PRMT1 Inhibitors and Uses Thereof

Abstract

Described herein are compounds of Formula (I-a) and (I-b), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT1 activity. Methods of using the compounds for treating PRMT1-mediated disorders are also described.

1 . A compound of Formula (I-a) or (I-b): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
 X is N, Z is NR 4 , and Y is CR 5 ; or 
 X is NR 4 , Z is N, and Y is CR 5 ; or 
 X is CR 5 , Z is NR 4 , and Y is N; or 
 X is CR 5 , Z is N, and Y is NR 4 ; 
 R G  is —CF 3  or —CF 2 H; 
 
         R 1  is hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —(CR z R z ) n C(O)N(R B ) 2 , —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)2R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ;
 R 2  is hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —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)2R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ; 
 R 6  is hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —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)2R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ; 
 R 7  and R 8  are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —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 ; wherein at least one of R 7  and R 8  is not hydrogen; 
 each R A  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, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; 
 each R B  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, and optionally substituted heteroaryl, and a nitrogen protecting group, or two R B  groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; 
 R 1  and R 2  are optionally taken together to form a carbocyclic, heterocyclic, or aryl ring; or 
 R 2  and R 8  are optionally taken together to form a carbocyclic, heterocyclic, or aryl ring; or 
 R 6  and R 7  are optionally taken together to form a carbocyclic, heterocyclic, or aryl ring; 
 R 3  is hydrogen, C 1-4  alkyl, or C 3-4  cycloalkyl; 
 R 4  is hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3-7  cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4  alkyl-Cy; 
 Cy is optionally substituted C 3-7  cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 5  is hydrogen, halo, —CN, optionally substituted C 1-4  alkyl, or optionally substituted C 3-4  cycloalkyl; 
 R x  is optionally substituted C 1-4  alkyl or optionally substituted C 3-4  cycloalkyl; 
 R y  is —NR B C(O)R A , —NR B SO 2 R A , or —(CR z R z ) n C(O)N(R B ) 2 ; 
 each RZ is independently hydrogen or fluoro; and 
 n is 0, 1, 2, 3, or 4. 
 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is of Formula (II-a), Formula (II-b), Formula (III-a), Formula (III-b), Formula (IV-a), Formula (IV-b), Formula (V-a), or Formula (V-b): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 .- 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is R y , wherein
 R y  is —NR B C(O)R A , —NR B SO 2 R A , or —(CR z R z ) n C(O)N(R B ) 2 ;   each R z  is independently hydrogen or fluoro; and   n is 0, 1, 2, 3, or 4.   
     
     
         11 .- 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen, —OR A , halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, or —CN. 
     
     
         18 .- 47 . (canceled) 
     
     
         48 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is hydrogen, —OR A , halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, or —CN. 
     
     
         49 .- 87 . (canceled) 
     
     
         88 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen, —OR A , halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, or —CN. 
     
     
         89 .- 128 . (canceled) 
     
     
         129 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7  is hydrogen or halo. 
     
     
         130 . (canceled) 
     
     
         131 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8  is hydrogen or halo. 
     
     
         132 . (canceled) 
     
     
         133 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen, C 1-4  alkyl, cyclopropyl, or cyclobutyl. 
     
     
         134 .- 136 . (canceled) 
     
     
         137 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is hydrogen or optionally substituted C 1-6  alkyl, . 
     
     
         138 .- 140 . (canceled) 
     
     
         141 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is hydrogen or optionally substituted C 1-4  alkyl. 
     
     
         142 .- 144 . (canceled) 
     
     
         145 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R x  is optionally substituted C 1-4  alkyl or optionally substituted C 3-4  cycloalkyl. 
     
     
         146 .- 153 . (canceled) 
     
     
         154 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof. 
     
     
         155 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         156 .- 161 . (canceled) 
     
     
         162 . A method of treating a PRMT1-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. 
     
     
         163 . The method of  claim 162 , wherein the disorder is a proliferative disorder, a neurological disorder, a muscular dystrophy, an autoimmune disorder, a vascular disorder, or a vascular disorder. 
     
     
         164 . The method of  claim 163 , wherein the disorder is cancer. 
     
     
         165 . (canceled) 
     
     
         166 . The method of  claim 163 , wherein the disorder is amyotrophic lateral sclerosis. 
     
     
         167 .- 170 . (canceled)