Isoquinolinone compound for inhibiting ssao/vap-1, and use thereof

Patent metadata

Field	Value
Publication number	US-12258317-B2
Application number	US-202017608842-A
Country	US
Kind code	B2
Filing date	May 20, 2020
Priority date	May 20, 2019
Publication date	Mar 25, 2025
Grant date	Mar 25, 2025

Abstract

An isoquinolinone compound acts as an inhibitor of semicarbazide-sensitive oxidase (SSAO) and/or vascular adhesion protein-1 (VAP-1), and the use thereof, and further relates to a pharmaceutical composition containing the compound. The compound or the pharmaceutical composition can be used to prepare a drug for preventing, treating or ameliorating inflammation and/or inflammation-related diseases, diabetes and/or diabetes-related diseases in patients, and especially can be used to prepare a drug for preventing, treating or ameliorating non-alcoholic fatty liver diseases in patients.

First claim

What is claimed is:

1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a pharmaceutically acceptable salt thereof,

wherein,
R 1 is F, Cl, Br or I;
R 2 is H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl or

each of R 3a , R 3b and R 3c is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , —C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, carboxy C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;
W is -L-R 4 or —(CR a R b ) t —P(═O)(R 5 )(R 6 );
L is —(CR a R b ) p —C(═O)—NR c , —(CR a R b ) q —S—, —(CR a R b ) q —S(═O)—, —(CR a R b ) s —S(═O) 2 —, —(CR a R b ) q —S(═O) 2 —NR c — or —(CR a R b ) q —S(═O)—NR c —;
each of q, p, s and t is independently 0, 1, 2, 3, 4 or 5;
each of R a , R b and R c is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, carboxyl C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;
R 4 is H, deuterium, C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein each of the C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;
or R c and R 4 together with the nitrogen atom to which they are attached, form 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 3-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;
each of R 5 and R 6 is independently OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy or 5-6 membered heteroarylamino, wherein each of the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and 5-6 membered heteroarylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;
or R 5 and R 6 together with the phosphorus atom to which they are attached, form 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 3-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;
each R y is independently deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , —SH, —C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkoxy, —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, carboxy C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.

2. The compound according to claim 1 , wherein the R 4 is H, deuterium, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein each of the C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;
or R c and R 4 together with the nitrogen atom to which they are attached, form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 5-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y .

3. The compound according to claim 1 , wherein the R 4 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, propenyl, ethynyl, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, propenyl, ethynyl, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently unsubstituted or substituted by 1, 2, 3 or 4 R y ;
or R c and R 4 together with the nitrogen atom to which they are attached, form pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, pyrazinyl, thiazolyl or pyrimidinyl, wherein each of the pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, pyrazinyl, thiazolyl and pyrimidinyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y .

4. The compound according to claim 1 , wherein each of the R 5 and R 6 is independently OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 5-6 membered heterocyclyl, 5-6 membered heterocyclyloxy, 5-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy or 5-6 membered heteroarylamino, wherein each of the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 5-6 membered heterocyclyl, 5-6 membered heterocyclyloxy, 5-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and 5-6 membered heteroarylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;
or R 5 and R 6 together with the phosphorus atom to which they are attached, form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 5-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y .

5. The compound according to claim 1 , wherein each of the R 5 and R 6 is independently OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropy

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Gu Zheng
• Li Jianhao
• Wang Weihua
• Qin Haoxiong
• Deng xinshan

Classifications

• C07F9/4006

  Esters of acyclic acids which can have further substituents on alkyl · CPC title

• C07F9/3817

  Acids containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se) · CPC title

• C07D401/06

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

• A61P1/16 Primary

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

• C07F9/62

  Isoquinoline or hydrogenated isoquinoline ring systems · CPC title