Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof

Patent metadata

Field	Value
Publication number	US-10344034-B2
Application number	US-201815969098-A
Country	US
Kind code	B2
Filing date	May 2, 2018
Priority date	Oct 30, 2013
Publication date	Jul 9, 2019
Grant date	Jul 9, 2019

Abstract

Methods of preparation and pharmaceutical uses of pyrazolopyrimidone derivatives are described. Specifically, methods of preparation and pharmaceutical uses of pyrazolopyrimidone derivatives represented by the general formula (II) and pharmaceutically acceptable salts thereof are described, wherein the definitions of substituents in the general formula (II) are the same as the definitions in the specification. The pyrazolopyrimidone derivatives are useful as gonadotropin releasing hormone (GnRH) antagonists, such as for therapeutic agents for endometriosis.

First claim

We claim:

1. A process for preparing the compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

the process comprising:
(a) reacting a compound of formula (IA) with an amine of formula NH(R 4 )(CH 2 )nR; and optionally reducing and/or acylating the resulting product to obtain the compound of formula (II); or
(b) reacting a compound of formula (IB) with R 2 X in the presence of an alkaline reagent; and optionally reducing and/or acylating the resulting product to obtain the compound of formula (II):

wherein:
X is halogen;
G is C;
D and E are each N;
R 1 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —OR 6 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently and optionally further substituted with one or more groups selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 6 , —C(O)OR 6 , —OC(O)R 6 , —NHS(O) m R 6 , —C(O)R 6 , —NHC(O)R 6 , —NHC(O)OR 6 , —NR 7 R 8 , —OC(O)NR 7 R 8 , —C(O)NR 7 R 8 , —NHC(O)NHR 6 , and —NHC(O)NHOR 6 ;
R 2 is alkyl, wherein the alkyl is further substituted with one or more groups selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally further substituted with one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, —C(O)OR 6 , —C(O)NR 7 R 8 , —OC(O)NR 7 R 8 , —OR 6 , —NHS(O) m R 6 , —NHC(O)R 6 , and —NR 7 R 8 ;
R 3 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally further substituted with one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, —OR 6 , —C(O)OR 6 , —OC(O)R 6 , —C(O)R 6 , —NR 7 R 8 , —OC(O)NR 7 R 8 , —C(O)NR 7 R 8 , —NHS(O) m R 6 , —NHC(O)R 6 , —NHC(O)OR 6 , —NHC(O)NHR 6 , and —NHC(O)NHOR 6 ;
R 4 is alkyl;
R 5 is selected from the group consisting of hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —NR 7 R 8 , and —NR 7 S(O) m R 6 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted with one or more groups selected from the group consisting of halogen, oxo, alkyl, haloalkyl, hydroxyalkyl, —OR 6 , —C(O)OR 6 , —OC(O)R 6 , —NR 7 S(O) m R 6 , —S(O) m R 6 , —C(O)R 6 , and —NHC(O)R 6 ;
R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently and optionally further substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and carboxylic ester;
R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently and optionally further substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and carboxylic ester;
or, R 7 and R 8 are taken together with the attached N atom to form a heterocyclyl, wherein the heterocyclyl contains one or more heteroatoms selected from the group consisting of N, O, and S(O) m , and the heterocyclyl is optionally further substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and carboxylic ester;
m is 0, 1, or 2;
n is 1, 2, 3, or 4; and
p is 0, 1, or 2.

2. The process according to claim 1 , wherein the process comprises reacting a compound of formula (IA) with an amine of formula NH(R 4 )(CH 2 )nR 5 ; and optionally reducing and/or acylating the resulting product to obtain the compound of formula (II).

3. The process according to claim 1 , wherein the process comprises reacting a compound of formula (IB) with R 2 X in the presence of an alkaline reagent; and optionally reducing and/or acylating the resulting product to obtain the compound of formula (II).

4. The process according to claim 1 , wherein R 1 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally further substituted with one or more groups selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, and —OR 6 .

5. The process according to claim 1 , wherein R 2 is benzyl, wherein the benzyl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, and —OR 6 .

6. The process according to claim 1 , wherein R 3 is aryl, wherein the aryl is optionally further substituted with one or more groups selected from the group consisting of —NHC(O)R 6 , —NHC(O)OR 6 , —NHC(O)NHR 6 and —NHC(O)NHOR 6 .

7. The process according to claim 1 , wherein R 4 is methyl.

8. The process according to claim 1 , wherein R 5 is hydrogen, and n is 1 or 2.

9. The process according to claim 1 , wherein R 1 is optionally substituted phenyl or optionally substituted pyridazinyl.

10. The process according to claim 1 , wherein the compound is a compound of formula (IV), a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:
G is C;
D and E are each N;

R a is selected from the group consisting of alkyl and —OR 6 , wherein the alkyl is optionally further substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and carboxylic ester; and
R 6 is alkyl, wherein the alkyl is optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and carboxylic ester.

11. The process according to claim 1 , wherein the compound is selected from the group consisting of:

Assignees

• Shanghai hengrui pharmaceutical co ltd
• Jiangsu Hengrui Medicine Co

Inventors

• Lu Hejun
• Sun Piaoyang
• Gui Bin
• Dong Qing

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/32

  Antioestrogens · CPC title

• A61P5/24

  of the sex hormones · CPC title

• A61P5/04

  for decreasing, blocking or antagonising the activity of the hypothalamic hormones · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title