Prmt5 inhibitors and uses thereof

Abstract

Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.

What is claimed is: 
     
         1 .- 90 . (canceled) 
     
     
         91 . A method of inhibiting PRMT5, altering gene expression, or altering transcription, comprising contacting a cell with an effective amount of a compound of formula (A), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
    represents a single or double bond; 
 R 12  is hydrogen, halogen, or optionally substituted C 1-3 alkyl, and R 13  is —NR A1 R A2 , halogen, or optionally substituted C 1-3 alkyl; or 
 R 12  is halogen or optionally substituted C 1-3 alkyl, and R 13  is hydrogen, halogen, optionally substituted C 1-3 alkyl, —NR A1 R A2 , or —OR 1 ; 
 R A1  and R A2  are each independently hydrogen, optionally substituted C 1-3  alkyl, a nitrogen protecting group, or R A1  and R A2  are taken together with the intervening nitrogen atom to form an optionally substituted 3-6 membered heterocyclic ring; 
 R 1  is hydrogen, R z , or —C(O)R z , wherein R z  is optionally substituted C 1-6  alkyl; 
 L is —O—, —N(R)—, —C(R 2 )(R 3 )—, —O—CR 2 R 3 , —N(R)—CR 2 R 3 —, —O—CR 2 R 3 —O—, —N(R)—CR 2 R 3 —O, —N(R)—CR 2 R 3 —N(R)—, —O—CR 2 R 3 —N(R)—, —CR 2 R 3 —O—, —CR 2 R 3 —N(R)—, —O—CR 2 R 3 —CR 9 R 10 —, —N(R)—CR 2 R 3 —CR 9 R 10 —, —CR 2 R 3 —CR 9 R 10 —O—, —CR 2 R 3 —CR 9 R 10 —N(R)—, or —CR 2 R 3 —CR 9 R 10 —; 
 each R is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted phenyl, 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 ; or R 2  and R 3  are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring; 
 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; 
 Ring A is a monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 R 4  is -L 1 -Cy; 
 L 1  is a bond, —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —OC(O)—, —C(O)O—, or an optionally substituted, straight or branched, C 1-6  aliphatic chain wherein one, two, or three methylene units of L 1  are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —O—C(O)—, or —C(O)O—; 
 Cy is an optionally substituted, monocyclic, bicyclic or tricyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 R 5 , R 6 , R 7 , and R 8  are independently hydrogen, halo, or optionally substituted aliphatic; 
 R 9  and R 10  are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted phenyl, 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 ; or R 9  and R 10  are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring; 
 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 , and —SO 2 N(R B ) 2 ; 
 each R x  is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, and —N(R″) 2 ; 
 R′ is 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; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; 
 m is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; and 
 p is 0 or 1. 
 
     
     
         92 .- 95 . (canceled) 
     
     
         96 . A method of treating a PRMT5-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
    represents a single or double bond; 
 R 12  is hydrogen, halogen, or optionally substituted C 1-3 alkyl, and R 13  is —NR A1 R A2 , halogen, or optionally substituted C 1-3 alkyl; or 
 R 12  is halogen or optionally substituted C 1-3 alkyl, and R 13  is hydrogen, halogen, optionally substituted C 1-3 alkyl, NR A1 R A2 , or —OR 1 ; 
 R A1  and R A2  are each independently hydrogen, optionally substituted C 1-3  alkyl, a nitrogen protecting group, or R A1  and R A2  are taken together with the intervening nitrogen atom to form an optionally substituted 3-6 membered heterocyclic ring; 
 R 1  is hydrogen, R z , or —C(O)R z , wherein R z  is optionally substituted C 1-6  alkyl; 
 L is —O—, —N(R)—, —C(R 2 )(R 3 )—, —O—CR 2 R 3 , —N(R)—CR 2 R 3 —, —O—CR 2 R 3 —O—, —N(R)—CR 2 R 3 —O, —N(R)—CR 2 R 3 —N(R)—, —O—CR 2 R 3 —N(R)—, —CR 2 R 3 —O—, —CR 2 R 3 —N(R)—, —O—CR 2 R 3 —CR 9 R 10 —, —N(R)—CR 2 R 3 —CR 9 R 10 —, —CR 2 R 3 —CR 9 R 10 —O—, —CR 2 R 3 —CR 9 R 10 —N(R)—, or CR 2 R 3 —CR 9 R 10 —; 
 each R is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted phenyl, 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 ; or R 2  and R 3  are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring; 
 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; 
 Ring A is a monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 R 4  is -L 1 -Cy; 
 L 1  is a bond, —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —OC(O)—, —C(O)O—, or an optionally substituted, straight or branched, C 1-6  aliphatic chain wherein one, two, or three methylene units of L 1  are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —OC(O)—, or —C(O)O—; 
 Cy is an optionally substituted, monocyclic, bicyclic or tricyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 R 5 , R 6 , R 7 , and R 8  are independently hydrogen, halo, or optionally substituted aliphatic; 
 R 9  and R i ° are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted phenyl, 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 ; or R 9  and R 10  are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring; 
 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 , and —SO 2 N(R B ) 2 ; 
 each R x  is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, and —N(R″) 2 ; 
 R′ is 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; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; 
 m is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; and 
 p is 0 or 1. 
 
     
     
         97 . The method of  claim 96 , wherein the disorder is a proliferative disorder, a metabolic disorder, a blood disorder, or a hemoglobinopathy. 
     
     
         98 . The method of  claim 97 , wherein the disorder is cancer. 
     
     
         99 . The method of  claim 98 , wherein the cancer is hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer. 
     
     
         100 . (canceled) 
     
     
         101 . The method of  claim 97 , wherein the metabolic disorder is diabetes or obesity. 
     
     
         102 .- 104 . (canceled) 
     
     
         105 . The method of  claim 97 , wherein the disorder is sickle cell anemia or β-thalessemia. 
     
     
         106 . (canceled) 
     
     
         107 . The method of  claim 96 , wherein L is —CR 2 R 3 —O— or —CR 2 R 3 —N(R)—. 
     
     
         108 . The method of  claim 96 , wherein R 1  is hydrogen. 
     
     
         109 . The method of  claim 96 , wherein n is 0, 1, or 2. 
     
     
         110 . The method of  claim 96 , wherein R 2  and R 3  are each hydrogen. 
     
     
         111 . The method of  claim 96 , wherein Ring A is an aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         112 . The method of  claim 96 , wherein the compound is of formula (A-15): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4  are independently selected from the group consisting of N, CH, and CR y , provided that at least one of X 2 , X 3 , and X 4  is not N. 
     
     
         113 . The method of  claim 96 , wherein p is 1, and L 1  is a bond. 
     
     
         114 . The method of  claim 96 , wherein Cy is optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         115 . The method of  claim 96 , wherein Cy is optionally substituted pyrazole, optionally substituted pyridyl, or optionally substituted pyrimidyl. 
     
     
         116 . The method of  claim 96 , wherein Cy is optionally substituted indazole, optionally substituted quinoline, optionally substituted benzimidazole, optionally substituted benzothiazole, optionally substituted deazapurine, optionally substituted indole, optionally substituted purine, optionally substituted pyrazolopyridine, optionally substituted pyrrolopyridine, optionally substituted pyrrolopyrimidine, optionally substituted imidazopyridine, or optionally substituted imidazopyridine. 
     
     
         117 . The method of  claim 96 , wherein Cy is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         118 . The method of  claim 96 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         119 . A method of treating a PRMT5-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof.