Aminopyridine compounds and methods for the preparation and use thereof

Abstract

The present invention relates generally to therapeutics targeting the bacterium Porphyromonas gingivalis, including its proteases arginine gingipain A/B (Rgp), and their use for the treatment of disorders associated with P. gingivalis infection, including brain disorders such as Alzheimer's disease. In certain embodiments, the invention provides compounds according to Formula I and Formula III, as described herein, and pharmaceutically acceptable salts thereof.

What is claimed is: 
     
         1 . A compound according to Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 11  and R 12a  are taken together to form 4- to 10-membered heterocyclyl which is optionally substituted with one or more R 17 ; 
         R 12b  is H; 
         R 13a  and R 13b  are independently selected from the group consisting of H, —OH, and C 1-6  alkyl; 
         R 14  is H, or 
         R 14  and R 13a  are taken together to form a 5- to 8-membered ring, which is optionally substituted with one or more R 18 ; 
         R 15a  and R 15b  are H; 
         R 16  is independently selected from the group consisting of C 1-6  alkyl and halogen; 
         Y is selected from the group consisting of O, S, C(R 19a ) 2 , and NR 19b ; 
         each R 18  is independently selected from the group consisting of C 1-6  alkyl and halogen; 
         each R 19a  is selected from the group consisting of H and C 1-6  alkyl, or
 one R 19a  and R 13b  are taken together to form a double bond; 
 
         R 19b  is selected from the group consisting of H and C 1-6  alkyl; 
         subscript m is 0 or 1; and 
         subscript q is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is C(R 19a ) 2 , and wherein one R 19a  and R 13b  are taken together to form a double bond. 
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 14  and R 13a  are taken together to form a 5- to 8-membered ring. 
     
     
         4 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 12a  and R 11  are taken together to form pyrrolidin-1,2-diyl. 
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt thereof, wherein subscript q is 0. 
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         7 . A method of treating a disease or condition associated with  P. gingivalis  infection, the method comprising administering to a subject in need thereof an effective amount of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 7 , wherein the disease or condition is selected from the group consisting of a brain disorder, periodontal disease, diabetes, a cardiovascular disease, arthritis, rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, elevated risk of preterm birth, pneumonia, cancer, a kidney disease, a liver disease, a retinal disorder, and glaucoma. 
     
     
         9 . The method of  claim 8 , wherein the disease or condition is a brain disorder. 
     
     
         10 . The method of  claim 9 , wherein the brain disorder is Alzheimer's disease. 
     
     
         11 . The method of  claim 10 , further comprising administering to the subject one or more active agents selected from the group consisting of a cholinesterase inhibitor, a serotonin modulator, an NMDA modulator, an Aβ targeted therapy, an ApoE targeted therapy, a microglia targeted therapy, a blood brain barrier targeted therapy, a tau targeted therapy, a complement targeted therapy, and an anti-inflammatory. 
     
     
         12 . The method of  claim 8 , wherein the disease or condition is periodontal disease. 
     
     
         13 . The method of  claim 7 , wherein the compound is administered to the subject for at least one year. 
     
     
         14 . The method of  claim 13 , wherein the compound is administered to the subject for at least 10 years. 
     
     
         15 . The method of  claim 7 , wherein the subject is a human, a canine, or a feline.