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.

1 . A method of modulating activity of a muscarinic receptor, comprising the step of contacting said receptor with a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 X is —NR 50 — or —O—, wherein R 50  is independently hydrogen or an optionally substituted C 1-6  aliphatic; 
 R 1  is an optionally substituted aliphatic, an optionally substituted cycloaliphatic, or an optionally substituted heterocycloaliphatic; 
 R 2  is —Z B R 5 , wherein each Z B  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z B  are optionally and independently replaced by —CO—, —CS—, —CONR B —, —CONR B NR B —, —CO 2 —, —OCO—, —NR B CO 2 —, —O—, —NR B CONR B —, —OCONR B —, —NR B NR B —, —NR B CO—, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, —NR B SO 2 —, or —NR B SO 2 NR B —; 
 Each R 5  is independently R B , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and 
 Each R B  is independently hydrogen, optionally substituted C 1-4  aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl; 
 Each R 3  is independently hydrogen, halo, nitro, cyano, hydroxy, optionally substituted aliphatic, optionally substituted (aliphatic)oxy, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl; and 
 n is 0-4. 
 
   
   
       2 . The method of  claim 1 , wherein R 1  is independently —Z A R 4 , wherein:
 Each Z A  is independently a bond or an optionally substituted branched or straight C 1-12  aliphatic chain wherein up to two carbon units of Z A  are optionally and independently replaced by —CO—, —CS—, —CONR A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A —, —NR A CO—, —S—, —SO—, —SO 2 —, —NR A —-, —SO 2 NR A —, —NR A SO 2 —, or —NR A SO 2 NR A —;   Each R 4  is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and   Each R A  is independently hydrogen, optionally substituted C 1-8  aliphatic group, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or an optionally substituted heteroaryl,   Provided that when Z A  is a bond and R 4  is R A , then R A  is optionally substituted aliphatic, optionally substituted cycloaliphatic, or optionally substituted heterocycloaliphatic.   
   
   
       3 . The method of  claim 2 , wherein each Z A  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z A  are optionally and independently replaced by —CO—, —CS—, —CONR A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A —, —NR A CO—, —S—, —SO—, —SO 2 —, —NR A —, —SO 2 NR A —, —NR A SO 2 —, or —NR A SO 2 NR A —;
 Each R 4  is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and   Each R A  is independently hydrogen, optionally substituted C 1-6  aliphatic group, optionally substituted cycloaliphatic, or optionally substituted heterocycloaliphatic,   Provided that when Z A  is a bond, and R 4  is R A , then R A  is optionally substituted C 1-6  aliphatic group, optionally substituted cycloaliphatic, or optionally substituted heterocycloaliphatic.   
   
   
       4 . The method of  claims 1 , wherein R 1  is optionally substituted cycloaliphatic. 
   
   
       5 . The method of  claim 4 , wherein R 1  is monocyclic, bicyclic, or tricyclic cycloaliphatic, each of which is optionally substituted. 
   
   
       6 . The method of  claim 5 , wherein R 1  is optionally substituted 3-8 membered monocyclic cycloaliphatic that is optionally substituted with 1-3 of halo, oxo, hydroxy, nitro, cyano, or optionally substituted aliphatic, optionally substituted oxime, optionally substituted (aliphatic)oxy, optionally substituted carboxy, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or combinations thereof. 
   
   
       7 . The method of  claim 6 , wherein R 1  is cyclopropane-yl, cyclobutane-yl, cyclopentane-yl, cyclohexane-yl, cycloheptane-yl, or cyclooctane-yl, each of which is optionally subsitituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, optionally substituted oxime, (aliphatic)carbonyl, (aliphatic)oxy, (aralkyl(oxy))imino, (aliphatic(oxy))carbonyl, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       8 . The method of  claim 5 , wherein R 1  is an optionally substituted bicyclic cycloaliphatic. 
   
   
       9 . The method of  claim 8 , wherein R 1  is bridged bicyclic cycloaliphatic, fused bicyclic cycloaliphatic, or Spiro bicyclic cycloaliphatic, each of which is optionally substituted. 
   
   
       10 . The method of  claim 9 , wherein R 1  is optionally substituted 6-9 membered bridged bicyclic cycloaliphatic. 
   
   
       11 . The method of  claim 10 , wherein R 1  is bicyclo[2.1.1]hexane-yl, bicyclo[3.1.0]hexane-yl, bicyclo[2.2.1]heptane-yl, bicyclo[2.2.2]octane-yl, bicyclo[3.1.1]heptane-yl, bicyclo[3.2.1]octane-yl, or bicyclo[3.3.1]nonane-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, alkoxycarbonyl, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       12 . The method of  claim 9 , wherein R 1  is optionally substituted 6-10 membered fused bicyclic cycloaliphatic. 
   
   
       13 . The method of  claim 12 , wherein R 1  is octahydropentalene-yl, octahydro-1H-indene-yl, or decahydronaphthalene-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, alkoxycarbonyl, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       14 . The method of  claim 9 , wherein R 1  is optionally substituted 9-12 membered Spiro bicyclic cycloaliphatic. 
   
   
       15 . The method of  claim 14 , wherein R 1  is spiro[5.5]undecane-yl, spiro[4.5]decane-yl, or spiro[5.6]dodecane-yl, each of which is optionally substituted. 
   
   
       16 . The method of  claim 5 , wherein R 1  is optionally substituted adamantyl. 
   
   
       17 . The method of  claim 1 , wherein R 1  is optionally substituted heterocycloaliphatic. 
   
   
       18 . The method of  claim 17 , wherein R 1  is optionally substituted monocyclic or optionally substituted bicyclic heterocycloaliphatic having 1-3 heteroatoms independently selected from N, O, and S. 
   
   
       19 . The method of  claim 18 , wherein R 1  is optionally substituted 4-8 membered monocyclic heterocycloaliphatic having 1-3 heteroatoms independently selected from N, O, and S. 
   
   
       20 . The method of  claim 19 , wherein R 1  is tetrahydrofuran-yl, pyrroline-yl, pyrrolidine-yl, 1,3-dioxolane-yl, imidazolidine-yl, 2-imidazoline-yl, pyrazoline-yl, pyrazolidine-yl, tetrahydropyranyl, piperidine-yl, 1,4-dioxane-yl, morpholine-yl, 1,4-dithiane, thiomorpholine, or piperazine-yl, each of which is optionally subsitituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, carboxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, (aliphatic)heteroaryl, (aliphatic)heterocycloaliphatic, (aliphatic)carbonyl, or combinations thereof. 
   
   
       21 . The method of  claim 18 , wherein R 1  is optionally substituted 6-10 membered bridged bicyclic heterocycloaliphatic, fused bicyclic heterocycloaliphatic, or spiro bicyclic heterocycloaliphatic, each of which is optionally substituted. 
   
   
       22 . The method of  claim 21 , wherein R 1  is optionally substituted 6-9 membered bridged bicyclic heterocycloaliphatic. 
   
   
       23 . The method of  claim 22 , wherein R 1  is 5-azabicyclo[2.1.1]hexane-yl, 7-azabicyclo[2.2.1]heptane-yl, or 8-azabicyclo[3.2.1]octane-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, carboxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       24 . The method of  claim 18 , wherein R 1  is optionally substituted spiro bicyclic heterocycloaliphatic. 
   
   
       25 . The method of  claim 24 , wherein R 1  is 1,4-dioxaspiro[4.5]decane-yl; 1,4-dioxaspiro[4.4]nonane-yl; 1,5-dioxaspiro[5.5]undecane-yl; or 6,10-dioxaspiro[4.5]decane-yl; each of which is optionally substituted. 
   
   
       26 . The method of  claim 1 , wherein R 1  is optionally substituted aliphatic. 
   
   
       27 . The method of  claim 26 , wherein R 1  is optionally substituted straight or branched C 1-8  aliphatic. 
   
   
       28 . The method of  claim 27 , wherein R 1  is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neohexyl, each of which is optionally substituted with 1-3 of halo, oxo, or optionally substituted alkoxy, optionally substituted amino, optionally substituted aliphaticsulfonyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, or combinations thereof. 
   
   
       29 . The method of  claim 1 , wherein R 1  is one selected from hydrogen; tetrahydrofuran-3-yl-methyl; 4-(hydroxy)cyclohexyl; 4-(ethoxy(imino)cyclohexyl; cyclohexyl; cycloheptanyl; N-(methyl(carbonyl))piperidyl; (bicyclo[2.2.1]hept-2-yl)methyl; 3-(methyl)cyclohexyl; bicyclo[2.2.1]heptyl; isopropyl; tetrahydro-2H-pyran-3-yl; N-(but-3-ynyl(oxy(carbonyl)))piperidine-4-yl; N-(ethoxy(carbonyl(piperidine-4-yl)methyl; 4-propylcyclohexyl; 2-methoxycyclohexyl; 4-(phenyl(methyl(oxy(imino))))cyclohexyl; cycloheptyl; N-(isopropyl(oxy(carbonyl)))piperidine-4-yl; 4-(cyclohexane-yl)cyclohexyl; (cyclopropane-yl)methyl; cyclooctyl; 4-(methoxy(imino))cyclohexyl; N-(propoxy(carbonyl))piperidine-4-yl; N-(pent-2-ynyl(oxy(carbonyl)))piperidine-4-yl; 4-(tertbutyl(oxy(imino)))cyclohexyl; (cyclohexyl)methyl; 4-(ethyl)cyclohexyl; 2,6,6-(trimethyl(cyclohexa-1,3-diene-yl))methyl; N-(methoxy(ethoxy(carbonyl)))piperidine-4-yl; decahydronaphthalene-2-yl; 1,1-dimethylpropyl; propyl; 4-(ethoxy(carbonyl))cyclohexyl; tetrahydro-2H-pyran-4-yl; 3-(methyl)cyclopentyl; 4-(methyl)cyclohexyl; 2-(ethyl)butyl; 4,4-(dimethyl)cyclohex-2-ene-yl; ethyl; bicyclo[2.2.1]hept-2-yl; 2-(methyl)cyclohexyl; 1,4-dioxaspiro[4.5]dec-8-yl; N-(prop-2-yn-yl(oxy(carbonyl)))piperidine-4-yl; piperidine-4-yl; bicyclo[2.2.2]octane-2-yl; methyl; (tetrahydro-2H-pyran-4-yl)methyl; 4-(isopropoxy(imino))cyclohexyl; N-(phenyl(carbonyl))piperidine-4-yl; phenylmethyl; N-(methoxy(carbonyl))piperidine-4-yl; cyclopentyl; 4-(tertbutyl)cyclohexyl; 3,3-dimethylbutyl; 2,4-(dimethyl(cyclohex-3-ene-yl))methyl; 4-oxocyclohexyl; 3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-9-yl; 4-(ethoxy(imino))cyclohexyl; bicyclo[3.2.1]octane-3-yl; bicyclo[3.2.1]octane-2-yl; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-yl; ethylpropyl; N-(pyrazine-2-yl)piperidine-4-yl; 4-(trifluoromethyl)cyclohexyl; 3-methylbutyl; 4-(phenyl(oxy(imino)))cyclohexyl; (cyclohex-1-ene-yl)methyl; 4-(cyano-4-(phenyl))cyclohexyl; 4-(prop-2-ene-yl(oxy(imino)))cyclohexyl; tetrahydro-2H-thiopyran-4-yl; cyclopentylmethyl; cyclononyl; cyclobuty; adamantyl; 8-ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-yl; 3-(trifluoromethyl)cyclohexyl; bicyclo[3.3.1]nonane-9-yl; N-(cyclopropyl(carbonyl))piperidine-4-yl; 4-isopropyl; spiro[5.5]undecane-2-yl; 4-(phenyl)cyclohexyl; (tetrahydro-2H-pyran-4-yl)methyl; (bicyclo[2.2.1]hept-2-yl)methyl; 4-(3-ethyl-1,2,4-thiadiazole-5-yl)cyclohexyl; N-(3-ethyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl; cyclohexylmethyl; and 4-(3-methyl-1,2,4-thiadiazole-5-yl)cyclohexyl. 
   
   
       30 . The method of  claim 1 , wherein R 2  is hydrogen or an optionally substituted straight or branched C 1-6  aliphatic. 
   
   
       31 . The method of  claim 30 , wherein R 2  is an optionally substituted straight or branched C 1-6  alkyl. 
   
   
       32 . The method of  claim 31 , wherein R 2  is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neohexyl, each of which is optionally substituted. 
   
   
       33 . The method of  claim 32 , wherein R 2  is methyl, ethyl, or propyl, each of which is optionally substituted with 1-3 of halo, hydroxy, oxo, cyano, or optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy. 
   
   
       34 . The method of  claim 30 , wherein R 2  is optionally substituted C 2-6  alkenyl or an optionally substituted C 2-6  alkynyl. 
   
   
       35 . The method of  claim 34 , wherein R 2  is prop-2-ene-yl, but-2-ene-yl, but-3-ene-yl, but-2-yn-yl, or but-3-yn-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, oxo, cyano, or optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy. 
   
   
       36 . The method of  claim 31 , wherein R 2  is one selected from hydrogen, but-2-yn-yl; isopropyl, propyl, 2-(oxo)propyl, ethyl, (methoxy)ethyl, 2-(methyl)propyl, methyl, (phenyl)methyl, prop-2-ene-yl, and 2-(phenyl-2-(oxo))ethyl. 
   
   
       37 . The method of  claim 1 , wherein R 3  is independently —Z C R 6 , wherein each Z C  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z C  are optionally and independently replaced by —CO—, —CS—, —CONR C —, —CONR C NR C —, CO 2 —, —OCO—, NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C —, NR C CO—, —S—, —SO—, —SO 2 —, —NR C —, —SO 2 NR C —, —NR C SO 2 —, or —NR C SO 2 NR C —; each R 6  is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and each R C  is independently hydrogen, optionally substituted C 1-8  aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl. 
   
   
       38 . The method of  claim 37 , wherein R 3  is —Z C R 6 , Z C  is a bond, and R 6  is hydrogen. 
   
   
       39 . The method of  claim 1 , wherein X is —O—. 
   
   
       40 . A method of modulating activity of a muscarinic receptor, comprising the step of contacting said receptor with a compound selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       41 . A compound of formula Ia 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 X is —NR 50 — or —O—, 
 R 50  is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 R 1a  is optionally substituted aliphatic, optionally substituted cycloaliphatic, or optionally substituted heterocycloaliphatic; 
 R 2  is —Z B R 5 , wherein each Z B  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z B  are optionally and independently replaced by —CO—, —CS—, —CONR B —, —CONR B NR B —, —CO 2 —, —OCO—, —NR B CO 2 —, —O—, —NR B CONR B —, —OCONR B —, —NR B NR B —, —NR B CO—, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, —NR B SO 2 —, or —NR B SO 2 NR B —; 
 Each R 5  is independently R B , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and 
 Each R B  is independently hydrogen, optionally substituted C 1-4  aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or an optionally substituted heteroaryl; 
 Each R 3  is independently hydrogen, halo, optionally substituted aliphatic, optionally substituted (aliphatic)oxy, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl; and 
 n is 0-4, 
 Provided that
 when R 1a  is substituted aliphatic, R 1a  is substituted with 1-3 of halo, cyano, nitro, hydroxy, —NH 2 , optionally substituted alkoxy, optionally substituted cycloaliphatic, or optionally substituted heterocycloaliphatic; 
 when R 1a  is aliphatic substituted with a monocyclic heterocycloaliphatic, the monocyclic heterocycloaliphatic is not substituted with aryl; and 
 when R 1a  is optionally substituted cycloaliphatic, R 1a  is not substituted with a substituted monocyclic heterocycloaliphic. 
 
 
   
   
       42 . The compound of  claim 41 , wherein R 1a  is optionally substituted cycloaliphatic. 
   
   
       43 . The compound of  claim 42 , wherein R 1a  is monocyclic, bicyclic, or tricyclic cycloaliphatic, each of which is optionally substituted. 
   
   
       44 . The compound of  claim 43 , wherein R 1  is optionally substituted 3-8 membered monocyclic cycloaliphatic that is optionally substituted with 1-3 of halo, oxo, oxime, hydroxy, nitro, cyano, or optionally substituted aliphatic, optionally substituted (aliphatic)oxy, optionally substituted (aliphatic(oxy))carbonyl, optionally substituted cycloaliphatic, unsubstituted monocyclic heterocycloaliphatic, optionally substituted bicyclic heterocycloaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or combinations thereof. 
   
   
       45 . The compound of  claim 44 , wherein R ia  is cyclopropane-yl, cyclobutane-yl, cyclopentane-yl, cyclohexane-yl, cycloheptane-yl, or cyclooctane-yl, each of which is optionally subsitituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, oxime, (aliphatic)carbonyl, (aliphatic)oxy, carboxy, cycloaliphatic, unsubstituted monocyclic heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       46 . The compound of  claim 43 , wherein R 1a  is bridged bicyclic cycloaliphatic, fused bicyclic cycloaliphatic, or Spiro bicyclic cycloaliphatic, each of which is optionally substituted. 
   
   
       47 . The compound of  claim 46 , wherein R 1a  is optionally substituted 6-9 membered bridged bicyclic cycloaliphatic. 
   
   
       48 . The compound of  claim 47 , wherein R 1a  is bicyclo[2.1.1]hexane-yl, bicyclo[3.1.0]hexane-yl, bicyclo[2.2.1]heptane-yl, bicyclo[2.2.2]octane-yl, bicyclo[3.1.1]heptane-yl, bicyclo[3.2.1]octane-yl, or bicyclo[3.3.1]nonane-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, alkoxycarbonyl, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       49 . The compound of  claim 43 , wherein R 1a  is optionally substituted 6-10 membered fused bicyclic cycloaliphatic. 
   
   
       50 . The compound of  claim 49 , wherein R 1a  is octahydropentalene-yl, octahydro-1H-indene-yl, or decahydronaphthalene-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, alkoxycarbonyl, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       51 . The compound of  claim 43 , wherein R 1a  is optionally substituted 9-12 membered spiro bicyclic cycloaliphatic. 
   
   
       52 . The compound of  claim 51 , wherein R 1a  is spiro[5.5]undecane-yl, spiro[4.5]decane-yl, or spiro[5.6]dodecane-yl, each of which is optionally substituted. 
   
   
       53 . The compound of  claim 43 , wherein R 1a  is optionally substituted adamantyl. 
   
   
       54 . The compound of  claim 41 , wherein R 1a  is optionally substituted heterocycloaliphatic. 
   
   
       55 . The compound of  claim 54 , wherein R 1a  is optionally substituted monocyclic or bicyclic heterocycloaliphatic having 1-3 heteroatoms independently selected from N, O, and S. 
   
   
       56 . The compound of  claim 55 , wherein R 1a  is optionally substituted 4-8 membered monocyclic heterocycloaliphatic having 1-3 heteroatoms independently selected from N, O, and S. 
   
   
       57 . The compound of  claim 56 , wherein R 1a  is tetrahydrofuran-yl, pyrroline-yl, pyrrolidine-yl, 1,3-dioxolane-yl, imidazolidine-yl, 2-imidazoline-yl, pyrazoline-yl, pyrazolidine-yl, tetrahydropyranyl, piperidine-yl, 1,4-dioxane-yl, morpholine-yl, 1,4-dithiane, thiomorpholine, or piperazine-yl, each of which is optionally subsitituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, (aliphatic(oxy))carbonyl, cycloaliphatic, heterocycloaliphatic, heteroaryl, (aliphatic)heteroaryl, (aliphatic)heterocycloaliphatic, (aliphatic)carbonyl, or combinations thereof. 
   
   
       58 . The compound of  claim 54 , wherein R 1a  is optionally substituted 6-9 membered bridged bicyclic heterocycloaliphatic. 
   
   
       59 . The compound of  claim 58 , wherein R 1a  is 5-azabicyclo[2.1.1]hexane-yl, 7-azabicyclo[2.2.1]heptane-yl, or 8-azabicyclo[3.2.1]octane-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, nitro, cyano, aliphatic, alkoxycarbonyl, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 
   
   
       60 . The compound of  claim 54 , wherein R 1a  is optionally substituted 9-12 membered spiro bicyclic heterocycloaliphatic. 
   
   
       61 . The compound of  claim 60 , wherein R 1a  is 1,4-dioxaspiro[4.5]decane-yl; 1,4-dioxaspiro[4.4]nonane-yl; 1,5-dioxaspiro[5.5]undecane-yl; or 6,10-dioxaspiro[4.5]decane-yl; each of which is optionally substituted. 
   
   
       62 . The compound of  claim 41 , wherein R 1a  is optionally substituted aliphatic. 
   
   
       63 . The compound of  claim 62 , wherein R 1a  is optionally substituted straight or branched C 1-8  aliphatic. 
   
   
       64 . The compound of  claim 63 , wherein R 1a  is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neohexyl, each of which is optionally substituted with 1-3 of halo, oxo, or optionally substituted alkoxy, optionally substituted amino, optionally substituted aliphaticsulfonyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, or combinations thereof. 
   
   
       65 . The compound of  claim 41 , wherein R 1  is one selected from hydrogen; tetrahydrofuran-3-yl-methyl; 4-(hydroxy)cyclohexyl; 4-(ethoxy(imino)cyclohexyl; cyclohexyl; cycloheptanyl; N-(methyl(carbonyl))piperidyl; (bicyclo[2.2.1]hept-2-yl)methyl; 3-(methyl)cyclohexyl; bicyclo[2.2.1]heptyl; isopropyl; tetrahydro-2H-pyran-3-yl; N-(but-3-ynyl(oxy(carbonyl)))piperidine-4-yl; N-(ethoxy(carbonyl(piperidine-4-yl)methyl; 4-propylcyclohexyl; 2-methoxycyclohexyl; 4-(phenyl(methyl(oxy(imino))))cyclohexyl; cycloheptyl; N-(isopropyl(oxy(carbonyl)))piperidine-4-yl; 4-(cyclohexane-yl)cyclohexyl; (cyclopropane-yl)methyl; cyclooctyl; 4-(methoxy(imino))cyclohexyl; N-(propoxy(carbonyl))piperidine-4-yl; N-(pent-2-ynyl(oxy(carbonyl)))piperidine-4-yl; 4-(tertbutyl(oxy(imino)))cyclohexyl; (cyclohexyl)methyl; 4-(ethyl)cyclohexyl; 2,6,6-(trimethyl(cyclohexa-1,3-diene-yl))methyl; N-(methoxy(ethoxy(carbonyl)))piperidine-4-yl; decahydronaphthalene-2-yl; 1,1-dimethylpropyl; propyl; 4-(ethoxy(carbonyl))cyclohexyl; tetrahydro-2H-pyran-4-yl; 3-(methyl)cyclopentyl; 4-(methyl)cyclohexyl; 2-(ethyl)butyl; 4,4-(dimethyl)cyclohex-2-ene-yl; ethyl; bicyclo[2.2.1]hept-2-yl; 2-(methyl)cyclohexyl; 1,4-dioxaspiro[4.5]dec-8-yl; N-(prop-2-yn-yl(oxy(carbonyl)))piperidine-4-yl; piperidine-4-yl; bicyclo[2.2.2]octane-2-yl; methyl; (tetrahydro-2H-pyran-4-yl)methyl; 4-(isopropoxy(imino))cyclohexyl; N-(phenyl(carbonyl))piperidine-4-yl; phenylmethyl; N-(methoxy(carbonyl))piperidine-4-yl; cyclopentyl; 4-(tertbutyl)cyclohexyl; 3,3-dimethylbutyl; 2,4-(dimethyl(cyclohex-3-ene-yl))methyl; 4-oxocyclohexyl; 3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-9-yl; 4-(ethoxy(imino))cyclohexyl; bicyclo[3.2.1]octane-3-yl; bicyclo[3.2.1]octane-2-yl; 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-yl; ethylpropyl; N-(pyrazine-2-yl)piperidine-4-yl; 4-(trifluoromethyl)cyclohexyl; 3-methylbutyl; 4-(phenyl(oxy(imino)))cyclohexyl; (cyclohex-1-ene-yl)methyl; 4-(cyano-4-(phenyl))cyclohexyl; 4-(prop-2-ene-yl(oxy(imino)))cyclohexyl; tetrahydro-2H-thiopyran-4-yl; cyclopentylmethyl; cyclononyl; cyclobuty; adamantyl; 8-ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-yl; 3-(trifluoromethyl)cyclohexyl; bicyclo[3.3.1]nonane-9-yl; N-(cyclopropyl(carbonyl)piperidine-4-yl; 4-isopropyl; spiro[5.5]undecane-2-yl; 4-(phenyl)cyclohexyl; (tetrahydro-2H-pyran-4-yl)methyl; (bicyclo[2.2.1]hept-2-yl)methyl; 4-(3-ethyl-1,2,4-thiadiazole-5-yl)cyclohexyl; N-(3-ethyl-1,2,4-thiadiazole-5-yl)piperidine-4-yl; cyclohexylmethyl; and 4-(3-methyl-1,2,4-thiadiazole-5-yl)cyclohexyl. 
   
   
       66 . The compound of  claim 41 , wherein R 2  is hydrogen or optionally substituted straight or branched C 1-6  aliphatic. 
   
   
       67 . The compound of  claim 66 , wherein R 2  is optionally substituted straight or branched C 1-6  alkyl. 
   
   
       68 . The compound of  claim 67 , wherein R 2  is optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, or neohexyl. 
   
   
       69 . The compound of  claim 68 , wherein R 2  is methyl, ethyl, or propyl, each of which is optionally substituted with 1-3 of halo, hydroxy, oxo, cyano, or optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy. 
   
   
       70 . The compound of  claim 66 , wherein R 2  is optionally substituted C 2-6  alkenyl or optionally substituted C 2-6  alkynyl. 
   
   
       71 . The compound of  claim 70 , wherein R 2  is prop-2-ene-yl, but-2-ene-yl, but-3-ene-yl, but-2-yn-yl, or but-3-yn-yl, each of which is optionally substituted with 1-3 of halo, hydroxy, oxo, cyano, or optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy. 
   
   
       72 . The compound of  claim 67 , wherein R 2  is one selected from hydrogen, but-2-yn-yl; isopropyl, propyl, 2-(oxo)propyl, ethyl, (methoxy)ethyl, 2-(methyl)propyl, methyl, (phenyl)methyl, prop-2-ene-yl, and 2-(phenyl-2-(oxo))ethyl. 
   
   
       73 . The compound of  claim 41 , wherein R 3  is independently —Z C R 6 , wherein each Z C  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z C  are optionally and independently replaced by —CO—, —CS—, —CONR C —, —CONR C NR C —, —CO 2 —, —OCO—, —NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C , —NR C CO—, —S—, —SO—, —SO 2 —, —NR C —, —SO 2 NR C , —NR C SO 2 —, or —NR C SO 2 NR C —; each R 6  is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and each R C  is independently hydrogen, optionally substituted C 1-8  aliphatic group, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl. 
   
   
       74 . The compound of  claim 73 , wherein R 3  is —Z C R 6 , Z C  is a bond, and R 6  is hydrogen. 
   
   
       75 . The compound of  claim 41 , wherein X is —O—. 
   
   
       76 . A compound selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       77 . 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 76 . 
   
   
       78 . The method of  claim 77 , wherein said muscarinic receptor is M 4 . 
   
   
       79 . The method of  claim 77 , wherein said muscarinic receptor is M 1 . 
   
   
       80 . A method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis associated with CNS disorders including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes, Huntington's Chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, Parkinson's disease, peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjögren's Syndrome, bradhycardia, gastric acid secretion, asthma, GI disturbances, and wound healing, wherein said method comprises the step of contacting said patient with a compound as described in  claim 76 . 
   
   
       81 . A pharmaceutical composition comprising a compound according to  claim 76  and a pharmaceutical carrier.