Substituted 4-methyl-pyrrolo[1,2-a]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity

Abstract

Disclosed are new small molecules having a 4-methylpyrrolo[1,2-a]pyrimidine-8-carboxamide core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules which may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including neurological diseases and disorders such as Gaucher's disease and Parkinson's disease. The small molecules may contain a fluorophore or may be conjugated to a fluorophore in order to prepare a fluorescent probe for use in high throughput screening methods to identify new modulators of glucocerebrosidase activity via fluorescence polarization.

We claim: 
     
         1 . A compound or a salt or solvate thereof having a Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen; a C1-C6 alkyl group; a C2-C6 alkenyl group; a C2-C6 alkynyl group; a saturated or unsaturated homocycle or heterocycle comprising one 5- or 6-membered ring, a saturated or unsaturated homocycle or heterocycle comprising two fused 5- or 6-membered rings, or an alkylthiophene; and R 1  optionally is substituted at one or more positions with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halo group, a haloalkyl group, phenyl group which optionally is substituted with halo, a benzyl group which optionally is substituted with halo, a triazole group optionally substituted with a carboxyl group, a 2,5-dioxopyrrolidinyl-1-yl-carboxylate group, an amino group, an alkyl-N,N-dialkyl amino group, an alkyl-alkyoxy-amino group, an alkyl-alkyoxy-alkoxy-amino group, an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-morpholine group, an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-1-alkylpyrrolidine group, an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-cyclohexyl group, or an alkyl -alkyoxy-alkoxy-carboxamide-alkyl -cyclobutyl group; an imidazole group; a pyridyl group optionally substituted with phenoxy; a pyrrolidinyl group, a piperazinyl group, a 4-alkylpiperazine group, a 4-benzylpiperazine group, an alkyl-4-alkylpiperazine group; a piperidinyl group; a 4-alkylpiperidine group; a 4-N,N,diakylaminopiperidine group; a morpholinyl group; an alkylmorpholine group; an amino group; an alkylamino group; a dialkyl amino group; an alkyl-N,N-dialkylamino group; an azide group; a hydroxyl group; an alkylhydroxyl group; an alkynylphenyl group; a phenylmethanone group; an oxyphenyl group; an oxycarboxyl group, or R 1  has a formula selected from: 
       
       
         
           
           
               
               
           
         
       
       and R 3  has a formula selected from 
       
         
           
           
               
               
           
         
       
       and R 4  is H, C1-C8 alkyl, phenyl, or succinimidyl; and
 R 2  is C1-C6 alkyl or pyridinyl (e.g., 2-yl, 3-yl, or 4-yl). 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1  having Formula IA: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is hydrogen a C1-C6 alkyl group; a C2-C6 alkenyl group; a C2-C6 alkynyl group; a C1-C6 alkoxy group; a halo group; a haloalkyl group; a phenyl group; a benzyl group; a triazole group optionally substituted with a carboxylic acid group; a 2,5-dioxopyrrolidinyl-1-yl-carboxylate group; an amino group; an alkyl-N,N-dialkyl amino group; an alkyl-alkyoxy-amino group; an alkyl-alkyoxy-alkoxy-amino group; an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-morpholine group; an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-1-alkylpyrrolidine group; an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-cyclohexyl group; and an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-cyclobutyl group; an imidazole group; a pyrrolidine group; a piperazine group; a 4-alkylpiperazine group; a 4-benzylpiperazine group; an alkyl-4-alkylpiperazine group; a piperidine group; a 4-alkylpiperidine group; a 4-N,N,diakylaminopiperidine group; a morpholine group; an alkylmorpholine group; an amino group; an alkylamino group; a dialkyl amino group; an alkyl-N,N-dialkylamino group; an azide group; a hydroxyl group; an alkylhydroxyl group; an alkynylphenyl group; a phenylmethanone group; an oxyphenyl group; or an oxycarboxylic acid group. 
       
     
     
         4 . The compound of  claim 1  having Formula IB: 
       
         
           
           
               
               
           
         
         wherein: 
         R 3  is a carboxyl group, a 2,5-dioxopyrrolidinyl-1-yl-carboxylate group; an alkylamino group; an alkyl-N,N-dialkyl amino group; an alkyl-alkyoxy-amino group; an alkyl-alkyoxy-alkoxy-amino group; an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-morpholine group; an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-1-alkylpyrrolidine group; an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-cyclohexyl group; and an alkyl-alkyoxy-alkoxy-carboxamide-alkyl-cyclobutyl group. 
       
     
     
         5 . The compounds of  claim 1  wherein any of R 1 , R 2 , and R 3  comprises a fluorophore. 
     
     
         6 . The compound of  claim 1  having Formula ID: 
       
         
           
           
               
               
           
         
         wherein: 
         X is N or S; and 
         R 4 , R 5 , R 6 , and R 7 , are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and halogen. 
       
     
     
         7 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutical carrier. 
     
     
         8 . A method for treating a disease or disorder that is associated with glucocerebrosidase activity, the method comprising administering the composition of  claim 7 . 
     
     
         9 . The method of  claim 8 , wherein the disease or disorder is a neurological disease or disorder. 
     
     
         10 . The method of  claim 9 , wherein the neurological disease or disorder is a degenerative neurological disease or disorder. 
     
     
         11 . The method of  claim 10 , wherein the degenerative neurological disease or disorder is Gaucher's disease. 
     
     
         12 . The method of  claim 10 , wherein the degenerative neurological disease or disorder is Parkinson's disease. 
     
     
         13 . A fluorescent probe comprising the compound of  claim 5 . 
     
     
         14 . A method of screening for a compound that binds to glucocerebrosidase, the method comprising contacting glucocerebrosidase with the fluorescent probe of  claim 13  and observing fluorescence polarization. 
     
     
         15 . Activated glucocerebrosidase comprising glucocerebrosidase covalently attached to the compound of  claim 1 . 
     
     
         16 . A pharmaceutical composition comprising the activated glucocerebrosidase of  claim 15  and a pharmaceutical carrier. 
     
     
         17 . A method for treating a disease or disorder that is associated with glucocerebrosidase activity, the method comprising administering the composition of  claim 16 . 
     
     
         18 . The method of  claim 17 , wherein the disease or disorder is a neurological disease or disorder. 
     
     
         19 . The method of  claim 18 , wherein the disease or disorder is a degenerative neurological disease or disorder. 
     
     
         20 . The method of  claim 19 , wherein the degenerative neurological disease or disorder is Gaucher's disease.