Small molecule protein arginine methyltransferase 5 (prmt5) inhibitors and methods of treatment

Abstract

Provided are compounds of formulas (I), (II), (III), and (IV), which effectively inhibit protein arginine methyltransferase 5 (PRMT5). Also provided are methods of using the compounds, including a method of treating cancer, a method of inhibiting the activity of PRMT5 in a cell, and a method of treating a disease associated with increased activity of PRMT5.

1 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 R 5  is halo, aryl, substituted aryl, heterocycloalkyl, or heteroaryl; 
 R 6  is C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkylalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, C 1 -C 8  alkoxy, C 3 -C 6  cycloalkyloxy, aryloxy, halo, C 1 -C 8  haloalkoxy, C 1 -C 8  haloalkyl, haloaryl, haloaryloxy, —CN, —NO 2 , —(CH 2 ) n C(O)R 9 , —(CH 2 ) n CO 2 R 9 , —(CH 2 ) n C(O)NR 9 R 10 , —(CH 2 ) n NR 9 C(O)R 10 , —(CH 2 ) n NR 9 R 10 , —NR 11 (CH 2 ) n NR 9 R 10 ; or 
 two R 6  moieties and the phenyl group to which they are attached form a naphthyl group that is optionally substituted; 
 R 7  is hydroxy, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkylalkyl, C 1 -C 8  alkoxy, C 3 -C 6  cycloalkyloxy, heterocycloalkyl, aryl, arylalkyl, heteroaryl, aryloxy, halo, C 1 -C 8  haloalkyl, C 1 -C 8  haloalkoxy, haloaryl, haloaryloxy, —CN, —NO 2 , —C(O)R 9 , —CO 2 R 9 , —C(O)NR 9 R 10 , —NR 9 C(O)R 10 , —(CH 2 ) n NR 9 R 10 , —(CH 2 ) n SO 2 NR 9 R 10 , —(CH 2 ) n SO 2 R 9 , aryl; or 
 two R 7  moieties and the phenyl group to which they are attached form a naphthyl group that is optionally substituted; 
 R 8  is H, hydroxy, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 6  cycloalkyl, C 1 -C 8  haloalkyl, —CN, —NO 2 , —(CH 2 ) n NR 9 R 10 , heterocycloalkyl, aryl, or heteroaryl; 
 X is —(CH 2 ) o CR 9 R 10 —, —CR 9 R 10 (CH 2 ) o —, —(CH 2 ) o NR 9 —, —NR 9 (CH 2 ) o —, —(CH 2 ) o O—, or —O(CH 2 ) o —; 
 R 9 , R 10 , and R 11  are independently selected from the group consisting of H and C 1 -C 8  alkyl; 
 m, n, and o are each an integer independently selected from the range of 0-5; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein
 R 5  is halo, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;   R 6  is C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkylalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, C 1 -C 8  alkoxy, C 3 -C 6  cycloalkyloxy, aryloxy, halo, C 1 -C 8  haloalkoxy, C 1 -C 8  haloalkyl, haloaryl, haloaryloxy, —CN, —NO 2 , —(CH 2 ) n C(O)R 9 , —(CH 2 ) n CO 2 R 9 , —(CH 2 ) n C(O)NR 9 R 10 , —(CH 2 ) n NR 9 C(O)R 10 , —(CH 2 ) n NR 9 R 10 , or —NR 11 (CH 2 ) n NR 9 R 10 ;   R 7  is hydroxy, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkylalkyl, C 1 -C 8  alkoxy, C 3 -C 6  cycloalkyloxy, aryloxy, halo, C 1 -C 8  haloalkyl, C 1 -C 8  haloalkoxy, haloaryl, haloaryloxy, —CN, —NO 2 , —C(O)R 9 , —CO 2 R 9 , —C(O)NR 9 R 10 , —NR 9 C(O)R 10 , —(CH 2 ) n NR 9 R 10 , —(CH 2 ) n SO 2 NR 9 R 10 , or —(CH 2 ) n SO 2 R 9 ;   R 8  is H, hydroxy, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 6  cycloalkyl, C 1 -C 8  haloalkyl, —CN, —NO 2 , —(CH 2 ) n NR 9 R 10 , heterocycloalkyl, aryl, or heteroaryl;   X is —(CH 2 ) o CR 9 R 10 —, —CR 9 R 10 (CH 2 ) o —, —(CH 2 ) o NR 9 —, —NR 9 (CH 2 ) o —, —(CH 2 ) o O—, or —O(CH 2 ) o —;   R 9 , R 10 , and R 11  are independently selected from the group consisting of H and C 1 -C 8  alkyl;   m, n, and o are each an integer independently selected from the range of 0-5.   
     
     
         3 . The compound of  claim 2 , wherein R 6  is —NR 11 (CH 2 ) o NR 9 R 10 . 
     
     
         4 . The compound of  claim 2 , wherein R 7  is C 1 -C 8  alkyl, halo, or C 1 -C 8  haloalkyl. 
     
     
         5 . The compound of  claim 2 , wherein R 8  is H. 
     
     
         6 . The compound of  claim 2 , wherein X is —(CH 2 ) o NR 5 — or —NR 5 (CH 2 ) o —. 
     
     
         7 . The compound of  claim 1 , wherein m is 1. 
     
     
         8 . The compound of  claim 6 , wherein o is 1 or 2. 
     
     
         9 . The compound of  claim 1 , wherein
 R 5  is piperazinyl, pyrrolyl, pyranyl, piperidyl, morpholinyl, phenyl, substituted phenyl, and pyrrolidinyl;   R 6  is —NR 11 (CH 2 ) n NR 9 R 10 ;   R 7  is H, C 1 -C 8  alkyl, halo, or C 1 -C 8  haloalkyl;   R 8  is H;   X is —NR 9 —, —(CH 2 ) o CR 9 R 10 —, —CR 9 R 10 (CH 2 ) o —, or —(CH 2 ) o NR 9 —;   R 9 , R 10 , and R 11  are independently selected from H or C 1 -C 8  alkyl;   m is 1; and   o is 1 or 2.   
     
     
         10 . The compound of  claim 9  wherein R 5  is a 3,4-di-C 1 -C 8  alkylphenyl, optionally wherein the 3,4-di-C 1 -C 8  alkylphenyl is 3,4-dimethylphenyl. 
     
     
         11 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1  or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of treating a cancer in a subject, comprising administering the pharmaceutical composition of  claim 12  or a pharmaceutically acceptable salt thereof to the subject, whereby the cancer is treated. 
     
     
         14 . The method of  claim 13 , wherein the cancer has
 (i) increased activity of protein arginine methyltransferase 5 (PRMT5) compared to a non-cancer cell from the subject; and/or   (ii) the cancer has a constitutive activation of nuclear factor κB (NF-κB); and/or   (iii) the cancer is a gastrointestinal cancer, skin cancer, lung cancer, brain cancer, ovarian cancer, prostate cancer, lymphoma, melanoma, or breast cancer; and wherein the gastrointestinal cancer is optionally selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, pancreatic cancer, and liver cancer.   
     
     
         15 . The method of  claim 14 , wherein the compound or pharmaceutically acceptable salt thereof is administered in a composition comprising the compound or a salt thereof and a pharmaceutically acceptable carrier. 
     
     
         16 . A method of inhibiting the activity of PRMT5 in a cell, comprising administering a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to the cell, whereby the activity of PRMT5 is inhibited. 
     
     
         17 . The method of  claim 16 , wherein
 (i) the cell is a cancer cell; and/or   (ii) the cancer cell is optionally selected from a gastrointestinal cancer, skin cancer, lung cancer, brain cancer, ovarian cancer, prostate cancer, lymphoma, melanoma, or breast cancer; and wherein the gastrointestinal cancer is optionally selected from the group consisting of pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, pancreatic cancer, and liver cancer.   
     
     
         18 . The method of  claim 16  wherein said cell is present in a subject having a disease associated with increased activity of PRMT5, said method comprising administering a pharmaceutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof to the subject. 
     
     
         19 . The method of  claim 18 , wherein the disease associated with increased activity of PRMT5 is a cancer, an autoimmune disease, an inflammatory disease, a metabolic disorder, a neurological disorder, a cardiovascular disorder, or a blood disorder.