Phthalazinone compound, method for preparation thereof, pharmaceutical composition thereof, and use thereof

Patent metadata

Field	Value
Publication number	US-11040952-B2
Application number	US-202016786710-A
Country	US
Kind code	B2
Filing date	Feb 10, 2020
Priority date	Aug 10, 2017
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

Provided are a phthalazinone compound, method for preparation thereof, pharmaceutical composition thereof, and a use thereof; the structure of said phthalazinone compound is as represented by formula I; the compound of said formula I is targeted to a viral nucleocapsid; it can inhibit the replication of a virus by means of interference of the viral nucleocapsid, has a potent activity for inhibiting HBV DNA replication and a good liver targeting, can stably exist and enrich in the liver, and is a new and effective anti-HBV inhibitor.

First claim

The invention claimed is:

1. A compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

R is Cl or CN;
R 1 and R 2 are each independently H or D;
A is pyridyl, pyrimidinyl or pyrazinyl;
R 3 represents one or more substituents, each being independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, trifluoromethyl, methyl optionally substituted by one or more D, methylol, methoxymethyl optionally substituted by one or more D, acetoxymethyl, methoxy optionally substituted by one or more D, methoxyethoxy, amino, methylamino, dimethylamino, t-butylamino, cyclopropylamino, epoxypropylamino, acetylamino, oxetanylamino, methoxymethylamino, methoxyethylamino, methoxypropylamino, ethoxyethylamino, ethoxypropylamino, methoxycarbonylethylamino, methoxycarbonylpropylamino, ethoxycarbonylmethylamino, ethoxycarbonylethylamino, ethoxycarbonylpropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, cyclobutylamino, azetidinyl, N,N-dimethylaminomethylamino, N,N-dimethylaminoethylamino, N,N-dimethylaminopropylamino, N,N-dimethylaminobutylamino, t-butoxyacylaminobutylamino, 5-morpholinylmethyl, ethylaminoethylamino, ethylaminopropylamino, ethylaminobutylamino, methoxyethoxyethoxyethylamino, ethoxyethoxyethylamino, t-butoxycarbonylethylamino, t-butoxycarbonylpropylamino, t-butoxycarbonylmethoxyethylamino, carboxylethylamino, carboxylpropylamino, carboxymethoxyethylamino, 6-morpholinylmethyl, 6-(tetrahydrofuranyl)methylamino, methylsulfonylethylamino, (2,2-dimethyl-[1,3]-dioxolan-4-yl)-methylamino, 2,3-dihydroxypropylamino, 2-hydroxypropylamino, trifluoromethylethylamino, with the proviso that when A is pyridyl and R is Cl, R 3 is not H or D;
R 4 represents one or more substituents, each being independently selected from the group consisting of H, halogen, methyl, methoxy, cyano and trifluoromethyl.

2. The compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1 , wherein the compound of formula I is selected from the group consisting of the compounds having a structure represented by one of the following formulae I-I to I-V:

wherein, R, R 1 , R 2 , R 3 and R 4 are each independently defined as those in claim 1 , except that R 4 is not H.

3. The compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1 , wherein:
the compound of formula I includes one or more optical isomers enantiomers, diastereoisomers or racemate mixtures of the compound of formula I;
the pharmaceutically acceptable salt includes an anionic salt and a cationic salt of the compound of formula I;
the solvate is a complex formed by the compound of formula I or a salt thereof and a pharmaceutically acceptable solvent.

4. The compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1 , wherein the compound of formula I is one of the following compounds:

5. A method of preparing the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1 , wherein the method of preparing the compound of formula I includes steps of one of the following routes:
Route 1:

the compound I is obtained from the compound a-1 by a Suzuki reaction, wherein, R, R 1 , R 2 , R 3 , and A are each defined as those defined in claim 1 ;
Route 2:

the compound I is obtained from the compound b-1 and the compound b-2 by a nucleophilic substitution,
wherein, R, R 1 , R 2 , R 3 , R 4 and A are each defined as those defined in claim 1 .

6. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1 , and an optional pharmaceutically acceptable carrier.

7. A method for treating hepatitis B disease in a subject, comprising: administering an effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1 to the subject.

8. A method for inhibiting hepatitis B virus replication in a subject, comprising administering an effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof according to claim 1 to the subject.

9. A method for treating hepatitis B disease in a subject, comprising administering an effective amount of the pharmaceutical composition according to claim 6 to the subject.

10. A method for inhibiting hepatitis B virus replic

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Hu Youhong
• Zuo Jianping
• Lu Dong
• Yang Li
• Zeng Limin
• Liu Feifei
• Zhang Yunzhe
• Chen Wuhong
• Tong Xiankun

Classifications

• A61P31/20

  for DNA viruses · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P31/18

  for HIV · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title