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, wherein m is 0 or 1; 
 provided:
 (i) at least one of X, Y, Z or V is O or S; or 
 (ii) V is N(R N ) m  and Z is N(R N ) m ; or 
 (iii) X is N(R N ) m  and Y is N(R N ) m ; 
 
 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, or optionally substituted heteroaryl; 
 R 3  is hydrogen, C 1-4  alkyl, or C 3-4  carbocyclyl; and 
 R x  is optionally substituted C 1-4  alkyl or optionally substituted C 3-4  carbocylyl. 
 
       
     
     
         2 - 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein the compound is of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 provided:
 (i) at least one of X, Y, or Z is O or S; or 
 (ii) X is N(R N ) m  and Y is N(R N ) m ; 
 
 
         wherein:
 E is optionally substituted aryl or optionally substituted heteroaryl. 
 
       
     
     
         5 - 8 . (canceled) 
     
     
         9 . The compound of  claim 4 , wherein the compound is of Formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 - 32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein R x  is methyl, ethyl, isopropyl, propyl, butyl, hydroxyethyl, methoxyethyl, cyclopropyl, or cyclobutyl. 
     
     
         34 . The compound of  claim 1 , wherein R 3  is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, or cyclobutyl. 
     
     
         35 . (canceled) 
     
     
         36 . The compound of  claim 4 , wherein E is 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( , 0)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, or optionally substituted heteroaryl; and 
 q is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         37 . The compound of  claim 36 , wherein E is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         39 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         40 . (canceled) 
     
     
         41 . A kit or packaged pharmaceutical comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for use thereof. 
     
     
         42 . A method of inhibiting an arginine methyl transferase (RMT) comprising contacting a cell with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The method of  claim 42 , wherein the arginine methyl transferase is PRMT1, PRMT3, PRMT6, PRMT8, or CARM1. 
     
     
         44 - 47 . (canceled) 
     
     
         48 . A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A method of modulating transcription comprising contacting a cell with an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         50 - 51 . (canceled) 
     
     
         52 . 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 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claims 52 , wherein the RMT-mediated disorder is a PRMT1-mediated disorder, a PRMT3-mediated disorder, PRMT6-mediated disorder, a PRMT8-mediated disorder, or a CARM1-mediated disorder. 
     
     
         54 - 57 . (canceled) 
     
     
         58 . The method of  claim 52 , wherein the disorder is a proliferative disorder, a neurological disorder, a muscular dystrophy, an autoimmune disorder, a vascular disorder, or a metabolic disorder. 
     
     
         59 . The method of  claim 58 , wherein the disorder is a proliferative disorder, and the proliferative disorder is cancer. 
     
     
         60 . The method of  claim 59 , wherein the cancer is breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, or leukemia. 
     
     
         61 . The method of  claim 58 , wherein the disorder is an autoimmune disorder, and the autoimmune disorder is rheumatoid arthritis. 
     
     
         62 . The method of  claim 58 , wherein the disorder is a neurological disorder, and the neurological disorder is amyotrophic lateral sclerosis. 
     
     
         63 . A pharmaceutical composition comprising a compound of  claim 38 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         64 . The compound of  claim 1 , wherein V is NR N  or CR C , wherein R N  or R C  of V is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
         65 . The compound of  claim 1 , wherein V is NR N  or CR C , and R N  or R C  of V is 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 ; 
 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, or optionally substituted heteroaryl; and 
 q is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         66 . The compound of  claim 65 , wherein Formula (i) is: 
       
         
           
           
               
               
           
         
       
     
     
         67 . The compound of  claim 66 , wherein Formula (i) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         68 . The compound of  claim 36 , wherein Formula (i) is: