Nucleoside phosphate compound and preparation method and use thereof

Patent metadata

Field	Value
Publication number	US-10899786-B2
Application number	US-201716344317-A
Country	US
Kind code	B2
Filing date	Dec 19, 2017
Priority date	Dec 23, 2016
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

Provided in the present invention are a compound of Formula (I), a pharmaceutical composition comprising the same, a method for preparing the same, and use thereof as a NS5B polymerase inhibitor, a DNA polymerase inhibitor or a reverse transcriptase inhibitor for the prevention or treatment of viral diseases or cancers.

First claim

What is claimed is:

1. A compound represented by Formula (I), a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystalline form or racemate of the foregoing, a metabolite form of the foregoing, or a mixture of the foregoing,

wherein
L is selected from the group consisting of substituted or unsubstituted C 1-12 alkylene, C 2-12 alkenylene, C 2-12 alkynylene, and the alkylene, alkenylene or alkynylene is optionally interrupted by one or more —O—, —NR 8 — or —S—; or
L represents a group of Formula (c), Formula (d) or Formula (e), wherein represents a single bond or a double bond, position 1 is attached to the Base, and position 2 is attached to the phosphorus atom (P):

Base represents a group of Formula (a) or Formula (b):

represents a single bond or a double bond;
M represents N or NR 8 ;
W represents H, NR 8 R 9 , NR 8 , CH 2 , O or S;
Q represents O, S, NR 8 or CH 2 ;
each Z, at each occurrence, independently represents hydrogen, halogen, hydroxy, cyano, nitro, azido, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, or substituted or unsubstituted C 3-8 cycloalkyl, and if there are multiple Z groups, they each may be the same or different;
p represents 0, 1, 2, 3, 4 or 5;
provided that when M is attached by a double bond, W is attached by a single bond; and when M is attached by a single bond, W is attached by a double bond;
U represents O, S, NR 8 or CR 10 R 11 ;
E represents CR 10 , CR 10 R 11 or S, provided that when E is attached by a double bond, it is CR 10 ;
each G, at each occurrence, independently represents hydrogen, halogen, hydroxyl, cyano, nitro, azido, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, or substituted or unsubstituted C 3-8 cycloalkyl, and if there are multiple G groups, they each may be the same or different;
q represents an integer of from 0 to 5;
Ar 1 represents C 6-14 aryl or 5- to 14-membered heteroaryl;
each R 1 , at each occurrence, represents hydrogen, halogen, —OH, —CN, —NO 2 , —NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 haloalkyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C 2-10 alkenyl, or substituted or unsubstituted C 2-10 alkynyl, and if there are multiple R 1 groups, they each may be the same or different;
m represents an integer of from 0 to 7;
X represents CH 2 , —S—, —O— or —NR 8 —;
R 2 and R 3 , at each occurrence, each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted C 3-8 cycloalkyl; or R 2 and R 3 together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl;
R 4 and R 5 , at each occurrence, each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted C 3-8 cycloalkyl group; or R 4 and R 5 together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl; or
R 3 and R 4 are linked to each other, together with the carbon atoms to which they each are attached, form substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl;
R 6 represents hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-14 aryl group, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted C 1-6 alkoxy;
each R 7 , at each occurrence, independently represents hydrogen, halogen, —OH, —CN, —NO 2 , —NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 haloalkyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C 2-10 alkynyl, or substituted or unsubstituted C 1-6 alkoxy, and if there are multiple R 7 groups, they each may be the same or different; or
R 6 and R 7 are linked to each other, together with the carbon atoms therebetween, form substituted or unsubstituted C 3-8 carbocyclyl or 3- to 10-membered heterocyclyl;
n represents an integer of from 0 to 7;
Ar 2 represents C 6-14 aryl or 5- to 14-membered heteroaryl;
r and s each independently represent 1, 2 or 3;
R 8 and R 9 , at each occurrence, each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 3-8 cycloalkyl, if there are multiple R 8 and R 9 groups, they each may be the same or different, and preferably, R 8 represents hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl, and R 9 represents hydrogen; and
R 10 and R 11 , at each occurrence, each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 3-8 cycloalkyl, or R 10 and R 11 together form C 1-6 alkylene, and if there are multiple R 10 and R 11 groups, they each may be the same or different.

2. The compound of claim 1 , a pharmaceutically acceptable salt,
ester, solvate, isomer thereof, any crystalline form or racemate of the foregoing, a metabolite form of the foregoing, or a mixture of the foregoing, wherein the compound is a compound of Formula (Ia)

wherein
L-Base represents a group of Formula (f) or Formula (g):

Base represents a group of Formula (a) or Formula (b):

wherein
represents a single bond or a double bond;
M represents N or NW;
W represents NR 8 R 9 or O;
Q represents O or S;
each Z, at each occurrence, independently represents hydrogen, halogen, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, or substituted or unsubstituted C 3-8 cycloalkyl, and if there are multiple Z groups, they each may be the same or different;
p represents an integer of from 0 to 2;
provided that when M is attached by a double bond, W is attached by a single bond, M represents N, and W represents NR 8 R 9 ; and when M is attached by a single bond, W is attached by a double bond, M represents NR 8 , and W represents O;
U represents O, S or CR 10 R 11 ;
E represents CR 10 , CR 10 R 11 or S, provided that when E is attached by a double bond, it is CR 10 ;
each G, at each occurr

Assignees

• Sichuan Kelun Biotech Biopharmaceutical Co Ltd

Inventors

• Cai Jiaqiang
• Song Shuai
• Tian Qiang
• Zhang Yitao
• Huang Haitao
• Zhong Guoqing
• Zhong Wei
• Hao Yongjia
• Zhao Mingliang
• Zeng Hong
• Song Hongmei
• Zhou Xin
• Liu Yao
• Tan Yuting
• Wang Lichun
• Wang Jingyi

Classifications

• C07F9/65616

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title

• C07F9/6512

  having the nitrogen atoms in positions 1 and 3 · CPC title

• C07H1/02

  Phosphorylation · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07F9/65586

  at least one of the hetero rings does not contain nitrogen as ring hetero atom · CPC title