Inhibitors of the MYST family of lysine acetyl transferases
View Patent ↗Provided herein are compounds of Formula (I). Methods for the preparation of the compounds of Formula (I) and intermediates useful in the preparation of the compounds of Formula (I) are described herein. The compounds of Formula (I) may be useful as inhibitors of the MYST family of lysine acetyltransferases (KATs) for the treatment of and/or prophylaxis of hyperproliferative diseases, disorders or conditions such as cancer. In particular, the compounds of Formula (I) are useful for the inhibition of KAT6A and KAT6B which are enzymes frequently mutated, overexpressed, amplified and/or translocated in cancer altering their normal expression, activity and function. The use of the compounds of Formula (I) in the manufacture of pharmaceutical compositions or for treating cancers is further described, including for treating cancer in combination with other anti-cancer agents.
1. A compound of Formula (I):
wherein:
R 1 is phenyl substituted with 2 R 1b ;
each R 1b is independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
R 2 is:
one X 1 is CR 3 and the other X 1 are independently selected from CR 2b ;
each R 2b is independently hydrogen;
R 2d is C 1 -C 6 alkoxy;
R 3 is -(CH 2 ) 0-2 -L-Y;
L is a bond;
Y is a 5-membered monocyclic heteroaryl substituted with R Y ;
R Y is -(CH 2 ) 0-3 N 3b C(O)R 3a ;
R 3a is C 2 -C 6 alkynyl;
R 3b is hydrogen;
or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
2. The compound of claim 1 , wherein each R 1b is independently selected from C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
3. The compound of claim 1 , wherein one R 1b is independently selected from C 1 -C 6 alkyl; and the other Rib is independently selected from C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
4. The compound of claim 1 , wherein the X 1 that is CR 3 is in the meta position with respect to R 2d .
5. The compound of claim 1 , wherein R 3 is -(CH 2 )-Y; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
6. The compound of claim 1 , wherein Y is a pyrazolyl substituted with R Y ; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
7. The compound of claim 1 , wherein R Y is -(CH 2 ) 1 NHC(O)R 3a ; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
8. The compound of claim 1 , wherein R 3a is ethynyl; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
9. The compound of claim 1 , wherein R Y is
or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
10. A pharmaceutical composition comprising a compound of claim 1 or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The compound of claim 1 that is: