Pyrimidine compounds and pharmaceutical compositions for preventing or treating cancers including the same

Patent metadata

Field	Value
Publication number	US-11292786-B2
Application number	US-202016859413-A
Country	US
Kind code	B2
Filing date	Apr 27, 2020
Priority date	Jul 25, 2018
Publication date	Apr 5, 2022
Grant date	Apr 5, 2022

Abstract

Provided are a pyrimidine compound represented by Formula 1, a method of preparing the compound, and a pharmaceutical use of the compound for the prevention or treatment of cancer.

First claim

What is claimed is:

1. A method for treating a FLT3-mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from a compound represented by Formula 14, and a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof:

wherein, in Formula 14,
E a is hydrogen;
E b is hydrogen, a halogen, a C 1 -C 4 alkyl group, or a C 1 -C 4 fluoroalkyl group;
E c and E d are each independently hydrogen or a hydroxy group;
X′ is hydrogen or a hydroxy group;
k is an integer from 0 to 4;
each Q is independently hydroxy, a halogen, a C 1 -C 4 alkyl group, a hydroxy C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy group; and
Z′ is a monovalent functional group represented by Formula 15:

wherein, in Formula 15, n is an integer from 1 to 8;
each A is independently a functional group selected from hydroxy, a C 1 -C 4 alkyl group, and a hydroxy C 1 -C 4 alkyl group, wherein when n is two or more, two A may be spiro-connected to form a 4,7-diazaspiro[2.5]octane; and
L is hydrogen, a C 1 -C 4 alkyl, a hydroxy group, or a hydroxy C 1 -C 4 alkyl group,
wherein the FLT3-mediated disease is leukemia.

2. The method of claim 1 , wherein E b is a halogen, n is 2, and A is methyl.

3. The method of claim 1 , wherein Z′ is 3,5-dimethylpiperazine-1-yl.

4. The method of claim 1 , wherein E b is chlorine or fluorine.

5. The method of claim 1 , wherein the compound of Formula 14 is selected from compounds below:
1) 5-chloro-N-(3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-fluoro-1H-indole-3-yl)pyrimidine-2-amine;
2) 5-chloro-4-(6-chloro-1H-indole-3-yl)-N-(3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)pyrimidine-2-amine;
3) 2-((2R, 6S)-4-(345-chloro-4-(6-fluoro-1H-indole-3-yl)pyrimidine-2-yl)amino)-5-cyclopropylbenzyl)-2,6-dimethylpiperazine-1-yl)ethane-1-ol;
4) 2-((2R, 6S)-4-(3-((5-chloro-4-(1H-indole-3-yl)pyrimidine-2-yl)amino)-5-cyclopropylbenzyl)-2,6-dimethylpiperazine-1-yl)ethane-1-ol;
5) 2-((2R, 6S)-4-(3-((5-chloro-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-yl)amino)-5-cyclopropylbenzyl)-2,6-dimethylpiperazine-1-yl)ethane-1-ol;
6) (R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazine-1-yl)methyl)phenyl)-4-(1H-indole-3-yl)pyrimidine-2-amine;
7) (R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
8) 5-chloro-N-(3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
9) 5-chloro-N-(3-cyclopropyl-5-(((3S, 5R)-3-ethyl-5-methylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
10) 5-chloro-N-(3-cyclopropyl-5-((3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
11) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
12) N-(3-cyclopropyl-5-4(3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-5-fluoro-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
13) N-(3-cyclopropyl-5-4(3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(1H-indole-3-yl)-5-methylpyrimidine-2-amine;
14) N-(3-cyclopropyl-5-4(3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-5-methyl-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
15) N-(3-cyclopropyl-5-4(3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine;
16) (3-(5-chloro-2-((3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)amino)pyrimidine-4-yl)-1H-indole-6-yl)methanol;
17) 5-chloro-N-(3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(5-methoxy-6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
18) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)amino)pyrimidine-4-yl)-6-methyl-1H-indole-5-ol;
19) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)amino)pyrimidine-4-yl)-6-methylindoline-2-one;
20) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)amino)pyrimidine-4-yl)-6-methyl-1H-indole-7-ol;
21) 3-((5-chloro-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-yl)amino)-4-cyclopropyl-6-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenol;
22) 4-((5-chloro-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-yl)amino)-2-cyclopropyl-6-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenol;
23) (R)-5-chloro-N-(3-cyclopropyl-5-((3,3,5-trimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
24) ((2R, 6R)-4-(3-((5-chloro-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-yl)amino)-5-cyclopropylbenzyl)-6-methylpiperazine-2-yl)methanol;
25) (R)-5-chloro-N-(3-cyclopropyl-5-((5-methyl-4,7-diazaspiro[2.5]octan-7-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
26) 5-chloro-N-(3-cyclopropyl-5-(((3R, 5R)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
27) 5-chloro-N-(3-cyclopropyl-5-(((3S, 5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
28) 5-chloro-N-(3-cyclopropyl-5-(((3R, 5S)-3,4,5-trimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine;
29) (2R, 6S)-4-(3-((5-chloro-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-yl)amino)-5-cyclopropylbenzyl)-2,6-dimethylpiperazine-1-ol; and
30) (2R, 6S)-4-(3-cyclopropyl-5-(((4-(6-methyl-1H-indole-3-yl)pyrimidine-2-yl)amino)benzyl)-2,6-dimethylpiperazine-1-ol.

6. The method of claim 1 , wherein the leukemia comprises acute myelogenous leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia.

7. A method for inhibiting FLT3 kinase activity in a subject, the method comprising: administering to the subject a therapeutically effective amount of a compound selected from a compound represented by Formula 14, and a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof

wherein, in Formula 14,
E a is hydrogen;
E b is hydrogen, a halogen, a C 1 -C 4 alkyl group, or a C 1 -C 4 fluoroalkyl group;
E c and E d are each independently hydrogen or a hydroxy group;
X′ is hydrogen or a hydroxy group;
k is an integer from 0 to 4;
each Q is independently hydroxy, a halogen, a C 1 -C 4 alkyl group, a hydroxy C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy group; and
Z′ is a monovalent functional group represented by Formula 15;

wherein, in Formula 15, n is an integer from 1 to 8;
each A is independently a functional group selected from hydroxy, a C 1 -C 4 alkyl group, and a hydroxy C 1 -C 4 alkyl group, wherein when n is two or more, two A may be spiro-connected to form 4,7-diazaspiro[2.5]octane; and
L is hydrogen, a C 1 -C 4 alkyl, a hydroxy group, or a hydroxyC 1 -C 4 alkyl group.

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Bae In Hwan
• Kim Ji Sook
• Choi Jae Yul
• Kang Seok Jong
• Ahn Young Gil
• Suh Kwee Hyun

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/4025

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

• A61P35/00

  Antineoplastic agents · CPC title