Substituted Pyrrolo[2,3-D]Pyrimidines As Inhibitors Of Protein Arginine Methyl Transferase 5 (PRMT5)

Abstract

The disclosure is directed to compounds of Formula (I) and Formula (II), Formula (I) and Formula (II) and pharmaceutically acceptable salts or solvates thereof. Pharmaceutical compositions comprising compounds of Formula (I) or Formula (II), as well as methods of their use and preparation, are also described.

1 . A compound of Formula I or Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof; 
         wherein 
         A is N, C—H, C—R 4 , wherein R 4  is halo or CF 3 ; 
         R 1  is —CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), —CH(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), —CH(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), —CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl), —CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl), —CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl), —CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl), —CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl), —CH(OH)-(2,3-dihydro-1H-inden-5-yl), —CH(OH)-(2,3-dihydrobenzofuran-6-yl), —CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl), —C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), —C(Me)(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), —C(Me)(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), —C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl), —C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl), —C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl), —C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl), —C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl), or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl), —C(Me)(OH)-(2,3-dihydrobenzofuran-6-yl), —C(Me)(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); 
         R 2  is halo, —C 1 -C 6 alkyl, —C 2 -C 4 alkenyl, —C 1 -C 6 alk-OH, —C 1 -C 6 alk-halo, —C 1 -C 6 alk-O—C 1 -C 6 alkyl, —C 1 -C 6 alk-O—C 1 -C 6 alk-aryl, —O—C 1 -C 6 alkyl, —NR 5 R 5 ′, —NHC(O)NR 5 R 5 ′, —NHC(S)NR 5 R 5 ′, —NH—O—R 5 , or —NH—NR 5 R 5 ′; 
         R 3  is H; 
         R 5  and R 5 ′ are each independently H, C 1 -C 6 alkyl, or —C 1 -C 6 alk-OC 1 -C 6 alkyl; 
         or R 5  and R 5 ′, together with the atom to which they are attached, form a C 2 -C 6 heterocycloalkyl ring; and 
         R 6  is H or —CH 3 . 
       
     
     
         2 . The compound of  claim 1 , wherein R 2  is —Cl. 
     
     
         3 . The compound of  claim 1 , wherein R 2  is methyl, butyl, or isopropyl. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is vinyl or isopropenyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is —CH 2 OH or —CH 2 CH 2 OH. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is —CH 2 Cl or —CH 2 F. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is —CH 2 —O—CH 2 CH 3  or —CH 2 CH 2 —O—CH 3 . 
     
     
         8 . The compound of  claim 1 , wherein R 2  is —CH 2 CH 2 —O—CH 2 -phenyl. 
     
     
         9 . The compound of  claim 1 , wherein R 2  is —OCH 3 . 
     
     
         10 . The compound of  claim 1 , wherein R 2  is —NR 5 R 5 ′, and R 5  and R 5 ′ are both H. 
     
     
         11 . The compound of  claim 1 , wherein R 2  is —NR 5 R 5 ′, and R 5  is methyl and R 5 ′ is H. 
     
     
         12 . The compound of  claim 1 , wherein R 2  is —NH—O—R 5 , and R 5  is H or C 1 -C 6 alkyl. 
     
     
         13 . The compound of  claim 1 , wherein R 2  is —NHC(0)NR 5 R 5 ′, and R 5  and R 5 ′ are each —C 1 -C 6 alkyl. 
     
     
         14 . The compound of  claim 1 , wherein R 2  is —NHC(O)NR 5 R 5 ′, and R 5  and R 5 ′ together with the atom to which they are attached, form a C 2 -C 6 heterocycloalkyl ring. 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
 (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2S,3 S,4R,5R)-2-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(6-methyl-9H-purin-9-yl)tetrahydrofuran-3,4-diol;   (2S,3 S,4R,5R)-2-((R)-1-(bicyclo[4.2.0]octa- 1 (6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2 S,3 S,4R,5R)-2-((R)-1-(bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(6-methyl-9H-purin-9-yl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R, 5R)-2-((R)-(2,3-dihydrobenzofuran-6-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3R,4 S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(2,3-dihydrobenzofuran-6-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3R,4 S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1R)-(7-fluorobicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R,5R)-2-((1R)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3R,4 S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R,5R)-2-((R)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol;   7-((2R,3R,4 S,5R)-5-((R)-bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one O-methyl oxime;   7-((2R,3R,4 S,5R)-5-((R)-bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one O-ethyl oxime;   7-((2R,3R,4 S,5 S)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one O-ethyl oxime;   3-(7-((2R,3R,4S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-dimethylurea;   N-(7-((2R,3R,4S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide;   (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)cyclopentane-1,2-diol;   (1R,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)cyclopentane-1,2-diol;   3-(7-((1R,2S,3R,4R)-4-((S)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-2,3-dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-dimethylurea;   N-(7-((1R,2S,3R,4R)-4-((S)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-2,3-dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide;   3-(7-((1R,2S,3R,4S)-4-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-2,3-dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-dimethylurea;   (2R,3 S,4R, 5R)-2-((1R)-hydroxy(7-methylbicyclo[4.2.0] octa-1 (6),2,4-trien-3-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   3-((R)-((2R,3 S,4R,5R)-3,4-dihydroxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)(hydroxy)methyl)bicyclo[4.2.0]octa-1(6),2,4-trien-7-one;   (2R,3 S,4R, 5R)-2-((1R)-hydroxy(7-hydroxybicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-(7,7-dimethylbicyclo[4.2 0]octa-1 (6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   3-((R)-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)(hydroxy)methyl)-7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile;   (2R,3 S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-methoxypyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(4-amino-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3R,4 S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-1-(bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(prop-1-en-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-butyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-(2,3-dihydro-1H-inden-5-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(2,3-dihydro-1H-inden-5-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-vinyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3 S,4R,5R)-2-((S)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(fluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(chloromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2 S,3S,4R,5R)-2-((S)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;   (2R,3R,4S,5R)-2-(4-(2-(benzyloxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol; or   (2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.   
     
     
         16 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         17 . A method of inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with an effective amount of a compound of  claim 1 . 
     
     
         18 . A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound of  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as 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, or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD); CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers; glioblastoma multiforme (GBM), NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma. 
     
     
         20 . The method of  claim 19 , wherein the compound is administered in combination with one or more other agents.