Prmt5 inhibitor compounds

Abstract

A series of PRMT5 inhibitor compounds are described. The compounds are useful as PRMT5 inhibitor compounds and in the treatment of PRMT5 mediated diseases, disorders, and symptoms thereof.

1 . A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         Ar 1  is a monocyclic or bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar 1  is substituted with 0, 1, 2, 3, 4, or 5 R y  groups, as valency permits; each R y  is independently selected from the group consisting of halo, —CN, —NO 2 , optionally substituted aliphatic, 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 , or —SO 2 N(R B ) 2 ; 
         each R A  is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         each R B  is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B  groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring, which may be optionally substituted with 0, 1, 2, 3, 4, or 5 R x  groups; 
         each R A  and R B , can be optionally substituted by one or more independent R 5 , R 6 , R 7 , and R 8 ; 
         each R 5 , R 6 , R 7 , and R 8  is independently hydrogen, halo, or optionally substituted aliphatic, 
         each R x  is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, and —N(R″) 2 ; 
         each R′ is independently hydrogen or optionally substituted aliphatic; 
         each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form a heterocyclic ring, and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; 
         L is 
       
       
         
           
           
               
               
           
         
         Ar 2  is any one of the following groups: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein:
 Ar 1  is any one of the following groups,   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. 
     
     
         4 . The compound of  claim 1 , wherein L is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. 
     
     
         5 . The compound of  claim 1 , wherein Ar 2  is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. 
       
     
     
         7 . A compound, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, represented by Formula (IV) or (V): 
       
         
           
           
               
               
           
         
         wherein 
         each R 1  is independently one of: 
       
       
         
           
           
               
               
           
         
         Each L is independently: 
       
       
         
           
           
               
               
           
         
         Each R 2  is independently one of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, of  claim 7 , wherein each R 1  is independently one of 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, of  claim 7 , wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, of  claim 7 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, of  claim 7 , wherein the compound is of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. 
       
     
     
         12 . A compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         each R 1  is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, or optionally substituted hydroxyalkyl; 
         each L is independently 
       
       
         
           
           
               
               
           
         
       
       and
 each R 2  is independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C(O)—NH-aryl, or optionally substituted —C(O)-heterocycloalkyl. 
 
     
     
         13 . A compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein each R 1  is independently 
       
       
         
           
           
               
               
           
         
         each L is independently 
       
       
         
           
           
               
               
           
         
         each R 2  is independently 
       
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 13 , or pharmaceutically acceptable salt thereof, that is any one of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . A method of treating a subject suffering from or susceptible to a proliferative disease, the method comprising administering to the subject a compound of  claim 1 . 
     
     
         19 . A method of treating a proliferative disease in a subject identified as in need thereof, the method comprising administering to the subject a compound of  claim 1 . 
     
     
         20 . A method of treating a subject suffering from or susceptible to a proliferative disease, the method comprising administering to the subject a compound of  claim 1 , such that said subject is treated for said proliferative disease. 
     
     
         21 . A method of treating a proliferative disease in a subject identified as in need thereof, the method comprising administering to the subject a compound of  claim 1 , such that said subject is treated for said proliferative disease. 
     
     
         22 . The method of  claim 19 , wherein the proliferative disease is cancer. 
     
     
         23 . (canceled)