# US 11,306,085 B2 · Method for preparing pyrimidone heteroaryl derivative and intermediate of pyrimidone heteroaryl derivative

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- Number: US 11,306,085 B2
- Document ID: US11306085B2
- Status: Granted
- Kind: B2
- Application number: 16/632,698
- Filed: 2018-07-27
- Published: 2020-05-07
- Granted: 2022-04-19
- Earliest claimed: 2017-07-28
- Assignees: Jiangsu Hengrui Medicine Co., Ltd.
- Applicants: Jiangsu Hengrui Medicine Co., Ltd.
- Inventors: Junlei Jia; Bing Liu; Xiaohui Gao
- Web page: https://patentgrep.com/patent/US11306085B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a method for preparing a pyrimidone heteroaryl derivative and an intermediate of the pyrimidone heteroaryl derivative. Specifically, the pyrimidone heteroaryl derivative of the formula is prepared by changing a starting raw material and an intermediate.

## Claims

### Claim 1

A method for preparing a compound of formula (I) or a stereoisomer thereof, wherein the method comprises reacting a compound of formula (III), a salt thereof or a stereoisomer thereof, with a compound of formula (II) or a salt thereof to obtain the compound of formula (I):
wherein:
G is C, D and E are N;
R1 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and —OR5, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently and optionally further substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR5, —C(O)OR5, —OC(O)R5, —NHS(O)mR5, —C(O)R5, —NHC(O)R5, —NHC(O)OR5, —NR6R7, —OC(O)NR6R7, —C(O)NR6R7, —NHC(O)NHR5 and —NHC(O)NHOR5;
R2 is alkyl, wherein the alkyl is further substituted by one or more substituents selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are optionally further substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, —C(O)OR5, —C(O)NR6R7, —OC(O)NR6R7, —OR5, —NHS(O)mR5, —NHC(O)R5 and —NR6R7;
R3 is alkyl;
R4 is selected from the group consisting of hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR5, —NR6R7 and —NR6S(O)mR5, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted by one or more substituents selected from the group consisting of halogen, oxo, alkyl, haloalkyl, hydroxyalkyl, —OR5, —C(O)OR5, —OC(O)R5, —NR7S(O)mR5, —S(O)mR5, —C(O)R5 and —NHC(O)R5;
R5 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 by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy and alkoxycarbonyl;
R6 and R7 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 by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy and alkoxycarbonyl;
or, R6 and R7 together with the nitrogen atom to which they are attached 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 by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy and alkoxycarbonyl;
Ra is alkyl, wherein the alkyl is optionally further substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy and alkoxycarbonyl;
m is 0, 1 or 2; and
n is 1, 2, 3 or 4.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound of formula (III), a salt thereof or a stereoisomer thereof, is prepared by the following method:
wherein:
X is halogen;
the compound of formula (VI) is a mono-metal alkoxide or a bi-metal alkoxide; and
M is selected from the group consisting of a monovalent metal cation, a divalent metal cation, a trivalent metal cation and a tetravalent metal cation.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound of formula (VI) is prepared by the following method:
wherein:
Rb is alkyl.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is a compound of formula (I-1) or a stereoisomer thereof, the compound of formula (II) is a compound of formula (II-1) or a salt thereof, and the compound of formula (III) is a compound of formula (III-1), a salt thereof or a stereoisomer thereof, wherein the method is as follows:

### Claim 5 (depends on 4)

The method according to claim 4, wherein the compound of formula (III-1) is prepared by the following method:
wherein the compound of formula (VI-1) is a mono-metal alkoxide or a bi-metal alkoxide; and
M is selected from the group consisting of a monovalent metal cation, a divalent metal cation, a trivalent metal cation and a tetravalent metal cation.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the compound of formula (VI-1) is prepared by the following method:
wherein no acid is added in the post-treatment step of the method for preparing the compound of formula (VI-1) from the compound of formula (VII-1), and the acid is selected from the group consisting of an organic acid and an inorganic acid.

### Claim 7

A method for preparing a compound of formula (I-1), wherein the method comprises
wherein no acid is added in the post-treatment step of preparing the compound of formula (VI-1-1) from the compound of formula (VII-1), and the acid is selected from the group consisting of an organic acid and an inorganic acid.