Modulators of Muscarinic Receptors

Abstract

The present invention relates to modulators of muscarinic receptors. The present invention also provides compositions comprising such modulators, and methods therewith for treating muscarinic receptor mediated diseases.

What is claimed is: 
     
         1 - 71 . (canceled) 
     
     
         72 . A method of modulating activity of a muscarinic receptor, comprising the step of contacting said receptor with a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein
 Each of R 1 , R 2 , R 3  is independently Q 1  or Q 2 , or R 2  and R 3  together form oxo; 
 Z 1  is —C(Q 1 ) 2 -, —C(H)(Q 1 )-, —C(H)(Q 5 )-, or —C(O)—; 
 Z 2  is N; 
 L is a bond or —CH 2 —; 
 G is an adamantyl, or a bicyclic or a tricyclic group of the formula (III) 
 
       
         
           
           
               
               
           
         
         in which the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X 1  and ring B, and the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ 4 , fluorine, Q z , or —C(O)—X 2 -aliphatic, in which X 2  is absent, —O—, —NH—, —NQ 2 -, or —S(O) z - and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 ; 
         Bond r is a single or double bond and when ring B is present, bond r is fused with B; 
         Ring B, when present, is a 5-6 membered cycloaliphatic or a 3-10 membered heterocycloaliphatic ring, and is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 ; 
         X 1  is —(CH 2 ) i —, —O—, —S—, —N(Q 2 )-, or —N(C(O)—X 2 -aliphatic) in which X 2  is absent, —O—, —NH—, —NQ 2 -, or —S(O) z — and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 ; 
         Each Q 1  is independently halo, —CN, —NO 2 , —OQ 2 , —S(O) z Q 2 , —S(O) z N(Q 2 ) 2 , —N(Q 2 ) 2 , —C(O)OQ 2 , —C(O)-Q 2 , —C(O)N(Q 2 ) 2 , —C(O)N(Q 2 )(OQ 2 ), —N(Q 2 )C(O)-Q 2 , —N(Q 2 )C(O)N(Q 2 ) 2 , —N(Q 2 )C(O)O-Q 2 , —N(Q 2 )S(O) z -Q 2  or aliphatic optionally including 1-3 substituents independently selected from Q 2  or Q 3 ; 
         Each Q 2  is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, a 3-10 membered heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q 3 ; 
         Each Q 3  is halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —S(O) z Q 4 , —N(Q 4 ) 2 , —COOQ 4 , —C(O)Q 4 , —OQ 4 , or C 1 -C 4  alkyl optionally substituted with halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —SH, —S(O) z H, —NH 2 , or —COOH; 
         Each Q 4  is aliphatic, cycloaliphatic, aryl, aralkyl, a 3-10 membered heterocycloaliphatic, heteroaralkyl, or heteroaryl, each optionally including 1-3 substituents selected from halo, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, SH, —S(O) z H, —NH 2 , or COOH; 
         Each Q 5  is a 3-10 membered heterocyclic ring optionally including 1-3 substituents selected from halo, C 1 -C 4 alkyl, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, SH, —S(O) z H, —NH 2 , COOH; 
         Each i is independently 1, 2, or 3; 
         Each m and n are each 2; 
         Each p is 0; 
         Each y is independently 0 or 1; 
         Each z is independently 0, 1, or 2; and 
         Each t is 1 to 4. 
       
     
     
         73 . The method according to  claim 72 , wherein G is an optionally substituted bicyclic group of formula (III) in which ring B is absent. 
     
     
         74 . The method according to  claim 73 , wherein X 1  is —(CH 2 ) i —. 
     
     
         75 . The method according to  claim 74 , wherein G is optionally substituted bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptanyl. 
     
     
         76 . The method according to  claim 75 , wherein G is substituted with 1 to 2 substituents independently selected from Q 2 , and —C(O)—X 2 -aliphatic, where X 2  is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 . 
     
     
         77 . The method according to  claim 73 , wherein X 1  is —N(Q 2 )— or —N(C(O)—X 2 -aliphatic), where X 2  is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 . 
     
     
         78 . The method according to  claim 77 , wherein G is an optionally substituted tropane. 
     
     
         79 . The method according to  claim 78 , wherein the tropane is substituted with Q 2 , or —C(O)—X 2 -aliphatic, where X 2  is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 . 
     
     
         80 . The method according to  claim 78 , wherein the tropane is substituted at the tropane ring nitrogen atom with alkoxycarbonyl, alkoxyalkoxycarbonyl, heterocycloalkoxy carbonyl, cycloalkoxycarbonyl, alkoxyaryloxycarbonyl, alkylaminocarbonyl, haloalkoxy carbonyl, alkynyloxycarbonyl, or heterocycloalkylalkoxycarbonyl. 
     
     
         81 . The method according to  claim 80 , wherein the tropane is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         82 . The method according to  claim 72 , wherein G is adamantyl. 
     
     
         83 . The method according to  claim 72 , wherein Z 1  is —CH(Q 1 )-, and wherein Q 1  is alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, aminocarbonyl, alkylcarbonylalkyl, alkoxyalkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, alkoxycarbonyl, haloarylcarbonyl, haloarylsulfonyl, alkylheteroarylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, haloarylaminocarbonyl, alkylheteroarylsulfonyl, cyanoalkylaryl carbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkoxyarylcarbonyl, haloalkoxycarbonyl, alkylarylcarbonyl, haloalkoxyarylcarbonyl, or arylaminocarbonyl. 
     
     
         84 . The method according to  claim 72 , wherein Z 1  is —C(O)—, 
       
         
           
           
               
               
           
         
       
     
     
         85 . The method according to  claim 72 , wherein R 1  is selected from hydrogen, halo, or optionally substituted alkyl, heteroaryl, alkoxy, alkenyl, cycloalkyl, cyanoalkylaryl, alkylaryl, alkylsulfonylaryl, alkylcarbonylaryl, aryl, aminocarbonylaryl, alkylcarbonylaminoaryl, cycloalkenyl, and alkoxyaryl. 
     
     
         86 . The method according to  claim 72 , wherein R 1  is selected from hydrogen, halo, methyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         87 . The method according to  claim 72 , wherein R 2  and R 3  are independently hydrogen, alkyl, or R 2  and R 3  together form an oxo. 
     
     
         88 . The method according to  claim 87 , wherein R 2  and R 3  are both hydrogen. 
     
     
         89 . The method according to  claim 72 , wherein L is a bond. 
     
     
         90 . The method according to  claim 72 , wherein L is —CH 2 —. 
     
     
         91 . The method according to  claim 72 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         92 . The method of claim  1 , wherein the compound selectively modulates a M 1  or M 4  muscarinic receptor. 
     
     
         93 . A method of treating or reducing the severity of a muscarinic receptor mediated disease in a mammal, comprising the step of administering to said mammal a compound as described in claim  1 . 
     
     
         94 . The method according to claim  35 , wherein said muscarinic receptor is M 1  or M 4 . 
     
     
         95 . A method of treating or reducing the severity of a disease or condition in a patient, wherein said disease or condition is selected from pain, schizophrenia, Parkinson's disease, glaucoma, or Attention Deficit Hyperactivity Disorder (ADHD), wherein said method comprises the step of contacting said patient with a compound as described in of claim  1 . 
     
     
         96 . The method of  claim 95 , wherein the disease or condition is selected from Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, Parkinson's disease and Glaucoma. 
     
     
         97 . The method of  claim 95 , wherein the disease or condition is pain.