HK1136283B

HK1136283B - Compounds for the prevention and treatment of cardiovascular diseases

Info

Publication number: HK1136283B
Application number: HK10102977.1A
Authority: HK
Inventors: Henrik Hansen
Original assignee: Resverlogix Corp.
Filing date: 2007-02-01
Publication date: 2013-12-27

Description

Compounds for the prevention and treatment of cardiovascular diseases

Technical Field

The present disclosure relates to compounds useful for modulating apolipoprotein a-I (ApoA-I) expression and their use in the treatment and prevention of cardiovascular diseases and related disease states, including cholesterol or lipid related disorders, such as atherosclerosis.

Background

Epidemiological data indicate that there is an inverse correlation between circulating levels of high density lipoprotein cholesterol (HDL-C) and the incidence of clinically significant atherosclerosis. (ii) cardiovascular risk is reduced by 2-3% for every 1mg/dL increase in HDL-C serum levels; a1% decrease in LDL-C reduces the risk of Coronary Heart Disease (CHD) by 2% (Gordon et al (1997) am. J. Med.62, 707-. Experimental evidence further supports the protective role of HDL-C against cardiovascular disease. For example, in subjects with low HDL-C, administration of gemfibrozil increased HDL-C levels by 6%, and correspondingly reduced the risk of CHD by 22% (Rubins et al (1999) N.Engl.J.Med.341, 410-. Observations in genetic disorders associated with low HDL-C caused by reduced ApoA-I expression also indicate a link between high CHD risk and low HDL-C.

HDL-C is shown to exert an anti-atherosclerotic effect by mediating Reverse Cholesterol Transport (RCT), in which cholesterol is recruited from peripheral tissues and transported to the liver. In addition, HDL-C also exerts anti-inflammatory and antioxidant effects as well as fibrinolytic effects. HDL-C particles prevent LDL oxidation, which is an important initial step in the promotion of cholesterol uptake by arterial macrophages. HDL-C exists in two major forms, one containing both apolipoprotein A-I (ApoA-I) and apolipoprotein A-II (ApoA-II), and the other containing ApoA-I but not ApoA-II (Schultz et al (1993) Nature 365, 762-764). The cardioprotective effects of HDL-C may be caused primarily, but not exclusively, by ApoA-I.

Clinical and experimental data suggest that the production of ApoA-I is a key determinant of circulating HDL-C. For example, people with familial hyperalpha-lipoproteinemia (high ApoA-I) have been shown to avoid atherosclerosis, while those with ApoA-I deficiency (hypoalphalipoproteinemia) have been shown to accelerate cardiovascular disease. In addition, various experimental procedures that increase ApoA-I production were accompanied by a decrease in atherogenesis. For example, human ApoA-I is protective in transgenic animal models (Shah et al (1998) Circulation 97, 780-785; Rubin et al (1991) Nature 353, 265-267) and is used in human patients with ApoA-I_MilanoTreatment can arrest atherosclerotic lesions and allow atherosclerotic plaque reduction (Nissen et al (2003) JAMA 290, 2292-. Additional lines of research demonstrate that ApoA-I plays a role in enhancing retrograde cholesterol transport, attenuating oxidative stress, increasing paraoxonase activity, enhancing anticoagulant activity and increasing anti-inflammatory activity (Andersson (1997) curr. Opin. Lipidol.8, 225-. Thus, ApoA-I is an attractive target for therapeutic intervention.

Currently available therapeutic agents that increase ApoA-I plasma concentrations, such as recombinant ApoA-I or ApoA-I mimicking peptides, have potential disadvantages in terms of stability during storage, delivery of active products and in vivo half-life, for example. Thus, small molecule compounds that up-regulate endogenous ApoA-I production, e.g., up-regulators of ApoA-I expression, would be very attractive as new therapeutics for cardiovascular diseases. Such small molecule compounds have been described in WO 2006/045096.

The compounds of the present invention represent a major improvement over the compounds disclosed in WO 2006/045096. In particular, the compounds of the present invention are more than an order of magnitude more potent than the most active compounds described in this publication, such as 2- (4-hydroxy-phenyl) -pyrano [2, 3-b ] pyridin-4-one.

2- (4-hydroxy-phenyl) -pyrano [2, 3-b ] pyridin-4-one

SUMMARY

The present invention includes non-naturally occurring compounds that are useful for modulating apolipoprotein a-I (ApoA-I) expression and their use in the treatment and prevention of cardiovascular diseases and related disease states, including cholesterol and lipid related disorders, such as atherosclerosis.

The methods of the present invention comprise administering to a mammal (e.g., a human) in need thereof a therapeutically effective amount of a compound of formula II:

wherein:

x is selected from CR₁₁N and NR₁₁；

Y is selected from CO, CS and SO₂；

R₁₁Selected from hydrogen, unsubstituted alkyl (preferably C)_1-3Alkyl), unsubstituted alkenyl (preferably C)_1-3Alkenyl) and unsubstituted alkynyl (preferably C)_1-3Alkynyl groups);

R₁and R₃Each independently selected from alkoxy (preferably methoxy), alkyl, amino, halogen (preferably chloro) and hydrogen;

R₂selected from alkoxy, alkyl, alkenyl, amido, amino, halogen (preferably bromine or chlorine) and hydrogen;

R₆and R₈Each independently selected from alkoxy, alkyl (preferably methyl), amino, halogen (preferably chloro and fluoro), and hydrogen;

R₅and R₉Each independently selected from halogen (preferably chlorine) and hydrogen;

R₇selected from alkoxy, alkyl, alkenyl, amide, amino, ether, hydrogen and hydroxyl;

R₁₀selected from hydrogen and alkyl (preferably methyl); or

Two adjacent selected from R₁、R₂、R₃、R₆、R₇、R₈、R₁₀And R₁₁Are linked to form a group selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

each W is independently selected from C and N, wherein if W is N, p is 0 or 1, and if W is C, p is 1;

for W- (R)₄)_pFor W is C, p is 1 and R₄Is H, or W is N and p is 0;

Z₁、Z₂and Z₃Each independently selected from single and double bonds, wherein Z is₁Or Z₂At least one of which is a double bond.

The invention also includes certain compounds within the scope of formula II and methods of administering therapeutically effective amounts of those compounds and pharmaceutically acceptable salts and hydrates thereof to a mammal (e.g., a human) in need thereof,

wherein:

x is selected from N and CH;

y is CO;

R₁and R₃Each independently selected from alkoxy and hydrogen;

R₂selected from alkoxy, alkyl and hydrogen;

R₆and R₈Each independently selected from alkyl, alkoxy, chloro and hydrogen;

R₅and R₉Each is hydrogen;

R₇selected from the group consisting of amino, hydroxy, alkoxy (preferably substituted ethoxy), and alkyl substituted with a heterocyclic group;

R₁₀is hydrogen; or

Two adjacent selected from R₆、R₇And R₈The substituents of (a) are linked to form a heterocyclic group;

for W- (R)₁₀)_pW is N and p is 1;

for W- (R)₄)_pFor W is C, p is 1 and R₄Is H, or W is N and p is 0;

Z₁is a double bond, and Z₂And Z₃Each is a single bond;

with the following conditions: if R is₂Selected from alkoxy and hydrogen, then R₁And R₃At least one is an alkoxy group;

with the following conditions: if R is₇Selected from hydroxy and alkoxy, then R₆And R₈At least one is independently selected from alkyl, alkoxy, and chloro;

with the following conditions: if R is₇Is amino, then X is N;

with the following conditions: if for W- (R)₇)_pWith W being N and p being 0, then R₆And R₈At least one of which is chlorine.

In some embodiments of the invention, R₇Is an amino or alkoxy group selected from the group represented by formula III:

wherein:

a is selected from O and N;

n is selected from 0, 1, 2, 3, 4 and 5;

b is selected from-C (O) N (R)_h)₂-、-S(O)₂N(R_h)₂-、-C(O)-、-S(O)₂-, -C (O) O-, wherein R_hEach selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and is

R₂₀Is selected from (C)₁-C₆) Alkyl, (C)₁-C₆) Alkenyl, (C)₁-C₆) Alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen.

In another embodiment, if A is O and B is-C (O) NH-, then R is₂₀Is not an unsaturated cycloalkyl group.

In certain embodiments, the methods, compounds, and compositions of the present invention are useful for the prevention or treatment of diseases benefiting from an increase in ApoA-I or HDL, as well as diseases characterized by a decrease in ApoA-I and/or HDL-C, abnormal lipid parameters, or lipid parameters indicative of high cholesterol. The methods, compounds and compositions of the invention can be used to increase expression of ApoA-I. Increased expression of ApoA-I may refer to, but is not limited to, transcriptionally modulating expression of an ApoA-I gene, thereby affecting the level of ApoA-I protein produced (synthesized and secreted). An increase in ApoA-I levels may result in increased levels of HDL-C and/or increased function of HDL-C particles. Thus, the methods, compounds, and compounds of the invention may also be used to lower cholesterol levels. Thus, the methods, compounds and compositions of the present invention may be used to treat and prevent cardiovascular diseases and related disease states, particularly cholesterol or lipid related disorders, such as atherosclerosis.

Brief Description of Drawings

FIG. 1 depicts the plasma levels of ApoA-I in hApoA-I transgenic mice receiving 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7) (10, 30 and 60mg/kg body weight) by oral gavage twice daily for a total of 7 days.

FIG. 2 depicts plasma levels of HDL cholesterol in hApoA-I transgenic mice receiving 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7) (10 and 30mg/kg body weight) by oral gavage twice daily for a total of 7 days.

FIG. 3 depicts the plasma levels of ApoA-I in wild-type C57BL/6 mice receiving 2- (4- (2-hydroxyethyloxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7) (10, 30 and 60mg/kg body weight) by intraperitoneal administration twice daily for a total of 3 days.

FIG. 4 depicts plasma levels of HDL cholesterol in wild-type C57/Bl mice receiving 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7) (10, 30, and 60mg/kg body weight) by oral gavage twice daily for a total of 3 days.

FIG. 5 depicts the plasma levels of ApoA-I and tissue levels of ApoA-I mRNA in hApoA-I transgenic mice administered 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7) (30mg/kg body weight) by oral gavage twice daily for a total of 7 days.

Detailed description of the invention

Definition of

The term "aldehyde" or "formyl" as used herein refers to — CHO.

The term "alkenyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond, e.g., a straight or branched chain group of 2-22, 2-8, or 2-6 carbon atoms, which are referred to herein as (C), respectively₂-C₂₂) Alkenyl, (C)₂-C₈) Alkenyl and (C)₂-C₆) An alkenyl group. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butene) -pentenyl, and the like.

The term "alkoxy" as used herein refers to an alkyl (-O-alkyl-) group attached to an oxygen. "alkoxy" also includes oxygen-linked alkenyl ("alkenyloxy") or oxygen-linked alkynyl ("alkynyloxy"). Exemplary alkoxy groups include, but are not limited to, alkyl, alkenyl, or alkynyl groups having 1-22, 1-8, or 1-6 carbon atoms, each of which is referred to herein as (C)₁-C₂₂) Alkoxy group, (C)₁-C₈) Alkoxy and (C)₁-C₆) An alkoxy group. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and the like.

The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon, e.g., a straight or branched chain group of 1-22, 1-8, or 1-6 carbon atoms, which are referred to herein as (C), respectively₁-C₂₂) Alkyl, (C)₁-C₈) Alkyl and (C)₁-C₆) An alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-di-methylMethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like.

The term "alkynyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond, e.g., a straight or branched chain group of 2-22, 2-8, or 2-6 carbon atoms, referred to herein as (C), respectively₂-C₂₂) Alkynyl, (C)₂-C₈) Alkynyl and (C)₂-C₆) Alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, 4-butyl-2-hexynyl, and the like.

The term "amido" as used herein refers to the form-NR_aC(O)(R_b) -or-C (O) NR_bR_cWherein R is_a、R_bAnd R_cEach independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amide group may be through carbon, nitrogen, R_bOr R_cTo another group. The amide group may also be cyclic, e.g. R_bAnd R_cMay be joined to form a 3 to 12 membered ring, for example a 3 to 10 membered ring or a5 to 6 membered ring. The term "amide" includes groups such as sulfonamide, urea, urethane, carbamate, and cyclic variations thereof. The term "amide" also includes amide groups attached to a carboxyl group, e.g., -amide-COOH or salts such as-amide-COONa and the like, amino groups attached to a carboxyl group, e.g., -amino-COOH or salts such as-amino-COONa and the like.

The term "amino" or "amino" as used herein refers to the form-NR_dR_eor-N (R)_d)R_e-, wherein R_dAnd R_eIndependently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamateAlkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen. The amino group may be attached to the parent molecular group through a nitrogen. The amino group may also be cyclic, e.g. any two R_dAnd R_eMay be joined together or with the N to form a 3 to 12 membered ring, for example morpholino or piperidinyl. The term amino also includes the corresponding quaternary ammonium salts of any amino group. Exemplary amino groups include alkylamino groups, wherein R is_dOr R_eAt least one of which is an alkyl group.

The term "aryl" as used herein refers to a mono, bi, or other multi-carbocyclic aromatic ring system. The aryl group may be optionally fused with one or more rings selected from aryl, cycloalkyl and heterocyclyl. The aryl groups of the present invention may be substituted with groups selected from: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, and thioketo groups. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5, 6, 7, 8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, monocyclic aromatic ring systems in which the ring contains 6 carbon atoms, referred to herein as "(C)₆) Aryl ".

The term "arylalkyl" as used herein refers to an alkyl group having at least one aryl substituent, e.g., -aryl-alkyl-. Exemplary arylalkyl groups include, but are not limited to, arylalkyl groups having a monocyclic aromatic ring system in which the ring contains 6 carbon atoms, which are referred to herein as "(C)₆) An arylalkyl group ".

The term "aryloxy" as used herein refers to an aryl group attached to an oxygen atom. Exemplary aryloxy groups include, but are not limited to, aryloxy groups having a monocyclic aromatic ring system wherein the ring comprises 6 carbon atoms, referred to herein as "(C)₆) Aryloxy ".

The term "arylthio" as used herein refers to an aryl group attached to a sulfur atom. Exemplary arylthio groups include, but are not limited to, arylthio groups having a monocyclic aromatic ring system in which the ring contains 6 carbon atoms, which are referred to herein as "(C)₆) An arylthio group ".

The term "arylsulfonyl" as used herein refers to an aryl group attached to a sulfonyl group, e.g., -S (O)₂-aryl-. Exemplary arylsulfonyl groups include, but are not limited to, arylsulfonyl groups having a monocyclic aromatic ring system in which the ring contains 6 carbon atoms, which is referred to herein as "(C)₆) Arylsulfonyl ".

The term "benzyl" as used herein refers to the group-CH₂-phenyl.

The term "bicyclic aryl" as used herein refers to an aryl group fused to another aromatic or non-aromatic carbocyclic or heterocyclic ring. Exemplary bicyclic aryl groups include, but are not limited to, naphthyl or a partially reduced form thereof such as di-, tetra-or hexahydronaphthyl.

The term "bicyclic heteroaryl" as used herein refers to a heteroaryl group fused to another aromatic or non-aromatic carbocyclic or heterocyclic ring. Exemplary bicyclic heteroaryl groups include, but are not limited to, 5, 6 or 6, 6-fused systems wherein one or both rings contain a heteroatom. The term "bicyclic heteroaryl" also includes reduced or partially reduced forms of fused aromatic systems in which one or both rings contain a ring heteroatom. The ring system may contain up to three heteroatoms independently selected from oxygen, nitrogen or sulfur. The bicyclic system may be optionally substituted with one or more groups selected from: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, and thioketo groups. Exemplary bicyclic heteroaryl groups include, but are not limited to, quinazolinyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridyl, and benzofuranyl.

The term "carbamate" as used herein refers to the form-R_gOC(O)N(R_h)-、-R_gOC(O)N(R_h)R_i-or-OC (O) NR_hR_iWherein R is_g、R_hAnd R_iEach independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamate groups include, but are not limited to, arylcarbamate groups or heteroarylcarbamate groups, e.g., wherein R is_g、R_hAnd R_iAt least one of which is independently selected from aryl or heteroaryl groups such as pyridine, pyridazine, pyrimidine and pyrazine.

The term "carbonyl" as used herein refers to-C (O) -.

The term "carboxy" as used herein refers to-COOH or its corresponding carboxylate salt such as-COONa and the like. The term carboxy also includes "carboxycarbonyl," e.g., carboxy attached to a carbonyl group, such as-C (O) -COOH or a salt such as-C (O) -COONa, and the like.

The term "cyano" as used herein refers to — CN.

The term "cycloalkoxy" as used herein refers to a cycloalkyl group attached to an oxygen.

The term "cycloalkyl" as used herein refers to 3-12 carbons or 3-8 carbons derived from a cycloalkane (which are referred to herein as "(C)₃-C₈) Cycloalkyl ") saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl groups may be substituted with the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, and the likeNitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, and thioketone groups. The cycloalkyl group may be fused with other saturated or unsaturated cycloalkyl, aryl, or heterocyclic groups.

The term "dicarboxylic acid" as used herein refers to groups containing at least two carboxylic acid groups, for example saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylic acids include alkyl dicarboxylic acids. The dicarboxylic acids may be substituted with the following groups: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, keto, nitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, and thioketo. Dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-) -malic acid, (+)/(-) tartaric acid, isophthalic acid and terephthalic acid. Dicarboxylic acids also include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides, and the like, such as succinic anhydride, succinimide, and the like.

The term "ester group" refers to the structures-C (O) O-, -C (O) O-R_j-、-R_kC(O)O-R_j-or-R_kC (O) O-, wherein O is not bound to hydrogen, and R_jAnd R_kMay be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, heterocyclic. R_kMay be hydrogen, but R_jAnd cannot be hydrogen. The ester group may be cyclic, e.g. a carbon atom and R_jOxygen atom and R_kOr R_jAnd R_kMay be joined to form a 3 to 12 membered ring. Exemplary ester groups include, but are not limited to, those wherein R_jOr R_kAlkyl ester groups in which at least one is an alkyl group, such as-O-C (O) -alkyl, -C (O) -O-alkyl-, -alkyl-C (O) -O-alkyl-, and the like. Exemplary ester groups also include aryl or heteroaryl estersRadicals, e.g. wherein R_jOr R_kAt least one of which is a heteroaryl group such as pyridine, pyridazine, pyrimidine and pyrazine, for example, a nicotinate group. Exemplary ester groups also include those having the structure-R wherein oxygen is bonded to the parent molecule_kC (O) a reverse ester group of O-. Exemplary reverse ester groups include succinate groups, D-arginine ester groups, L-lysine ester groups, and D-lysine ester groups. Ester groups also include carboxylic acid anhydrides and acid halides.

The term "ether group" refers to the structure-R₁O-R_m-, wherein R_lAnd R_mMay be independently an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl or ether group. The ether group can be represented by R_lOr R_mAttached to the parent molecular moiety. Exemplary ether groups include, but are not limited to, alkoxyalkyl groups and alkoxyaryl groups. Ether groups also include polyether groups, e.g. wherein R_lAnd R_mOne or both are ether groups.

The term "halo" or "halogen" or "halo" as used herein refers to F, Cl, Br or I.

The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms. "haloalkyl" also includes alkenyl or alkynyl groups substituted with one or more halogen atoms.

The term "heteroaryl" as used herein refers to a mono-, di-or polycyclic aromatic ring system containing one or more heteroatoms, e.g. 1 to 3 heteroatoms, such as nitrogen, oxygen and sulfur. Heteroaryl groups may be substituted with one or more substituents including: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, and thioketo groups. Heteroaryl groups may also be fused to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl(pyrazyl), triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3) -and (1, 2, 4) -triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, furanyl, phenyl, isoxazolyl and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings in which the ring contains 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "(C)₂-C₅) Heteroaryl group ".

The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein refers to a saturated or unsaturated 3, 4, 5, 6 or 7 membered ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Heterocycles can be aromatic (heteroaryl) or non-aromatic. The heterocyclic ring may be substituted with one or more substituents including: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, and thioketo groups. Heterocyclic also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocycles are fused to one or two rings independently selected from aryl, cycloalkyl and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuranyl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furanyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, pyridalyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidyl, pyrrolinyl, pyrrolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, and the like, Tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl and triazolyl.

The term "hydroxy" as used herein refers to-OH.

The term "hydroxyalkyl" as used herein refers to a hydroxyl group attached to an alkyl group.

The term "hydroxyaryl" as used herein refers to a hydroxyl group attached to an aryl group.

The term "keto" as used herein refers to the structure-C (O) -R_n(e.g., acetyl, -C (O) CH₃) or-R_n-C(O)-R_o-. The keto group may be represented by R_nOr R_oTo another group. R_nOr R_oMay be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R_nOr R_oMay be joined to form a 3 to 12 membered ring.

The term "monoester" as used herein refers to an analogue of a dicarboxylic acid in which one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or a carboxylate salt. Examples of monoesters include, but are not limited to, monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic acid, and maleic acid.

The term "nitro" as used herein refers to-NO₂。

The term "perfluoroalkoxy" as used herein refers to an alkoxy group in which all hydrogen atoms have been replaced by fluorine atoms.

The term "perfluoroalkyl" as used herein refers to an alkyl group in which all hydrogen atoms have been replaced by fluorine atoms. Exemplary perfluoroalkyl groups include, but are not limited to, C_1-5Perfluoroalkyl groups such as trifluoromethyl, and the like.

The term "perfluorocycloalkyl" as used herein refers to a cycloalkyl group in which all hydrogen atoms have been replaced by fluorine atoms.

The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. The phenyl group may be substituted with one or more substituents including: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, and thioketo groups.

The term "phosphate group" as used herein refers to the structure-OP (O) O₂-、-R_xOP(O)O₂-、-OP(O)O₂R_y-or-R_xOP(O)O₂R_y-, wherein R_xAnd R_yCan be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, hydrogen.

The term "thio" as used herein refers to the structure-R_zS-, wherein R_zMay be alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl. The thio group may be cyclic, thereby forming a 3 to 12 membered ring. The term "alkylthio" as used herein refers to an alkyl group attached to a sulfur atom.

The term "sulfinyl" as used herein refers to the structures-S (O) O-, -R-_pS(O)O-、-R_pS(O)OR_q-OR-S (O) OR_q-, wherein R_pAnd R_qCan be alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxy. Exemplary sulfinyl groups include, but are not limited to, those wherein R_pOr R_qIs alkylsulfinyl which is alkyl, alkenyl or alkynyl.

The term "sulfonamide" as used herein refers to the structure- (R)_r)-N-S(O)₂-R_s-or-R_t(R_r)-N-S(O)₂-R_sWherein R is_t、R_rAnd R_sThere may be mentioned, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl. Exemplary sulfonamide groups include alkylsulfonamide groups (e.g., where R is_sIs an alkyl group), an arylsulfonamide group (e.g., wherein R is_sIs aryl), cycloalkylsulfonamide (e.g. wherein R is_sIs cycloalkyl) and heterocyclylsulfonamido (e.g. wherein R is_sIs a heterocyclic group), etc.

The term "sulfonate group" as used herein refers to-OSO₃ ^-. Sulfonate groups include salts such as-OSO₃Na、-OSO₃K, et al and acid-OSO₃H。

The term "sulfonic acid group" means-SO₃H-and corresponding salts thereof, e.g. -SO₃K-、-SO₃Na--。

The term "sulfonyl" as used herein refers to the structure R_uSO₂-, wherein R_uThere may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl groups, for example alkylsulfonyl. The term "alkylsulfonyl" as used herein refers to an alkyl group attached to a sulfonyl group. "alkylsulfonyl" may optionally contain alkenyl or alkynyl groups.

The term "thioketo" refers to the structure-R_v-C(S)-R_w-. The keto group may be represented by R_vOr R_wTo another group. R_vOr R_wMay be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R_vOr R_wMay be joined to form a 3 to 12 membered ring.

"alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and "amido" may be substituted or interrupted or branched by at least one group selected from: alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, thio, sulfinyl, sulfonyl, sulfonic, sulfonamide, thioketo, ureido, and N. The substituents may be branched to form a substituted or unsubstituted heterocyclic or cycloalkyl group.

As used herein, "suitable substituents" refer to groups that do not negate the synthetic or pharmaceutical efficacy of the compounds of the present invention or the intermediates used to prepare them. Examples of suitable substituents include, but are not limited to: c_1-22、C_1-8And C_1-6Alkyl, alkenyl or alkynyl; c_1-6Aryl radical, C_2-5A heteroaryl group; c_3-7A cycloalkyl group; c_1-22、C_1-8And C_1-6An alkoxy group; c₆An aryloxy group; -CN; -OH; an oxo group; halo, carboxy; amino radicals, e.g. NH (C)_1-22、C_1-8Or C_1-6Alkyl), -N (C)_1-22、C_1-8And C_1-6Alkyl radical)₂、-NH((C₆) Aryl) or-N ((C)₆) Aryl radical)₂(ii) a A formyl group; keto group, e.g. -CO (C)_1-22、 C_1-8And C_1-6Alkyl), -CO ((C)₆Aryl) esters, e.g. -CO₂(C_1-22、C_1-8And C_1-6Alkyl) and-CO₂(C₆Aryl). Those skilled in the art can readily select suitable substituents based on the stability and pharmacological and synthetic activity of the compounds of the invention.

The term "pharmaceutically acceptable carrier" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents and the like, which are compatible with pharmaceutical administration. The use of such media and substances in pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

The term "pharmaceutically acceptable composition" as used herein refers to a composition comprising at least one compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable prodrug" as used herein denotes those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. Discussion is provided in Higuchi et al "prodrugs as New Delivery Systems" (Pro-drugs as Novel Delivery Systems, ACS discussing Congress, Vol.14) and "Bioreversible Cariers in Drug Design" edited by Roche, E.B. (Bioreversable Cariers in Drug Design, American pharmaceutical Association and Pergamon Press, 1987), both of which are incorporated herein by reference.

The term "pharmaceutically acceptable salt" refers to salts of acidic or basic groups that may be present in the compounds used in the present compositions. The compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfate, citrate, malate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate)). In addition to the acids mentioned above, the compounds included in the present compositions that include an amino moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts and especially calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and thus may exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. The term "stereoisomer" when used herein includes all geometric isomers, enantiomers or diastereomers. Depending on the configuration of the substituents around the stereogenic carbon atom, these compounds may be designated by the symbol "R" or "S". The present invention includes various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "(±)" according to nomenclature, but the skilled artisan will know that a structure may implicitly represent a chiral center.

The individual stereoisomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. Examples of such splitting methods are: (1) the mixture of enantiomers is linked to a chiral auxiliary, and the resulting mixture of diastereomers and the optically pure product liberated from the auxiliary are separated by recrystallization or chromatography, (2) salts are formed using optically active resolving agents, or (3) the mixture of optically active enantiomers is separated directly on a chiral chromatographic column. Stereoisomeric mixtures may also be resolved into their component stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of a compound as a chiral salt complex, or crystallization of a compound in a chiral solvent. Stereoisomers may also be obtained from stereoisomerically pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.

Geometric isomers may also be present in the compounds of the present invention. The present invention includes various geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbocyclic ring, and mixtures thereof. Substituents around a carbon-carbon double bond are designated as either the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with the IUPAC standard. Unless otherwise indicated, structures depicting double bonds include both the E and Z isomers.

Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" indicates that the substituent is on the same side of the double bond and "trans" indicates that the substituent is on the opposite side of the double bond. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans". The term "cis" denotes that the substituent is on the same side of the ring plane and the term "trans" denotes that the substituent is on the opposite side of the ring plane. Mixtures of compounds in which the substituents are arranged both on the same side and on opposite sides of the ring plane are designated as "cis/trans".

Embodiments of the invention

Disclosed herein are methods of increasing ApoA-I expression in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of formula II:

wherein:

x is selected from CR₁₁N and NR₁₁，

Y is selected from CO, CS and SO₂，

R₁and R₃Each independently selected from alkoxy (preferably methoxy), alkyl, ammoniaHalogen (preferably chlorine) and hydrogen;

R₁₀selected from hydrogen and alkyl (preferably methyl); or

for W- (R)₄)_pFor W is C, p is 1 and R₄Is H, or W is N and p is 0;

Another embodiment includes a method of increasing ApoA-I expression in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of formula II:

wherein:

x is selected from N and CH;

y is CO;

R₁and R₃Each independently selected from alkoxy and hydrogen;

R₂selected from alkoxy, alkyl and hydrogen;

R₅and R₉Each is hydrogen;

R₁₀is hydrogen; or

for W- (R)₁₀)_pW is N and p is 1;

for W- (R)₄)_pFor W is C, p is 1 and R₄Is H, or W is N and p is 0;

Z₁is a double bond, and Z₂And Z₃Each is a single bond;

with the following conditions: if R is₇Is amino, then X is N;

Specific exemplary embodiments encompassed by the present invention are listed below:

1. a method of increasing ApoA-I expression in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of formula II:

wherein:

x is selected from N and CH;

y is CO;

R₁and R₃Each independently selected from alkoxy and hydrogen;

R₂selected from alkoxy, alkyl and hydrogen;

R₅and R₉Each is hydrogen;

R₁₀is hydrogen; or

for W- (R)₁₀)_pW is N and p is 1;

for W- (R)₄)_pFor W is C, p is 1 and R₄Is H, or W is N and p is 0;

Z₁is a double bond, and Z₂And Z₃Each is a single bond;

with the following conditions: if R is₇Is amino, then X is N;

2. The method according to embodiment 1, wherein W- (R)₅)_pIs C- (R)₅)₁And R is₆And R₈At least one of which is selected from alkyl, alkoxy and chlorine.

3. The method according to embodiment 1, wherein R₆And R₈Each is hydrogen, and W- (R)₇)_pIs C- (R)₇)₁。

4. The method according to embodiment 1, wherein R₆、R₇And R₈Each of which is not hydrogen.

5. The method according to embodiment 1, wherein X is CH;

for W- (R)₁₀)_pIn general, W is N and R₁₀Is hydrogen;

y is CO;

R₁and R₃Each independently is an alkoxy group;

R₆and R₈Each independently is an alkyl group; and is

R₇Is a hydroxyl group.

6. The method according to embodiment 1, wherein X is N;

for W- (R)₁₀)_pIn general, W is N and R₁₀Is hydrogen;

y is CO;

R₁and R₃Each independently is an alkoxy group;

R₆and R₈Each independently is an alkyl group; and is

R₇Is alkoxy substituted by hydroxy.

7. The method according to embodiment 1, wherein R₇Not a diethylamino group or an alkoxy group substituted by a carboxylate group.

8. The method according to embodiment 1, wherein R₇Selected from hydroxyl and alkoxy.

9. A process according to embodiment 1 wherein the compound of formula II is 3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (example 1).

10. A process according to embodiment 1 wherein the compound of formula II is 7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6-naphthyridin-5 (6H) -one (example 6).

11. A process according to embodiment 1 wherein the compound of formula II is 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7).

12. The method according to embodiment 1, wherein the compound of formula II is selected from:

3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (example 1);

3- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (example 2);

3- (4-hydroxy-3, 5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) -one (example 3);

2- (4-hydroxy-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 4);

3- (4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (example 5);

7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6-naphthyridin-5 (6H) -one (example 6);

2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7);

3- (3, 5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (example 8);

2- (4-hydroxy-3-methoxyphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 9);

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 10);

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6, 7-dimethoxyquinazolin-4 (3H) -one (example 11);

2- (2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-yl) -6, 7-dimethoxyquinazolin-4 (3H) -one (example 12);

2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 13);

2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxypyrido [2, 3-d ] pyrimidin-4 (3H) -one (example 14);

2- (2-chloro-6-methylpyridin-4-yl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 15);

5, 7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinazolin-4 (3H) -one (example 16);

2- (4-amino-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 17);

n1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide (example 18);

2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 18); and

4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide (example 20).

13. The method according to embodiment 1, wherein R7 is amino or alkoxy selected from the group represented by formula III:

wherein:

a is selected from O and N;

n is selected from 0, 1, 2, 3, 4 and 5;

b is selected from-C (O) N (R)_h)₂-、-S(O)₂N(R_h)₂-、-C(O)-、-S(O)₂-, -C (O) O-, wherein R_hEach selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkylHaloalkyl, heteroaryl, heterocyclyl and hydrogen; and is

14. The method of embodiment 13 wherein the compound of formula II is selected from:

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (example 19);

n1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide (example 21);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (example 22);

4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide (example 23);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) methanesulfonamide (example 24);

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl propylcarbamate (example 25);

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl methylcarbamate (example 26);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methylbenzamide (example 27);

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl cyclohexylcarbamate (example 28);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide (example 29);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide (example 30);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzamide (example 31);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) acetamide (example 32);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzamide (example 33);

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) isobutyramide (example 34);

1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -3-methylurea (example 35);

1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea (example 36);

1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -3-phenylurea (example 37); and

3- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -1, 1-dimethylurea (example 38).

15. The method of embodiment 1 wherein a therapeutically effective amount of the compound of formula II is administered in a pharmaceutically acceptable composition with a pharmaceutically acceptable carrier.

16. The method of embodiment 1, further comprising treating or preventing a cardiovascular disorder, a cholesterol or lipid related disorder.

17. A compound of formula II:

wherein:

x is selected from N and CH;

y is CO;

R₁and R₃Each independently selected from alkoxy and hydrogen;

R₂selected from alkoxy, alkyl and hydrogen;

R₅and R₉Each is hydrogen;

R₁₀is hydrogen; or

for W- (R)₁₀)_pW is N and p is 1;

for W- (R)₄)_pFor W is C, p is 1 and R₄Is H, or W is N and p is 0;

Z₁is a double bond, and Z₂And Z₃Each is a single bond;

with the following conditions: if R is₇Is amino, then X is N;

with the following conditions: if for W- (R)₇)_pWith W being N and p being 0, then R₆And_Rat least one of 8 is chlorine.

18. A compound according to embodiment 17 wherein the compound is 3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (example 1).

19. A compound according to embodiment 17 wherein the compound is 7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6-naphthyridin-5 (6H) -one (example 6).

20. A compound according to embodiment 17 wherein the compound is 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (example 7).

21. A compound according to embodiment 17, wherein the compound of formula II is selected from:

22. A compound according to embodiment 17 wherein R₇Is an amino or alkoxy group selected from the group represented by formula III:

wherein:

a is selected from O and N;

n is selected from 0, 1, 2, 3, 4 and 5;

R₂₀Is selected from (C)₁-C₆) Alkane (I) and its preparation methodBase, (C)₁-C₆) Alkenyl, (C)₁-C₆) Alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen.

23. A compound according to embodiment 22, wherein the compound of formula II is selected from:

24. A pharmaceutical composition comprising a compound of embodiment 17 and a pharmaceutically acceptable carrier.

25. A method of treating cardiovascular disorders, cholesterol or lipid related disorders comprising administering a therapeutically effective amount of a compound of embodiment 17.

26. A method of increasing ApoA-I expression in a mammal comprising administering a therapeutically effective amount of a compound of embodiment 17.

27. A method of increasing ApoA-I expression in a mammal (e.g. a human) comprising administering a therapeutically effective amount of a compound selected from: 6, 8-dimethoxy-3- (4-hydroxy-3, 5-dimethylphenyl) -2H-1, 2-benzothiazine-1, 1-dioxide and 3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxy-7- (morpholinomethyl) isoquinolin-1 (2H) -one.

28. A compound selected from the group consisting of: 6, 8-dimethoxy-3- (4-hydroxy-3, 5-dimethylphenyl) -2H-1, 2-benzothiazine-1, 1-dioxide and 3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxy-7- (morpholinomethyl) isoquinolin-1 (2H) -one.

Pharmaceutical formulations and methods of treatment

The present disclosure also provides pharmaceutical compositions comprising a compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and the nature of the particular compound being used.

Formulations suitable for oral administration may be provided as: in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the compound as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable pharmaceutical process which includes the step of bringing into association the active compound with a carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient thereof. The carrier may be a solid or a liquid, or both, and may be formulated with the compound as a unit dose formulation, such as a tablet, which may contain from about 0.05% to about 95% by weight of the active compound. Other pharmacologically active substances, including other compounds, may also be present. The formulations of the present invention may be prepared by any of the well-known pharmaceutical techniques, essentially involving mixing the components.

For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. Pharmacologically administrable liquid compositions can be prepared, for example, by the following method: the active compounds as described herein and optional pharmaceutical adjuvants are dissolved, dispersed, etc. in excipients such as water, saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming a solution or suspension. In general, suitable formulations can be prepared by the following method: the active compound is mixed homogeneously and intimately with liquid carriers or finely divided solid carriers or both, and the product is then shaped if necessary. For example, a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or surfactant/dispersant. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.

Formulations suitable for buccal (sublingual) administration include: lozenges comprising the compound in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the compound in an inert base, such as gelatin and glycerin or sucrose and acacia.

Formulations of the invention suitable for parenteral administration include sterile aqueous formulations of the compounds which are approximately isotonic with the blood of the intended recipient. These formulations may be administered intravenously, although administration may also be achieved by subcutaneous, intramuscular or intradermal injection. Such formulations can be conveniently prepared by mixing the compound with water and allowing the resulting solution to be sterile and isotonic with blood. The injectable compositions of the invention may contain from about 0.1 to about 5% w/w of the active compound.

Formulations suitable for rectal administration are provided as unit dose suppositories. These formulations can be prepared by mixing the compound with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin may take the form of: an ointment, cream, lotion, paste, gel, spray, aerosol or oil. Carriers and excipients that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is typically present at a concentration of about 0.1% to about 15% w/w of the composition, for example about 0.5 to about 2%.

The amount of active compound administered may depend on the subject being treated, the weight of the subject, the mode of administration and the judgment of the prescribing physician. For example, a dosage regimen may comprise administering an approved dose (approved dose) of the encapsulated compound of about 1 μ g to about 1000mg daily or semi-daily. In another embodiment, intermittent administration, such as administration of a dose of the encapsulated compound on a monthly or yearly basis, may be employed. Encapsulation helps to reach the site of action and allows simultaneous administration of the active ingredients, theoretically resulting in a synergistic effect. In accordance with standard dosage regimens, the physician will readily determine the optimal dosage and will be able to readily modify the administration to obtain such dosages.

A therapeutically effective amount of a compound or composition disclosed herein can be determined by the therapeutic efficacy of the compound. However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated and the compound used. In one embodiment, a therapeutically effective amount of the disclosed compounds is sufficient to establish a maximum plasma concentration. Adjustment of the initial dose and the dose for human administration, as determined, for example, in accordance with animal testing, can be performed in accordance with art-accepted practice.

Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining LD₅₀(dose lethal to 50% of the population) and ED₅₀(a dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD₅₀/ED₅₀. Compositions that exhibit high therapeutic indices are preferred.

Data from cell culture assays or animal studies can be used to formulate a range of dosages for use in humans. Therapeutically effective doses obtained in one animal model can be transformed using art-known transformation factors for use in another animal, including humans (see, e.g., Freirich et al, Cancer Chemother. reports 50 (4): 219-244(1966) and Table 1 for equivalent surface area dose factors).

TABLE 1

The dosage of such compounds preferably includes ED₅₀And in a range of circulating concentrations with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. In general, the therapeutically effective amount will vary with the age, condition and sex of the subject and the severity of the medical condition of the subjectAnd (6) changing. The dosage can be determined by a physician and adjusted as necessary to suit the observed therapeutic effect.

In one embodiment, a compound as disclosed herein, or a pharmaceutically acceptable salt or hydrate thereof, is administered in combination with other therapeutic agents. Other therapeutic agents may provide additional or synergistic value relative to the administration of the compounds of the invention alone. The therapeutic agent may be, for example: statins (statins); PPAR agonists, such as thiazolidinediones or fibrates; a nicotinic acid, RVX, FXR or LXR agonist; a bile acid reuptake inhibitor; cholesterol absorption inhibitors; cholesterol synthesis inhibitors; an ion exchange resin; an antioxidant; an AcylCoA cholesterol acyltransferase inhibitor (ACAT inhibitor); tyrophostine; sulfonylurea-based drugs; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E modulator; HMG-CoA reductase inhibitors; a microsomal triglyceride transfer protein; a LDL-lowering agent; HDL-raising agents; an HDL enhancer; apolipoprotein a-IV and/or apolipoprotein gene modulators; or any cardiovascular agent.

In one embodiment, a method of treating or preventing a cardiovascular disease, cholesterol or lipid related disorder, comprises administering to a mammal (e.g., a human) a therapeutically effective amount of a disclosed compound. The disclosed compounds can be administered as a pharmaceutically acceptable composition comprising the disclosed compounds and a pharmaceutically acceptable carrier.

The term "cardiovascular disease" as used herein refers to diseases and disorders of the heart and circulatory system. Exemplary cardiovascular diseases, including cholesterol or lipid related disorders, include, but are not limited to, acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary artery disease, coronary plaque stabilization (coronary plaque stabilization), dyslipidemia, dyslipoproteinemia, endothelial dysfunction, familial hypercholesterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia reperfusion injury, ischemic heart disease, myocardial ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, cardiovascular disease, cerebrovascular disease, and cardiovascular disease, Reperfusion injury, restenosis, renal atherosclerosis, rheumatic heart disease, stroke, thrombotic disorders, transient ischemic attacks and lipoprotein abnormalities associated with alzheimer's disease, obesity, diabetes, syndrome X, impotence, multiple sclerosis, parkinson's disease and inflammatory diseases.

One embodiment provides a method of altering lipid metabolism in a patient, for example increasing the ratio of HDL to LDL or ApoA-I to ApoB in the blood of a patient, comprising administering to the patient a composition of the invention in an amount effective to alter lipid metabolism.

One embodiment provides a method of increasing the level of ApoA-I associated molecules, such as HDL, in the blood of a mammal, comprising administering to the mammal a composition comprising a disclosed compound or composition in an amount effective to increase the level of ApoA-I and HDL associated proteins in the mammal.

In one embodiment, "treating" or "treatment" refers to ameliorating the disease or disorder or at least one discernible symptom thereof. In another embodiment, "treating" or "treatment" refers to improving at least one measurable physical parameter, which is not necessarily discernible by the patient. In another embodiment, "treating" or "treatment" refers to inhibiting the development of the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both physically and physiologically. In another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder. For example, treating a cholesterol disorder may include lowering blood cholesterol levels.

One embodiment provides compounds for administration to a patient, such as a human, as a prophylactic measure against cardiovascular disease, including cholesterol or lipid related disorders. As used herein, "preventing" refers to reducing the risk of acquiring a given disease or disorder. Additional aspects provide methods of preventing the development of atherosclerotic lesions, including the development of new atherosclerotic lesions, in a mammal. In another aspect, the invention provides a method of reducing arteriosclerotic lesions.

In another embodiment, the present composition is administered as a prophylactic measure to a patient, such as a human, having a genetic predisposition to: cardiovascular diseases, including cholesterol-or lipid-related disorders, such as familial hypercholesterolemia, familial combined hyperlipidemia, atherosclerosis, dyslipidemia, dyslipoproteinemia, or Alzheimer's disease.

In another embodiment, the compositions of the present invention are administered as a prophylactic measure to a patient having a non-genetic predisposition to cardiovascular disease, including cholesterol-or lipid-related disorders. Examples of such non-genetic predisposition include, but are not limited to, cardiac bypass surgery and percutaneous transluminal coronary angioplasty, which often lead to restenosis-an accelerated form of atherosclerosis; female diabetes, which often leads to polycystic ovarian disease; and cardiovascular disease that often leads to impotence.

Angioplasty and open heart surgery such as coronary artery bypass surgery may be required to treat cardiovascular disease such as atherosclerosis. These surgical procedures require the use of invasive surgical devices and/or implants and are associated with a high risk of restenosis and thrombosis. Thus, the compounds of the present invention may be used as coatings on surgical devices (e.g., catheters) and implants (e.g., stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used in the treatment of cardiovascular diseases.

In another embodiment, the present compositions can be used to prevent one disease or disorder while treating another (e.g., preventing polycystic ovarian disease while treating diabetes; preventing impotence while treating cardiovascular disease).

Diseases and conditions associated with "diabetes" as defined herein refer to chronic metabolic disorders caused by absolute or relative insulin deficiency, including, but not limited to, hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, skin and connective tissue disorders, foot ulceration, metabolic acidosis, arthritis, osteoporosis, and impaired glucose tolerance.

Preparation of the Compounds

Exemplary compounds of the invention represented by formula a can be synthesized from readily available starting materials according to the methods outlined in the exemplary schemes below:

wherein:

R_amay be selected from the group including, but not limited to: alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ether, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, and hydroxyl; r_bMay be selected from the group including, but not limited to, alkyl and hydrogen; x may be selected from, for example, CR_cN and NR_cWherein R is_cRepresents a substituent such as alkyl, alkenyl, alkynyl and hydrogen; y may be selected from, for example, CO, CS and SO₂(ii) a And Z is₃May be a single bond or a double bond. It should be understood that these names are non-limiting examples.

Scheme 1 descriptionThe condensation of amide 1 and aldehyde 2 followed by oxidation can provide quinazolinone 3. The condensation can be carried out under a variety of conditions, for example NaHSO₃And p-TsOH and in dimethylacetamide, I₂And at K₂CO₃And treated with catalytic trifluoroacetic acid followed by oxidation of DDQ.

Condensation of amide 4 with nitrile 5 in the presence of n-BuLi can afford isoquinolinone 6, as shown in scheme 2.

Scheme 3 provides a method for synthesizing benzothiazine-1, 1-dioxide 9. Amide coupling of sulfonamide 7 with carboxylic acid 8 followed by treatment with n-BuLi affords 9.

Examples

Abbreviations used herein refer to the following compounds, reagents and substituents: acetic acid (AcOH); 2, 2' -Azobisisobutyronitrile (AIBN); n-bromosuccinimide (NBS); n-tert-butoxycarbonyl (Boc); tert-butyldimethylsilyl (TBDMS); m-chloroperbenzoic acid (mCPBA); dimethylaminopyridine (DMAP); dichloromethane (DCM); dimethylformamide (DMF); dimethyl sulfoxide (DMSO); ethanol (EtOH); ethyl acetate (EtOAc); 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI); 1-hydroxybenzotriazole (HOBt); methyl iodide (MeI); lithium Hexamethyldisilazide (LHMDS); methanol (MeOH); methoxymethyl (MOM); tetrahydrofuran (THF); triethylamine (Et)₃N); lithium Aluminum Hydride (LAH); p-toluenesulfonic acid (p-TSA); tetrabutylammonium fluoride (TBAF); n-methylmorpholine (NMM); n, N-Dimethylacetamide (DMA)) (ii) a Twice daily (BID), once daily (QD).

Example 1

3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one

To 2-methyl-4, 6-dimethoxybenzoic acid (2.61g, 13.1mmol) in CH₂Cl₂To the suspension (50mL) was added oxalyl chloride (3.38g, 26.6mmol) and the mixture was stirred at room temperature for 16 h. The solvent and excess oxalyl chloride were removed under reduced pressure. Dissolve the solid in CH with cooling₂Cl₂(10mL) and methylamine (1.24g, 39.9mmol), stirred at room temperature for 4 hours. Removing the solvent, subjecting the crude product to chromatography on CH₂Cl₂Purification was performed with 5% methanol to give the amide (2.27g, 82%). To a solution of the above amide (2.27g, 10.9mmol) in THF (50mL) under nitrogen under cooling was slowly added n-butyllithium (9.98mL, 25.0mmol, 2.5M solution in hexane) while keeping the temperature below 20 ℃. The mixture was stirred at 0 ℃ for 1 hour, then cooled to-50 ℃, a solution of 4-O-TBDMS-3, 5-dimethylbenzonitrile (2.97g, 11.39mmol) in THF (10mL) was added quickly, the cooling bath was removed, and the mixture was stirred at rt for 16 hours. Adding saturated NH under cooling₄And (4) Cl aqueous solution, and separating layers. The organic layer was washed with water, brine, and then washed with Na₂SO₄Drying and concentration gave 3.9g of crude product mixture. A suspension of the crude product mixture (3.9g) in ethanol (20mL) was heated with concentrated HCl (2mL) at 80 ℃ for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed. The solid was dissolved in water and NaHCO was used₃Neutralizing with CH₂Cl₂And (4) extracting. The product was purified by chromatography to give two products:3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxy-2-methylisoquinolin-1 (2H) -one (128mg, 5%) and 3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (340mg, 9%). Selected data for 3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one: MS (ES) m/z: 326.00, respectively; MP 226-.

Example 2

3- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one

To a solution of 3, 5-dimethyl-4-hydroxybenzonitrile (1.0g, 6.79mmol) in DMF (100mL) were added NaH (1.065g, 26.63mmol) and (2-bromoethoxy) -tert-butyldimethylsilane (1.95g, 8.15 mmol). The reaction mixture was stirred at room temperature under nitrogen for 10 days. The reaction mixture was poured into ice-water and the product was extracted with ethyl acetate. The organic layer was separated, washed with water, dried, and concentrated to give a crude product, which was purified by column chromatography to give 1.9g of a 92% yield of B-ring structural unit.

N-butyllithium (2.84mL, 7.1mmol, 2.5M solution in hexanes) was slowly added to a solution of 2, 4-dimethoxy-6-methylbenzamide (650mg, 3.1mmol) in THF (30mL) under nitrogen, with cooling (ice-salt bath), while maintaining the temperature below 20 ℃. After the addition was complete, the mixture was stirred at 0 ℃ for 1 hour, then cooled to-50 ℃ and a solution of 4- (2-tert-butyldimethylsilyloxy) ethoxy) -3, 5-dimethylbenzonitrile (above B-ring structure unit) (996mg, 3.26mmol) in THF (10mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. Adding saturated NH under cooling₄Cl solution, and layering. The organic layer was washed with water, brine, and then washed with Na₂SO₄Drying and concentration gave 1.2g of crude product.

The above crude product (1.2g) was treated with ethanol (10mL) and concentrated HCl (2mL) for 1 hour at 80 ℃. The solvent was removed, the residue was dissolved in methanol and NaHCO was used₃And (4) neutralizing. The solvent was evaporated and the crude product was purified by column chromatography to give 3- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (100mg, 11%). The selected data: MP 193 and 195 ℃.

Example 3

3- (4-hydroxy-3, 5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) -one

Hydrogen bromide in acetic acid (13mL, 33 wt%) was added to a mixture of 2-methylbenzoic acid (4.08g, 30mmol), paraformaldehyde (2.50g, 83.0mmol) and orthophosphoric acid (7mL, 85%). The reaction mixture was stirred at 115 ℃ for 15 hours. It was cooled to room temperature and poured into ice-cold water. A white precipitate formed. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100mL), brine (100mL) and passed over anhydrous Na₂SO₄And (5) drying. The solvent was removed to give 6.84g of a white solid, which was used in the next step without further purification. The above compound (6.8g) was dissolved in anhydrous dichloromethane (150 mL). Oxalyl chloride (7.8mL) was added dropwise. After the addition was complete, 3 drops of anhydrous DMF were added. Vigorous reaction occurred and stirring was continued overnight. The solvent and excess oxalyl chloride were removed under reduced pressure and the residue was dried under vacuum to give 7.02g of a brown liquid which was used in the next step without further purification. The above compound (7.02g, 28.36mmol) was dissolved in anhydrous THF (60mL)And cooling to 0 ℃. A solution of N-methylamine (2.0M in THF, 19mL, 38.03mmol) was added dropwise under nitrogen. Stirring was continued for 15 minutes at 0 ℃. The ice bath was removed and stirring was continued at room temperature for 3 hours. A white precipitate formed. Water (100mL) was added and the mixture was extracted with ethyl acetate (150 mL). The organic layer was separated and washed with water (50mL), saturated NaHCO₃The solution (2X 50mL), water (50mL) and brine (50mL) were washed over anhydrous Na₂SO₄And (5) drying. The solvent was removed to give 5.64g of 5-bromomethyl-2, N-dimethylbenzamide as a white solid, which was used in the next step without further purification. To a solution of the above compound (2.42g, 10mmol) in anhydrous THF at room temperature under nitrogen was added morpholine (1.92g, 22 mmol). A white precipitate formed. Stirring was continued overnight. Water (100mL) was added and the mixture was extracted with ethyl acetate (150 mL). The organic layer was separated, washed with water (50mL) and brine (50mL), and dried (Na)₂SO₄). The solvent was removed to give a colorless oil which was purified by column chromatography (silica gel 230-₂Cl₂0-5% methanol as eluent) to give the desired benzamide intermediate (yield 0.50g, 20%). N-butyllithium (1.6M solution in hexane, 4.1mL, 6.6mmol) was added dropwise to a solution of benzamide (0.5g, 2.0mmol) in anhydrous THF (4mL) under nitrogen at-10 ℃ over 10 minutes. Stirring was continued for 1 hour at 0 ℃. The reaction mixture was cooled to-50 ℃. A solution of 4- (tert-butyldimethylsilyloxy) -3, 5-dimethylbenzonitrile (0.653g, 2.5mmol) in dry THF (3mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued at room temperature for 1 hour. Aqueous ammonium chloride (5mL) was added followed by ethyl acetate (50 mL). The organic layer was separated, washed with water (5mL) and dried (Na)₂SO₄). The solvent was removed to give 1.23g of a pale yellow gummy material which was used in the next step without further purification. The above compound (1.2g) was dissolved in 10mL of anhydrous ethanol. Concentrated HCl (1mL) was added and the mixture was refluxed for 15 minutes and then cooled to room temperature. The solvent was removed under reduced pressure. The crude compound was basified with methanolic ammonia (methanolic ammonia) and purified by column chromatography (silica gel 230-In CH₂Cl₂0-5% methanol as eluent) to give 3- (4-hydroxy-3, 5-dimethylphenyl) -7-morpholin-4-ylmethyl-2H-isoquinolin-1-one (35mg) as a white solid (free base). To the above compound (35mg) in CH under nitrogen₂Cl₂To a solution in (5mL) and MeOH (1mL) was added hydrogen chloride in ether (0.5mL, 1.0M) dropwise. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and dried under vacuum to give the hydrochloride salt of 3- (4-hydroxy-3, 5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) -one (36mg, 93%) as a yellow solid. The selected data: MP 281 + 283 ℃ (hydrochloride).

Example 4

2- (4-hydroxy-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one

A solution of 3, 5-dimethoxyaniline (199g, 1.30mol) in diethyl ether (5.0L) was cooled to 0 ℃ in a 5L 3 neck flask. HCl gas (227g) was bubbled into the solution over 45 minutes. After 45 minutes at 10 ℃, the mixture was filtered, washed with isopropyl acetate (4L) and dried under high vacuum at 45 ℃ overnight to give the hydrochloride salt as a white solid (242.3g, 98%). A mixture of the above hydrochloride salt (20g, 0.105mol) and oxalyl chloride (33mL) was heated with stirring in a 3-neck flask equipped with a reflux condenser for 2 hours (170 ℃ external temperature) to distill oxalyl chloride from the reaction mixture. The flask was cooled to 0 ℃ and methanol (40mL) was added. The reaction mixture was heated under reflux for 45 minutes, filtered while hot and washed with methanol (80mL) to give 4, 6-dimethoxyisatin (17.2g, 79%) as a yellow-green solid. To a heated solution (external temperature 70 ℃) of isatin (162g, 0.78mol) in aqueous NaOH (40%, 1.5L) was slowly added H over 2 hours₂O₂(35%, 405 mL). Adding each batch of H₂O₂After that, the internal reaction temperature (initially 64 ℃) was raised (to a maximum temperature of 80 ℃). After the addition was complete, the foamed reaction mixture was then stirred at 70 ℃ for an additional 2 hours and the mixture was stirred overnight while cooling to room temperature. The mixture was heated to 70 ℃. Addition of additional H₂O₂(75mL), the mixture was stirred at 70 ℃ for an additional 2 hours until the reaction was complete. Cooling to 10 deg.C (bath temperature), adding Na₂S₂O₃Aqueous solution (150mL, saturated). The mixture was adjusted to pH8 with HCl (37%, 1.6L) and to pH6 with acetic acid (glacial acetic acid, 75mL) without allowing the reaction mixture to warm more than 40 ℃. The reaction mixture was filtered and washed with water (4L) to give the desired amino acid as a tan solid (83.7g, 55%). To a solution of the amino acid (82.7g, 0.42mol) in anhydrous THF (4.2L) were added EDCl (89.2g, 0.48mol), HOBT (65g, 0.48mol) and NMM (51.3mL), and the mixture was stirred at room temperature for 3 hours. Addition of NH₃Aqueous solution (83mL, 50%) the mixture was stirred at room temperature for 16 h. Water (1.25L) was added and the mixture was extracted with DCM (2X 250 mL). The combined extracts were then washed with water (2X 500 mL). Concentration, slurried with ether (550mL), filtered, and dried under high vacuum to give 2-amino-4, 6-dimethoxybenzamide (46.7g, 57%) as a brown solid.

2-amino-4, 6-dimethoxy-benzamide (1.06g, 5.4mmol), 3, 5-dimethyl-4-hydroxybenzaldehyde (0.810g, 5.4mmol), K₂CO₃(0.747g, 5.4mmol) and I₂(1.645g, 6.5mmol) were combined in DMF (20mL) and the reaction mixture was heated at 80 ℃ for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2- (4-hydroxy-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one as a white solid (0.9g, 51%). The selected data: MP 291-293 ℃.

Example 5

3- (4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one

To a solution of 4-hydroxy-3, 5-dimethylbenzonitrile (2.00g, 13.5mmol) and 1-chloro-2-methylpropan-2-ol (8.85g, 81.5mmol) in ethanol (50mL) were added potassium carbonate (7.5g, 54mmol) and water (5 mL). The reaction mixture was stirred at reflux for 24 hours and cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100mL), washed with water (50mL), brine (50mL), and passed over anhydrous Na₂SO₄And (5) drying. The solvent was removed to give 4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylbenzonitrile (2.9g, 97%) as a white solid.

To a solution of 4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylbenzonitrile (2.90g, 13.2mmol) in anhydrous DMF (20mL) was added imidazole (2.7g, 40mmol) and tert-butyldimethylsilyl chloride (2.19g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 days. Water (200mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2X 100mL) and brine (100mL) and passed over anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4- [2- (tert-butyldimethylsilyloxy) -2-methylpropyloxy)]3, 5-dimethylbenzonitrile (2.24g, 54%). N-butyllithium (6.2mL, 6.6mmol, 1.6M solution in hexanes) was added dropwise to a solution of 2, 4-dimethoxy-6-N-dimethylbenzamide (0.9g, 4.3mmol) in anhydrous THF (10mL) at-10 ℃ over 10 minutes under nitrogen. Stirring was continued for 1 hour at 0 ℃. The reaction mixture was cooled to-50 ℃. Rapid addition of 4- [2- (tert-butyldimethylsilyloxy) -2-methylpropoxy]-a solution of 3, 5-dimethylbenzonitrile (1.58g, 4.73mmol) in dry THF (5 mL). Removing the cooling bath to mix the reactionThe mixture was warmed to room temperature. Stirring was continued at room temperature for 1 hour. Aqueous ammonium chloride (10mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10mL) and dried (Na)₂SO₄). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-₂Cl₂0-5% methanol as eluent) to give 3- {4- [2- (tert-butyldimethylsilyloxy) -2-methylpropyloxy ] ethyl acetate as a white solid]-3, 5-dimethylphenyl } -6, 8-dimethoxy-2H-isoquinolin-1-one (0.82g, 37%).

The above compound (0.42g, 0.82mmol) was dissolved in anhydrous THF (20 mL). Tetrabutylammonium fluoride (4.1mL of a 1.0M solution in THF) was added at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 10 minutes, then at room temperature for 2 hours, then at 70 ℃ for 24 hours. The mixture was cooled to room temperature. Saturated aqueous ammonium chloride (30mL) was added. The organic layer was separated, washed with water, brine and passed over anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel 230-₂Cl₂0-4% methanol as eluent) to give 3- (4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one as a white solid (0.15-g, 46%). The selected data: MS (ES) m/z: 397.98, respectively; MP 252 and 254 ℃ for decomposition.

Example 6

7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6-naphthyridin-5 (6H) -one

A mixture of malonic acid (20g, 192mmol), 2, 4, 6-trichlorophenol (72g, 365mmol) and phosphorus oxychloride (38mL, 403.2mmol) was addedStirred at reflux for 12 hours. The reaction mixture was cooled to 70 ℃ and poured into ice water. The solid was collected by filtration, washed with water and dried to give bis- (2, 4, 6-trichloro-phenyl) malonate (85g, 95%). A solution of bis- (2, 4, 6-trichloro-phenyl) malonate (85g, 184mmol) and ethyl 3-aminocrotonate (26.08g, 201.9mmol) in bromobenzene (100mL) was stirred at reflux for 50 minutes. The reaction mixture was cooled to 50 ℃ and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water and dried to give ethyl 4, 6-dihydroxy-2-methylnicotinate (31g, 86%). A solution of ethyl 4, 6-dihydroxy-2-methylnicotinate (31g, 157mmol) in phosphorus oxychloride (60mL, 629mmol) was stirred at reflux for 1.5 hours. Excess phosphorus oxychloride was removed and the reaction mixture was poured into ice water. The solids were removed by filtration. The filtrate was extracted with dichloromethane (3X 100mL) and concentrated. The residue was further purified by column chromatography to give ethyl 4, 6-dichloro-2-methylnicotinate (16.9g, 46%). A solution of ethyl 4, 6-dichloro-2-methylnicotinate (16.9g, 71.3mmol) in MeOH (60mL) was combined with sodium methoxide (58mL, 256.68mmol) and stirred at reflux for 12 h. The reaction was quenched by the addition of HOAc (50 mL). The mixture was diluted with water (200mL), extracted with dichloromethane (3X 100mL) and concentrated. The residue was purified by column chromatography (SiO)₂hexane/EtOAc 6: 1) to give methyl 4, 6-dimethoxy-2-methylnicotinate (10g, 67%). A solution of methyl 4, 6-dimethoxy-2-methylnicotinate (2.6g, 12.3mmol), lithium hydroxide (1.06g, 44.08mmol) in water (40mL), MeOH (30mL), and THF (20mL) was stirred at reflux for 4 h. The reaction mixture was concentrated to dryness. The residue was combined with HCl (conc., 20mL) and concentrated again to dryness under high vacuum to give crude 4, 6-dimethoxy-2-methylnicotinic acid (quantitative yield). To a solution of 4, 6-dimethoxy-2-methylnicotinic acid (2.5g, 12.0mmol) in dichloromethane (50mL) and THF (50mL) at room temperature was added oxalyl chloride (2.57mL, 29.4mmol) and DMF (3 drops). The reaction mixture was stirred at room temperature for 0.5 h and concentrated to dryness using a rotary evaporator to give crude 4, 6-dimethoxy-2-methylnicotinoyl chloride HCl salt (2.8g, quant.). 4, 6-dimethoxy-2-methylnicotinoyl chloride HCl salt (4.8g, 23.5 mm) was added at room temperatureol) solution in dichloromethane (100mL) was poured into a beaker of ammonium hydroxide (200 mL). The reaction mixture was stirred at room temperature for 1 hour, extracted with dichloromethane (3 × 100mL) and concentrated using a rotary evaporator to give 4, 6-dimethoxy-2-methyl-nicotinamide (2.4g, 52%) as a pale yellow solid. A solution of 4-hydroxy-3, 5-dimethylbenzonitrile (2.00g, 13.59mmol) in DMF (20mL) was mixed with sodium hydride (0.706g, 17.6mmol) at room temperature and stirred for 0.5 h. Benzyl bromide (1.62mL, 13.59mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by addition of water (200mL), extracted with EtOAc (3X 100mL) and concentrated. The residue was purified by column chromatography to give 4-benzyloxy-3, 5-dimethylbenzonitrile (3.25g, 100%) as a white solid. To a solution of 4, 6-dimethoxy-2-methyl-nicotinamide (1g, 5.1mmol) in THF (120mL) at-20 deg.C was added n-BuLi (9.6mL, 15.3 mmol). The reaction was stirred at-20-0 ℃ for 2.5 hours and then cooled to-78 ℃. 4-benzyloxy-3, 5-dimethylbenzonitrile (1.21g, 5.1mmol) was added, the cooling bath was removed, and the reaction was allowed to gradually warm to room temperature. After stirring at room temperature for 20 h, the reaction was quenched by addition of water (100mL), extracted with dichloromethane (3X 100mL) and concentrated using a rotary evaporator. The residue was passed through a column (SiO)₂Hexane/EtOAc/MeOH ═ 3: 2: 1) to give 7- (4-benzyloxy-3, 5-dimethyl-phenyl) -2, 4-dimethoxy- [1, 6]Naphthyridin-5-ylamine (0.4g, 19%) and 7- (4-benzyloxy-3, 5-dimethyl-phenyl) -2, 4-dimethoxy-6H- [1, 6%]Naphthyridin-5-one (0.34g, 16%). Reacting 7- (4-benzyloxy-3, 5-dimethyl-phenyl) -2, 4-dimethoxy-6H- [1, 6]A solution of naphthyridin-5-one (0.34g, 0.82mmol) in DMF (100mL) and MeOH (100mL) was combined with palladium on carbon (0.1g) and hydrogenated (50psi) for 2 h. The mixture was filtered through a pad of Celite. Concentrating the filtrate under high vacuum to obtain 7- (4-hydroxy-3, 5-dimethyl-phenyl) -2, 4-dimethoxy-6H- [1, 6]Naphthyridin-5-one (0.23g, 88%). Reacting 7- (4-hydroxy-3, 5-dimethyl-phenyl) -2, 4-dimethoxy-6H- [1, 6]A solution of naphthyridin-5-one (0.23g, 0.7mmol) in MeOH (20mL) and DCM (20mL) was combined with HCl in ether (7mL, 7mmol) and stirred for 0.5 h. The reaction was concentrated using a rotary evaporator to give a solid residue. Mixing the solidWashed with DCM, collected by filtration and washed with DCM to give 7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6-naphthyridin-5 (6H) -one (0.15g, 59%) as the HCl salt as a pale yellow solid. The selected data: MS (ES) m/z: 327.06, respectively; MP > 324 ℃ and decomposes (HCl salt).

Example 7

2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one

2-amino-4, 6-dimethoxybenzamide (0.60g, 3.06mmol) and 4- [2- (tert-butyldimethylsilyloxy) ethoxy were reacted at 70 deg.C]A solution of (E) -3, 5-dimethylbenzaldehyde (0.856g, 2.78mmol) in N, N-dimethylformamide (20mL) was stirred for 1 hour. Iodine (0.846g, 3.33mmol) and potassium carbonate (0.384g, 2.78mmol) were added and the reaction mixture was stirred at 70 ℃ for 16 h. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with water, brine, and then over anhydrous Na₂SO₄And (5) drying. The solvent was removed to give a crude product which was purified by column chromatography to give 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one as a white solid (444mg, 39%). The selected data: 229 ℃ and 231 ℃.

Alternatively, 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one may be synthesized by the following method. 3, 5-dimethyl-4-hydroxybenzaldehyde (26.9g, 0.179mol) in ethanol (350mL) was placed in a 2L dry round bottom flask with reflux condenser and magnetic stirrer. 2-chloroethanol (87.6g, 1.074mol) and K were added₂CO₃(99g, 0.716mol), the reaction mixture was heated to reflux for 24 hours. Cooling the reaction mixture toAnd (4) filtering at room temperature. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine and over Na₂SO₄And (5) drying. After removal of the solvent 45g of crude product are obtained. The crude product was purified by column chromatography (silica gel 230-. To a solution of 2-amino-4, 6-dimethoxy-benzamide (33.45g, 0.170mol) and 4- (2-hydroxyethoxy) -3, 5-dimethylbenzaldehyde (33.3g, 0.170mol) in N, N-dimethylacetamide (300mL) was added NaHSO₃(33.3g, 0.187mol) and p-TSA (3.2g, 17.1mmol), and the reaction mixture was heated at 150 ℃ for 14 hours. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred at room temperature for 30 minutes. The isolated solid was filtered and dried to give the crude product. The crude product was purified by column chromatography (silica gel 230-₂Cl₂5% methanol as eluent) to give 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (33g, 52%).

Example 8

3- (3, 5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6, 8-dimethoxyisoquinoline

-1(2H) -one

The compound 3- [4- (2-chloro-ethoxy) -3, 5-dimethyl-phenyl]-6, 8-dimethoxy-isochromen-1-one (298mg, 0.767mmol) was dissolved in DMSO (5mL), N-methylpiperazine (388mg, 3.83mmol) and Et were added₃N (392mg, 3.83 mmol). The reaction mixture was heated at 110 ℃ for 16 hours, and thenAnd cooling to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated in vacuo leaving a residue which was purified by column chromatography. Yield 60mg (17%). The compound 3- [3, 5-dimethyl-4- (2- (4-methylpiperazin-1-yl-ethoxy) -phenyl) -6, 8-dimethoxy-isochromen-1-one (60mg, 0.13mmol) and NH were added₃(2.0M solution in ethanol, 20mL) were mixed in a steel cylinder and heated at 130 ℃ for 16 hours. The solvent was removed and the crude compound was purified by column chromatography. The compound was then converted to the hydrochloride salt of 3- (3, 5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one (40mg, 62%) as an off-white solid. The selected data: MS (ES) m/z: 452.1; MP 195-.

Example 9

2- (4-hydroxy-3-methoxyphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one

2- (4-hydroxy-3-methoxyphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4, 6-dimethoxybenzamide and 4-hydroxy-3-methoxybenzaldehyde using the method described for 5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4-hydroxy-3-methoxyphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one was isolated as a white solid (90mg, 36%). The selected data: MS (m/z): 329.06, respectively; MP 294-.

Example 10

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4, 6-dimethoxybenzamide and 4- [ bis- (2-hydroxy-ethyl) -amino ] -benzaldehyde using the method described for 5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5, 7-dimethoxy-quinazolin-4 (3H) -one (120mg, 41%) was isolated as a yellow solid. The selected data: MS (m/z): 386.15, respectively; MP 249-251 ℃.

Example 11

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6, 7-dimethoxyquinazolin-4 (3H) -one

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6, 7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4, 5-dimethoxy-benzamide and 4- (N, N-bis (2-hydroxyethyl) amino) benzaldehyde using the method described for 5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6, 7-dimethoxyquinazolin-4 (3H) -one (72mg, 24%) was isolated as a yellow solid. The selected data: MS (m/z): 386.15, respectively; MP 268 and 270 ℃.

Example 12

2- (2, 3-dihydrobenzo [ b ]][1，4]Dioxine-6-yl) -6, 7-dimethoxyquinazolin-4 (3H) -one

2- (2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-yl) -6, 7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4, 5-dimethoxybenzamide and 2, 3-dihydro-benzo [1, 4] dioxin-6-carbaldehyde using the method described for 5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-yl) -6, 7-dimethoxy-quinazolin-4 (3H) -one was isolated as a pale yellow solid (180mg, 69%). The selected data: MS (m/z): 341.03, respectively; MP 316.4-318.2 ℃.

Example 13

2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one

To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0g, 16.46mmol) in THF (30mL) was added N-ethylpiperazine (3.76g, 32.92mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and over Na₂SO₄And (5) drying. The solvent was removed to give 4.61g of crude 4- (4-ethylpiperazin-1-ylmethyl) -benzoic acid ethyl ester (100% yield). LAH (0.792g, 20.86mmol) was added to a dry 3-neck flask and THF (60mL) was added with cooling. A solution of 4- (4-ethylpiperazin-1-ylmethyl) -benzoic acid ethyl ester (4.61g, 16.69mmol) in THF (10mL) was added slowly with cooling. After the addition was complete, the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to 0 ℃, 10% NaOH solution was added, and then water was added. Is divided intoThe organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and over Na₂SO₄And (5) drying. The solvent was removed to give 2.78g of crude (4- (4-ethylpiperazin-1-ylmethyl) phenyl) -methanol in 78% yield. To a solution containing anhydrous CH cooled to-78 deg.C₂Cl₂A3-neck flask (100mL) was charged with oxalyl chloride (1.8g, 14.25mmol) and DMSO (1.85g, 23.76mmol), and the mixture was stirred at-78 deg.C for 15 min. (4- (4-ethylpiperazin-1-ylmethyl) phenyl) -methanol (2.78g, 11.88mmol) in CH was added at-78 deg.C₂Cl₂The solution in (10mL) was stirred at-78 ℃ for 1 hour. Et was then added at-78 deg.C₃N (4.8g, 47.52 mmol). The reaction mixture was allowed to reach room temperature. Water was added and the organic layer was separated. The aqueous layer is replaced by CH₂Cl₂And (4) extracting. The combined organic layers were washed with water, brine and over Na₂SO₄And (5) drying. Then, the solvent was removed to give crude 4- (4-ethylpiperazin-1-ylmethyl) benzaldehyde (2.5g, 91%).

To a solution of 2-amino-4, 6-dimethoxy-benzamide (150mg, 0.76mmol) and 4- (4-ethylpiperazin-1-ylmethyl) benzaldehyde (177mg, 0.76mmol) in N, N-dimethylacetamide (10mL) was added NaHSO₃(150mg, 0.84mmol) and p-TSA (319mg, 1.68mmol), and the reaction mixture was heated at 150 ℃ for 5 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was washed with NaHCO₃And (4) neutralizing. The solvent was removed under reduced pressure to give a crude product which was purified by column chromatography to give 2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) -5, 7-dimethoxy-quinazolin-4 (3H) -one (87mg, 27%) which was converted to the hydrochloride salt. The selected data: MS (ES) m/z: 409.11, respectively; MP 278 and 280 deg.C (decomposition).

Example 14

2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxypyrido [2, 3-d]Pyrimidines

-4(3H) -one

To 2-amino-4, 6-dimethoxy-nicotinamide (1.07g, 5.42mmol) and 4- [2- (tert-butyldimethylsilyloxy) ethoxy]To a solution of (1.67g, 5.42mmol) of (E) -3, 5-dimethylbenzaldehyde in N, N-dimethylacetamide (25mL) was added NaHSO₃(1.06g, 5.97mmol) and p-TSA (1.14g, 5.97mmol), the reaction mixture was heated at 150 ℃ for 16 h, cooled to room temperature and poured into water. The solid was collected to yield 3.25g of crude product. TBAF (3.5g, 13.4mmol) was added to a solution of the crude product (3.25g, 6.70mmol) in THF (50mL) at 0 deg.C and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and over Na₂SO₄And (5) drying. The solvent was removed and the crude product was purified by column chromatography (silica gel 230-400 mesh; applied on CH)₂Cl₂2% methanol as eluent) to give 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxypyrido [2, 3-d)]Pyrimidin-4 (3H) -one (132mg, 6%). The selected data: MS (ES) m/z: 371.99, respectively; MP255-256 ℃.

Example 15

2- (2-chloro-6-methylpyridin-4-yl) -5, 7-dimethoxyquinazolin-4 (3H) -one

2-amino-4, 6-dimethyl-4 (3H) -one from 5, 7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinazolin-4 (3H) -one according to the method describedOxybenzamide and 2-chloro-6-methylisonicotyl chloride synthesized 2- (2-chloro-6-methylpyridin-4-yl) -5, 7-dimethoxyquinazolin-4 (3H) -one as a white solid in 75% yield. The selected data:¹H NMR(300MHz，CDCl₃)δ10.95(s，1H)，7.90(s，2H)，6.74(d，J＝2.33Hz，1H)，6.51(d，J＝2.32Hz，1H)，3.88(s，3H)，3.86(s，3H)，2.29(s，3H)；MS(APCI)m/z 332[M+H]⁺。

example 16

5, 7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinazolin-4 (3H) -one

To 4-methoxy-3, 5-dimethylbenzoic acid (0.100g, 0.555mmol) in CH cooled to 0-5 deg.C₂Cl₂To a solution in (2.77mL) was added oxalyl chloride (67.8. mu.L, 0.777mmol), followed by dropwise addition of DMF (4.3. mu.L, 0.056 mmol). The mixture was stirred for 50 minutes, the volatiles were removed under vacuum and the crude acid chloride was used immediately without further purification.

To a mixture of 2-amino-4, 6-dimethoxybenzamide (0.0990g, 0.555mmol) and pyridine (44.9 μ L, 0.555mmol) in THF (2.02mL) was added dropwise a solution of the acid chloride (crude residue above) in THF (925 μ L). After 16 h, the mixture was diluted with EtOAc (300mL) and saturated NH₄Aqueous Cl (3X 75mL), saturated NaHCO₃Aqueous (3X 75mL) and brine (75 mL). The insoluble yellow solid was isolated by filtration to give the amide (0.150g, 83%). A mixture of amide (0.148g, 0.413mmol) and 2M NaOH (7.00mL) was heated at 85 ℃ for 19 hours, cooled to 5 ℃, and neutralized with 4M HCl in dioxane. The white solid was filtered and washed with acetone to give 5, 7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinolineOxazolin-4 (3H) -one (0.144g, 100%). The selected data:¹H NMR(300MHz，CDCl₃)δ11.00(s，1H)，7.90(s，2H)，6.74(d，J＝2.33Hz，1H)，6.51(d，J＝2.32Hz，1H)，3.88(s，3H)，3.86(s，3H)，3.72(s，3H)，2.29(s，6H)；MS(APCI)m/z 341[M+H]⁺。

example 17

2- (4-amino-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one

To a solution of 3, 5-dimethyl-4-nitrobenzoic acid (1.00g, 5.12mmol) in CH cooled to 0-5 deg.C₂Cl₂To a solution in (25.6mL) was added oxalyl chloride (0.626mL, 7.17mmol), followed by dropwise addition of DMF (39.8. mu.L). The mixture was stirred for 2 hours, the volatiles were removed under vacuum, and the crude acid chloride was used immediately without further purification. To a mixture of 2-amino-4, 6-dimethoxybenzamide (0.913g, 4.65mmol) and pyridine (414. mu.L, 5.12mmol) in THF (18.6mL) was added dropwise a solution of acid chloride (crude residue above) in THF (8.53 mL). After 16 h, the mixture was diluted with EtOAc (500mL) and saturated NH₄Aqueous Cl (3X 100mL), saturated NaHCO₃Aqueous (3X 100mL) and brine (100 mL). The insoluble yellow solid was isolated by filtration to give the amide (1.51g, 87%). A mixture of the amide (1.50g, 4.03mmol) and 2M aqueous NaOH (25.0mL) was heated at 85 deg.C for 17 h, then THF (50mL) was added and stirred at reflux for 25 h. Volatiles were removed under vacuum and the mixture was cooled to 5 ℃ and neutralized with 4M HCl in dioxane. After stirring for 30 min, the white solid was filtered from MeCN/H₂Lyophilization in O afforded the cyclized compound (1.36g, 95%). Cyclized Compound (0.200g, 0.563mmol), Na at 70 deg.C₂S₂O₄A mixture of (0.980g, 5.63mmol), water (5.00mL), and MeOH (15.0mL) was stirred for 2 hours. Volatiles were removed under vacuum, then diluted with EtOAc (200mL) and saturated NaHCO₃(2X 100mL) and brine (75 mL). The organic layer was dried over sodium sulfate, filtered, and the volatiles removed in vacuo to give 2- (4-amino-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (0.062g, 34%) as a yellow solid. The selected data:¹H NMR(300MHz，DMSO-d₆)δ11.45(s，1H)，7.78(s，2H)，6.66(d，J＝2.25Hz，1H)，6.42(d，J＝2.24Hz，1H)，5.26(s，2H)，3.88(s，3H)，3.86(s，3H)，2.14(s，6H)；MS(APCI)m/z 326[M+H]⁺。

example 18

N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl ester

Yl) -N2-Methylphthalamide (left)

And

2- (4- (2-Aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (Right)

3, 5-dimethyl-4-hydroxybenzaldehyde (0.600g, 4.00mmol), N- (2-bromoethyl) -phthalimide (1.22g, 4.80mmol), K were combined at 80 deg.C₂CO₃A mixture of (0.829g, 6.00mmol), NaI (3.00g, 20.0mmol) in DMF (40.0mL) was heated for 2.5 hours. The reaction was cooled to room temperature, diluted with EtOAc (200mL), and washed with 1M NaOH (2X 100mL), 1M HCl (2X 100mL), brine (7)5mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (40g, hexanes/EtOAc) to give the expected ether as a yellow solid (0.300g, 23%). The above ether (0.293g, 0.907mmol), 2-amino-4, 6-dimethoxybenzamide (0.178g, 0.907mmol), NaHSO, were added under reflux₃(94%, 0.100g, 0.907mmol) and p-TsOH. H₂A mixture of O (0.0173g, 0.0907mmol) in DMA (11.3mL) was stirred for 1.5 h, then cooled to room temperature. The mixture was diluted with EtOAc (250mL), washed with saturated aqueous ammonium chloride (3X 75mL) and brine (75mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was washed with silica gel (40g, CH)₂Cl₂/CH₃OH) to yield the expected product as a pale yellow solid (0.075g, 17%). A mixture of the above compound (0.213g, 0.426mmol) and 2M methylamine in THF (25.0mL) was stirred at room temperature for 17 h. The volatiles were removed in vacuo and the residue was chromatographed on silica gel to give the compound N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide (0.0493g, 22%) and the compound 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (0.0360g, 23%) as white solids. Selected data for N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide:¹H NMR(300MHz，DMSO-d₆)δ11.80(s，1H)，8.51(t，J＝5.57Hz，1H)，8.18(q，J＝4.57Hz，1H)，7.89(s，2H)，7.53-7.42(m，4H)，6.74(d，J＝2.31Hz，1H)，6.52(d，J＝2.29Hz，1H)，3.96-3.80(m，8H)，3.61(q，J＝5.73Hz，2H)，2.71(d，J＝4.62Hz，3H)，2.32(s，6H)；MS(APCI)m/z 531[M+H]⁺. Selected data for 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one:¹H NMR(300MHz，DMSO-d₆)δ7.90(s，2H)，6.74(d，J＝2.31Hz，1H)，6.51(d，J＝2.32Hz，1H)，3.88(s，3H)，3.85(s，3H)，3.77(t，J＝5.76Hz，2H)，2.91(t，J＝5.75Hz，2H)，2.30(s，6H)；MS(APCI)m/z 370[M+H]⁺。

example 19

N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl ester

4-methoxybenzenesulphonamide radical

2- (4- (2-Aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (0.060g, 0.162mmol), 4-methoxybenzenesulfonyl chloride (0.044mg, 0.211mmol) and triethylamine (29.4. mu.L, 0.211mmol) in CH at room temperature₂Cl₂The mixture in (812. mu.L) was stirred for 3 hours. The mixture was chromatographed directly on silica gel from MeCN/H₂Freeze-drying in O gave N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide as a white solid (0.046g, 53%). The selected data:¹H NMR(300MHz，DMSO-d₆)δppm 11.81(s，1H)，7.88(s，2H)，7.83-7.73(m，3H)，7.17-7.07(m，2H)，6.73(d，J＝2.31Hz，1H)，6.52(d，J＝2.29Hz，1H)，3.91-3.75(m，11H)，3.12(q，J＝5.75Hz，2H)，2.24(s，6H)；MS(APCI)m/z 540[M+H]⁺。

example 20

4-chloro group-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy)

Ethyl) benzenesulfonamides

The compound 4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide was prepared from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one following the procedure described for N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide, yield 51%, obtained from MeCN/H₂Isolated as a white solid after lyophilization in O. The selected data:¹H NMR(300MHz，DMSO-d₆)δppm 11.8(s，1H)，8.1(s，1H)，7.9-7.6(m， 6H)，6.75(1H)，6.5(1H)，3.9-3.7(m，8H)，3.15(m，2H)，2.2(s，6H)；MS(APCI)m/z 544[M+H]⁺。

example 21

Yl) -N2-Methylphthalamide

3, 5-dimethyl-4-hydroxybenzaldehyde (0.600g, 4.00mmol), N- (2-bromoethyl) -phthalimide (1.22g, 4.80mmol), K were combined at 80 deg.C₂CO₃A mixture of (0.829g, 6.00mmol), NaI (3.00g, 20.0mmol) in DMF (40.0mL) was heated for 2.5 hours. The reaction was cooled to room temperature, diluted with EtOAc (200mL), and treated with 1M NaOH (2)100mL), 1M HCl (2X 100mL), brine (75mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (40g, hexanes/EtOAc) to give the expected ether as a yellow solid (0.300g, 23%). The above ether (0.293g, 0.907mmol), 2-amino-4, 6-dimethoxybenzamide (0.178g, 0.907mmol), NaHSO, were added under reflux₃(94%, 0.100g, 0.907mmol) and p-TsOH. H₂A mixture of O (0.0173g, 0.0907mmol) in DMA (11.3mL) was stirred for 1.5 h, then cooled to room temperature. The mixture was diluted with EtOAc (250mL), washed with saturated aqueous ammonium chloride (3X 75mL) and brine (75mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was washed with silica gel (40g, CH)₂Cl₂/CH₃OH) to yield the expected product as a pale yellow solid (0.075g, 17%). A mixture of the above compound (0.213g, 0.426mmol) and 2M methylamine in THF (25.0mL) was stirred at room temperature for 17 h. The volatiles were removed in vacuo and the residue was chromatographed on silica gel to give the compound N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide (0.0493g, 22%) and the compound 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (0.0360g, 23%) as white solids. Selected data for N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide:¹H NMR(300MHz，DMSO-d₆)δ11.80(s，1H)，8.51(t，J＝5.57Hz，1H)，8.18(q，J＝4.57Hz，1H)，7.89(s，2H)，7.53-7.42(m，4H)，6.74(d，J＝2.31Hz，1H)，6.52(d，J＝2.29Hz，1H)，3.96-3.80(m，8H)，3.61(q，J＝5.73Hz，2H)，2.71(d，J＝4.62Hz，3H)，2.32(s，6H)；MS(APCI)m/z 531[M+H]⁺。

example 22

4-methoxybenzenesulphonamide radical

example 23

4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy)

Ethyl) benzenesulfonamides

According to the pair N-, (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide, the compound 4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide was prepared from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one in 51% yield from MeCN/H.₂Isolated as a white solid after lyophilization in O. The selected data:¹H NMR(300MHz，DMSO-d₆)δppm 11.8(s，1H)，8.1(s，1H)，7.9-7.6(m，6H)，6.75(1H)，6.5(1H)，3.9-3.7(m，8H)，3.15(m，2H)，2.2(s，6H)；MS(APCI)m/z 544[M+H]⁺。

example 24

N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) methanesulfonamide

The compound N- (2- (4- (5, 7-methoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) methanesulfonamide was prepared from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one in 42% yield from N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide as described for N- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide in MeCN/H.₂Isolated as a white solid after lyophilization in O. The selected data:¹HNMR(300MHz，DMSO-d₆)δppm 11.82(s，1H)，7.90(s，2H)，7.33(t，J＝5.94Hz，1H)，6.74(d，J＝2.31Hz，1H)，6.52(d，J＝2.30Hz，1H)，3.92-3.81(m，8H)，3.41-3.34(m，2H)，2.97(s，3H)，2.32(s，6H)；MS(APCI)m/z 448[M+H]⁺。

example 25

Propylcarbamic acid 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-benzene

Oxy) ethyl ester

A mixture of 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (0.070g, 0.19mmol), propyl isocyanate (0.088mL, 0.94mmol) and TEA (0.14g, 1.1mmol) in THF (4.0mL) was stirred at 70 deg.C for 16H. The mixture was filtered, washed with THF and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50mL), washed with saturated aqueous sodium bicarbonate (50mL), dried, and the solvent removed under reduced pressure. The resulting solid was chromatographed on silica gel to give 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl propylcarbamate (0.035g, 41%) as an off-white solid. The selected data:¹H NMR(300MHz，DMSO-d₆)δ11.82(s，1H)，7.90(s，2H)，7.23(t，J＝5.27Hz，1H)，6.74(d，J＝2.32Hz，1H)，6.52(d，J＝2.31Hz，1H)，4.27(t，J＝4.29Hz，2H)，3.99(t，J＝4.29Hz，2H)，3.89(s，3H)，3.84(s，3H)，3.02-2.86(m，2H)，2.29(s，6H)，1.50-1.30(m，2H)，0.84(t，J＝7.33Hz，3H)；MS(APCI)m/z 456[M+H]⁺。

example 26

Methylcarbamic acid 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-benzene

Oxy) ethyl ester

The compound 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl methylcarbamate was prepared from 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one as described for 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl p-propylcarbamate in 11% yield isolated as an off-white solid:¹H NMR(300MHz，DMSO-d₆)δ11.82(s，1H)，7.90(s，2H)，7.08(m，1H)，6.74(d，J＝2.29Hz，1H)，6.52(d，J＝2.27Hz，1H)，4.27(t，J＝4.55Hz，2H)，3.99(t，J＝4.55Hz，2H)，3.89(s，3H)，3.84(s，3H)，2.60(d，J＝4.57Hz，3H)，2.29(s，6H)；MS(APCI)m/z428[M+H]⁺。

example 27

4-methylbenzamide

The compound 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazoline was reacted at room temperature-4(3H) -one (0.060g, 0.16mmol), p-toluoyl chloride (0.028mL, 0.21mmol) and PS-DIEA (0.057g, 0.21mmol) in CH₂Cl₂The mixture in (4.0mL) was stirred for 16 h. The mixture was filtered and washed with CH₂Cl₂Washed and the solvent removed under reduced pressure. The resulting residue was chromatographed on silica gel to give N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methylbenzamide as an off-white solid (0.037g, 51%):¹HNMR(300MHz，DMSO-d₆)δ11.80-11.00(s，1H)，8.69(t，J＝5.43Hz，1H)，7.88(s，2H)，7.79(d，J＝8.19Hz，2H)，7.28(d，J＝8.00Hz，2H)，6.73(d，J＝2.31Hz，1H)，6.51(d，J＝2.31Hz，1H)，3.94(t，J＝5.59Hz，2H)，3.88(s，3H)，3.84(s，3H)，3.72-3.60(m，2H)，2.36(s，3H)，2.27(s，6H)；MS(APCI)m/z488[M+H]⁺。

example 28

Cyclohexylcarbamic acid 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl

Phenoxy) ethyl ester

4- (6, 8-Dimethoxyisoquinolin-3-yl) -2, 6-dimethylphenol (0.100g, 0.270mmol), cyclohexyl isocyanate (172. mu.L, 1.35mmol) and Et are added under reflux₃A mixture of N (263. mu.L, 1.89mmol) in THF (1.00mL) was stirred for 4 h, then diluted with EtOAc (200mL), washed with saturated aqueous ammonium chloride (3X 75mL) and brine (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was washed with silica gel (12g, CH)₂Cl₂/CH₃OH) is subjected to chromatography on a chromatographic column,the product is separated from MeCN/H₂Freeze-drying in O gave 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl cyclohexylcarbamate as a white solid (0.0981g, 73%).¹H NMR(300MHz，DMSO-d₆δ)11.82(s，1H)，7.90(s，2H)，7.24-7.05(m，1H)，6.73(d，J＝2.30Hz，1H)，6.52(d，J＝2.31Hz，1H)，4.30-4.22(m，1H)，4.03-3.95(m，1H)，3.88(s，3H)，3.85(s，3H)，2.29(s，6H)，1.82-1.46(m，5H)，1.18(m，5H)；MS(APCI)m/z 496[M+H]⁺。

Reference example A

4- (2- (4- (6, 8-Dimethoxyisoquinolin-3-yl) -2, 6-dimethylphenoxy) ethyl) morpholine

To a solution of 4- (6, 8-dimethoxyisoquinolin-3-yl) -2, 6-dimethylphenol (0.309g, 1.0mol) in anhydrous THF (20mL) was added triphenylphosphine (0.52g, 2.0mmol), 4- (2-hydroxyethyl) morpholine (0.262g, 2.0mmol) and N, N-diisopropylethylamine (0.387g, 3.0 mmol). To the stirred solution was added diethyl azodicarboxylate (0.348g, 2.0 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen and then diluted with ethyl acetate (100 mL). The organic layer was washed with water and brine, over anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure. The crude material was purified by column chromatography to give 3- [3, 5-dimethyl-4- (2-morpholin-4-ylethoxy) phenyl as a white solid]-6, 8-Dimethoxyisoquinoline (0.54 g).

To the above compound (0.54g, impure) in 1: 1 ether-CH₂Cl₂To the solution in (10mL) was added a 1.0M solution of hydrogen chloride in ether (2mL), and the reaction mixture was stirred at room temperature for 30 minutes. Removing under reduced pressureAnd (4) removing the solvent. The residue was triturated with 10% methanol in ether to give 4- (2- (4- (6, 8-dimethoxyisoquinolin-3-yl) -2, 6-dimethylphenoxy) ethyl) morpholine as a yellow solid (0.323g, 70% yield over two steps). The selected data: MS (ES) m/z: 423.1, respectively; MP 239-.

Example 29

Yl) benzenesulfonamides

The title compound was prepared from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one in 41% yield and isolated as an off-white solid as described for reference example a: MS (APCI) M/z 510[ M + H]⁺。

Example 30

4-methylbenzenesulfonamides

Following the procedure described for reference example AThe title compound was prepared from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one in 50% yield and was isolated as an off-white solid: MS (APCI) M/z 524[ M + H]⁺。

Reference example B

5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one

To a solution of 2-amino-4, 6-dimethoxybenzamide (0.15g, 0.764mmol) in N, N-dimethylacetamide (5mL) was added 2-pyridinecarboxaldehyde (0.082g, 0.764mmol), sodium bisulfite (58.5%, 0.15g, 0.84mmol), and p-toluenesulfonic acid (15mg, 0.0764 mmol). The reaction mixture was stirred at 150 ℃ overnight. The mixture was cooled to room temperature. Water (40mL) was added and the reaction mixture was extracted with dichloromethane (2X 50 mL). The combined organic layers were washed with water and passed over anhydrous Na₂SO₄And (5) drying. The solvent was removed and the crude compound was purified by column chromatography (silica gel 230-₂Cl₂1% methanol as eluent) to yield 5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one as a white solid (0.077g, 36%). Converting 5, 7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one to the corresponding hydrochloride salt. The selected data: MS (m/z): 284.0, respectively; MP 215 + 217 deg.C (hydrochloride).

Reference example C

5, 7-dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one

5, 7-dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one was synthesized from 2-amino-4, 6-dimethoxybenzamide and 3-pyridinecarboxaldehyde using the method described for reference example B. 5, 7-dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one was isolated (105mg, 48%) as a white solid. The selected data: MS (m/z): 284.0, respectively; MP 257 ℃ and 259 ℃ (hydrochloride).

Example 31

N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzamide

The title compound was prepared in 46% yield from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one according to the method described for reference example C and was isolated as a white solid: MS (APCI) M/z 526[ M + Na ]]⁺。

Example 32

Yl) acetamide

The title compound was obtained in 40% yield from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one and isolated as a white solid as described for example 27: MS (APCI) M/z 412[ M + H]⁺。

Example 33

Yl) benzamide

The title compound was prepared from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one in 66% yield and isolated as a white solid as described for example 27: MS (APCI) M/z 474[ M + H]⁺。

Example 34

Yl) isobutyramide

According to the method described for example 27, from2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one the title compound was prepared in 59% yield and was isolated as a white solid: MS (APCI) M/z 440[ M + H]⁺。

Example 35

1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl ester

Yl) -3-methylurea

The compound 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (0.10g, 0.27mmol), methyl isocyanate (0.020g, 0.35mmol) and Et at room temperature₃A mixture of N (0.034g, 0.35mmol) in THF (4.0mL) was stirred for 16 h. The mixture was filtered and washed with CH₂Cl₂Washed and the solvent removed under reduced pressure. The resulting residue was chromatographed on silica gel to give the title compound (0.082g, 71%) as a white solid: MS (APCI) M/z 449[ M + Na ]]⁺。

Example 36

3- (4-methoxyphenyl) urea

The title compound was obtained in 57% yield from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one and isolated as a white solid as described for example 35: MS (APCI) M/z 541[ M + Na ]]⁺。

Example 37

3-phenylurea

The title compound was prepared as described for example 35 from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one in 59% yield and isolated as a light yellow solid: MS (APCI) M/z 489[ M + H ]]⁺。

Example 38

3- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl ester

Radical) -1, 1-diMethyl urea

The title compound was obtained in 59% yield from 2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one and isolated as a white solid as described for example 35: MS (APCI) M/z 441[ M + H]⁺。

Example 39

6, 8-dimethoxy-3- (4-hydroxy-3, 5-dimethylphenyl) -2H-1, 2-benzothiazine-1, 1-dioxide

To a 3-neck round-bottom flask were added 3, 5-dimethoxytoluene (6.088g, 40mmol) and cyclohexane (28mL) under nitrogen. Dimethyl carbonate (30.3g, 336m mol) was added and the reaction mixture was heated at 60 ℃. Excess chlorosulfonic acid was added over 15 minutes. The HCl gas evolved was removed by inserting the tube into solid sodium hydroxide. After the addition was complete, the reaction mixture was heated at 70-72 ℃ for 1 hour and then cooled to room temperature. The solid was filtered off and washed with dimethyl carbonate/cyclohexane (1: 1, 20 mL). The solid was dried in vacuo to give pure material (6.13g, 66%). To a mixture of sulfonic acid (from the product above, 4.65g, 20mmol) and triethylamine (2.03g, 2.79mL) in acetone (40mL) was added 2, 4, 6-trichloro-1, 3, 5-triazine (cyanuric chloride, 3.69g, 20 mmol). The reaction mixture was heated to reflux for 20 hours and then cooled to room temperature. The solution was passed through a pad of Celite and evaporated in vacuo to leave a solid which was filtered off and washed with hexane. The product and a mixture of the salt of cyanuric acid hydroxide and triethylamine (7.58g) was used in the next step without further purification.

To a 3-neck round-bottom flask equipped with a condenser (acetone-dry ice cooling) was added the mixture from the previous step (7.58g) and acetone (100 mL). The reaction mixture was cooled to-78 ℃ and ammonia gas was bubbled through the solution for 0.5 h. The reaction mixture was left overnight to allow ammonia gas to evaporate slowly and then the solvent was evaporated. Water was added and the product was extracted with DCM. The solvent was dried and evaporated to leave a mixture of solid and thick liquid. The solid was filtered off and washed with hexane to leave the pure sulfonamide (3.23g, 70%).

To a round bottom flask was added 3, 5-dimethyl-4-hydroxybenzoic acid (2.99g, 18 mmol). Anhydrous DMF (20mL) was added followed by sodium hydride (1.8g, 45 mmol). The reaction mixture was stirred at room temperature for 1 hour. P-methoxybenzyl chloride (6.20g, 39.6mmol) was added and the mixture was stirred at room temperature overnight (. about.20 h). The reaction mixture was poured into water, acidified with 1N HCl and stirred for 1 hour. The precipitated solid was filtered off, washed with water and hexane to give pure B-ring structural units (6.93g, 95%).

The B-ring structure unit (6.93g, 17.1mmol) was dissolved in a mixture of methanol (50mL) and tetrahydrofuran (50 mL). Potassium hydroxide (1.25g, 22.2mmol) in water (20mL) was added. The reaction mixture was refluxed at 70 ℃ for 24 hours. The solvent was evaporated in vacuo. Water was added and the reaction mixture was acidified with 1N HCl (pH 4-5). The solid was filtered off and washed with water and hexane. Yield 4.61g (94%). The product (1.932g, 6.75mmol) and the sulfonamide from above (1.04g, 4.5mmol) were charged to a 3-neck round bottom flask under nitrogen. Dichloromethane (100mL) was added with stirring. To the stirred mixture was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDCI. HCl, 1.36g, 7.09mmol) followed by N, N-dimethylaminopyridine (2.06g, 16.9 mmol). The reaction mixture was stirred at room temperature for 24 hours, then washed with 1N HCl, 2.5% NaOH, and saturated sodium bicarbonate solution. The organic layer was dried and evaporated in vacuo to leave a residue which was purified by column chromatography on silica gel (100g) using 20-50% ethyl acetate in hexane and 5% methanol in dichloromethane as eluent. Fractions 30-66 were combined to give pure material (1.35g, 60%). The compound from the previous step (0.105g, 0.21mmol) was dissolved in tetrahydrofuran under nitrogen and cooled to-78 ℃. N-butyllithium was added and the reaction mixture was allowed to warm slowly to room temperature and stirred overnight (. about.14 h). TLC indicated incomplete conversion. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The solvent was evaporated in vacuo leaving a residue which was purified by column chromatography on silica gel (15g) using 20-50% ethyl acetate in hexane as eluent. The product was not pure enough, so another column was used, 0.5% methanol in hexane was used as eluent, and the material was finally purified by preparative TLC. The compound from the previous step (0.277g) was dissolved in trifluoroacetic acid (10mL) under nitrogen and the reaction mixture was refluxed (bath temperature 80 ℃ C.) for 4 days. The solvent was evaporated in vacuo and the residue was dissolved in 0.25N NaOH (20mL) and acidified with acetic acid. At this point, solids had precipitated out. The solid was filtered off, washed with water, hexane and dried. 0.005g of pure material was isolated from one batch. 0.060g of compound, which was not sufficiently pure, was isolated from another batch. This compound was further purified by preparative HPLC to give pure 6, 8-dimethoxy-3- (4-hydroxy-3, 5-dimethylphenyl) -2H-1, 2-benzothiazine-1, 1-dioxide (0.010 g). The selected data: MP 246.6-247.4 ℃.

Example 40

3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxy-7- (morpholinomethyl) isoquinoline-1 (2H) -one

Ketones

Methyl acetoacetate (69.67g, 0.6mol) in dry THF (350mL) was cooled to-5 deg.C and sodium hydride (24.5g, 60%) in mineral oil was added over 30 minutes at-5 to 0 deg.C. Diketene diacetate (50.4g) in dry THF (80mL) was added dropwise over 20 minutes at 5 ℃. The resulting solution was stirred at-5 ℃ for 1.0 h, then allowed to warm to room temperature and stirred overnight. Acetic acid (35mL) was added and the THF solvent was removed. Water (200mL) and ethyl acetate (300mL) were added to the residue, and HCl solution was added to adjust the pH to 5.0. The organic layer was separated, washed with brine and dried over sodium sulfate. After column purification and recrystallization, compound a (26.6g, 24.3%) was obtained.

Sodium hydride in mineral oil (11.2g, 0.279mol, 60%) was added to Compound A (24.8g, 0.136mol) in DMF (150 mL). The reaction was cooled to-30 ℃, methyl iodide (21.3mL, 0.341mol) was added, and the reaction was kept at room temperature overnight. The sodium iodide was filtered off and the DMF was removed. The residue was mixed with water (100mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude mixture was purified by column chromatography to give compound B (11.40g, 39.9%). To compound B (11.4g, 0.054 mol) in anhydrous CCl₄To the solution in (90mL) was added N-bromosuccinimide (10.6g, 0.0596 mol). The mixture was refluxed overnight to remove CCl₄A solvent. Water (100mL) was added to the residue. After stirring for a period of time, the solid was filtered off and washed with water, ethyl acetate (10mL) and hexane (30mL) to give compound (13.1g, 83.9%). Compound C (12.5g, 0.043mol), chloromethyl methyl ether (81.0g) and anhydrous zinc chloride (7.0g, 0.051mol) were kept at room temperature overnight. Chloromethyl methyl ether was removed, the residue was mixed with water and the pH was adjusted to 7.0 using sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After column chromatography, Compound D (7.39g, 50.6%) was obtained. A solution of compound D (7.39g, 0.022mol), morpholine (7.62g, 0.088mol) and anhydrous THF (20mL) was kept at room temperature overnight. The solvent was evaporated. Water and ethyl acetate were added to the residue and the pH was adjusted to 9.0 with sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. After column chromatography, compound E (5.4g, 63.8%) was obtained. Compound E (5.4g, 0.014mol) in THF (100mL) and triethylamine (3.9mL) at 50psi with 10% Pd/C(2.6g) As a catalyst, hydrogenation was carried out for 2 days. After the catalyst was filtered off, the organic layer was purified by column chromatography to give product F (3.20g, 74.4%). Compound F (3.20g, 0.0103mol) was dissolved in ethanol (30mL), potassium hydroxide (2.31g, 0.041mol) in water (20mL) was added, and the reaction mixture was heated at 100 ℃ overnight. The solvent was removed, the pH adjusted to 6.0 and water was removed. The residue was further dried under high vacuum and the compound was extracted with ethanol to give compound G (2.95G, 99%). Compound G (1.80G, 6.1mmol) and thionyl chloride (3mL, 0.0411mol) were refluxed for 1 hour, then excess thionyl chloride was removed and the residue was dried under high vacuum. Anhydrous THF (20mL) was added and ammonia gas was bubbled through the reaction mixture for 2 hours. THF was removed and the pH was adjusted to 8.0-9.0. The mixture was extracted with dichloromethane and dried over sodium sulfate to give compound H (1.30g, 72.4%).

NaH in mineral oil (1.14g, 0.0285mol, 60%) was added to 4-hydroxy-3, 5-dimethylbenzonitrile (4.0g, 0.027mol) in anhydrous DMF (20mL), followed by benzyl bromide (3.27mL, 0.027 mol). The reaction was kept at room temperature overnight. The reaction mixture was poured into water and the solid was filtered off and washed with hexane to give compound I (5.7g, 89%). Compound I was used in the next reaction without further purification. BuLi (1.60M, 10.2mL) was added dropwise to compound H (0.8g, 2.72mmol) in dry THF (25mL) at-10 ℃. The reaction mixture was kept at 0 ℃ for 1 hour, and then the cooling bath was removed. The reaction mixture was stirred for 45 minutes. Compound I (0.65g, 2.72mmol) in dry THF (5mL) was added dropwise at-10 deg.C and the reaction was continued for an additional 45 minutes. Water (20mL) was added. The mixture was extracted with ethyl acetate. The solvent was removed and the residue was purified by column chromatography to give compound J (0.180g, 12.8%). Compound J (180mg) in methanol (80mL) was hydrogenated using 10% Pd/C as the catalyst at 50psi for 3 hours. The catalyst and solvent were removed and the residue was purified by column chromatography to give 3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxy-7- (morpholinomethyl) isoquinolin-1 (2H) -one as a white solid (28mg, 18.8%). The selected data: MS (m/z): 424.21, respectively; MP 158-.

Example 41: quantification of ApoA-I mRNA

In this example, ApoA-I mRNA in tissue culture cells was quantified to determine the up-regulation of ApoA-I transcription when treated with a compound of the invention.

HepG2 cells (. about.2X 10) in 24-well plates⁵One/well) was placed in-400 μ L MEM supplemented with 0.5% (v/v) FBS for 24 hours, and then the target compound was added. At the time of harvest, the spent media was removed from HepG2 cells, either immediately on ice (for immediate use) or at-80 ℃ in an ApoA-I and albumin ELISA (for future use). The remaining cells in the wells of the plate were washed with 200 μ L PBS. PBS was carefully removed to avoid removing any loosely attached cells.

Once the PBS was removed, 85. mu.L of cell lysis solution was added to the cells in each well and incubated at room temperature for 5-10 minutes to allow complete lysis and detachment of the cells. The mRNA was then prepared according to the protocol provided using an "mRNA collector PLUS plate" from Invitrogen corporation. After the final wash, aspirate as much wash buffer as possible but not allow the wells to be blotted dry. Elution buffer (E3, 80 μ L) was then added to each well. The mRNA was then eluted by incubating the mRNA collector PLUS plates with elution buffer for 5 minutes at 68 ℃ and then immediately placing the plates on ice.

The eluted mRNA isolates were then used in a one-step real-time RT-PCR reaction using the components of the Ultra Sense kit and the primer-probe mix from applied biosystems. Real-time PCR data was analyzed using Ct values to determine the fold induction (fold induction) of each unknown sample relative to the control (i.e., relative to the control for each independent DMSO concentration).

An active compound is a compound that increases ApoA-I mRNA by > 15% at a concentration of less than or equal to 100 μ M.

Example numbering	Name of Compound	For ApoA-I mRNA waterFlat effect
			38	3- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -1, 1-dimethylurea	Activity of
37	1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -3-phenylurea	Activity of
			36	1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea	Activity of

[0583]

Example numbering	Name of Compound	Effect on ApoA-I mRNA levels
			35	1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -3-methylurea	Activity of
34	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) isobutyramide	Activity of
			33	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) benzamide	Activity of
32	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) acetamide	Activity of
			31	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -4-methoxybenzamide	Activity of
30	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)Yl) -2, 6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide	Activity of
			29	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) benzenesulfonamide	Activity of
28	Cyclohexylcarbamic acid 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl ester	Activity of
			27	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -4-methylbenzamide	Activity of
26	Methyl carbamic acid 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl ester	Activity of
			25	Propylcarbamic acid 2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl ester	Activity of
24	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) methanesulfonamide	Activity of

Example numbering	Name of Compound	For ApoA-I mRNA waterFlat effect
			23	4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide	Activity of
22	N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)Yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulphonamide	Activity of
			21	N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)Base) -26-dimethylphenoxy) ethyl) -N2-methylphthalamide	Activity of
20	4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide	Activity of
			18	2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinolineAzolin-4 (3H) -ones	Activity of
18	N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide	Activity of
			17	2- (4-amino-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazoline-4(3H) -one	Activity of
16	5, 7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinazolin-4 (3H) -one	Activity of
			15	2- (2-chloro-6-methylpyridin-4-yl) -5, 7-dimethoxyquinazoline-4 (3H) -oneKetones	Activity of
14	2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxypyridinePyrido [2, 3-d]Pyrimidin-4 (3H) -ones	Activity of
			13	2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one	Activity of
12	2- (2, 3-dihydrobenzo [ b ]][1，4]Dioxine-6-yl) -6, 7-dimethoxyquinazolin-4 (3H) -one	Activity of

[0585]

Example numbering	Name of Compound	For ApoA-I mRNA waterFlat effect
			11	2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6, 7-dimethoxyquinazolin-4 (3H) -one	Activity of
10	2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one	Activity of
			9	2- (4-hydroxy-3-methoxyphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one	Activity of
8	3- (3, 5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one	Activity of
			7	2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinolineAzolin-4 (3H) -ones	Activity of
6	7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6-naphthyridin-5 (6H) -one	Activity of
			5	3- (4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylphenyl) -6, 8-dime thoxyisoquinolin-1 (2H) -one	Activity of
4	2- (4-hydroxy-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazoline-4(3H) -one	Activity of
			3	3- (4-hydroxy-3, 5-dimethylphenyl) -7- (morpholinomethyl) isoquinoline-1(2H) -one	Activity of
2	3- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoQuinolin-1 (2H) -ones	Activity of
			1	3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinoline-1(2H) -one	Activity of

Example 42: ApoA-I mRNA and protein induction

In this example, ApoA-I mRNA and secreted protein from tissue culture cells were quantified. This assay can be used to determine the potency of target compounds, including those of the present invention.

HepG2 cells and primary human hepatocytes (BD Gentest, batch 107) (-2X 10) in 24-well plates⁵One/well) was placed in-400 μ L MEM supplemented with 0.5% (v/v) FBS for 24 hours, and then the target compound was added. The target compound was dissolved in DMSO at 0.05% (v/v). An appropriate volume of a stock of compound in DMSO is then added to an appropriate volume of MEM supplemented with 0.5% (v/v) FBS to give the desired concentration (e.g., 1 μ L of a stock of compound is added to 1mL of MEM supplemented with 0.5% (v/v) FBS).

Just prior to adding the compounds to the cells, the growth medium was aspirated and replaced with 300 μ L of fresh MEM supplemented with 0.5% (v/v) FBS, then 300 μ L of the target compound in MEM supplemented with 0.5% (v/v) FBS was added to give the desired final compound concentration in a total volume of 600 μ L. The final concentration of Diluent (DMSO) was 0.05% (v/v).

Cells were incubated for the desired time. The cell culture medium is then collected as cells. ApoA-I mRNA was determined as described in example 39. Secreted ApoA-I was determined using ApoA-IELISA as follows:

ApoA-I ELISA

in this example, ApoA-I secreted into culture medium by tissue culture cells was quantified to assess the induction of endogenous ApoA-I protein secretion from cells treated with various small molecule compounds, such as the compounds of the invention.

At the time of harvest, spent media was removed from HepG2 cell cultures or primary cell cultures and stored in 1.5mL microcentrifuge tubes (microfuge tubes) at-80 ℃.

For human ApoA-I ELISA, ELISA plates were coated with-100. mu.L/well human ApoA-I capture antibody (diluted to-2. mu.g/mL with coating buffer) for-1 hour at room temperature. The plate was then washed 3 times with wash buffer. The plates were then blocked with-200 μ L/well human ApoA-I blocking buffer for at least-30 minutes at room temperature.

Samples for generating standard curves were prepared from spent media (MEM, supplemented with 0.5% (v/v) FBS) from HepG2 or primary cells treated with DMSO for 48 hours. Serial 2-fold dilutions of medium were made in MEM supplemented with 0.5% (v/v) FBS. Unknown samples from cultures treated with the compounds of interest were also diluted in MEM supplemented with 0.5% (v/v) FBS. The plate was washed 3 times with wash buffer. The standard curve and unknown sample (100 μ L/well) were added to the plate in triplicate and incubated for 1.5 hours at room temperature.

The plate was washed 3 times with wash buffer. Human ApoA-I detection antibody (100. mu.L/well) diluted 1: 1000 in PBS was added and the plates were incubated for 1 hour at room temperature. The plate was washed 3 times with wash buffer.

Goat anti-rabbit IgG H & L chain-specific peroxidase conjugate (100. mu.L/well) diluted 1: 2000 in PBS was added and the plates were incubated at room temperature in the dark for 40 minutes. The plate was washed 6 times with wash buffer.

TMB liquid substrate (100 μ L/well) was added and the plates incubated under tin foil during development on a shaker. Once sufficient "blue" color has been achieved, stop solution (50. mu.L/well, 1 MH) is added₂SO₄) And mixed well on a plate shaker. The air bubbles were removed and the absorbance was measured at 450nm using a Molecular devices SpectraMax 190 plate reader and human ApoA-I ELISA Softmax software.

Example numbering	Name of Compound	EC50 protein (μ M)
			20	4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide	0.32
18	2- (4- (2-amino)Ethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinolineAzolin-4 (3H) -ones	7.22
			18	N1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazoline-2-)2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide	7.29
17	2- (4-amino-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazoline-4(3H) -one	7.63
			16	5, 7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinazolin-4 (3H) -one	16.46
15	2- (2-chloro-6-methylpyridin-4-yl) -5, 7-dimethoxyquinazoline-4 (3H) -oneKetones	3.96
			14	2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxypyridinePyrido [2, 3-d]Pyrimidin-4 (3H) -ones	9.20
13	2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one	13.72

[0600]

Example numbering	Name of Compound	EC50 protein (μ M)
			12	2- (2, 3-dihydrobenzo [ b ]][1，4]Dioxine-6-yl) -6, 7-dimethoxyquinazolin-4 (3H) -one	9.07
11	2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6, 7-dimethoxyquinazolin-4 (3H) -one	13.30
			10	2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one	12.11
9	2- (4-hydroxy-3-methoxyphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one	12.08
			8	3- (3, 5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6, 8-dimethoxyisoquinolin-1 (2H) -one	2.82
7	2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinolineAzolin-4 (3H) -ones	12.16
			6	7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6-naphthyridin-5 (6H) -one	6.52
5	3- (4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylphenyl) -6, 8-dimethyloxyisoquinolin-1 (2H) -one	6.27
			4	2- (4-hydroxy-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazoline-4(3H) -one	7.93
3	3- (4-hydroxy-3, 5-dimethylphenyl) -7- (morpholinomethyl) isoquinoline-1(2H) -one	11.09
			2	3- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -6, 8-dimethoxyisoQuinolin-1 (2H) -ones	11.35
1	3- (4-hydroxy-3, 5-dimethylphenyl) -6, 8-dimethoxyisoquinoline-1(2H) -one	5.42
				2- (4-hydroxy-phenyl) -pyrano [2, 3-b]Pyridin-4-ones	179.47

[0601] Example 43: in vivo efficacy

To examine whether the potency of the compounds of the invention observed in vitro extends to in vivo models, transgenic mice (Bisaha et al (1995) J.biol.chem.34, 19979-88) or wild type mice (C57BL/6 (cat. 000664), Jackson laboratories (Bar Harbor, ME)) carrying multiple copies of the human ApoA-I gene were contacted with the compounds of the invention. In transgenic mice, the exogenous human ApoA-I genes in these mice enable them to express human ApoA-I protein under the control of their own promoters.

Male mice, 7 to 8 weeks old, were fed with ready-to-use pelleted rodent chow [ Purina5001] and water, 5 per cage (10 ". times.20". times.8 "with aspen sheet bedding). After 1 week of acclimation, animals were individually identified by numbering on the tail and weighed. Mice were pre-bled by the retro-orbital plexus and 100 μ L of blood was collected in 1.5mL Eppendorf tubes containing 5 μ L of 0.5mM EDTA and cooled on ice. Whole blood was centrifuged at 14000rpm for 10 minutes at 4 ℃ in a TOMY high speed microfreefer centrifuge NTX-150, and then plasma was collected and frozen at-80 ℃. Mice were grouped according to having an average weight of 25 g.

The following day after blood pre-fetching, 20 days by oral gavage or by intraperitoneal administrationNo. 11/2' bent disposable needle (Popper)&Sons) was administered to mice; when given twice daily (BID), mice were gavaged in the morning and afternoon (8am and 5 pm); when dosed daily (QD), mice were gavaged in the morning (8 am). The compounds were prepared daily in vehicle. The day before necropsy, mice were weighed and fasted overnight. On the last day of administration, 2 hours after administration by inhalation of CO₂Mice were sacrificed and blood (0.7-1.0mL) was taken by cardiac puncture. Plasma was collected and frozen at-80 ℃. ApoA-I in the samples was measured by ELISA and HDL-C in the samples was measured by HPLC (Polaris 200 with autosampler Prostar 410 from Varian on Superose 610/30 column from Amersham). During necropsy, liver and intestinal cells from duodenum and small intestine jejunum were collected, washed with cold PBS, and frozen at-80 ℃ for further analysis of compound and mRNA levels by Q-PCR.

Experiment A: 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (10, 30, and 60mg/kg body weight, mpk) was administered to hAPoA-I transgenic mice twice daily for 7 days by oral gavage in 1% DMSO, 2.5% Tween-80, 10% PEG-300 (q.s.water). Plasma ApoA-I (figure 1) and HDL cholesterol (figure 2) were determined.

Experiment B: 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (10, 30, and 60mg/kg body weight) was administered intraperitoneally twice daily for 3 days in 1% DMSO, 2.5% Tween-80, 10% PEG-300 (q.s.water) to wild-type C57BL/6 mice daily. Plasma ApoA-I (figure 3) and HDL cholesterol (figure 4) were determined.

Experiment C: 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one (30mg/kg body weight) was administered to hAPoA-I transgenic mice by oral gavage twice daily for 7 days in 1% DMSO, 2.5% Tween-80, 10% PEG-300 (q.s. to water) daily. Plasma ApoA-I was measured and tissue mRNA was measured (fig. 5).

These results indicate that the compounds of the invention are useful for increasing ApoA-I transcription in vivo and increasing ApoA-I plasma levels and HDL-C circulating levels in wild type and hApoA-I transgenic mice. These results demonstrate that the compounds of the invention activate the human ApoA-I transgene in mice, thereby increasing circulating ApoA-I.

All references used herein are incorporated by reference in their entirety. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. A compound of formula II and pharmaceutically acceptable salts thereof,

wherein:

x is N;

R₁and R₃Each independently selected from C_1-8Alkoxy and hydrogen;

R₂is selected from C_1-8Alkoxy radical, C_1-8Alkyl and hydrogen;

R₆and R₈Each independently selected from C_1-8Alkyl radical, C_1-8Alkoxy, chlorine and hydrogen;

R₄and R₅Is hydrogen;

R₇selected from amino, hydroxy, C_1-8Alkoxy and C substituted by heterocyclyl_1-8Alkyl, or two adjacent R₆、R₇And R₈The substituents of (a) are linked to form a heterocyclic group;

each W is independently selected from C and N,

p is 1, except when W is N, then p is 0;

with the following conditions: if R is₂Is C_1-8Alkoxy or hydrogen, then R₁And R₃At least one is an alkoxy group;

with the following conditions: if R is₇Is hydroxy or C_1-8Alkoxy radical, then R₆And R₈At least one of which is independently selected from C_1-8Alkyl radical, C_1-8Alkoxy and chlorine;

with the following conditions: if for W- (R)₇)_pWith W being N and p being 0, then R₆And R₈At least one of which is chlorine; wherein heterocyclyl means a saturated or unsaturated 3, 4, 5, 6 or 7 membered ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur.

2. A compound according to claim 1, wherein R₆And R₈At least one of them being selected from C_1-8Alkyl radical, C_1-8Alkoxy and chlorine.

3. A compound according to claim 1, wherein R₆And R₈Each independently is C_1-8An alkyl group.

4. A compound according to claim 1, wherein R₇Selected from hydroxy, amino and C_1-8An alkoxy group.

5. A compound according to claim 1, wherein R₇Is an amino group.

6. A compound of formula II and pharmaceutically acceptable salts thereof,

wherein X is N;

R₁and R₃Is C_1-8An alkoxy group;

R₂is selected from C_1-8Alkoxy radical, C_1-8Alkyl and hydrogen;

R₆and R₈Is C_1-8An alkyl group; and is

R₄And R₅Is hydrogen;

R₇is C substituted by hydroxy_1-8An alkoxy group;

each W is independently selected from C and N, p is 1, except when W is N, then p is 0.

7. A compound selected from

2- (4-hydroxy-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

2- (4-hydroxy-3-methoxyphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6, 7-dimethoxyquinazolin-4 (3H) -one;

2- (2, 3-dihydrobenzo [ b ]][1，4]IIEn-6-yl) -6, 7-dimethoxyquinazolin-4 (3H) -one;

2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxypyrido [2, 3-d ] pyrimidin-4 (3H) -one;

2- (2-chloro-6-methylpyridin-4-yl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

5, 7-dimethoxy-2- (4-methoxy-3, 5-dimethylphenyl) quinazolin-4 (3H) -one;

2- (4-amino-3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

n1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -N2-methylphthalamide;

2- (4- (2-aminoethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one;

4-chloro-N- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide;

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) methanesulfonamide;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl propylcarbamate;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethyl-phenoxy) ethyl methylcarbamate;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methylbenzamide;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl cyclohexylcarbamate;

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzenesulfonamide;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -4-methoxybenzamide;

2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) acetamide;

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) benzamide;

n- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) isobutyramide;

1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -3-methylurea;

1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea;

1- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -3-phenylurea; and

3- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) -2, 6-dimethylphenoxy) ethyl) -1, 1-dimethylurea,

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein the compound is 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5, 7-dimethoxyquinazolin-4 (3H) -one or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. Use of a therapeutically effective amount of a compound of any one of claims 1 to 8 in the manufacture of a medicament for the treatment of cardiovascular, cholesterol, or lipid related disorders.

11. Use of a therapeutically effective amount of a compound of any one of claims 1 to 8 in the manufacture of a medicament for increasing ApoA-I and/or HDL-C in a mammal.