Substituted imidazopyrimidin-5(6h)-ones as allosteric modulators of mglur5 receptors

Abstract

In one aspect, the invention relates to imidazopyrimidin-5(6H)-one 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 .- 13 . (canceled) 
     
     
         14 . 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 ----- is an optional covalent bond, wherein valence is satisfied; 
         wherein Ar 1  is phenyl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar 1  is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein when ----- is present and A 1  and A 2  are joined by a covalent double bond, A 1  is CR 1s , and A 2  is CR 2a ;
 wherein R 1a  is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 wherein R 2a  is selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 
         wherein when ----- is not present and A 1  and A 2  are joined by a covalent single bond, A 1  is CR 1b R 1c , and A 2  is CR 2b R 2c ;
 wherein each of R 1b  and R 1c  are independently selected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 wherein each of R 2b  and R 2c  are independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 
         wherein R 3 , when ----- is present, is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar 2 ;
 wherein Ar 2  is phenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH 2 , —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar 2  is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH 2 , —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl); and, 
 
         wherein R 3 , when ----- is not present, is Ar 2 ; 
         wherein R 4  is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, and C1-C4 alkoxy; 
         wherein each of R 5a  and R 5b  is independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         or a pharmaceutically acceptable salt or solvate, thereof. 
       
     
     
         15 . The method of  claim 14 , wherein the disorder is a neurological and/or psychiatric disorder associated with mGluR5 dysfunction. 
     
     
         16 . The method of  claim 15 , wherein the disorder is selected from dementia, delirium, amnestic disorders, age-related cognitive decline, schizophrenia, psychosis including schizophrenia, 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. 
     
     
         17 . A method for the treatment of a disease of uncontrolled cellular proliferation 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 ----- is an optional covalent bond, wherein valence is satisfied; 
         wherein Ar 1  is phenyl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar 1  is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein when ----- is present and A 1  and A 2  are joined by a covalent double bond, A 1  is CR 1a , and A 2  is CR 2a ;
 wherein R 1a  is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 wherein R 2a  is selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 
         wherein when ----- is not present and A 1  and A 2  are joined by a covalent single bond, A 1  is CR 1b R 1c , and A 2  is CR 2b R 2c ;
 wherein each of R 1b  and R 1c  are independently selected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 wherein each of R 2b  and R 2c  are independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
 
         wherein R 3 , when ----- is present, is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar 2 ;
 wherein Ar 2  is phenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH 2 , —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar 2  is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH 2 , —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl); and, 
 
         wherein R 3 , when ----- is not present, is Ar 2 ; 
         wherein R 4  is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, and C1-C4 alkoxy; 
         wherein each of R 5a  and R 5b  is independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         or a pharmaceutically acceptable salt or solvate, thereof. 
       
     
     
         18 . The method of  claim 17 , wherein the disease is cancer. 
     
     
         19 . The method of  claim 17 , wherein the disease is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer. 
     
     
         20 . The method of  claim 17 , wherein the disease is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma. 
     
     
         21 . The method of  claim 14 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 14 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The method of  claim 14 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 7  and R 8  are independently selected from hydrogen and C1-C4 alkyl. 
       
     
     
         24 . The method of  claim 14 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 6  is C1-C4 alkyl. 
       
     
     
         25 . The method of  claim 14 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 14 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 15 , wherein the disorder is absence epilepsy. 
     
     
         28 . The method of  claim 17 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The method of  claim 17 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The method of  claim 17 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 7  and R 8  are independently selected from hydrogen and C1-C4 alkyl. 
       
     
     
         31 . The method of  claim 17 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of  claim 17 , wherein the compound administered has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 17 , wherein the compound administered has a structure represented by a formula: