Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof

Abstract

Provided herein are compounds and methods of synthesis thereof. The compounds set forth herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders, neurodegenerative disorders, neuropsychiatric disorders, disorders of cognition, learning or memory, gastrointestinal disorders, lower urinary tract disorder, and cancer. Compounds set forth herein modulate the activity of metabotropic glutamate receptor 5 (mGluR5) in the central nervous system or the periphery. Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl or heteroaryl, each of which is optionally substituted; 
 R 2  is hydrogen, lower alkyl, lower alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl, heteroaryl, —C(O)OR 12 , or —CO—NR 12 , each of which is optionally substituted; 
 R 3  is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl or heteroaryl, each of which is optionally substituted; or 
 R 2  and R 3  are optionally joined, together with the atoms to which they are attached, to form a mono or bicyclic ring that is carbocyclic or heterocyclic, each of which is optionally substituted; 
 G is CHR 2  or NR 2  when b and c are both single bonds, or G is CR 2  or N when one of b and c is a double bond; 
 Q is NH or CH 2  when d and e are single bonds, or N or CH when one of d or e is a double bond, or; 
 X is N; 
 Z is CH 2 , C═O, C═S or a bond when b is a single bond, or CH or N when b is a double bond; 
 b, c, d, e, and f are each independently a single bond or a double bond, provided that when b is a double bond, c is a single bond; when c is a double bond, b and d are single bonds; 
 when d is a double bond, c and e are single bonds; when e is a double bond, d and f are single bonds; and when f is a double bond, e is a single bond; 
 Y 1 , Y 2  and Y 3  are each CH; 
 L 1  is —C≡C—, —HC═CH—, -(lower alkyl)C═C(lower alkyl)-, —CH 2 —CH 2 —, —CO—CH 2 —, —CH(OH)—CH 2 , —CH 2 —CO—, —C O-6 alkyl-O—C O-6 alkyl-, —NR 12 SO—, —SONR 12 —, —NR 12 SO 2 —, —SO 2 NR 12 —, —NR 12 —CO—, —CO—NR 12 —, 
 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         R 12  is hydrogen or lower alkyl; 
         W 1  and W 2  are each independently N or CH; 
         W 3  is O, S or NR 4 ; and 
         R 4  is hydrogen or lower alkyl; 
         or a pharmaceutically acceptable salt thereof; 
         provided that at least one of c and d is a double bond. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is of formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1a  is aryl, heteroaryl or cycloalkyl, each of which is optionally substituted; 
 L 1a  is —C≡C—, —HC═CH—, —CH 2 CH 2 —, —C(O)NH—, —NHC(O)—, CH(OH)CH 2 —, C(O)CH 2 , 
 
       
         
           
           
               
               
           
         
         Y 1a , Y 2a  and Y 3a  are each independently CH; 
         c, d e, and f are each independently single or double bonds; provided that when c is a double bond, d is a single bond; when d is a double bond, c and e are single bonds; when e is a double bond, d and fare single bonds; and when f is a double bond, e is a single bond; 
         X a  is N; 
         Q a  is NH when d and e are single bonds or N or CH when one of d or e is a double bond; 
         Z a  is C═O or CH 2 ; 
         G a  is NR 2a  when c is a single bond, or G a  is CR 2a  when c is a double bond; 
         R 2a  is hydrogen, lower alkyl, lower alkenyl, heteroalkyl, —C(O)R 12a , —CONR 12a , or cycloalkyl, each of which is optionally substituted; 
         R 3a  is hydrogen, lower alkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl, each of which is optionally substituted; or 
         R 2a  and R 3a , together with the atoms to which they are attached are linked to form a mononcyclic or bicyclic cycloalkyl or heterocyclic ring, each of which is optionally substituted; and R 12a  is hydrogen or lower alkyl. 
       
     
     
         3 . The compound of  claim 1 , wherein L 1  is —C≡C— or —HC═CH—. 
     
     
         4 . The compound of  claim 1 , wherein either Q and X or Q and G are both N. 
     
     
         5 . The compound of  claim 2 , wherein R 1a  is aryl. 
     
     
         6 . The compound of  claim 5 , wherein R 1a  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 2 , wherein R 1a  is heteroaryl. 
     
     
         8 . The compound of  claim 7 , wherein R 1a  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2 , wherein R 1a  is cycloalkyl. 
     
     
         10 . The compound of  claim 9 , wherein R 1a  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 2 , wherein R 2a  is lower alkyl. 
     
     
         12 . The compound of  claim 11 , wherein R 2a  is selected from methyl, propyl, cyclopropylmethyl, isobutyl and sec-butyl. 
     
     
         13 . The compound of  claim 2 , wherein R 2a  is lower alkenyl. 
     
     
         14 . The compound of  claim 11 , wherein R 2a  is CH 2 ═CH—. 
     
     
         15 . The compound of  claim 2 , wherein R 2a  is heteroalkyl. 
     
     
         16 . The compound of  claim 15 , wherein R 2a  is selected from methoxymethyl, hydroxymethyl, methoxyethyl, hydroxyethyl, ethoxymethyl, ethoxyethyl, 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 2 , wherein R 2a  is cycloalkyl. 
     
     
         18 . The compound of  claim 17 , wherein R 2a  is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 2 , wherein R 2a  is heterocycloalkyl-lower alkyl. 
     
     
         20 . The compound of  claim 19 , wherein R 2a  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 2 , wherein R 2s  is heteroarylalkyl. 
     
     
         22 . The compound of  claim 21 , wherein R 2a  is 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 2 , wherein R 2a  is —C(O)OR 12a . 
     
     
         24 . The compound of  claim 23 , wherein R 12a  is methyl. 
     
     
         25 . The compound of  claim 2 , wherein R 2a  is —CO—NR 12a . 
     
     
         26 . The compound of  claim 25 , wherein R 12a  is ethyl. 
     
     
         27 . The compound of  claim 2 , wherein R 3a  is heterocycloalkyl. 
     
     
         28 . The compound of  claim 27 , wherein R 3a  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 2 , wherein R 3a  is cycloalkyl. 
     
     
         30 . The compound of  claim 29 , wherein R 3a  is 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound of  claim 2 , wherein R 3a  is heteroalkyl. 
     
     
         32 . The compound of  claim 31 , wherein R 3a  is selected from methoxymethyl, methoxyethyl, dimethylaminoethyl, dimethylaminomethyl, 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 2 , wherein R 3a  is lower alkyl. 
     
     
         34 . The compound of  claim 33 , wherein R 3a  is isobutyl or sec-butyl. 
     
     
         35 . The compound of  claim 2 , wherein R 2a  and R 3a , together with the atoms to which they are attached are linked to form a mononcyclic or bicyclic ring that is cycloalkyl or heterocyclic. 
     
     
         36 . The compound of  claim 35 , wherein R 2a  and R 3a  are linked to form a ring selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         37 . A compound, selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A pharmaceutical composition, comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         39 . A method of treating or ameliorating a neurological disorder, comprising administering a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 
     
     
         40 . The method of  claim 39 , wherein the neurological disorder is selected from neurodegenerative diseases, neuropsychiatric diseases, affective disorders, and loss of cognitive function, learning and memory disorders. 
     
     
         41 . A method of  claim 39 , wherein the neurological disorder is selected from schizophrenia, psychosis, and a cognitive disorder. 
     
     
         42 . The method of  claim 39 , wherein the neurological disorder is schizophrenia. 
     
     
         43 . The method of  claim 39 , wherein the neurological disorder is psychosis. 
     
     
         44 . The method of  claim 39 , wherein the neurological disorder is a cognitive disorder. 
     
     
         45 . The method of  claim 39 , wherein the neurological disorder is Alzheimer's disease.