Lrrk2 inhibitors and methods of making and using the same

Abstract

are provided. Compounds of the present disclosure are useful for the treatment of neurodegenerative diseases, such as Parkinson's Disease.

1 . A compound of formula II, or III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R X  is NR A R B , 
 
       
         
           
           
               
               
           
         
       
       or a ring system comprising one or two 6-membered heterocycles selected from: 
       
         
           
           
               
               
           
         
       
       wherein each of the ring systems is optionally substituted with 1, 2, 3, 4, 5, or 6 R 51 ;
 each R 51  is independently unsubstituted or substituted C 1 -C 6  alkyl, C(O)NR 61 R 62 , C(O)OR 63 , or NR 64 R 65 ; 
 R 52  is H or R 51 ; 
 R 53  is H, OH, or R 51 ; 
 R 61 , R 62 , and R 63  are each independently H, unsubstituted or substituted C 1 -C 6  alkyl, or unsubstituted or substituted C 2 -C 6  alkenyl; 
 R 64  and R 65  are each independently H or unsubstituted or substituted C 1 -C 6  alkyl; 
 
       
         
           
           
               
               
           
         
       
       is a ring system comprising one or two 6-membered heterocycles selected from: 
       
         
           
           
               
               
           
         
         each R 4  is independently unsubstituted or substituted C 1 -C 6  alkyl; 
         n is 0, 1, 2, 3, 4, 5, or 6; 
         R A  and R B  are each independently unsubstituted or substituted C 1 -C 6  alkyl, or C(O)R 7 ; 
         R 7  is unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 2 -C 6  alkenyl, or unsubstituted or substituted C 2 -C 6  alkynyl; 
         X 1 , X 2 , and X 3  are each independently N, NR 31 , or CR 32 , wherein at least one of X 1 , X 2 , and X 3  is N or NR 31 ; 
         each R 31  is independently H or unsubstituted or substituted C 1 -C 6  alkyl; 
         each R 32  is independently H, unsubstituted or substituted C 1 -C 6  alkyl, halogen, or NR 81 R 82 ; 
         R 81  is H or unsubstituted or substituted C 1 -C 6  alkyl; 
         R 82  is C(O)R 83 ; 
         R 83  is unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 2 -C 6  alkenyl, or unsubstituted or substituted C 2 -C 6  alkynyl; 
         R N  is H or unsubstituted or substituted C 1 -C 6  alkyl; 
         each R 1  is independently unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 1 -C 6  alkoxy, or halogen; 
         m is 0, 1, 2, or 3; 
         R 2  is H, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 1 -C 6  alkoxy,-halogen, NR N1 R N2 , or OR N3 ; 
         R N1  and R N2  are each independently H, unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 2 -C 6  alkenyl, (CH 2 ) 1-3 —O—C 1 -C 6  alkyl, or (CH 2 ) 0-3 —R 91 , or R N1  and R N2 , together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N and 0; 
         R N3  is (CH 2 ) 0-3 —R 92 ; 
         R 91  is unsubstituted or substituted C 3 -C 8  cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, or phenyl substituted with S(O) 2 R 10 , NHC(O)R 1 , C(O)R 12 , or C(O)NHR 13 ; 
         R 92  is unsubstituted or substituted C 3 -C 8  cycloalkyl, unsubstituted or substituted 5- or 6-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, or phenyl substituted with NO 2 , S(O) 2 R 10 , NHC(O)R 1 , C(O)R 12 , or C(O)NHR 13 ; and 
         R 10 , R 1 , R 12 , and R 13  are each independently unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 2 -C 6  alkenyl, NH—C 1 -C 6  alkyl, unsubstituted or substituted 5- or 6-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S, unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S. 
       
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         6 .- 14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein R X  is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         18 .- 20 . (canceled) 
     
     
         21 . The compound of  claim 1 , wherein R X  is a ring system selected from: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1 , wherein R X  is a ring system selected from: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1 , wherein R X  is NR A R B . 
     
     
         24 .- 47 . (canceled) 
     
     
         48 . The compound of  claim 1 , having formula IIa, or IIIa: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R O  is unsubstituted or substituted C 1 -C 6  alkyl. 
     
     
         49 .- 53 . (canceled) 
     
     
         54 . A compound selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         55 . (canceled) 
     
     
         56 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         57 . (canceled) 
     
     
         58 . A method of treating Parkinson's disease in a subject, comprising administering to the subject an effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         59 .- 61 . (canceled)