Arginine methyltransferase inhibitors and uses thereof

Abstract

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 each of X, Y, Z, and V is independently O, S, N(R N ) m , or CR C  as valence permits; 
 m is 0 or 1; 
 each instance of R N  is independently selected from the group consisting of each instance of R N  is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —C(═S)R A , —C(═S)N(R B ) 2 , —S(═O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and a nitrogen protecting group; 
 each instance of R C  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═O)N(R B )N(R B ) 2 , —OC(═O)R A , —OC(═O)N(R B ) 2 , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —NR B C(═O)N(R B )N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —OS(═O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; 
 each instance of R A  is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; 
 each instance of R B  is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, and a nitrogen protecting group, or two R B  groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; 
 each instance of Cy is independently optionally substituted C 3-7  cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
 R 3  is independently hydrogen, C 1-4  alkyl, or C 3-4  carbocyclyl; 
 R x  is independently optionally substituted C 1-4  alkyl, or optionally substituted C 3-4  carbocyclyl; 
 provided that at least one of X, Y, Z, and V is O, S, or N(R N ) m ; and 
 provided that when
 V is CR C , X is N, Z is NR N , and Y is CR C ; or 
 V is CR C , X is NR N , Z is N, Y is CR C ; or 
 V is CR C , X is CR C , Z is NR N , Y is N; or 
 V is CR C , X is CR C , Z is N, Y is NR N ; then 
 each instance of R N  is optionally substituted aryl or optionally substituted heteroaryl; and 
 each instance of R C  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═O)N(R B )N(R B ) 2 , —OC(═O)R A , —OC(═O)N(R B ) 2 , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —NR B C(═O)N(R B )N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —OS(═O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; 
 or 
 each instance of R C  is independently selected from the group consisting of optionally substituted C 5-8  alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 5-8  cycloalkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted alkyl-Cy, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═O)N(R B )N(R B ) 2 , —OC(═O)R A , —OC(═O)N(R B ) 2 , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —NR B C(═O)N(R B )N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —OS(═O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; and 
 each instance of R N  is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —C(═S)R A , —C(═S)N(R B ) 2 , —S(═O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and a nitrogen protecting group. 
 
 
     
     
         2 .- 59 . (canceled) 
     
     
         60 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, provided that only one of X, Y, Z and V is O, S, or NR N . 
     
     
         61 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, provided that only one of X, Y, Z and V is NR N . 
     
     
         62 . A compound of one of the following formulae: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein each instance of R N  is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , C(═NR B )N(R B ) 2 , —C(═S)R A , —C(═S)N(R B ) 2 , —S(═O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and a nitrogen protecting group; 
         each instance of R C  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═O)N(R B )N(R B ) 2 , —OC(═O)R A , —OC(═O)N(R B ) 2 , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —NR B C(═O)N(R B )N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —OS(═O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; 
         each instance of R A  is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; 
         each instance of R B  is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, and a nitrogen protecting group, or two R B  groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; 
         each instance of Cy is independently optionally substituted C 3-7  cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
         R 3  is independently hydrogen, C 1-4  alkyl, or C 3-4  carbocyclyl; 
         R x  is independently optionally substituted C 1-4  alkyl, or optionally substituted C 3-4  carbocyclyl; and 
         each instance of e is independently 0, 1, 2, 3, or 4, as valence permits. 
       
     
     
         63 . The compound of  claim 62 , or a pharmaceutically acceptable salt thereof, according to one of the following formulae: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         each instance of L is independently a bond, —O—, —S—, —NR B —, —NR B C(═O)—, —C(═O)NR B —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR B C(═S)—, —C(═S)NR B —, trans-CR C =CR C —, cis-CR C =CR C —, —C≡C—, —OC(R C ) 2 —, —C(R C ) 2 O—, —NR B C(R C ) 2 —, —C(R C ) 2 NR B —, —SC(R C ) 2 —, —C(R C ) 2 S—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR B —, —NR B S(═O) 2 —, or an optionally substituted C 1-6  hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR B —, —NR B C(═O)—, —C(═O)NR B —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR B C(═S)—, —C(═S)NR B —, trans-CR C =CR C —, cis-CR C =CR C —, —C≡C—, —OC(R C ) 2 —, —C(R C ) 2 O—, —NR B C(R C ) 2 —, —C(R C ) 2 NR B —, —SC(R C ) 2 —, —C(R C ) 2 S—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR B —, —NR B S(═O) 2 —; and 
         each instance of E is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 
       
     
     
         64 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of L is independently selected from the group consisting of a bond, —O—, —NR B —, —NR B C(═O)—, —C(═O)NR B —, —(CH 2 ) s —O—, —(CH 2 ) s —, —C≡C—, trans-CR C =CR C —, cis-CR C =CR C —, —S(═O) 2 NR B —, and —NR B S(═O) 2 —;
 wherein s is 1, 2, 3, 4, or 5. 
 
     
     
         65 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of L is a bond. 
     
     
         66 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of E is independently optionally substituted aryl. 
     
     
         67 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of R N  is hydrogen. 
     
     
         68 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of E is independently optionally substituted aryl and each instance of L is a bond. 
     
     
         69 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of E is independently optionally substituted aryl, each instance of L is a bond, and each instance of R N  is hydrogen. 
     
     
         70 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of R x  is independently hydrogen or CH 3 . 
     
     
         71 . The compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein each instance of E is independently of Formula (i): 
       
         
           
           
               
               
           
         
       
       wherein:
 each occurrence of R 2  is independently selected from the group consisting of hydrogen, halogen, —N 3 , —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —OR A , N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═O)N(R B )N(R B ) 2 , —OC(═O)R A , —OC(═O)N(R B ) 2 , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —NR B C(═O)N(R B )N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —OS(═O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; and 
 q is 0, 1, 2, 3, 4, or 5 as valence permits. 
 
     
     
         72 . The compound of  claim 71 , or a pharmaceutically acceptable salt thereof, wherein each instance of E is independently selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         73 . A pharmaceutical composition comprising a compound of  claim 62 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         74 . A kit or packaged pharmaceutical comprising a compound of  claim 62 , or a pharmaceutically acceptable salt thereof, and instructions for use thereof. 
     
     
         75 . A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of  claim 60 , or a pharmaceutically acceptable salt thereof. 
     
     
         76 . The method of  claim 75 , wherein the arginine methyl transferase is PRMT1, PRMT3, CARM1, PRMT6, or PRMT8. 
     
     
         77 . A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of  claim 62 , or a pharmaceutically acceptable salt thereof. 
     
     
         78 . A method of treating a RMT-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 62 , or a pharmaceutically acceptable salt thereof.