MTA-Cooperative PRMT5 Inhibitors

Abstract

The present invention relates to compounds that inhibit Protein Arginine N-Methyl Transferase 5 (PRMT5) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.

1 - 33 . (canceled) 
     
     
         34 . A compound of Formula (I-D): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 2  is —X-aryl optionally substituted with one or more R 5 ; 
         each R 5  is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, —X-haloalkyl, —Z-cycloalkyl, —X-arylC1-C3alkyl, —X-arylC1-C3alkyl substituted with cyano, —X-L-cycloalkyl, —X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or —X-aryl; 
         each X is independently a bond, O, S, —NR 4 — or —NR 4 C(O)—; 
         each Z is independently a bond, —SO—, —SO 2 —, —CH(OH)— or —C(O)—; 
         each L is independently a bond or C1-C3 alkylene; 
         each R 4  is independently hydrogen or C1-C3 alkyl; and 
         R 6  is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy. 
       
     
     
         35 . A compound according to  claim 34 , wherein the X in —X-aryl is a bond and the aryl is phenyl or naphthyl substituted with one, two or three R 5 . 
     
     
         36 . A compound according to  claim 35 , wherein the aryl is naphthyl and the naphthyl is substituted with two R 5  groups. 
     
     
         37 . A compound according to  claim 36 , wherein one R 5  is cyano and the second R 5  is halogen, alkoxy or cyano. 
     
     
         38 . A compound according to  claim 36 , wherein one R 5  is cyano and the second R 5  is halogen or cyano. 
     
     
         39 . A compound according to  claim 36 , wherein one R 5  is cyano and the second R 5  is halogen. 
     
     
         40 . A compound according to  claim 35 , wherein the aryl is naphthyl and the naphthyl is substituted with three R 5  groups. 
     
     
         41 . A compound according to  claim 40 , wherein one R 5  is cyano, the second R 5  is X-haloalkyl and the third R 5  is —X-L-cycloalkyl. 
     
     
         42 . A compound according to  claim 35 , wherein R 6  is hydrogen. 
     
     
         43 . A compound according to  claim 34 , wherein —X-aryl is phenyl and the phenyl is substituted with one or more R 5 . 
     
     
         44 . A compound according to  claim 43 , wherein each R 5  is selected from the group consisting of cyano, halogen, —X-L-cycloalkyl, —X-haloalkyl, heterocyclyl, X-heteroaryl, C1-C3 alkyl and alkoxy, wherein each X is a bond or O. 
     
     
         45 . A compound according to  claim 43 , wherein each R 5  is selected from the group consisting of cyano, halogen, —O-cycloalkyl. 
     
     
         46 . A compound according to  claim 45 , wherein R 6  is hydrogen. 
     
     
         47 . A pharmaceutical composition comprising a compound according to  claim 34 . 
     
     
         48 . A compound according to  claim 34 , which is 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile. 
     
     
         49 . A compound which is a salt of the compound of  claim 34 , wherein the compound is 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile. 
     
     
         50 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) according to  claim 34  or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 
     
     
         51 . A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I) according to  claim 34  or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents. 
     
     
         52 . The method according to  claim 51 , wherein the cancer wherein the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer and uterine cancer. 
     
     
         53 . The method according to  claim 51 , wherein the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, squamous cell lung cancer, lung adenocarcinoma, mesothelioma; esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, kidney adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, cholangiocarcinoma; osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma and thyroid carcinoma. 
     
     
         54 . The method according to  claim 52 , wherein the cancer is a MTAP-associated cancer. 
     
     
         55 . The method of  claim 51 , wherein the cancer is hepatocellular carcinoma breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer. 
     
     
         56 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein
 R 2  is —X-aryl optionally substituted with one or more R 5 ; 
 each R 5  is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, —X-haloalkyl, —Z-cycloalkyl, —X-arylC1-C3alkyl, —X-arylC1-C3alkyl substituted with cyano, —X-L-cycloalkyl, —X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or —X-aryl; 
 each X is independently a bond, O, S, —NR 4 — or —NR 4 C(O)—; 
 each Z is independently a bond, —SO—, —SO 2 —, —CH(OH)— or —C(O)—; 
 each L is independently a bond or C1-C3 alkylene; 
 each R 4  is independently hydrogen or C1-C3 alkyl; 
 R 6  is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy; and 
 Protect represents a nitrogen protecting group. 
 
       
     
     
         57 . A compound according to  claim 56 , wherein R 6  is fluoro or chloro.