CHROMANE, ISOCHROMANE AND DIHYDROISOBENZOFURAN DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE

Abstract

and ring B, n, R1, R2, R2A, R3, and R3A are as defined herein. The compounds of the invention are useful as mGuR2 inhibitors, or mGluR2 negative allosteric modulators (NAMs), and may be useful in methods of treating a patient for diseases or disorders in which the mGuR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, mild cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

1 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising:
 (i) a compound having the formula (I):   
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein:
 ring A is a moiety selected from: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is selected from H, cyclopropyl, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-OH, —(C 1 -C 4 )alkyl-OCH 3 , —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )haloalkyl, —CH(CH 3 ) 2 , —CH 2 —O—(C 1 -C 4 )haloalkyl, —CH(CH 3 )—O—(C 1 -C 4 )haloalkyl, —CH 2 —NH—(C 1 -C 4 )haloalkyl, and —CH 2 —N(CH 3 )—(C 1 -C 4 )haloalkyl, 
 R 2A  is selected from H and methyl; 
 R 3  is selected from H and methyl; 
 R 3A  is selected from H and methyl; 
 ring B is a moiety selected from the group consisting of phenyl, heteroaryl, —(C 5 -C 6 ) cycloalkyl, and —(C 5 -C 6 ) cycloalkenyl; 
 n is 0, 1, 2, or 3, provided that the value of n does not exceed the maximum number of substitutable hydrogen atoms on ring B; and 
 each R 1  (when present) is independently selected from the group consisting of halogen, —CN, —OH, —(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) haloalkyl, —O—(C 1 -C 6 ) haloalkyl, cyclopropyl, cyclobutyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —C(O)O(C 1 -C 6 ) alkyl, and phenyl; 
 (ii) an additional therapeutic agent; and 
 (iii) a pharmaceutically acceptable carrier. 
 
     
     
         32 . The composition of claim  1 , wherein the additional therapeutic agent is an acetylcholinesterase inhibitor. 
     
     
         33 . The composition of claim  1 , wherein the acetylcholinesterase inhibitor is donepezil. 
     
     
         34 . The composition of claim  1 , wherein the compound of formula (I) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer. 
     
     
         35 . The composition of  claim 34 , wherein the additional therapeutic agent is an acetylcholinesterase inhibitor. 
     
     
         36 . The composition of claim  5 , wherein the acetylcholinesterase inhibitor is donepezil. 
     
     
         37 . A method of treating Alzheimer's disease, mild cognitive impairment, schizophrenia, mood disorder, or sleep disorder, said method comprising administering an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein:
 ring A is a moiety selected from: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is selected from H, cyclopropyl, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-OH, —(C 1 -C 4 )alkyl-OCH 3 , —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )haloalkyl, —CH(CH 3 ) 2 , —CH 2 —O—(C 1 -C 4 )haloalkyl, —CH(CH 3 )—O—(C 1 -C 4 )haloalkyl, —CH 2 —NH—(C 1 -C 4 )haloalkyl, and —CH 2 —N(CH 3 )—(C 1 -C 4 )haloalkyl, 
 R 2A  is selected from H and methyl; 
 R 3  is selected from H and methyl; 
 R 3A  is selected from H and methyl; 
 ring B is a moiety selected from the group consisting of phenyl, heteroaryl, —(C 5 -C 6 ) cycloalkyl, and —(C 5 -C 6 ) cycloalkenyl; 
 n is 0, 1, 2, or 3, provided that the value of n does not exceed the maximum number of substitutable hydrogen atoms on ring B; and 
 each R 1  (when present) is independently selected from the group consisting of halogen, —CN, —OH, —(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) haloalkyl, —O—(C 1 -C 6 ) haloalkyl, cyclopropyl, cyclobutyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —C(O)O(C 1 -C 6 ) alkyl, and phenyl. 
 
     
     
         38 . The method of  claim 37 , wherein the treating is for Alzheimer's Disease. 
     
     
         39 . The method of  claim 38 , wherein the treating is for mood disorder. 
     
     
         40 . The method of  claim 39 , wherein the mood disorder is depression. 
     
     
         41 . The method of  claim 38 , further comprising administration of an acetylcholinesterase inhibitor. 
     
     
         42 . The method of  claim 41 , wherein the acetylcholinesterase inhibitor is donepezil. 
     
     
         43 . The method of  claim 37 , wherein the compound of formula (I) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer. 
     
     
         44 . The method of  claim 43 , wherein the treating is for Alzheimer's Disease. 
     
     
         45 . The method of  claim 43 , wherein the treating is for mood disorder. 
     
     
         46 . The method of  claim 45 , wherein the mood disorder is depression. 
     
     
         47 . The method of  claim 44 , further comprising administration of an acetylcholinesterase inhibitor. 
     
     
         48 . The method of  claim 47 , wherein the acetylcholinesterase inhibitor is donepezil.