Selective Inhibitors Of Protein Arginine Methytransterase 5 (PRMT5)

Abstract

The disclosure is directed to compounds of Formula I Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

1 . A compound of Formula I-A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, 
         wherein 
         R 1  is —C 0 -C 6 alk-C 1 -C 6 alkyl, —C 0 -C 6 alk-C 1 -C 6 haloalkyl, —C 1 -C 6 alk-O—C 1 -C 6 alkyl, —C 1 -C 6 alk-S—C 1 -C 6 alkyl, —C 1 -C 6 alk-S—C 1 -C 6 alk-CO 2 H, —C 1 -C 6 alk-aryl, —C 1 -C 6 alk-O-aryl, —C 0 -C 6 alk-heteroaryl, —C 1 -C 6 alk-O-heteroaryl, —C 1 -C 6 alk-S-heteroaryl, or —C 1 -C 6 alk-NH-heteroaryl; 
         R 2  is methyl, trifluoromethyl, ethynyl, or vinyl; 
         R 4  is halo, C 1 -C 6 alkyl, —NHC(O)NR 6 R 6′ , —NR 6 R 6′ , —NH—O—R 6  or —NH—NR 6 R 6′ ; R 5  is H or F; and 
         R 6  and R 6′  are each independently H or —C 1 -C 6 alkyl. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 2  is methyl, ethynyl, or vinyl. 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is —C 1 -C 6 alk-aryl or —C 1 -C 6 alk-O-heteroaryl. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is —C 1 -C 6 alk-O-heteroaryl; and R 2  is methyl, ethynyl, or vinyl. 
     
     
         5 . The compound according to  claim 1 , wherein R 1  is —C 1 -C 6 alk-aryl; and R 2  is methyl, ethynyl, or vinyl. 
     
     
         6 . The compound according to  claim 1 , wherein R 1  is —C 1 -C 6 alk-aryl wherein the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted with a halogen atom, a —C 1 -C 3  alkyl group, an amino-substituted —C 1 -C 3  alkyl group, a C 1 -C 3 haloalkyl group, an amino group (i.e., —NH 2 ), or a substituted amino group; and R 2  is methyl, ethynyl, or vinyl. 
     
     
         7 . The compound according to  claim 1 , wherein R 1  is —C 1 -C 6 alk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, or -3-chloro-4-fluorophenyl. 
     
     
         8 . The compound according to  claim 7 , wherein R 1  is —CH 2 -difluorophenyl, —CH 2 -3,4-difluorophenyl, —CH 2 -4-chlorophenyl, —CH 2 -3-chloro-4-fluorophenyl, —CH 2 -4-chloro-3-fluorophenyl, —CH 2 -dichlorophenyl, —CH 2 -3,4-dichlorophenyl, —CH 2 -3-methyl-4-chlorophenyl, —CH 2 -3-fluoro-4-trifluoromethylphenyl, —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl, —CH(OH)-3-fluoro-4-chlorophenyl, —CH(OH)-3-chloro-4-fluorophenyl, —CH(OH)-3-methyl-4-chlorophenyl, —CH(OH)-3-fluoro-4-trifluoromethylphenyl, —CH(F)-4-chlorophenyl, —CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl, —CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl, —CH(F)-3-methyl-4-chlorophenyl, —CH(F)-3-fluoro-4-trifluoromethylphenyl, —CH(NH 2 )-4-chlorophenyl, —CH(NH 2 )-3,4-dichlorophenyl, —CH(NH 2 )-3,4-difluorophenyl, —CH(NH 2 )-3-fluoro-4-chlorophenyl, —CH(NH 2 )-3-chloro-4-fluorophenyl, —CH(NH 2 )-3-methyl-4-chlorophenyl, —CH(NH 2 )-3-fluoro-4-trifluoromethylphenyl, —CH(Me)-4-chlorophenyl, —CH(Me)-3,4-dichlorophenyl, —CH(Me)-3,4-difluorophenyl, —CH(Me)-3-fluoro-4-chlorophenyl, —CH(Me)-3-chloro-4-fluorophenyl, —CH(Me)-3-methyl-4-chlorophenyl, —CH(Me)-3-fluoro-4-trifluoromethylphenyl, —C(Me)(OH)-4-chlorophenyl, —C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl, —C(Me)(OH)-3-fluoro-4-chlorophenyl, —C(Me)(OH)-3-chloro-4-fluorophenyl, —C(Me)(OH)-3-methyl-4-chlorophenyl, or —C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl. 
     
     
         9 . A compound of Formula I-B, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, 
         wherein 
         R 1  is —C 0 -C 6 alk-heteroaryl, —C 1 -C 6 alk-O-heteroaryl, —C 1 -C 6 alk-S-heteroaryl, or —C 1 -C 6 alk-NH-heteroaryl; 
         R 4  is —NR 6 R 6′ , —NH—O—R 6  or —NH—NR 6 R 6′ ; 
         R 5  is H or F; and 
         R 6  and R 6′  are each independently H or —C 1 -C 6 alkyl. 
       
     
     
         10 . The compound according to  claim 9 , wherein R 1  is —C 1 -C 6 alk-O-heteroaryl. 
     
     
         11 . The compound according to  claim 9 , wherein R 1  is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e., —CH 2 —O-(2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl)oxy)methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy)methyl, ((2-(methylamino)quinolin-7-yl)oxy)methyl, ((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl, ((indazol-6-yl)oxy)methyl, 2-(2-aminoquinolin-7-yl)ethyl, ((2-aminoquinolin-7-yl)thio)methyl, or ((2-aminoquinolin-7-yl)amino)methyl; and R 4  is —NH 2 , —NH—O—CH 3  or —NH—NHCH 3 . 
     
     
         12 . The compound according to  claim 9 , wherein R 1  is ((quinolin-7-yl)oxy)methyl, ((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e., —CH 2 —O-(2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl)oxy)methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy)methyl, ((2-(methylamino)quinolin-7-yl)oxy)methyl, ((2-(methoxyamino)quinolin-7-yl)oxy)methyl, ((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl, ((indazol-6-yl)oxy)methyl, 2-(2-aminoquinolin-7-yl)ethyl, ((2-aminoquinolin-7-yl)thio)methyl, ((3-methylimidazo[1,2-a]pyridine-7yl)oxy)methyl, or ((2-aminoquinolin-7-yl)amino)methyl; R 4  is —NH 2 , —NH—OH, —NH—O—CH 3  or —NH—NHCH 3 ; and R 5  is H or F. 
     
     
         13 . The compound according to  claim 9 , wherein R 1  is ((quinolin-7-yl)oxy)methyl, ((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e., —CH 2 —O-(2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl)oxy)methyl, ((2-amino-3-fluoroquinolin-7-yl)oxy)methyl, ((2-(methylamino)quinolin-7-yl)oxy)methyl, ((2-(methoxyamino)quinolin-7-yl)oxy)methyl, ((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl, ((indazol-6-yl)oxy)methyl, 2-(2-aminoquinolin-7-yl)ethyl, ((2-aminoquinolin-7-yl)thio)methyl, ((3-methylimidazo[1,2-a]pyridine-7yl)oxy)methyl, or ((2-aminoquinolin-7-yl)amino)methyl. 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         16 . A method of treating a disease in a subject comprising administering to the subject a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease is adenoid cystic carcinoma (ACC), a myeloproliferative disorder, glioblastoma, primary central nervous system lymphoma, fallopian tube cancer, non-Hodgkin lymphoma, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, a hemoglobinopathy, b-thalassemia, or sickle cell disease (SCD). 
     
     
         17 . A method of treating a disease in a subject comprising administering to the subject a compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein the disease is adenoid cystic carcinoma (ACC), a myeloproliferative disorder, glioblastoma, primary central nervous system lymphoma, fallopian tube cancer, non-Hodgkin lymphoma, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, a hemoglobinopathy, b-thalassemia, or sickle cell disease (SCD).