DIHYDROPYRIMIDO LOOP DERIVATIVE AS HBV INHIBITOR

• US 20170197986A1
• Filed: 05/27/2015
• Published: 07/13/2017
• Est. Priority Date: 05/30/2014
• Status: Active Grant

• Current Assignee: QILU Pharmaceutical Company Limited
• Original Assignee: Medshine Discovery Inc.
• Inventors: HE, Haiying, ZHOU, Kai, QIN, Hua, LI, Xiaolin, ZHOU, Yuedong, WANG, Xiaofei, CHI, Xuemei, LI, Jian, CHEN, Shuhui
• Granted Patent: US 9,938,301 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/527 spiro-condensed
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Disclosed is a dihydropyrimido fused ring derivative as a HBV inhibitor, and in particular relates to a compound shown as formula (I) or a pharmaceutically acceptable salt thereof.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, having a structure shown as formula (II):

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R₀₁ is selected from halogen, CN, ═

NH, ═

O, ═

S, COOH, or the following groups optionally substituted by 1, 2 or 3 R₀₀₁;

hydroxy, amino, C_1-4 alkyl, C_1-4 alkoxy, C_0-4 alkyl-C(═

O)O—

C_1-4 alkyl.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R₃′

, R₂₁, R_d1-d8, R_31-32 are separately and independently selected from H, F, Cl, Br, I, OH, NH₂, CN, —

COOH, or selected from the following groups optionally substituted by 1, 2 or 3 R₀₁;

CH₃,

5. The compound or pharmaceutically acceptable salt thereof according to claim 4, wherein R₃′

, R₂₁, R_d1-d₈, and R_31-32 are separately and independently selected from;

H, F, Cl, Br, I, OH, NH₂, CN, —

COOH, CH₃,

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit

7. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein the structural unit

8. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L, D₂₁ are selected from a single bond, —

O—

, —

NH—

;

or R₂₁ is selected from C_1-4 alkyl, C_1-4 alkylamino, N,N-di(C_1-4 alkyl) amino, C_1-4 alkylamino-C_1-4 alkyl-, N,N-di(C_1-4 alkyl) amino-C_1-4 alkyl-, C_1-4 alkoxy, C_1-4 alkoxy-C_1-4 alkyl-, haloC_1-4 alkyl-, dihaloC_1-4 alkyl-, aminooxy C_1-4 alkyl-, hydroxyl C_1-4 alkyloxy-, hydroxyl C_1-3 alkylamino-.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein R₂₁ is selected from methyl, ethyl, n-propyl, isopropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylaminoethyl, ethylaminoethyl, propylaminoethyl, dimethylaminoethyl, diethylaminomethyl, dimethylaminomethyl, diethylaminoethyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, propoxymethyl, ethoxyethyl, propoxypropyl, fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoroethyl, difluoropropyl, aminooxymethyl, aminooxyethyl, aminooxypropyl, hydroxymethyloxy, hydroxyethyloxy, hydroxypropoxy.

10. The compound or pharmaceutically acceptable salt thereof according to claim 9, wherein the structural unit

11. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R₃ or R₄ is separately and independently selected from the following groups optionally substituted by 1, 2 or 3 R₀₀₁:

phenyl, pyridyl, quinolyl, isoquinolyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, isothiazole, furyl, pyrrolyl, pyrrolidinyl, 1,3-dioxolanyl, 2-pyrazolinyl, pyrazolidinyl, imidazolyl, 1,2,3-azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, piperidyl, 1,4-dioxanyl, morpholinyl, piperazinyl, piperidyl, pyrimidinyl, pyrazinyl, 1,3,5-trithianyl, 1,3,5-triazinyl, indenyl, naphthyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzocyclopentyl, cyclopropyl;

or the structural unit

12. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R₃ is selected from

13. The compound or pharmaceutically acceptable salt thereof according to claim 1, selected from:

14. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R₀₁ is selected from F, Cl, Br, I, OH, CN, NH₂, ═

NH, ═

O, ═

S, —

SMe, Me, Et,