , —S(O) 2 NR 16 R 17 ; and —R 18 NR 19 R 20 , wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms or hydrogen radicals. 
     
     
         74 . A pharmaceutical composition comprising:
 (a) the compound of  claim 73 , or a pharmaceutically acceptable salt, ester, or amide thereof, and   (b) a pharmaceutically acceptable carrier.   
     
     
         75 . A method for treating nicotine addiction in a subject comprising:
 administering to a subject suffering from nicotine addiction an effective amount of a compound having the formula set forth in  claim 73 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein said compound selectively inhibits CYP2A6.   
     
     
         76 - 77 . (canceled) 
     
     
         78 . A method for reducing the risk of developing cancer in a subject comprising:
 administering to the subject an effective amount of a compound having the formula set forth in  claim 73 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein the compound selectively inhibits CYP2A6 and thereby inhibits mutagenic activation of a promutagen metabolized by CYP2A6.   
     
     
         79 - 80 . (canceled) 
     
     
         81 . A pharmaceutical composition comprising:
 (a) the compound of  claim 73 , or a pharmaceutically acceptable salt, ester, or amide thereof, and   (b) a pharmaceutically acceptable carrier.   
     
     
         82 . A method for treating nicotine addiction in a subject comprising:
 administering to a subject suffering from nicotine addiction an effective amount of a compound having the formula set forth in  claim 73 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein said compound selectively inhibits CYP2A6.   
     
     
         83 . (canceled) 
     
     
         84 . (canceled) 
     
     
         85 . A method for reducing the risk of developing cancer in a subject comprising:
 administering to the subject an effective amount of a compound having the formula set forth in  claim 73 , or a pharmaceutically acceptable salt, ester, or amide thereof, wherein the compound selectively inhibits CYP2A6 and thereby inhibits mutagenic activation of a promutagen metabolized by CYP2A6.   
     
     
         86 - 88 . (canceled)