Compounds targeting PRMT5

Patent metadata

Field	Value
Publication number	US-11198699-B2
Application number	US-202016836132-A
Country	US
Kind code	B2
Filing date	Mar 31, 2020
Priority date	Apr 2, 2019
Publication date	Dec 14, 2021
Grant date	Dec 14, 2021

Abstract

Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

wherein:
B 1 is an optionally substituted

 an optionally substituted

 an optionally substituted

 or an optionally substituted

wherein X 1 is N or CR C1 ; X 2 is N or CR C2 ; X 3 is N or CR C3 ; X 4 is N or CR C4 ; X 5 is N or CR C5 ; and R C1 , R C2 , R C3 , R C4 and R C5 are independently hydrogen, halogen or an unsubstituted C 1-4 alkyl;
R 1B , R 1C , R 1D and R 1E are independently hydrogen, halogen, hydroxy, an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 3 -C 6 cycloalkyl, an unsubstituted C 1-4 alkoxy or NR A1 R A2 ; and
R A1 and R A2 are independently selected from the group consisting of hydrogen, hydroxy, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 alkoxy and —C(═O)R C6 , wherein R C6 is hydrogen, an unsubstituted C 1-4 alkyl or an unsubstituted C 3-4 monocyclic cycloalkyl;

R 1 is hydrogen;
R 2A is hydrogen or an unsubstituted C 1-4 alkyl;
R 2B is halogen, OH, —O—C(═O)—C 1-4 alkyl or —O—C(═O)—CH(R 1 ′)—NH 2 , wherein R 1 ′ is H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH(CH 3 ) 2 or —CH(CH 3 )—CH(CH 3 ) 2 ;
R 3A is hydrogen, an unsubstituted or a substituted C 1-4 alkyl, an unsubstituted or a substituted C 2-4 alkenyl or an unsubstituted or a substituted C 2-4 alkynyl, wherein when the C 1-4 alkyl, the C 2-4 alkenyl and the C 2-4 alkynyl are substituted, each is independently substituted with 1 or more fluoros;
R 3B is halogen, OH, —O—C(═O)—C 1-4 alkyl or —O—C(═O)—CH(R 1 ″)—NH 2 , wherein R 1 ″ is H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH(CH 3 ) 2 or —CH(CH 3 )—CH(CH 3 ) 2 ;
R 4A is —(CR D1 R E1 )(CR D2 R E2 )n-R F1 , —(CR G1 R H1 )—O—R J1 , —O—(CR K1 R L1 )—R M1 or —(CR N1 R O1 )p-R P1 ;
wherein R D1 , R E1 , R D2 and R E2 are independently selected from the group consisting of hydrogen, halogen, hydroxy and an unsubstituted C 1-3 alkyl; n is 0 or 1; and R F1 is an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl; or
R D1 and R E1 are taken together with the carbon to which R D1 and R E1 are attached to form an unsubstituted cyclopropyl ring; and R D2 and R E2 are independently selected from the group consisting of hydrogen, halogen, hydroxy and an unsubstituted C 1-3 alkyl; n is 1; and R F1 is an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl; or
R D1 and R E2 are independently selected from the group consisting of hydrogen, halogen, hydroxy and an unsubstituted C 1-3 alkyl; R E1 and R D2 are taken together with the carbon to which R E1 and R D2 are attached to form an unsubstituted cyclopropyl ring; n is 1; and R F1 is an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl; or
R D1 and R E2 are independently selected from the group consisting of hydrogen, halogen and hydroxy; R E1 and R D2 together form a double bond; n is 1; and R F1 is an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl;
R G1 , R H1 , R K1 , R L1 , R N1 and R O1 are independently selected from the group consisting of hydrogen, halogen, hydroxy and an unsubstituted C 1-3 alkyl; R J1 and R M1 are independently an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl; R P1 is an unsubstituted or a substituted heteroaryl; and p is 3 or 4;

R 4B is C 1-4 alkyl substituted with OCH 3 , an unsubstituted C 2-4 alkenyl or an unsubstituted C 2-4 alkynyl,
Z 1 is CR 5A R 5B , O, S or N (an unsubstituted C 1-4 alkyl);
R 5A and R 5B are independently hydrogen, halogen, cyano or an unsubstituted or a substituted C 1-4 alkyl, wherein when the C 1-4 alkyl is substituted, the C 1-4 alkyl is substituted with 1 or more substituents independently selected from the group consisting of fluoro and hydroxy; or
R 5A and R 5B together with the carbon R 5A and R 5B are attached form a double bond optionally substituted with one or two halogen, R 5A and R 5B together with the carbon R 5A and R 5B are attached form an unsubstituted cyclopropyl or R 5A and R 5B together with the carbon R 5A and R 5B are attached form an unsubstituted or a substituted oxetane, wherein when the oxetane is substituted, the oxetane is substituted independently with 1 or 2 halogens; or
R 2A and R 2B together with the carbon R 2A and R 2B are attached form a 3, 4 or 5 membered monocyclic cycloalkyl or a 3, 4 or 5 membered monocyclic heterocyclyl; or
R 3A and R 3B together with the carbon R 3A and R 3B are attached form a 3, 4 or 5 membered monocyclic cycloalkyl or a 3, 4 or 5 membered monocyclic heterocyclyl; or
R 1 and R 5B together with the carbon R 1 and R 5B are attached form an unsubstituted cyclopropyl.

2. The compound of claim 1 , wherein Z 1 is CR 5A R 5B ; and R 5A and R 5B are each hydrogen.

3. The compound of claim 1 , wherein R 2A is hydrogen; and R 3A is hydrogen.

4. The compound of claim 1 , wherein R 2B is OH; and R 3B is OH.

5. The compound of claim 1 , wherein R 2B is —O—C(═O)—C 1-4 alkyl; and R 3B is —O—C(═O)—C 1-4 alkyl.

6. The compound of claim 1 , wherein R 4A is —(CR D1 R E1 )(CR D2 R E2 )n-R F1 ; n is 0; and R D1 and R E1 are each hydrogen.

7. The compound of claim 1 , wherein R 4A is —(CR D1 R E1 )(CR D2 R E2 )n-R F1 ; n is 1; and R D1 , R E1 , R D2 and R E2 are each hydrogen.

8. The compound of claim 6 , wherein R F1 is an unsubstituted or a substituted heteroaryl.

9. The compound of claim 7 , wherein R F1 is selected from the group consisting of:

10. The compound of claim 1 , wherein R 4A is —(CR G1 R H1 )—O—R J1 , —O—(CR K1 R L1 )—R M1 or —(CR N1 R O1 )p-R P1 .

11. The compound of claim 1 , wherein R 4B is a C 1 alkyl substituted with OCH 3 .

12. The compound of claim 1 , wherein R 4B is an unsubstituted C 2-4 alkenyl.

13. The compound of claim 1 , wherein B 1 is selected from the group consisting of:

Assignees

• Aligos Therapeutics Inc

Inventors

• Vandyck Koen
• Raboisson Pierre Jean-Marie Bernard
• Deval Jerome
• Beigelman Leonid
• Mcgowan David
• Debing Yannick

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title