Triazolopyrimidine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11931363-B2
Application number	US-202117505271-A
Country	US
Kind code	B2
Filing date	Oct 19, 2021
Priority date	Dec 23, 2014
Publication date	Mar 19, 2024
Grant date	Mar 19, 2024

Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder:wherein R1, R2, R3, R4, R5, and n are as defined herein.

First claim

What is claimed is:

1. A method of making a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
is a single bond or a double bond;
R 1 and R 2 are independently H or halogen;
R 3 is independently selected from: halogen, phenyl, and a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said phenyl and heteroaryl are substituted with 0-3 R 3A ;
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 3B ), C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, R 3C , —OR 3C , —C(═O)R 3D , NR 3E R 3F , —C(═O)NR 3E R 3F , —NHC(═O)R 3D , —S(═O) 2 R 3D , —S(═O) 2 NR 3E R 3F ,
—NHS(═O) 2 (C 1 -C 4 alkyl), and —CR 3C R 3E R 3G ;

R 3B is independently selected from: OH, NR e R f , C 1 -C 4 alkoxy, —C(═O)NR e R f , —S(═O) 2 (C 1 -C 4 alkyl), —NHC(═O)(C 1 -C 4 alkyl), and a 5- to 6-membered heterocycloalkyl comprising carbon atoms and 1-2 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycloalkyl is substituted with 0-2 R e ;
each R 3C is independently selected from: C 3 -C 6 cycloalkyl, phenyl, and a 4- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein each moiety is substituted with 0-2 R c ;
each R 3D is independently selected from: C 1 -C 4 alkyl and R 3C ;
R 3E and R 3G are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each R 3F is independently selected from: H and C 1 -C 4 alkyl substituted with 0-1 R d ;
R 4 is independently selected from: H, halogen and C 1 -C 4 alkyl;
R 5 is independently selected from OH and C 1 -C 4 alkyl;
each R a is independently selected from: H, →O, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, and benzyl;
R b is independently selected from: halogen, OH and C 1 -C 4 alkoxy;
each R c is independently selected from: ═O, halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy;
R d is independently selected from: OH and NR e R f ;
R e and R f are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each p is independently selected from 0, 1 and 2; and
m and n are, at each occurrence, independently selected from 0 and 1;

wherein the method comprises the following steps:
i) treating pyrimidine (1) with hydrazine to produce a 4-hydrazinyl pyrimidine (2)

where X is Br or F;
ii) converting 4-hydrazinyl pyrimidine (2) with trimethyl orthoformate to triazole product (3)

where X is Br or F;
iii) conducting a substitution reaction of triazole product (3) with a compound (A) to produce compound (4)

where X is Br or F;
iv) conducting a coupling reaction of compound (4) with reagent R 3 —B, in the presence of a palladium catalyst, to produce the compound of Formula (I)

where:
X is Br or F;
R 3 is as defined above, and
B is

2. The method of claim 1 , wherein compound (A) is selected from the group consisting of:

3. The method of claim 1 , wherein compound (A) is selected from the group consisting of:

4. The method of claim 1 , wherein compound (4) is selected from the group consisting of:

5. The method of claim 1 , wherein compound (4) is

6. The method of claim 1 , wherein R 3 —B is selected from the group consisting of:

7. The method of claim 1 , wherein R 3 —B is selected from the group consisting of:

8. The method of claim 1 , wherein:
compound (A) is

R 3 —B is

and
the compound of Formula (I) is

9. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein:
R 1 is H or halogen;
R 2 is H or halogen;
each R 5 is independently selected from OH and C 1 -C 4 alkyl;
and
n is selected from 0 and 1.

10. The compound of claim 9 , wherein the compound is selected from the group consisting of:

11. The compound of claim 9 , wherein the compound is

12. The compound of claim 9 , wherein the compound is

13. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein:
R 1 is H or halogen;
R 2 is H or halogen;
each R 5 is independently selected from OH and C 1 -C 4 alkyl;
P is an amine protecting group,
and
n is selected from 0 and 1.

14. The compound of claim 13 , wherein the compound is

15. A compound, or a pharmaceutically acceptable salt thereof, having the formula:

wherein:
R 1 is halogen;
R 2 is H or halogen;
each R 5 is independently selected from OH and C 1 -C 4 alkyl;
and
n is selected from 0 and 1.

16. The compound of claim 15 , wherein the compound is

17. A compound of F

Assignees

• Novartis Ag

Inventors

• Chan Ho Man
• Gu Xiang-Ju Justin
• Huang Ying
• Li Ling
• Mi Yuan
• Qi Wei
• Sendzik Martin
• Sun Yongfeng
• Wang Long
• Yu Zhengtian
• Zhang Hailong
• Zhang Ji Yue (Jeff)
• Zhang Man
• Zhang Qiong
• Zhao Kehao

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title