Modulators of Muscarinic Receptors

Abstract

The present invention relates to substituted piperazine compounds that are useful modulators of muscarinic receptors. The present invention also provides compositions comprising such compounds, and methods for treating muscarinic receptor mediated diseases.

1 . A method of modulating activity of a muscarinic receptor, comprising the step of contacting said receptor with a compound of formula (IV): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, 
     wherein
 A IV  is adamantanyl, adamantanylmethyl, or 
 
     
       
         
         
             
             
         
       
       Bond r is a single or double bond; 
       Each X 1  is independently selected from CH 2 , CH 2 —CH 2 , or NR 400 , 
       Each W 1  is independently selected from a bond, —(CH2) i —, —(CH 2 ) i NR i C(O)—, —(CH 2 ) i C(O)NR i —, —(CH 2 ) i NR i SO 2 —, —(CH 2 ) i SO 2 NR i —, C(O), O, S, NH, or S(O) 2 ; 
       R i  is H or R 2 ; 
       R 2  is aliphatic, wherein each R 2  optionally includes 1 to 2 substituents independently selected from R 100 , R 4 , or R 5 ; 
       R 4  is OR 5 , OR 6 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ; 
       Each R 5  is independently a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, each optionally including 1 to 3 R 100  substituents; 
       Each R 6  is independently H or aliphatic optionally substituted with R 7 ; 
       Each R 7  is independently a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, each optionally substituted with up to 2 substituents independently selected from H, (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 ) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z; 
       Each R 8  is independently selected from R 2 , R 3 , or R 4  or a protecting group. 
       Each Z is independently selected from halo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —S-aliphatic, —S(O)-aliphatic, —SO 2 -aliphatic, —COOH, —C(O)O(-aliphatic), or —O-aliphatic; 
       G is N or C(H); 
       C is 
     
     
       
         
         
             
             
         
       
     
     in which the benzotriazole is optional substituted with 1-3 of R 100 , R2, R4, R5, or R6;
 Each Z1 and Z3 is independently —N═, —C(H)═, or —C(R 100 )═; 
 Each Z2 is independently a carbon atom; 
 Each Z4 and Z6 is independently —N═, —C(H)═ or —C(R 100 )═; 
 Each Z5 is independently —N═, —C(H)═, or —C(R 200 )═, provided
 a) that at least one of Z1, Z3, and Z5 is —N═; 
 b) that no more than two of Z1, Z2, Z3, Z4, and Z5 are —N═; 
 c) that no more than three of Z1, Z3, Z4, Z5, and Z6 are other than —N═ or —C(H)═; 
 d) when Z4 or Z6 is —C(R 100 )═, that (i) one of Z1 and Z3 is —C(R 100 )═, (ii) Z5 is —C(R 200 )═, or (iii) both Z4 and Z6 are —C(R 100 )═; 
 
 Each R 100  is independently is —((C1-C4)aliphatic) p -Y2; 
 Y2 is halo, —CN, —NO 2 , —CF 3 , —OCF 3 , —SR 600 , —S(O)R 600 , —SO 2 R 600 , —SO 2 NR 600 , —COOR 600 , —C(O)N(R 600 ) 2 , or —OR 600 ; or 
 Each R 200  is independently R 100  or phenyl optionally substituted with 1-3 halo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH; 
 Each R 400  is independently OR 5 , OR 6 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , and C(NOR 5 )R 5 ; 
 Each R 600  is independently H or aliphatic optionally substituted with 1-3 substituents selected from halo, —CN, —NO 2 , —CF 3 , —OCF 3 , or —OH; 
 Each x is independently 1 or 2; 
 Each i is 0, 1 2, or 3; 
 Each m is independently 1 or 2; and 
 Each p is independently 0 or 1. 
 
   
   
       2 . The method according to  claim 1 , wherein A IV  is selected from: 
     
       
         
         
             
             
         
       
     
   
   
       3 . The method according to  claim 2 , wherein A IV  is (ia). 
   
   
       4 . The method according to  claim 3 , wherein A IV  is 
     
       
         
         
             
             
         
       
     
   
   
       5 . The method according to  claim 4 , wherein W 1  is a bond or —CH 2 —. 
   
   
       6 . The method according to  claim 2 , wherein A IV  is (ib). 
   
   
       7 . The method according to  claim 6 , wherein A IV  is 
     
       
         
         
             
             
         
       
     
   
   
       8 . The method according to  claim 7 , wherein W 1  is a bond or —CH 2 —. 
   
   
       9 . The method according to  claim 2 , wherein A IV  is (ic). 
   
   
       10 . The method according to  claim 2 , wherein W 1  is a bond or CH 2 . 
   
   
       11 . The method according to  claim 1 , wherein W 1  is a bond or CH 2 . 
   
   
       12 . The method according to  claim 1 , wherein A IV  is selected from: 
     
       
         
         
             
             
         
       
     
   
   
       13 . The method according to  claim 12 , wherein A IV  is (iia). 
   
   
       14 . The method according to  claim 12 , wherein A IV  is (iib). 
   
   
       15 . The method according to  claim 12 , wherein A IV  is (iic). 
   
   
       16 . The method according to  claim 12 , wherein W 1  is a bond or CH 2 . 
   
   
       17 . The method according to  claim 1 , wherein A IV  is 
     
       
         
         
             
             
         
       
     
   
   
       18 . The method according to  claim 17 , wherein W 1  is a bond or CH 2 . 
   
   
       19 . The method according to  claim 17 , wherein A IV  is 
     
       
         
         
             
             
         
       
     
   
   
       20 . The method according to  claim 19 , wherein W 1  is a bond. 
   
   
       21 . The method according to  claim 17 , wherein R 6  is aliphatic optionally substituted with R 7 . 
   
   
       22 . The method according to  claim 21 , wherein R 6  is alkyl optionally substituted with R 7 . 
   
   
       23 . The method according to  claim 22 , wherein R 6  is alkyl. 
   
   
       24 . The method according to  claim 1 , wherein A IV  is adamantyl or adamantylmethyl. 
   
   
       25 . The method according to  claim 1 , wherein ring C is 
     
       
         
         
             
             
         
       
     
   
   
       26 . The method according to  claim 25 , wherein Z 1  is —N═. 
   
   
       27 . The method according to  claim 26 , wherein Z 3  is —N═. 
   
   
       28 . The method according to  claim 26 , wherein Z 3  is —C(R 100 )═. 
   
   
       29 . The method according to  claim 28 , wherein R 100  is halo, nitro, —CN, S(O) 2 NH 2 , —CF 3 , alkoxy, acyl, —C(O)NH 2 , or aliphatic. 
   
   
       30 . The method according to  claim 25 , wherein Z 4  is —N═. 
   
   
       31 . The method according to  claim 25 , wherein Z 5  is —N═. 
   
   
       32 . The method according to  claim 1 , wherein ring C is selected from: 
     
       
         
         
             
             
         
       
     
   
   
       33 . The method according to  claim 32 , wherein each of C rings (a) through (j) are substituted with one R 100  substituent ortho or para relative to the point of attachment between ring C and the piperazine or piperidine ring, or one R 100  substituent ortho, meta, or para relative to the point of attachment between ring C and the piperazine or piperidine ring and one R 100  substituent meta relative to the point of attachment between ring C and the piperazine or piperidine ring. 
   
   
       34 . The method according to  claim 33 , wherein each R 100  is independently halo, nitro, —CN, S(O) 2 NH 2 , —CF 3 , alkoxy, acyl, —C(O)NH 2 , or aliphatic. 
   
   
       35 . The method according to  claim 33 , wherein ring C is 3-cyano-2-pyridyl or 5-cyano-2-pyridyl. 
   
   
       36 . The method according to  claim 1 , wherein ring C is 
     
       
         
         
             
             
         
       
     
   
   
       37 . The method according to  claim 36 , wherein the benzotriazole is optionally substituted with 1-4 substituents selected from halo, cyano, C1-C4 alkyl, and CF 3 . 
   
   
       38 . The method according to  claim 1 , wherein the compounds is
 1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-(3-nitro-2-pyridyl)-piperazine;   2-[4-(2-adamantyl)piperazin-1-yl]nicotinonitrile;   2-(4-norbornan-2-ylpiperazin-1-yl)-6-(trifluoromethyl)nicotinonitrile;   2-[1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-piperidyl]-4,6-dimethoxy-pyrimidine;   1-(3-nitro-2-pyridyl)-4-norbornan-2-yl-piperazine;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]nicotinamide;   1-(3-chloro-2-pyridyl)-4-norbornan-2-yl-piperazine;   2-[4-(norbornan-2-ylmethyl)piperazin-1-yl]-6-(trifluoromethyl)nicotinonitrile;   1-[1-(3-bicyclo[3.2.1]octyl)-4-piperidyl]-1H-benzotriazole;   2-(4-norbornan-2-ylpiperazin-1-yl)nicotinamide;   3-[4-(4-cyano-6-phenyl-pyridazin-3-yl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-(3-cyano-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   6-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]nicotinonitrile;   6-[4-(norbornan-2-ylmethyl)piperazin-1-yl]nicotinamide;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-(6-methyl-2-pyridyl)-piperazine;   3-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]-2,5-dimethyl-pyrazine;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]-3-methyl-pyrazine;   1-norbornan-2-yl-4-(4-pyridyl)piperazine;   6-(4-norbornan-2-ylpiperazin-1-yl)nicotinonitrile;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]-3-methyl-pyridine;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-(6-chloro-2-pyridyl)-piperazine;   5-ethyl-2-[4-(norbornan-2-ylmethyl)piperazin-1-yl]-pyrimidine;   3-[4-(4-bicyclo[3.2.1]octylmethyl)piperazin-1-yl]pyrazine-2-carbonitrile;   3-[4-[3-cyano-6-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-(4-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-(3,5-dichloro-4-pyridyl)-piperazine;   2-[4-(3-bicyclo[3.2.1]octyl)piperazin-1-yl]nicotinonitrile;   3-[4-[5-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-(1H-benzotriazol-1-yl)-1-piperidyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-(3-fluoro-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   6-methyl-2-(4-norbornan-2-ylpiperazin-1-yl)-nicotinonitrile;   2-(4-norbornan-2-ylpiperazin-1-yl)nicotinonitrile;   3-[4-(3-cyano-5-phenyl-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   6-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]nicotinonitrile;   1-(3-bicyclo[3.2.1]octyl)-4-(4-pyridyl)piperazine;   3-[4-(5-carbamoyl-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   1-[1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-piperidyl]-1H-benzotriazole;   3-[[4-(3-cyanopyrazin-2-yl)piperazin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]pyrazine;   2,5-dimethyl-3-(4-norbornan-2-ylpiperazin-1-yl)-pyrazine;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-(4-pyridyl)piperazine;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]nicotinonitrile;   3-(4-norbornan-2-ylpiperazin-1-yl)pyrazine-2-carbonitrile;   2-(4-norbornan-2-ylpiperazin-1-yl)pyrazine;   3-[4-(3-cyanopyrazin-2-ylpiperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   2-[4-(norbornan-2-ylmethyl)piperazin-1-yl]-5-phenyl-nicotinonitrile;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-[5-(trifluoromethyl)-2-pyridyl]-piperazine;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-(2-pyridyl)piperazine;   3-[4-(3-sulfamoyl-4-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   1-(1-norbornan-2-yl-4-piperidyl)-1H-benzotriazole;   3-[4-(5-acetyl-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-(3-chloro-2-pyridyl)-piperazine;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]-6-(trifluoromethyl)nicotinonitrile;   2-[1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-piperidyl]nicotinonitrile;   4-[4-(norbornan-2-ylmethyl)piperazin-1-yl]pyridine-3-sulfonamide;   3-[4-(4-cyano-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-(4,6-dimethoxypyrimidin-2-yl)-1-piperidyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-[6-chloro-3-cyano-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-(norbornan-2-ylmethyl)piperazin-1-yl]-6-phenyl-pyridazine-4-carbonitrile;   1-(3-methyl-2-pyridyl)-4-norbornan-2-yl-piperazine;   1-(2-bicyclo[3.2.1]octyl)-4-(4-pyridyl)piperazine;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]-6-methyl-nicotinonitrile;   2-methyl-3-(4-norbornan-2-ylpiperazin-1-yl)-pyrazine;   2-[4-(4-bicyclo[3.2.1]octylmethyl)piperazin-1-yl]nicotinonitrile;   1-norbornan-2-yl-4-(2-pyridyl)piperazine;   3-[4-(5-cyano-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[4-(5-ethylpyrimidin-2-ylpiperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   3-[[4-(3-cyano-2-pyridyl)piperazin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-[3-(trifluoromethyl)-2-pyridyl]-piperazine;   3-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]pyrazine-2-carbonitrile;   2-(4-norbornan-2-ylpiperazin-1-yl)pyrimidine;   4,6-dimethyl-2-(4-norbornan-2-ylpiperazin-1-yl)-pyrimidine;   6-methyl-2-[4-(norbornan-2-ylmethyl)piperazin-1-yl]-5-phenyl-nicotinonitrile;   1-(5-bicyclo[2.2.1]hept-2-enylmethyl)-4-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-piperazine;   1-(2-adamantyl)-4-(4-pyridyl)piperazine;   2-[4-(5-bicyclo[2.2.1]hept-2-enylmethyl)piperazin-1-yl]pyrimidine;   1-(6-methyl-2-pyridyl)-4-norbornan-2-yl-piperazine; or   3-[4-(3-cyano-4,6-dimethyl-2-pyridyl)piperazin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester.   
   
   
       39 . The method according to  claim 1 , wherein said muscarinic receptor is M1. 
   
   
       40 . The method according to  claim 1 , wherein said muscarinic receptor is M4. 
   
   
       41 . The method according to  claim 1 , wherein the compounds modulate M1 and M4 muscarinic receptors more than M2 and M3 muscarinic receptors.