Compounds, compositions, and methods

Abstract

The present disclosure relates generally to LRRK2 inhibitors, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and methods of making and using thereof.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: 
         R 1  is optionally substituted cycloalkyl or, when R 5  is —CR 5a R 6 R 7  where R 5a  is optionally substituted triazol-2-yl, R 1  is optionally substituted cycloalkyl or C 1-6  alkyl optionally substituted with halo; 
         R 2  is halo, cyano, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkenyl, optionally substituted C 1-6  alkynyl, optionally substituted cycloalkyl, optionally substituted C 1-6  alkoxy, optionally substituted cycloalkoxy, optionally substituted C 1-6  alkylthio, optionally substituted C 1-6  alkylsulfonyl, —C(O)R 10 , or —C(O)N(R 11 )(R 12 ); 
         R 3  is optionally substituted C 1-6  alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C 1-6  alkylthio, optionally substituted C 1-6  alkylsulfonyl, or 
       
       —N(R 11 )(R 12 );
 R 4  is hydrogen or halo; 
 R 5  is hydrogen, halo, cyano, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkenyl, optionally substituted C 1-6  alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted C 1-6  alkylthio, optionally substituted C 1-6  alkyl sulfonyl, —C(O)R 10 , or —C(O)N(R 11 )(R 12 ); 
 each R 10  is independently optionally substituted C 1-6  alkyl or optionally substituted C 1-6  alkoxy; and 
 R 11  and R 12  are each independently hydrogen, optionally substituted C 1-6  alkyl, or optionally substituted cycloalkyl. 
 
     
     
         2 . A compound of  claim 1  of formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: 
         R 1  is optionally substituted cycloalkyl or C 1-6  alkyl optionally substituted with halo; 
         R 6  and R 7  are each independently hydrogen or C 1-6  alkyl optionally substituted with halo; and 
         R 8  and R 9  are each independently hydrogen, cyano, halo, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkoxy, or optionally substituted heteroaryl. 
       
     
     
         3 . The compound of  claim 2 , wherein R 6  and R 7  are methyl. 
     
     
         4 . The compound of  claim 2 , wherein at least one of R 8  and R 9  is hydrogen. 
     
     
         5 . The compound of  claim 4 , wherein both R 8  and R 9  are hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is optionally substituted cyclopropyl or optionally substituted cyclobutyl. 
     
     
         7 . The compound of  claim 6 , wherein R 1  is cycloalkyl independently substituted with one or more halo, hydroxy, cyano, or heteroaryl. 
     
     
         8 . The compound of  claim 7 , wherein R 1  is cyclopropyl, cyclobutyl, hydroxycylobut-3-yl, cyanocylobut-3-yl, triazol-2yl-cyclobut-3-yl, triazol-1-yl-cyclobut-3-yl, or fluorocyclobut-3-yl. 
     
     
         9 . The compound of  claim 1 , wherein R 1  is CD 3 , ethyl, or prop-2-yl. 
     
     
         10 . The compound of  claim 1 , wherein R 2  is halo, cyano, C 1-6  alkyl optionally substituted with halo. 
     
     
         11 . The compound of  claim 10 , wherein R 2  is bromo. 
     
     
         12 . The compound of  claim 10 , wherein R 2  is —CF 3 . 
     
     
         13 . The compound of  claim 1 , wherein R 3  is optionally substituted cycloalkyl, optionally substituted C 1-6  alkoxy, or —N(R 11 )(R 12 ). 
     
     
         14 . The compound of  claim 1 , wherein R 3  is cyclopropyl, methoxy, 1,1-difluoroethy-2-ylamino, cyclopropylamino, —NH(CH 3 ), or —NH(CH 2 CH 3 ). 
     
     
         15 . The compound of  claim 1 , wherein R 4  is hydrogen. 
     
     
         16 . The compound of  claim 1 , wherein R 5  is cyano, optionally substituted C 1-6  alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted C 1-6  alkylsulfonyl, —C(O)R 10 , or —C(O)N(R 11 )(R 12 ). 
     
     
         17 . The compound of  claim 16 , wherein R 5  is cyano, —C(O)R 10 , —C(O)N(R 11 )(R 12 ), C 1-6  alkylsulfonyl, acyl, heteroaryl optionally substituted with C 1-6  alkyl, cycloalkyl optionally substituted with one to three oxo or C 1-6  alkyl, heterocyclyl optionally substituted with one to three halo, C 1-6  alkyl, C 1-6  alkyl substituted with cyano, hydroxyl, alkylsulfonyl, heterocyclyl, hydroxy, alkoxy, or heteroaryl, or C 1-6  cycloalkyl substituted with cyano, aminocarbonyl, or alkoxycarbonyl. 
     
     
         18 . The compound of  claim 16 , wherein R 5  is 2-(triazol-2-yl)propan-2-yl, 2-pyrimidin-2-ylpropan-2-yl, N,N-dimethylamido, 2-methylpropan-2-yl, methyl sulfonyl, cyano, 2-hydroxypropan-2-yl, methylcarbonyl, 5-methylpyrrolidin-2-one-5-yl, 1-(triazol-2-yl)ethyl, 2-methyl sulfonylpropan-2-yl, 5-methyl-1,3-oxazol-4-yl)pyrazol-3-yl, 3-methyloxetan-3-yl, 1-cyano-cycloprop-2-yl,pyrrolidin-2-one-5-yl, 1, 1-dioxo-1,2-thiazolidin-2-yl, 7-methyl-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl, 1-ethoxycarbonyl-cycloprop-2-yl, 1-aminocarbonyl-cycloprop-2-yl, 7-methyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl, 2-methoxypropan-2-yl, 2-cyanopropan-2-yl, 3-methyloxolan-2-one-3-yl, oxabicyclo[3.1.0]hexan-2-one-3-yl, 1-methyl-pyrrolidin-2-one-yl, cyclopropyl, 1-ethyl-4,4-difluoropiperid-3-yl, 4,4-difluoropiperid-3-yl, or 2-methyl-1-oxo-cyclopent-2-yl. 
     
     
         19 . The compound of  claim 1 , wherein R 1  is cycloalkyl independently substituted with one or more hydroxy, cyano, or heteroaryl; R 2  is halo or C 1-6  fluoroalkyl; R 3  is —N(R 11 )(R 12 ) or C 1-6  alkoxy; and R 4  is H. 
     
     
         20 . A compound of Table 1A, Table 1B, Table 2A or Table 2B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof. 
     
     
         21 . A pharmaceutical composition comprising a compound of Table 1A, Table 1B, Table 2A or Table 2B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         22 . A method for treating a disease or condition mediated, at least in part, by LRRK2, the method comprising administering an effective amount of the pharmaceutical composition of  claim 21  to a subject in need thereof. 
     
     
         23 . The method of  claim 22 , wherein the disease or condition is a neurodegenerative disease. 
     
     
         24 . The method of  claim 23 , wherein the neurodegenerative disease is Parkinson's disease or dementia. 
     
     
         25 . The method of  claim 22 , wherein the disease or condition is a central nervous system (CNS) disorder. 
     
     
         26 . The method of  claim 25 , wherein the CNS disorder is Alzheimer's disease or L-Dopa induced dyskinesia. 
     
     
         27 . The method of  claim 22 , wherein the disease or condition is a cancer. 
     
     
         28 . The method of  claim 27 , wherein the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma. 
     
     
         29 . The method of  claim 22 , wherein the disease or condition is an inflammatory disease. 
     
     
         30 . The method of  claim 29 , wherein the inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis. 
     
     
         31 . A method for enhancing cognitive memory, the method comprising administering an effective amount of the pharmaceutical composition of  claim 21  to a subject in need thereof. 
     
     
         32 .- 36 . (canceled)