Tetrahydroisoquinoline derivatives, preparation process and use thereof

Patent metadata

Field	Value
Publication number	US-2021052576-A1
Application number	US-201916965450-A
Country	US
Kind code	A1
Filing date	Mar 18, 2019
Priority date	Mar 28, 2018
Publication date	Feb 25, 2021
Grant date	—

Abstract

Provided are tetrahydroisoquinoline derivatives, the preparation and use thereof. More specifically, provided are the tetrahydroisoquinoline derivatives or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof. Further provided are a preparation process of the compound, the intermediates, a pharmaceutical composition comprising the compound and the use thereof in the treatment or prevention of a thromboembolic disorder.

First claim

1 . A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of formula (I):

wherein:
“ ” represents a single bond or a double bond;
each R 1 , at each occurrence, is independently selected from the group consisting of halogen, halo C 1-6 alkyl, nitro, cyano and 5-6 membered heteroaryl;
Y is selected from the group consisting of

W is selected from the group consisting of CR 2 , CR 2a R 2b and C(═O);
Q is selected from the group consisting of N, C and CR 3 ;
each R 2 , R 2a , R b and R 3 is independently selected from the group consisting of H and C 1-6 alkyl;
L is selected from the group consisting of chemical bond, C 1-4 alkylene, and a bivalent radical formed by any combination of 1-4 groups selected from the group consisting of —CH 2 —, —C(═O)— and —NH—;
AAR represents amino acid residue; or
AAR is selected from the group consisting of

wherein
R 4 is selected from the group consisting of H and C 1-6 alkyl, wherein the alkyl is optionally substituted with 1, 2 or 3 groups selected from the group consisting of OR x , NR x R y and COOR x ;
R 5 is selected from the group consisting of H and C 1-6 alkyl;
each R x and R y , at each occurrence, is independently selected from the group consisting of H and C 1-6 alkyl;
p is 0 or 1;
q is 0, 1, 2, 3 or 4;
m is 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3, 4 or 5.

2 . The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein:
each R 1 , at each occurrence, is independently selected from the group consisting of halogen, cyano and 5-6 membered heteroaryl;
preferably, each R 1 , at each occurrence, is independently selected from the group consisting of fluorine, chlorine, bromine, cyano and 5-membered heteroaryl;
more preferably, each R 1 , at each occurrence, is independently selected from the group consisting of fluorine, chlorine, cyano and

3 . The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein:
L is selected from the group consisting of chemical bond, methylene, ethylene, —CH 2 —NH—, —NH—C(═O)— and —C(═O)—CH 2 —;
preferably, L is selected from the group consisting of chemical bond, ethylene and —C(═O)—CH 2 —;
more preferably, L is selected from the group consisting of chemical bond and —C(═O)—CH 2 —.

4 . The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein:
AAR represents amino acid residue;
preferably, AAR is selected from the group consisting of natural amino acid residues,
more preferably, the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, glutamic acid, lysine, glutamine, asparagine, serine, threonine, cysteine, proline, histidine, arginine and methionine;
further preferably, the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, aspartic acid, glutamic acid, lysine, serine and threonine;
more preferably, the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, aspartic acid, glutamic acid and lysine;
particularly preferably, the amino acid is selected from the group consisting of alanine, valine, glutamic acid and lysine; or
AAR is selected from the group consisting of

and
preferably, AAR is selected from the group consisting of

wherein
p is 0, and
R 4 is C 3-6 alkyl, preferably C 3-4 alkyl, wherein the alkyl is optionally substituted with 1 or 2 groups selected from the group consisting of OH, NH 2 and COOH; or R 4 is —CH 2 CH 2 COOH;
R 5 is H;
q is 2, 3 or 4;
or
p is 1, and
R 4 is C 2-6 alkyl, preferably C 2-4 alkyl, wherein the alkyl is optionally substituted with 1 or 2 groups selected from the group consisting of OH, NH 2 and COOH; or R 4 is —CH 2 COOH;
R 5 is H;
q is 1,2,3 or 4.

5 . The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein:
m is 2, 3, 4 or 5, preferably 2 or 3;
n is 0, 1 or 2, preferably 1.

6 . The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein
R 5 is H; p is 0.

7 . The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein,
AAR is selected from the group consisting of:

preferably, AAR is selected from the group consisting of:

particularly preferably, AAR is selected from the group consisting of:

8 . The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein,
-L-AAR is selected from the group consisting of:

preferably, -L-AAR is selected from the group consisting of:

particularly preferably, -L-AAR is selected from the group consisting of:

9 . The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, wherein,
Y is

each R 1 , at each occurrence, is independently selected from the group consisting of halogen and 5-membered heteroaryl; preferably, one R 1 is 5-membered heteroaryl, if m is not 1, other R 1 , at each occurrence, is each independently selected from the group consisting of halogen; more preferably, one R 1 is

if m is not 1, other R 1 , at each occurrence, is each independently selected from the group consisting of fluorine and chlorine; or

Assignees

• Sichuan Kelun Biotech Biopharmaceutical Co Ltd

Inventors

• Wu Yongyong
• Cai Jiaqiang
• Zhang Guangchao
• Duan Shuangshuang
• Wang Chaolei
• Wang Lichun
• Wang Jingyi

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title