Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors

Abstract

In one aspect, the invention relates to substituted bicyclic alkoxy pyrazole analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

1 - 16 . (canceled) 
     
     
         17 . A method for the treatment of a neurological and/or psychiatric disorder associated with glutamate dysfunction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein each of R 2a  and R 2b  is independently selected from hydrogen and C1-C4 alkyl: 
         wherein R 3  is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein each of R 4a  and R 4b  is hydrogen or C1-C4 alkyl; 
         wherein each of R 5a  and R 5b  is hydrogen or C1-C4 alkyl; 
         wherein each of R 6a  and R 6b  is hydrogen or C1-C4 alkyl; 
         wherein R 7  is selected from C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, hydroxy(C1-C8 alkyl), (C1-C6 alkyl)-O—(C1-C6 alkyl)-, (C1-C6 monohaloalkyl)-O—(C1-C6 alkyl)-, (C1-C6 polyhaloalkyl)-O—(C1-C6 alkyl)-, (C1-C6 alkyl)-NH—(C1-C6 alkyl)-, (C1-C6 alkyl)(C1-C6 alkyl)N—(C1-C6 alkyl)-, Cy 1 , Cy 1 -(C2-C6 alkyl)-, and Cy 1 -C(R 9a )(R 9b )—; and
 wherein Cy 1 , when present, is selected from C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl; and wherein Cy 1 , when present, is substituted with 0, 1, 2, or 3 non-hydrogen groups each independently selected from halo, cyano, —NH 2 , C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, and phenyl;
 wherein each of R 9a  and R 9b  is independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, and C1-C8 alkoxy; 
 
 
         wherein each of R 8a  and R 8b  is hydrogen or C1-C4 alkyl; 
         or pharmaceutically acceptable salt, solvate, or polymorph thereof. 
       
     
     
         18 . The method of  claim 17 , wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. 
     
     
         19 . The method of  claim 17 , wherein the disorder is a neurological and/or psychiatric disorder associated with mGluR5 dysfunction. 
     
     
         20 . The method of  claim 17 , wherein the disorder is selected from autism, dementia, delirium, amnestic disorders, schizophrenia, psychosis, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks, unipolar depression, bipolar disorder, and psychotic depression. 
     
     
         21 . The method of  claim 17 , wherein the disorder is absence epilepsy. 
     
     
         22 . The method of  claim 17 , wherein the disorder is selected from cognitive disorders, age-related cognition decline, learning deficit, intellectual impairment disorders, cognition impairment in schizophrenia, cognition impairment in Alzheimer's disease, and mild cognitive impairment. 
     
     
         23 . The method of  claim 17 , wherein R 1  is phenyl substituted with 0-1 groups selected from fluoro, cyano, methyl, and methoxy. 
     
     
         24 . The method of  claim 17 , wherein each of R 2a , R 2b , R 3 , R 5a , R 5b , and R 4b  are hydrogen, and wherein R 4a  is selected from hydrogen and methyl. 
     
     
         25 . The method of  claim 17 , wherein each of R 2a , R 2b , R 3 , R 4a , R 4b , and R 5b  are hydrogen, and wherein R 5a  is selected from hydrogen and methyl. 
     
     
         26 . The method of  claim 17 , wherein each of R 2a , R 2b , R 3 , R 4a , R 4b , R 5a , and R 5b  are hydrogen. 
     
     
         27 . The method of  claim 17 , wherein R 2a , R 2b , R 3 , R 4a , R 4b , R 5a , and R 5b , R 6a , and R 6b  are hydrogen. 
     
     
         28 . The method of  claim 17 , wherein Cy 1 , when present, is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, 1-methyl-pyrazolyl, pyrrolyl, 1-methyl-pyrrolyl, thiophenyl, furanyl, 5-methylfuranyl, indolyl, 1-methylindolyl, indazolyl, 1-methylindazolyl, cyclopentyl, cyclobutyl, and cyclopropyl, and wherein Cy 1 , when present, is substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, —NH 2 , C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, and phenyl. 
     
     
         29 . The method of  claim 28 , wherein Cy 1 , when present, is selected from phenyl, indazolyl, indolyl, thiophenyl, furanyl, 1-methylpyrrolyl, and cyclopentyl. 
     
     
         30 . The method of  claim 28 , wherein Cy 1 , when present, is selected from phenyl substituted with 0-2 groups independently selected from fluoro, chloro, cyano, methyl, trifluoromethyl, and methoxy. 
     
     
         31 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e  is independently selected from hydrogen, cyano, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, provided that at least two of R 10a , R 10b , R 10c , R 10d , and R 10e  are hydrogen; or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 4a , R 4b , R 5a , and R 5b  is independently selected from hydrogen and methyl; wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e  is independently selected from hydrogen, cyano, fluoro, methyl, and methoxy, provided that at least four of R 10a , R 10b , R 10c , R 10d , and R 10e  are hydrogen; or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 4a , R 4b , R 5a , and R 5b  is independently selected from hydrogen and methyl; wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e  is independently selected from hydrogen, cyano, fluoro, methyl, and methoxy, provided that at least four of R 10a , R 10b , R 10c , R 10d , and R 10e  are hydrogen; wherein each of R 11a , R 11b , R 11c , R 11d , and R 11e  is independently selected from hydrogen, fluoro, chloro, cyano, methyl, trifluoromethyl, and methoxy, provided that at least three of R 11a , R 11b , R 11c , R 11d , and R 11e  are hydrogen; or a pharmaceutically acceptable salt thereof. 
       
     
     
         36 . The method of  claim 17 , wherein R 3  is hydrogen. 
     
     
         37 . The method of  claim 17 , wherein each of R 6a  and R 6b  is hydrogen. 
     
     
         38 . The method of  claim 17 , wherein each of R 8a  and R 8b  is hydrogen. 
     
     
         39 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         41 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         43 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The method of  claim 17 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         45 . The method of  claim 17 , having a structure represented by a formula: