Granted Patent B2

US 12,544,374 · App. 17/632,990 · Granted Feb 10, 2026

Inventors: Ling Li (Shanghai, CN); Xuan Dai (Shanghai, CN); Michael Dore (Quebec, CA); Xiang-Ju Justin Gu (Shanghai, CN); Kun Chin Liu (Shanghai, CN); Sing Yeung Frankie Mak (Cintech IV, SG); Yuan Mi (Shanghai, CN); Counde Oyang (Sunnyvale, CA); Julien Papillon (Cambridge, MA); Wei (Vicky) Qi (Shanghai, CN); Xiaoxia Yan (Shanghai, CN); Zhengtian Yu (Shanghai, CN); Ji Yue (Jeff) Zhang (Shanghai, CN); Kehao Zhao (Newton, MA)

Assignee: NOVARTIS AG

A61K31/506A61K31/5377A61K31/541A61K45/06A61P35/00C07D471/04

Abstract

Claims (166)

1 . A compound of Formula (I)

or a stereoisomer, enantiomer, enantiomeric mixture or a pharmaceutically acceptable salt thereof, wherein:

Y is N or CR 4 ;

R 1 , R 3 and R 4 are H;

R 2 is —CN, —C 1 -C 6 alkyl, —C 1 -C 4 alkylene-hydroxy, —C 1 -C 6 alkyl substituted with —N(C 1 -C 4 alkyl) 2 , —C 1 -C 4 alkoxy, —C 2 -C 4 alkoxy substituted with 1-2 hydroxyl or cyano, —NH 2 , —NR 11 C(═O)R 15 , —C(═O) NH 2 , —(CH 2 ) n R 15 , —R 15 , —NHC(═O)R 11 , —NR 12 C(═O)OR 11 , —C(═O)NR 11 R 12 , —(CH 2 ) n C(═O)NR 11 R 12 , —(CH 2 ) n NR 11 R 15 , —(CH 2 ) n C(═O)NR 11 R 15 , —C(═O)NR 11 R 15 , —CR 13 R 14 C(═O)NR 11 R 15 ,

 —(CH 2 ) n C(═O)R 15 , —C(═O)R 15 , —CR 13 R 14 C(═O)R 15 , —(CH 2 ) n NR 11 C(═O)R 15 , —(CH 2 ) n NR 11 (CH 2 ) 2 C(═O)R 15 , —NR 12 C(═O)(CH 2 ) 2 C(═O)R 15 , —(CH 2 ) n OR 15 , —(CH 2 ) n NR 11 C(═O)OCH 2 R 15 , —NR 11 C(═O)OCH 2 R 15 , —(CH 2 ) n NR 11 (CH 2 ) n R 15 ,

 —C 1 -C 6 alkyl substituted with one R a , —C 1 -C 4 alkoxy substituted with one R b , or a 5- to 6-membered heteroaryl having 1 to 4 ring members independently selected from O, S, N and —NR c , wherein R a is —C 1 -C 4 alkoxy and R b is —C 1 -C 4 alkoxy;

R 5a , R 5b , R 5c , R 5d and R e are H;

R 6 , R 7 , R 8 and R 9 are H;

R 10 is H, halogen, —C 1 -C 4 alkoxy, —C 1 -C 4 haloalkoxy or —NH(C 1 -C 4 alkyl);

R 11 is H, —C 1 -C 4 alkyl, —SO 2 (C 1 -C 4 alkyl), —C 1 -C 4 alkylene-hydroxy, —C 1 -C 4 alkylene-cyano or —C 1 -C 4 alkyl substituted with —C 1 -C 4 alkoxy;

R 12 is H or —C 1 -C 4 alkyl;

R 13 is H, halogen, —CN, —OH, —C 1 -C 4 alkyl or —C 1 -C 4 alkylene-hydroxy;

R 14 is H, halogen or —C 1 -C 4 alkyl;

R 15 is

 —C 3 -C 6 cycloalkyl, or a 4- to 6-membered heterocycloalkyl having 1-2 ring members independently selected from O, S, S(═O) 2 , N and —NR 11 ; wherein said —C 3 -C 6 cycloalkyl and 4- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with 1-2 substituents selected from —OH, —C 1 -C 4 alkyl, —C 1 -C 4 alkylene-hydroxy, —C 1 -C 4 alkoxy and —N(C 1 -C 4 alkyl) 2 ;

R 16 , if present, is halogen, —CN, —OH, —C 1 -C 4 alkyl or -hydroxyC 1 -C 4 alkylene;

m is 0, 1 or 2; and

each n is independently selected from 1 and 2;

provided that the compound of Formula (I) is not (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone.

2 . The compound of claim 1 , wherein said compound is of Formula (I-4)

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

3 . The compound of claim 1 wherein

R 2 is —CN, —NH 2 , —C(═O) NH 2 , —NHC(═O)R 11 , —NR 12 C(═O)OR 11 , —C(═O)NR 11 R 12 , —(CH 2 ) n C(═O)NR 11 R 12 , —(CH 2 ) n NR 11 R 15 , —(CH 2 ) n C(═O)NR 11 R 15 , —C(═O)NR 11 R 15 , —CR 13 R 14 C(═O)NR 11 R 15 ,

 —(CH 2 ) n R 15 , —NR 12 C(═O)(CH 2 ) 2 C(═O)R 15 , —(CH 2 ) n NR 11 C(═O)OCH 2 R 15 , —NR 11 C(═O)OCH 2 R 15 , —(CH 2 ) n NR 11 (CH 2 ) n R 15 , —(CH 2 ) n C(═O)R 15 , —CR 13 R 14 C(═O)R 15 , —(CH 2 ) n NR 11 C(═O)R 15 , —NR 11 C(═O)R 15 , —(CH 2 ) n NR 11 (CH 2 ) 2 C(═O)R 15 , —(CH 2 ) n OR 15 ,

 —C 1 -C 6 alkyl substituted with one R a , —C 1 -C 4 alkoxy substituted with one R b , or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N and —NR c wherein R c is H or —C 1 -C 4 alkyl;

R a is C 1 -C 4 alkoxy; and

R b is C 1 -C 4 alkoxy.

4 . The compound of claim 1 , wherein

R 2 is —CN, —NH 2 , —C(═O) NH 2 , —NHC(═O)R 11 , —NR 12 C(═O)OR 11 , —C(═O)NR 11 R 12 , —CH 2 C(═O)NR 11 R 12 , triazolyl,

 C 1 -C 6 alkyl substituted with one R a , or C 1 -C 4 alkoxy substituted with one R b ,

R a is C 1 -C 4 alkoxy; and

R b is C 1 -C 4 alkoxy.

5 . The compound of claim 1 , wherein

R 2 is —CH 2 C(═O)NR 11 R 12 ,

 or C 1 -C 6 alkyl substituted with one R a ; and

R a is C 1 -C 4 alkoxy.

6 . The compound of claim 1 , wherein

R 2 is

 and

R a is C 1 -C 4 alkoxy.

7 . The compound of claim 1 , wherein

R 2 is —CN, —NH 2 , —C(═O) NH 2 , triazolyl,

8 . The compound of claim 1 , wherein

R 2 is

9 . The compound of claim 1 , wherein said compound is of Formula (II)

or a stereoisomer, enantiomer, enantiomeric mixture or a pharmaceutically acceptable salt thereof, wherein:

Y is CH or N;

R 1 , R 3 , R 5a , R 5b , R 5c and R 5d are H;

R 6 , R 7 , R 8 and R 9 are H;

R 10 is halogen or —C 1 -C 4 alkoxy;

R 11 is H, —C 1 -C 4 alkyl, —C 1 -C 4 alkylene-hydroxy, —C 1 -C 4 alkylene-cyano, or —C 1 -C 4 alkyl substituted with —C 1 -C 4 alkoxy;

R 13 is H, halogen, —OH, —C 1 -C 4 alkyl or —C 1 -C 4 alkylene-hydroxy;

R 14 is H, halogen or —C 1 -C 4 alkyl; and

R 15 is a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from O, S and N; and wherein said 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents selected from —OH, —C 1 -C 4 alkyl, —C 1 -C 4 alkylene-hydroxy, —C 1 -C 4 alkoxy and —N(C 1 -C 4 alkyl) 2 .

10 . The compound of claim 9 , wherein said compound is of Formula (II-2)

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

11 . The compound of claim 9 , wherein R 14 is H, F or —CH 3 .

12 . The compound of claim 9 , wherein R 15 is azetidinyl or oxetanyl, each of which is unsubstituted or substituted with —OH, —C 1 -C 4 alkyl or —C 1 -C 4 alkylene-hydroxy.

13 . The compound of claim 12 , wherein

R 15 is

R 16 , if present, is —C 1 -C 4 alkyl; and m is 0-1.

14 . The compound of claim 12 , wherein

R 15 is

15 . The compound of claim 1 , wherein R 11 is H, —C 1 -C 4 alkyl or —C 1 -C 4 alkyl substituted with one —CN, one —OH or one —OCH 3 .

16 . The compound of claim 1 , wherein R 13 is H, F, —CN, —OH, —CH 3 or —CH 2 OH.

17 . The compound of claim 1 , wherein the compound is selected from:

N 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine;

N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl) azetidine-3-carboxamide;

N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-methylazetidine-3-carboxamide;

2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile;

2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide;

N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide;

2-hydroxy-N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide;

(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl) methanone;

N-(2-hydroxypropyl)-2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide;

(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl) (morpholino) methanone;

(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl) (4-methylpiperazin-1-yl) methanone;

N-((1,4-trans)-4-(((5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine;

2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide;

N 2 -(((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine;

methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate;

2-methoxyethyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate;

2-hydroxyethyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate;

oxetan-3-ylmethyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate;

N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetamide;

N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-4-morpholino-4-oxobutanamide;

2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile;

(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl) (morpholino) methanone;

(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl) methanone;

2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)-N-(oxetan-3-yl)pyrimidine-5-carboxamide;

8-chloro-N-((1,4-trans)-4-(((5-((4-(methylsulfonyl) piperazin-1-yl)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-ylamino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

8-chloro-N-((1,4-trans)-4-(((5-(((3-methyloxetan-3-yl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

1-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl) azetidin-3-ol;

4-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl) thiomorpholine 1,1-dioxide;

8-chloro-N-((1,4-trans)-4-(((5-(((oxetan-3-ylmethyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

8-chloro-N-((1,4-trans)-4-(((5-(((3-methoxycyclobutyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

3-(((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)amino) cyclobutan-1-ol;

(2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1,3-dioxan-5-yl) methanol;

8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-yloxy)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl) ethan-1-one;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-(dimethylamino) pyrrolidin-1-yl) ethan-1-one;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-hydroxyethyl) piperazin-1-yl) ethan-1-one;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(piperazin-1-yl) ethan-1-one;

2-(6-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino) pyridin-3-yl)-N-(oxetan-3-yl)acetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-methylpiperazin-1-yl) ethan-1-one;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-cyclobutylacetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-methoxyethyl) piperazin-1-yl) ethan-1-one;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl) ethan-1-ol;

8-chloro-N-((1,4-trans)-4-(((5-(2-((3-methyloxetan-3-yl)amino) ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

8-chloro-N-((1,4-trans)-4-(((5-(2-(oxetan-3-ylamino) ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-(oxetan-3-yl)acetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-ethylacetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-hydroxyethyl)-N-(oxetan-3-yl)acetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide;

(S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide;

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide;

(S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide;

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide;

N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl) azetidine-2-carboxamide;

N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl) oxetane-3-carboxamide;

2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile;

2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide;

N 2 -((1,4-trans)-4-(((5-aminopyrimidin-2-yl)amino)methyl)cyclohexyl)-N8-methyl-1,7-naphthyridine-2,8-diamine;

N-(2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide;

3-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl) oxazolidin-2-one;

methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate;

N 2 -(((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine;

N-((1,4-trans)-4-(((5-(4H-1,2,4-triazol-3-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine;

2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propan-1-ol;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one;

(S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one;

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

(S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

(S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide;

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; and

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide;

or a pharmaceutically acceptable salt thereof.

18 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

19 . A pharmaceutical combination comprising the compound of claim 1 , and one or more therapeutically active agent, wherein said one or more therapeutically active agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, immunomodulator, or a combination thereof.

20 . A method for treating a disease or condition mediated by Enhancer of Zeste Homolog 2 (EZH2), Polycomb Repressive Complex 2 (PRC2), or a combination of EZH2 and PRC2, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , wherein said disease or condition is diffuse large B cell lymphoma (DLBCL) or follicular lymphoma.

21 . A compound selected from:

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide;

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide;

(S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; and

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide.

22 . The compound of claim 21 , wherein said compound is

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one.

23 . The compound of claim 21 , wherein said compound is

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide.

24 . The compound of claim 21 , wherein said compound is

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide.

25 . The compound of claim 21 , wherein said compound is(S)

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide.

26 . The compound of claim 21 , wherein said compound is

(R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide.

27 . The compound of claim 21 , wherein said compound is

2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide.

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Priority Claims (1)

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References Cited (19)