Piperidinyl-methyl-purineamines as NSD2 inhibitors and anti-cancer agents

Patent metadata

Field	Value
Publication number	US-12312353-B2
Application number	US-202217739855-A
Country	US
Kind code	B2
Filing date	May 9, 2022
Priority date	Aug 14, 2019
Publication date	May 27, 2025
Grant date	May 27, 2025

Abstract

The present invention provides a compound of Formula (I):

or an enantiomer, an enantiomeric mixture, or a pharmaceutically acceptable salt thereof; wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds; and methods of using such compounds for treating a disease or condition mediated by nuclear SET domain-containing protein 2 (NSD2).

First claim

The invention claimed is:

1. A method for treating multiple myeloma, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I):

or an enantiomer, an enantiomeric mixture, or a pharmaceutically acceptable salt thereof;
wherein:
A is N or CR 9 wherein R 9 is hydrogen or halo;
L is a bond;
R 1 is H; or
R 1 and R 2 together with NH forms a 5-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members; wherein said 5-8 membered heterocyclyl is unsubstituted or substituted by an oxo substituent;
R 2 is selected from the group consisting of:
(i) hydrogen, —C 1-6 alkyl, -haloC 1-6 alkyl, -hydroxyC 1-6 alkylene, -hydroxyhaloC 1-6 alkylene, —C 1-6 alkoxyC 1-6 alkylene, -haloC 1-6 alkoxyC 1-6 alkylene, difluoromethoxyl, 2,2,2-trifluoroethoxyl, or —C 3-8 cycloalkoxy(C 1-6 alkyl);
(ii) cyano; -cyanoC 1-6 alkylene; —C 1-6 alkylthioC 1-6 alkyl; —C 2-6 alkenyl; -haloC 2-6 alkenyl; —C 2-6 alkynyl; —C 1-4 alkylSOC 1-4 alkyl; —C 1-4 alkylSO 2 C 1-4 alkyl; —SO 2 R 8 or —C(C 1-4 alkyl)=N—O(C 1-4 alkyl);
(iii) —C 1-4 alkylcarbonyl; —(CR a R b ) p —C(═O)—OR 10 ; or —C(═O)—(CR a R b ) q R 11 ; wherein R 11 is C 3-7 cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, each of which is independently unsubstituted or substituted with C 1-6 alkyl or C 1-6 alkoxy;
(iv) —(CR a R b ) r —C(═O)—NR 12 R 3 wherein R 12 is hydrogen or C 1-6 alkyl; R 13 is hydrogen, —C 1-6 alkyl or a 5-6 membered heterocyclic ring; or R 12 and R 13 together form a 5-6 membered heterocyclic ring; wherein said 5-6 membered heterocyclic ring is unsubstituted or substituted with C 1-4 alkyl;
(v) 5-6 membered heterocyclylC 0-6 alkyl or 5-6 membered heterocyclyl(haloC 1-4 alkyl) wherein each said heterocyclyl radical is unsubstituted or substituted by oxo; and
(vi) 5-9 membered heteroarylC 0-6 alkyl or 5-9 membered heteroaryl(haloC 1-4 alkyl), wherein each said heteroaryl radical is unsubstituted or substituted by —C 1-4 alkyl, -haloC 1-4 alkyl, -hydroxyC 1-4 alkylene, —C 1-4 alkoxy, -haloC 1-4 alkoxy, halo, hydroxy, cyano, oxido, -aminocarbonylC 0-6 alkyl, —C 1-4 alkylaminocarbonylC 0-6 alkyl, -diC 1-4 alkylaminocarbonylC 0-6 alkyl or —C 3-7 cycloalkyl;
R 3a , R 3b , R 4a , and R 4b are independently hydrogen, halo, cyano, hydroxyl, —C 1-6 alkyl, -haloC 1-6 alkyl, -hydroxyC 1-6 alkylene, —C 1-6 alkoxy, or —C 1-6 alkoxyC 1-6 alkylene;
R 5a and R 5b are independently hydrogen or —C 1-6 alkyl;
R 6a and R 6b are independently hydrogen, —C 1-6 alkyl, -hydroxyC 1-6 alkylene, —C 1-6 alkoxyC 1-6 alkylene, -haloC 1-6 alkoxyC 1-6 alkylene, -hydroxyhaloC 1-6 alkylene, aryl, —C(═O)—OR 14 , or —(CR a R b ) s —C(═O)—NR 15 R 16 ; or
R 3a and R 3b , R 4a and R 4b , R 5a and R 5b or R 6a and R 6b forms an oxo substituent;
R 7 is H, —C 1-4 alkoxy, halo or C 1-4 alkyl;
R 8 is C 3-8 cycloalkyl(C 0-6 alkyl); 4-6 membered heterocyclylC 0-6 alkyl comprising 1-3 heteroatoms selected from N, O and S; aryl or 5-9 membered heteroarylC 0-6 alkyl comprising 1-3 heteroatoms selected from N, O and S; wherein R 8 is unsubstituted or substituted by 1-3 R 17 ;
R 17 is halo, hydroxy, cyano, —C 1-6 alkyl, -haloC 1-6 alkyl, —C 1-6 alkoxy, -haloC 1-6 alkoxy, —NR a C(═O)CR c ═C(R c ) 2 or —(CR a R b ) t —NR a —C(═O)—R 18 ;
R a , R b , R c , R 10 , R 14 , R 15 and R 16 are independently hydrogen or —C 1-4 alkyl;
R 18 is —C 1-4 alkyl or —C 1-4 haloalkyl; and
p, q, r, s and t are independently 0-4.

2. The method of claim 1 , wherein A is N.

3. The method of claim 2 , wherein:
R 3a is hydrogen or halo; and R 3b is hydrogen, halo, -hydroxyl, —C 1-6 alkoxy or cyano; or
R 4a is hydrogen or halo; and R 4b is hydrogen, halo, —C 1-6 alkoxyC 1-6 alkylene, —C 1-6 alkyl or -haloC 1-6 alkyl; or
R 5a is hydrogen and R 5b is hydrogen or —C 1-6 alkyl; or
R 5a and R 5b together form an oxo substituent.

4. The method of claim 2 , wherein:
R 6a is hydrogen;
R 6b is hydrogen, -haloC 1-6 alkoxyC 1-6 alkylene, -hydroxyC 1-6 alkylene, -hydroxyhaloC 1-6 alkylene, carboxyl, phenyl or —(CR a R b ) t —C(O)—NR 15 R 16 ;
R a , R b , R 15 and R 16 are independently hydrogen or —C 1-4 alkyl; and
t is 0-1; or
R 6a and R 6b together form an oxo substituent.

5. The method of claim 3 , wherein R 7 is H, —C 1-4 alkoxy or halo.

6. The method of claim 2 , wherein R 1 , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b and R 7 are hydrogen.

7. The method of claim 1 , wherein said compound is a compound of Formula (II):

or an enantiomer, an enantiomeric mixture, or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein R 2 is —C 1-6 alkyl, -haloC 1-6 alkyl, -hydroxyC 1-6 alkylene, -hydroxyhaloC 1-6 alkylene, —C 1-6 alkoxyC 1-6 alkylene, -haloC 1-6 alkoxyC 1-6 alkylene or —C 3-8 cycloalkoxy(C 1-6 alkyl).

9. The method of claim 7 , wherein R 2 is 2,2-difluoroethyl; 2-methyl-propan-1-olyl; ethan-1-olyl; 2,2-difluoroethan-1-olyl; 2-fluoroethan-1-olyl; 2,2,2-trifluoroethan-1-olyl; difluoromethoxyl; or 2,2,2-trifluoroethoxyl.

10. The method of claim 2 , wherein R 2 is 2,2-difluoroethyl; 2-methyl-propan-1-olyl; ethan-1-olyl; 2,2-difluoroethan-1-olyl; 2-fluoroethan-1-olyl; 2,2,2-trifluoroethan-1-olyl; difluoromethoxyl; or 2,2,2-trifluoroethoxyl.

11. The method of claim 7 , wherein R 2 is

12. The method of claim 7 , wherein R 8 is phenyl substituted with 1-3 R 17 ;
R 17 is halo, hydroxy, cyano, —C 1-6 alkyl, -haloC 1-6 alkyl, —C 1-6 alkoxy, -haloC 1-6 alkoxy, —NR d C(O)CR d ═C(R d ) 2 or —(CR a R b )—NR d —C(O)—R 18 ;
R a , R b and R d are independently hydrogen or —C 1-4 alkyl;
R 18 is C 1-4 haloalkyl; and
t is 0-1.

13. The method of claim 9 , wherein R 8 is phenyl substituted with 1-3 R 17 ; and R 17 is halo, hydroxy, —C 1-6 alkyl, -haloC 1-6 alkyl, —C 1-6 alkoxy or -haloC 1-6 alkoxy.

14. The method of claim 2 , wherein R 8 is phenyl substituted with 1-3 R 17 ; and R 17 is halo, hydroxy, —C 1-6 alkyl, -haloC 1-6 alkyl, —C 1-6 alkoxy or -haloC 1-6 alkoxy.

15. The method of claim 1 , wherein said compound has the following formula or a pharmaceutically acceptable salt thereof:

16. The method of claim 1 , wherein said compound has the following formula or a pharmaceutically acceptable salt thereof:

17. A method for treating multiple myeloma, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof:

18. The method of claim 17 , wherein the compound has the formula:

Assignees

• Novartis Ag

Inventors

• Deng Haibing
• Liu Jinbiao
• Oyang Counde
• Wang Ce
• Xiao Qitao
• Xun Guoliang
• Zeng Haiqiang

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title