5-heteroaryl-1H-pyrazol-3-amine derivative

Patent metadata

Field	Value
Publication number	US-11564920-B2
Application number	US-202217731163-A
Country	US
Kind code	B2
Filing date	Apr 27, 2022
Priority date	Nov 30, 2020
Publication date	Jan 31, 2023
Grant date	Jan 31, 2023

Abstract

The present disclosure provides a compound that exerts an anticancer action based on CHK1 inhibition. The present disclosure was completed by finding that a compound represented by formula (1) or a pharmaceutically acceptable salt thereof exhibits an excellent antitumor action by having a potent inhibitory action against CHK1:wherein R1, R2, L, V, W, and Q are as defined herein, X, Y, and Z each independently represent CR8 or a nitrogen atom, wherein X, Y, and Z are not simultaneously CR8, and R8 is as defined herein.

First claim

The invention claimed is:

1. A compound or a pharmaceutically acceptable salt thereof, selected from
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, or
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , which is
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile or pharmaceutically acceptable salt thereof.

3. The compound or pharmaceutically acceptable salt thereof of claim 1 , which is
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile or pharmaceutically acceptable salt thereof.

4. The compound or pharmaceutically acceptable salt thereof of claim 1 , which is
5-({S-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile or pharmaceutically acceptable salt thereof.

5. A liposome comprising the compound or pharmaceutically acceptable salt thereof of claim 1 .

6. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.

7. The pharmaceutical composition of claim 6 , further comprising a liposome encapsulating at least one compound or pharmaceutically acceptable salt thereof selected from the group consisting of
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, and
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

8. The pharmaceutical composition of claim 7 , wherein the liposome further comprises a phospholipid.

9. The pharmaceutical composition of claim 7 , wherein the liposome comprises
(1) at least one compound or pharmaceutically acceptable salt thereof selected from the group consisting of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, and
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile, and

(2) a phospholipid.

10. The pharmaceutical composition of claim 8 , wherein the phospholipid is one selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin or a combination of two or more thereof.

11. The pharmaceutical composition of claim 9 , wherein the phospholipid is one selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin or a combination of two or more thereof.

12. The pharmaceutical composition of claim 7 , wherein the liposome further comprises sterol.

13. The pharmaceutical composition of claim 12 , wherein the sterol is cholesterol.

14. The pharmaceutical composition of claim 7 , wherein the liposome further comprises a polymer modified lipid.

15. The pharmaceutical composition of claim 14 , wherein a polymer moiety of the polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone.

16. The pharmaceutical composition of claim 15 , wherein a lipid moiety of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.

17. The pharmaceutical composition of claim 7 , wherein the liposome comprises
(1) at least one compound or pharmaceutically acceptable salt thereof selected from the group consisting of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, and
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

(2) 40 to 70 mol % of phospholipid,
(3) 30 to 50 mol % of cholesterol, and
(4) 1 to 10 mol % of polymer-modified lipid.

18. The pharmaceutical composition of claim 7 , wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, saccharides, buffer, antioxidants, and polymers.

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Kamioka Seiji
• Ban Hitoshi
• Matsuoka Makoto
• Hirose Wataru
• Shimada Naoaki
• Hayashi Kento
• Umehara Hiroki

Classifications

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/282

  Platinum compounds · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title