A quinoline derivative and its pharmaceutical composition and application

Abstract

The present invention belongs to the field of pharmaceutical chemistry technology and specifically relates to a quinoline derivative and its pharmaceutical composition and its use in the preparation of a medicament for preventing or treating diseases associated with PDE4. The quinoline derivative of the present invention has a relatively novel structure and exhibits good PDE4 inhibitory activity. It can be used as a PDE4 inhibitor for preventing or treating diseases associated with PDE4, particularly inflammatory diseases. The quinoline derivative of the present invention is a compound represented by the general formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, or N-oxide on the pyridine ring thereof: #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a quinoline derivative and a pharmaceutical composition thereof, and application thereof in preparing a drug for preventing or treating diseases associated with PDE4. Background Art

[0002] Chronic respiratory disease refers to chronic conditions that occur in the respiratory tract and other structures of the lungs. Chronic obstructive pulmonary disease (COPD) is a relatively common chronic respiratory disease. COPD is a chronic inflammatory respiratory disease. When the airways are stimulated by external irritants (such as smoke, occupational dust, and air pollutants), it triggers an innate immune response in airway immune cells (epithelial cells, macrophages, and neutrophils). This leads to fibrosis of the epithelium and macrophages, resulting in bronchial fibrosis, inducing inflammation and airflow obstruction, causing COPD. There are various treatment options for COPD, aiming to relax airway smooth muscle as quickly as possible, clear airway mucus, and reduce the risk of inflammation. However, no single treatment or medication is suitable for everyone. Medications used for COPD primarily include bronchodilators, anti-inflammatory drugs, and combination medications. Phosphodiesterase type 4 (PDE4) inhibitors, with their unique anti-inflammatory and immunomodulatory properties, have become a potential treatment option for severe COPD.

[0003] PDE4 is expressed in various tissues and cell compartments and participates in numerous physiological processes, including airway immunity, central nervous system signaling, cardiovascular function, inflammation, cell adhesion, and metabolism. In inflammatory cells, cAMP inhibits inflammatory and cytokine release pathways. PDE4 is highly expressed in inflammatory and immune cells, and intracellular cAMP levels are regulated by PDE4. Therefore, inhibiting PDE4 activity in these cells effectively increases intracellular cAMP levels, thereby activating specific protein phosphorylation processes that trigger various functional responses. This, in turn, inhibits the release of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), interleukin-12 (IL-12), leukotriene B4 (LTB4), and interferon-γ (IFN-γ), while also suppressing inflammatory cell activity. Furthermore, increasing intracellular cAMP levels by inhibiting PDE4 activity leads to smooth muscle relaxation, which promotes bronchodilation. Therefore, the development of effective PDE4 inhibitors for the treatment of chronic respiratory diseases has become a focus of pharmaceutical researchers. Summary of the Invention

[0004] The present invention aims to provide a quinoline derivative and its pharmaceutical composition and application. The derivative exhibits good PDE4 inhibitory activity and can be used as a PDE4 inhibitor to prevent or treat diseases related to PDE4, especially inflammatory diseases.

[0005] Specifically, the present invention is achieved through the following technical solutions:

[0006] In the first aspect, the present invention provides a quinoline derivative, which is a compound represented by general formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer or N-oxide on the pyridine ring thereof;

[0007]

[0008] wherein R1 is selected from hydrogen, halogen, C1-C6 straight chain or branched chain alkyl, C1-C6 straight chain or branched chain haloalkyl, or C1-C6 straight chain or branched chain alkoxy, wherein the C1-C6 straight chain or branched chain alkoxy may be substituted with a C3-C7 cycloalkyl or a C3-C7 cycloalkyl containing 1-2 heteroatoms;

[0009] R2 and R3 may be the same or different, and are each independently selected from hydrogen, halogen, hydroxy, C1-C6 straight chain or branched haloalkyl, or C1-C6 straight chain or branched alkoxy, wherein the C1-C6 straight chain or branched alkoxy may be substituted with one or more halogen atoms, and the C1-C6 straight chain or branched alkoxy may be substituted with a C3-C7 cycloalkyl;

[0010] R4 and R5 may be the same or different, and are each independently selected from hydrogen, halogen, C1-C6 straight or branched alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, or C2-C6 alkynyloxy, wherein the C1-C6 alkoxy, C2-C6 alkenyloxy, or C2-C6 alkynyloxy may be substituted with a C3-C7 cycloalkyl group;

[0011] R6 is selected from one or more, the same or different, hydrogen, halogen, C1-C6 straight chain or branched alkyl, C1-C6 straight chain or branched haloalkyl, nitro, cyano, C1-C6 straight chain or branched alkoxy, or -NR a R b , where R a 、R b Each is independently selected from hydrogen or C1-C6 alkyl;

[0012] X1, X2, X3, X4 and X5 are each independently selected from -CH- or N; Ring B is selected from phenyl, pyridyl, pyrazinyl, quinolyl, pyrimidinyl or pyridazinyl, and the Ring B is optionally substituted by one or more, the same or different, hydrogen, halogen, C1-C6 straight or branched alkyl, nitro, cyano, C1-C6 straight or branched alkoxy, -NR a R b Substituted, where R a 、R b Each is independently selected from hydrogen or C1-C6 alkyl;

[0013] X is selected from:

[0014]

[0015] Wherein, W is CH2, O or NH;

[0016] Z is (CH2)m, wherein m=0 or 1, or Z is CR c R d , where R c is selected from H or linear or branched (C1-C4) alkyl, R d is a straight chain or branched (C1-C4) alkyl group;

[0017] A is selected from hydrogen, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl or heterocycloalkyl. When A is selected from aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl or heterocycloalkyl, the aromatic ring or heteroaromatic ring or heterocyclic ring may be substituted by one or more substituents that are the same or different and the substituents are selected from halogen, nitro, cyano, C1-C6 straight chain or branched chain alkyl, C1-C6 straight chain or branched chain haloalkyl, C1-C6 straight chain or branched chain alkoxy, -NHCOCH3 or -NR a R b , where R a 、R b Each is independently selected from hydrogen or C1-C6 alkyl, and the C1-C6 straight or branched alkoxy group may be substituted by a C3-C7 cycloalkyl group or a C3-C7 cycloalkyl group containing 1 to 2 heteroatoms.

[0018] In the general formula (I):

[0019] Preferably, R1 is selected from hydrogen, halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, ethyl, ethoxy, cyclopropylmethoxy.

[0020] Preferably, R2 and R3 may be the same or different and are each independently selected from hydrogen, halogen, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, trifluoromethyl, cyclopropylmethoxy, cyclohexylmethoxy, cyclopentylmethoxy, isobutyloxy, isopropyloxy, n-butyloxy, n-propyloxy, methoxy, ethoxy, and hydroxyl.

[0021] Preferably, R4 and R5 may be the same or different and are independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, allyloxy, propargyloxy.

[0022] Preferably, R6 is selected from one or more, same or different, hydrogen, halogen, nitro, cyano, methyl, methoxy, ethyl, ethoxy, -N(CH3)2, -NHCH3, trifluoromethyl, difluoromethyl.

[0023] Preferably, X1, X2, X3, X4 and X5 are each independently selected from -CH- or N; the B ring is selected from phenyl, pyridyl, pyrazinyl, quinolyl, pyrimidinyl or pyridazinyl, and the B ring is optionally substituted by one or more, the same or different, hydrogen, halogen, nitro, cyano, methyl, methoxy, ethyl, ethoxy, -N(CH3)2, -NHCH3, trifluoromethyl, difluoromethyl.

[0024] Preferably, X is selected from:

[0025]

[0026] Wherein, W is CH2, O or NH;

[0027] Z is (CH2)m, wherein m=0 or 1, or Z is CR c R d , where R c H, R d is -CH3, -CH2CH3 or -CH2CH2CH3;

[0028] A is selected from hydrogen, aryl or heteroaryl. When A is selected from aryl or heteroaryl, the aromatic ring or heteroaromatic ring may be substituted by one or more identical or different substituents selected from halogen, nitro, cyano, methyl, methoxy, ethyl, ethoxy, -NHCOCH3, -N(CH3)2, -NHCH3, trifluoromethyl or difluoromethyl.

[0029] In the general formula (I):

[0030] More preferably, R1 is hydrogen.

[0031] More preferably, R2 and R3 may be the same or different and are independently selected from halogen, difluoromethoxy, methoxy, and cyclopropylmethoxy.

[0032] More preferably, R4 and R5 are hydrogen.

[0033] More preferably, R6 is selected from one or more halogens.

[0034] More preferably, X1, X2, X3, X4 and X5 are each independently selected from -CH- or N, and only one is selected from N; Ring B is a pyridyl group, and the pyridine ring of the pyridyl group may be substituted by one or more halogens.

[0035] More preferably, X is selected from:

[0036]

[0037] Where W is O;

[0038] Z is (CH2)m, wherein m=0 or 1, or Z is CR c R d , where R c H, R d is -CH3, -CH2CH3 or -CH2CH2CH3;

[0039] A is selected from hydrogen, aryl or heteroaryl. When A is selected from aryl or heteroaryl, the aromatic ring or heteroaromatic ring may be substituted by one or more identical or different substituents selected from halogen, methyl, methoxy, -NHCOCH3, -N(CH3)2, -NHCH3, trifluoromethyl or difluoromethyl.

[0040] Further preferably, the quinoline derivatives of the present invention are selected from:

[0041] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one;

[0042] 2-(2-chloro-8-(difluoromethoxy)quinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one;

[0043] 2-(2-chloro-8-(cyclopropylmethoxy)quinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one;

[0044] 2-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-ol;

[0045] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl acetate;

[0046] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl propionate;

[0047] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl benzoate;

[0048] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-phenyl acetate;

[0049] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 3-phenylpropanoate;

[0050] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 3,4-dimethoxybenzoate;

[0051] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-(trifluoromethyl)benzoate;

[0052] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-(trifluoromethyl)benzoate;

[0053] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-methoxybenzoate;

[0054] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-chlorobenzoate;

[0055] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-methylbenzoate;

[0056] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-acetamidobenzoate;

[0057] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-methoxyphenyl)acetate;

[0058] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-chlorophenyl)acetate;

[0059] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-trifluoromethylphenyl)acetate;

[0060] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-methylphenyl)acetate;

[0061] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethylthiazole-2-carboxylate;

[0062] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethylthiophene-2-carboxylate;

[0063] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl tetrahydrothiophene-2-carboxylate;

[0064] 1-(2-Chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 1H-pyrrole-2-carboxylate.

[0065] Furthermore, the present invention also provides a method for preparing a quinoline derivative represented by general formula (I). The specific structure of the quinoline derivative represented by general formula (I) is shown in general formula 8. The preparation route of the quinoline derivative represented by general formula 8 is as follows:

[0066]

[0067] In the above preparation route, 8-hydroxyquinoline 1 is used as a starting material, which is oxidized with m-chloroperbenzoic acid to obtain intermediate 2, which is then rearranged under acetic anhydride conditions to produce intermediate 3. Intermediate 3 is rearranged through Fries to obtain intermediate 4. Intermediate 4 undergoes a substitution reaction to obtain intermediate 5, which is then oxidized under hydrobromic acid-dimethyl sulfoxide conditions to obtain intermediate 6, which is then oxidized with tert-butyl peroxide to obtain carboxylic acid 7. Finally, carboxylic acid 7 is condensed with 3,5-dichloro-4-methylpyridine to obtain the target compound, which is a quinoline derivative represented by general formula 8.

[0068] Furthermore, in the above preparation route, 8-hydroxyquinoline 1 is used as a starting material, and an oxidation reaction is carried out with m-chloroperbenzoic acid under low temperature conditions to obtain intermediate 2, the low temperature reaction temperature is -78 to 5°C, preferably 0°C, and the reaction solvent is acetonitrile, dichloromethane, chloroform, acetone or ethyl acetate, preferably dichloromethane; intermediate 2 is subjected to a high temperature reaction under acetic anhydride conditions to obtain intermediate 3, the high temperature reaction temperature is 100 to 140°C, preferably 120°C; then intermediate 3 is added under low temperature conditions in the presence of a Lewis acid, and then the temperature is raised to cause a Fries rearrangement reaction. Intermediate 4 should be obtained, the Lewis acid is aluminum trichloride, titanium tetrachloride, zinc chloride or tin tetrachloride, preferably aluminum trichloride, the low temperature reaction temperature is -10 to 10 ° C, preferably 0 ° C, and the reaction temperature after heating is 80 to 100 ° C, preferably 85 ° C, the reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride, preferably 1,2-dichloroethane; then the intermediate 4 is subjected to a nucleophilic substitution reaction with different halogenating agents under alkaline conditions to obtain intermediate 5, the halogenating agent is iodomethane, bromomethylcyclopropane, sodium difluorochloroacetate, bromoethane, bromocyclopentane, bromo Isobutane or isopropyl bromide, preferably methyl iodide, bromomethylcyclopropane or sodium difluorochloroacetate, the base in the reaction is triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate or sodium bicarbonate, preferably potassium carbonate; then intermediate 5 is oxidized under DMSO-HBr conditions to obtain intermediate 6, the reaction temperature is 60-150°C, preferably 90°C; intermediate 6 is oxidized to remove one carbon atom to obtain intermediate 7, the reaction solvent is DMSO, DMF, acetonitrile or acetone, preferably DMSO, and the oxidant is tert-butyl peroxide or m-chlorobenzene peroxide Acid, preferably tert-butyl peroxide; finally, the intermediate 7 is condensed with 3,5-dichloro-4-methylpyridine to obtain the target compound 8. In this step of the reaction: first, the acid chloride of the intermediate 7 is prepared, and the reaction solvent is anhydrous dichloromethane or anhydrous tetrahydrofuran, preferably anhydrous dichloromethane. Then, an alkaline reagent is reacted with 3,5-dichloro-4-methylpyridine, and then reacted with the acid chloride of the intermediate 7 to obtain the target compound 8. The alkaline reagent is n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide or lithium bistrimethylsilylamide, preferably lithium diisopropylamide.

[0069] Furthermore, the present invention also provides a method for preparing a quinoline derivative represented by general formula (I). The specific structure of the quinoline derivative represented by general formula (I) is shown in general formula 9 and general formula 10. The preparation routes of the quinoline derivatives represented by general formula 9 and general formula 10 are as follows:

[0070]

[0071] In the above preparation route, compound 8 in which R2 is a methoxy group undergoes a reduction reaction to obtain target compound 9, and then compound 9 undergoes a condensation reaction with different carboxyl compounds to obtain target compound 10.

[0072] Furthermore, in the above preparation route, compound 8 wherein R2 is methoxy is reacted with a reducing agent to obtain target compound 9, wherein the reducing agent is sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride or potassium borohydride, preferably sodium borohydride, and the solvent is methanol, ethanol, propanol, n-butanol or isopropanol, preferably methanol; then compound 9 is subjected to a condensation reaction with different carboxyl compounds to obtain target compound 10, wherein the condensation agent is EDC, EDCI, DCC, HATU or PPA, preferably EDC, and the solvent is N,N-dimethylformamide, tetrahydrofuran, dichloromethane, 1,4-dioxane, N,N-dimethylacetamide or acetonitrile, preferably N,N-dimethylformamide.

[0073] In a second aspect, the present invention provides use of the quinoline derivatives described in the first aspect in the preparation of drugs for preventing or treating diseases associated with PDE4.

[0074] Furthermore, the present invention provides use of the quinoline derivatives described in the first aspect above in the preparation of drugs for preventing or treating inflammatory diseases.

[0075] In a third aspect, the present invention provides a pharmaceutical composition comprising the quinoline derivative described in the first aspect and a pharmaceutically acceptable carrier or excipient.

[0076] In a fourth aspect, the present invention provides use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating diseases associated with PDE4.

[0077] Furthermore, the present invention provides use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating inflammatory diseases.

[0078] In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0079] In the present invention, the term "alkyl" (including when used alone and contained in other groups) means branched and straight-chain saturated hydrocarbon groups including 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof.

[0080] In the present invention, the term "alkoxy" refers to an alkyl group with the stated number of carbon atoms connected via an oxygen bridge. Thus, "alkoxy" encompasses the above definition of alkyl.

[0081] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon double bond. Preferably, there is one carbon-carbon double bond, and more preferably, the carbon-carbon double bond is connected to the rest of the compound. The number of carbon atoms can range from 2 to 12, preferably from 2 to 5, and more preferably 2, such as ethenyl, 1-propenyl, 1-butenyl, and the like.

[0082] In the present invention, the term "alkenyloxy" refers to an alkenyl group with the stated number of carbon atoms connected via an oxygen bridge. Thus, "alkenyloxy" encompasses the above definition of alkenyl.

[0083] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon triple bond. Preferably, there is one carbon-carbon triple bond, and more preferably, the carbon-carbon triple bond is used to connect the other moieties of the compound. The number of carbon atoms can range from 2 to 12, preferably from 2 to 5, and more preferably 2, such as ethynyl, 1-propynyl, 1-butynyl, and the like.

[0084] In the present invention, the term "alkynyloxy" refers to an alkynyl group with the stated number of carbon atoms connected via an oxygen bridge. Thus, "alkynyloxy" encompasses the above definition of alkynyl.

[0085] In the present invention, the term "cycloalkyl" refers to a non-aromatic saturated carbocyclic ring system containing a specified number of carbon atoms, which can be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system connected to the base molecule through the carbon atoms of the cycloalkyl ring. Typically, the cycloalkyl group of the present invention contains 3-12 carbon atoms, preferably 3-8 carbon atoms. Examples of cycloalkyl groups often include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0086] In the present invention, the term "aryl" refers to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having known aromatic characteristics, wherein at least one ring contains a completely conjugated π-electron system. Typically, an aryl group contains 6 to 20 carbon atoms as ring members, preferably 6 to 14 carbon atoms or more preferably 6 to 12 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl.

[0087] In the present invention, the term "heteroaryl" refers to a monocyclic or fused bicyclic or polycyclic ring system with a known aromaticity characteristic, which contains a specified number of ring atoms and includes at least one heteroatom selected from N, O and S as a ring member in the aromatic ring. The inclusion of heteroatoms allows for the aromaticity of 5-membered rings and 6-membered rings. Typically, the heteroaryl group contains 5-20 ring atoms, preferably 5-14 ring atoms, more preferably 5-12 ring atoms. The heteroaryl ring is connected to the base molecule through the ring atoms of the heteroaromatic ring, thereby maintaining aromaticity. Examples of heteroaryl groups often include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or benzotriazolyl.

[0088] In the present invention, the term "heterocyclyl" is used interchangeably to refer to a non-aromatic saturated ring system containing a specified number of ring atoms, which includes at least one heteroatom selected from N, O and S as a ring member. Typically, the heterocyclyl of the present invention contains 3-12 ring atoms, preferably 3-8 ring atoms, and more preferably 3-6 ring atoms. Examples of heterocyclyls often include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, etc.

[0089] In the present invention, the term "geometric isomer" means a compound that can exist in cis-, trans- (trans), anti- (anti), entgegen (E) and zusammen (Z) forms and mixtures thereof.

[0090] In the present invention, the term "enantiomer" refers to a compound with one or more chiral centers, each of which can exist in the R or S configuration. Enantiomers include all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.

[0091] Compared with the prior art, the present invention has the following beneficial effects:

[0092] The quinoline derivatives of the present invention have novel structures and exhibit good PDE4 inhibitory activity, and can be used as PDE4 inhibitors for preventing or treating diseases related to PDE4, especially inflammatory diseases. DETAILED DESCRIPTION

[0093] The embodiments of the present invention are described in detail below. The embodiments are given to better illustrate the contents of the present invention and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0094] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0095] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0096] Example 1

[0097] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one, i.e., compound 8

[0098]

[0099] The preparation route is as follows:

[0100]

[0101] The specific steps include:

[0102] (1) Synthesis of 8-hydroxyquinoline nitrogen oxide compound 2

[0103] 8-Hydroxyquinoline (20 g, 0.138 mol) was dissolved in DCM (500 mL). mCPBA (30 g, 0.174 mol) was added portionwise under an ice bath. After a short while, the reaction was allowed to proceed to room temperature. The reaction was allowed to proceed for 5 h. TLC confirmed the reaction was complete. The mixture was cooled to room temperature and poured into 8% NaHCO₃ (500 mL) with vigorous stirring. The mixture was stirred until no bubbles were generated. Stirring was stopped and the mixture was filtered through celite. The filtrate was collected and extracted. The organic layer was collected and dried to obtain 18 g of compound 2 as a red solid with a yield of 80.9%.

[0104] (2) Synthesis of 2-oxo-1,2-dihydroquinoline-8-acetate, Compound 3

[0105] Compound 2 (21 g, 0.13 mol) was dissolved in acetic anhydride (120 mL), heated to 100°C, and reacted for 3 h. The reaction was completed after monitoring by TLC. After cooling to room temperature, the mixture was stirred in an ice bath and filtered. The filter cake was washed with a small amount of acetic anhydride and dried to obtain 20 g of a white solid, namely compound 3, with a yield of 75.8%.

[0106] (3) Synthesis of 5-acetyl-8-hydroxyquinolin-2(1H)-one, compound 4

[0107] Anhydrous AlCl3 (5.67 g, 0.042 mol) was dissolved in DCE (36 mL), and compound 3 (5 g, 0.025 mol) was slowly added under ice bath. After the addition was completed, the mixture was returned to room temperature and heated to 85°C. 20 drops of acetyl chloride were added dropwise and the reaction was allowed to proceed for 3 h. The reaction was monitored to be complete by TLC. The mixture was cooled to room temperature and the reaction solution was slowly poured into 2N HCl (300 mL) solution under ice bath. The mixture was stirred for 2 h, filtered, and dried to obtain 4.5 g of a white solid, i.e., compound 4, with a yield of 88.6%.

[0108] (4) Synthesis of 5-acetyl-8-methoxyquinolin-2(1H)-one, Compound 5

[0109] Compound 4 (3 g, 0.0148 mol) and K2CO3 (3.05 g, 0.022 mol) were dissolved in DMF (35 mL), stirred at room temperature for 15 min, and MeI (1.0 mL, 0.016 mol) was added dropwise. The reaction was allowed to react at room temperature for 6 h. The reaction was completed after monitoring by TLC. The mixture was poured into saturated brine (200 mL), stirred, and filtered to obtain 2.9 g of a yellow solid, namely compound 5, with a yield of 90.6%.

[0110] (5) Synthesis of 5-(2,2-dihydroxyacetyl)-8-methoxyquinolin-2(1H)-one, Compound 6

[0111] Compound 5 (5 g, 0.023 mol) was dissolved in DMSO (50 mL), heated to 90°C, and 40% HBr (10.3 mL, 0.072 mol) solution was added dropwise. The reaction was allowed to proceed for 1 h. The reaction was monitored to be complete by TLC. After cooling to room temperature, the mixture was poured into water (400 mL), stirred, and filtered to obtain a light yellow solid, namely compound 6, totaling 4.8 g, with a yield of 90.6%.

[0112] (6) Synthesis of 8-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylic acid, compound 7

[0113] Compound 6 (8.7 g, 0.038 mol) was dissolved in DMSO (50 mL), heated to 90°C, and t-BuOOH (4.21 mL, 0.042 mol) was added. The reaction was allowed to proceed for 30 min. The reaction was completed as monitored by TLC. After cooling to room temperature, a yellow solid precipitated, which was filtered to obtain a light yellow solid, compound 7 (7 g, yield 84.3%).

[0114] (7) Synthesis of 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one, Compound 8

[0115] Compound 7 (100 mg, 0.456 mmol) was dissolved in anhydrous dichloromethane (5 mL), and SOCl2 (300 μL) was added. The mixture was heated to 40°C and allowed to react for 2 h. The reaction solution was then dried under reduced pressure and dissolved in anhydrous THF (5 mL). 3,5-Dichloro-4-methylpyridine (295 mg, 1.824 mmol) was dissolved in anhydrous THF (5 mL). LDA (1.09 mL, 2.189 mmol) was added at -78°C and stirred for 15 min. The above-mentioned acid chloride-THF solution was added dropwise to the reaction solution. The reaction was continued for 20 min after the addition. The reaction was complete after TLC monitoring. The reaction solution was poured into an ice-water mixture (50 mL), stirred, and filtered to obtain a white solid. The white solid, compound 8, was purified by column chromatography to obtain 35 mg of the white solid, with a yield of 20.1%. 1 H NMR (600MHz, DMSO-d6) δ9.19(d,J=9.1Hz,1H),8.69(d,J=8.7Hz,3H),7.74(d,J=9.1Hz,1H),7.42(d,J=8.4Hz,1H),4.92(s,2H),4.11(s,3H).Calcd.for C 17 H 12 Cl3N2O2 + [M+H] + 380.9959;found380.9963.

[0116] Example 2

[0117] 1-(2-Chloro-8-(difluoromethoxy)quinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one

[0118]

[0119] With reference to the preparation method of Example 1, the compound of Example 2 can be obtained by replacing iodomethane in step (4) with sodium difluorochloroacetate in equal proportions. 1 H NMR(600MHz,DMSO-d6)δ9.06(d,J=9.1Hz,1H),8.76–8.66(m,3H),7.84(d,J=9. 1Hz,1H),7.78(d,J=4.6Hz,1H),7.59(d,J=73.3Hz,1H),4.97(s,2H).Calcd.for C 17 H 10 Cl3F2N2O2 + [M+H] + 416.9770;found416.9755.

[0120] Example 3

[0121] 1-(2-chloro-8-(cyclopropylmethyloxy)quinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one

[0122]

[0123] With reference to the preparation method of Example 1, the iodomethane in step (4) was replaced with bromomethylcyclopropane in equal proportions to obtain the compound of Example 3 as a white solid in a yield of 25.7%. 1 H NMR (600MHz, DMSO-d6) δ9.21(d,J=9.1Hz,1H),8.69(s,2H),8.66(d,J=8.5Hz,1H),7.74(d,J=9.0Hz,1H),7.39(d,J= 8.5Hz,1H),4.92(s,2H),4.19(d,J=7.1Hz,2H),1.48–1.39(m,1H),0.71–0.66(m,2H),0.48–0.44(m,2H).Calcd.for C 20 H 16 Cl3N2O2 + [M+H] + 421.0272;found421.0260.

[0124] Example 4

[0125] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-ol, i.e., compound 9

[0126] The preparation route is as follows:

[0127]

[0128] The specific steps include:

[0129] Compound 8 (2 g, 0.00524 mol) was dissolved in a mixed solvent of methanol (40 mL) and dichloromethane (20 mL). Sodium borohydride (0.198 g, 0.0524 mol) was added portionwise under ice-bath conditions. The mixture was stirred for 2 h. The reaction was completed after monitoring by TLC. The mixture was filtered to obtain 1.7 g of a white solid, i.e., compound 9, with a yield of 85%.

[0130] Example 5

[0131] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl acetate

[0132]

[0133] The preparation steps include:

[0134] Compound 9 (100 mg, 0.26 mmol), acetic acid (20 mg, 0.34 mmol), EDC (150 mg, 0.78 mmol) and DMAP (32 mg, 0.26 mmol) were added to 10 mL of anhydrous dichloromethane. As the reaction continued, the system gradually became clear and transparent. The reaction was allowed to proceed for 2 h. The reaction was monitored by TLC to be complete. The product was extracted with 1N HCl, and the organic layer was collected and extracted with 1N NaHCO3. The organic layer was retained and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 43 mg of the compound of Example 5 as a white solid with a yield of 39.1%. 1 H NMR (600MHz, DMSO-d6) δ8.66–8.51(m,3H),7.71(d,J=9.0Hz,1H),7.63(d,J=8.2Hz,1H),7.26(d,J=8.3Hz,1H),6.58(d d,J=9.1,5.0Hz,1H),3.96(s,3H),3.67(dd,J=13.8,9.2Hz,1H),3.42(dd,J=13.8,5.0Hz,1H),1.94(s,3H).Calcd.for C 19 H 16 Cl3N2O3 + [M+H] + 425.0221; found 425.0201.

[0135] Example 6

[0136] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl propionate

[0137]

[0138] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 33.8%. 1 H NMR (600MHz, DMSO-d6) δ8.64(d,J=9.0Hz,1H),8.61(s,2H),7.74(d,J=8.9Hz,1H),7.66(d,J=8.2Hz,1H),7.29(d,J=8.3Hz,1H),6.63(dd,J=9 .5,4.9Hz,1H),3.98(s,3H),3.70(dd,J=13.8,9.4Hz,1H),3.44(dd,J=13.8,4.9Hz,1H),2.29–2.24(m,2H),0.90(t,J=7.5Hz,3H).Calcd.forC20 H 18 Cl3N2O3 + [M+H] + 439.0378;found439.0376.

[0139] Example 7

[0140] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl benzoate

[0141]

[0142] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 28.2%. 1 H NMR (600MHz, DMSO-d6) δ8.79(d,J=9.0Hz,1H),8.60(s,2H),7.99–7.95(m,2H),7.82–7.78(m,2H),7.69–7.64(m,1H),7.52(t,J=7.8Hz,2H ),7.31(d,J=8.3Hz,1H),6.87(dd,J=9.7,4.6Hz,1H),3.98(s,3H),3.88(dd,J=14.1,9.8Hz,1H),3.58(dd,J=14.0,4.7Hz,1H).Calcd.for C 24 H 18 Cl3N2O3 + [M+H] + 487.0378; found 487.0365.

[0143] Example 8

[0144] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-phenylacetate

[0145]

[0146] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 25.8%. 1H NMR (600MHz, DMSO-d6) δ8.56(d,J=9.0Hz,3H),7.66(d,J=8.9Hz,1H),7.57(d,J=8.2Hz,1H),7.25–7.22(m,4H),7.09–7.05(m,2 H),6.60(dd,J=9.5,4.8Hz,1H),3.97(s,3H),3.68(dd,J=13.9,9.5Hz,1H),3.65–3.58(m,2H),3.42(d,J=9.0Hz,1H).Calcd.for C 25 H 20 Cl3N2O3 + [M+H] + 501.0534;found501.0531.

[0147] Example 9

[0148] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 3-phenylpropanoate

[0149]

[0150] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 16.3%. 1 H NMR(600MHz,DMSO-d6)δ8.60(d,J=8.2Hz,3H),7.70(d,J=8.9Hz,1H),7.58(d ,J=8.2Hz,1H),7.24(d,J=8.3Hz,1H),7.18–7.13(m,3H),7.04–7.01(m,2H), 6.57(dd,J=9.4,4.9Hz,1H),3.98(s,3H),3.68(dd,J=13.9,9.4Hz,1H),3.42 (dd,J=13.9,5.0Hz,1H),2.73(t,J=7.4Hz,2H),2.60–2.57(m,2H).Calcd.for C 26 H 22 Cl3N2O3 + [M+H] + 515.0691; found 515.0673.

[0151] Example 10

[0152] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethylthiazole-2-carboxylate

[0153]

[0154] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 13.7%. 1 H NMR(600MHz,Chloroform-d)δ8.65(d,J=8.9Hz,1H),8.36(s,2H),7.97(d,J=3.0Hz,1H),7.65(d,J=8.2Hz,1H),7.57(d,J=3.1Hz,1H),7.46(d,J=8 .8Hz,1H),7.00(d,J=8.2Hz,1H),6.87(dd,J=9.1,5.6Hz,1H),4.00(s,3H),3.91(dd,J=13.7,9.1Hz,1H),3.55(dd,J=13.7,5.6Hz,1H).Calcd.forC 21 H 15 Cl3N3O3S + [M+H] + 493.9894;found493.9931.

[0155] Example 11

[0156] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethylthiophene-2-carboxylate

[0157]

[0158] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 13.7%. 1 H NMR(600MHz,Chloroform-d)δ8.68(d,J=9.0Hz,1H),8.40(s,2H),7.71(dd,J=3.8,1.2Hz,1H),7.63(d,J=8.2Hz,1H),7.50(dd,J=5.0,1.3Hz,1H),7.47 (d,J=8.9Hz,1H),7.04–6.99(m,2H),6.76(dd,J=10.1,4.6Hz,1H),4.00(s,3H),3.87(dd,J=13.8,10.1Hz,1H),3.41(dd,J=13.8,4.6Hz,1H).Calcd.for C 22 H 16 Cl3N2O3S + [M+H] + 492.9942;found492.9931.

[0159] Example 12

[0160] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl tetrahydrothiophene-2-carboxylate

[0161]

[0162] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 13.7%. 1 H NMR(600MHz,Chloroform-d)δ8.60(d,J=8.9Hz,1H),8.49(d,J=1.7Hz,2H),7.66(d,J=8.3 Hz,1H),7.50(d,J=9.0Hz,1H),7.09(d,J=8.3Hz,1H),6.61(dd,J=9.7,4.8Hz,1H),4.08(s, 3H),3.87(dd,J=7.2,4.7Hz,1H),3.79(dd,J=13.6,9.9Hz,1H),3.42(dd,J=13.5,4.8Hz,1 H),2.82–2.78(m,2H),2.15–2.10(m,1H),2.03–1.98(m,2H),1.91–1.86(m,1H).Calcd.for C 22 H 20 Cl3N2O3S + [M+H] + 497.0225; found 497.0233.

[0163] Example 13

[0164] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 1H-pyrrole-2-carboxylate

[0165]

[0166] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 11.2%. 1H NMR(600MHz,Chloroform-d)δ8.74(d,J=8.9Hz,1H),8.48(s,2H),7.70(d,J=8.1Hz,1H),7.53(d,J=8.9Hz,1H),7.08(d,J=8.1Hz,1H),7.00(s,1H),6 .94(s,1H),6.78(dd,J=10.4,4.4Hz,1H),6.26(q,J=3.0Hz,1H),4.07(s,3H),3.91(dd,J=13.8,10.3Hz,1H),3.45(dd,J=13.8,4.4Hz,1H).Calcd.for C 22 H 17 Cl3N3O3 + [M+H] + 476.0330; found 476.0327.

[0167] Example 14

[0168] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 3,4-dimethoxybenzoate

[0169]

[0170] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 17.6%. 1 H NMR (600MHz, DMSO-d6) δ8.81(d,J=9.0Hz,1H),8.63(s,2H),7.80(d,J=8.9Hz,1H),7. 76(d,J=8.2Hz,1H),7.59(dd,J=8.4,2.0Hz,1H),7.42(d,J=2.0Hz,1H),7.31(d,J=8. 3Hz,1H),7.06(d,J=8.5Hz,1H),6.81(dd,J=10.1,4.5Hz,1H),3.98(s,3H),3.86(dd, J=14.0,10.1Hz,1H),3.82(d,J=10.0Hz,6H),3.55(dd,J=14.1,4.6Hz,1H).Calcd.for C 26 H 22 Cl3N2O5 + [M+H] + 547.0589; found 547.0577.

[0171] Example 15

[0172] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-trifluoromethylbenzoate

[0173]

[0174] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 21.7%. 1 H NMR (600MHz, DMSO-d6) δ8.77(d,J=9.0Hz,1H),8.60(s,2H),8.16(d,J=8.4Hz,2H),7.91(d,J=8.3Hz,2H),7.80(dd,J=17.0,8.6Hz ,2H),7.31(d,J=8.3Hz,1H),6.90(dd,J=9.6,4.7Hz,1H),3.98(s,3H),3.93–3.88(m,1H),3.61(dd,J=14.1,4.7Hz,1H).Calcd.for C 25 H 17 Cl3F3N2O3 + [M+H] + 555.0251;found555.0241.

[0175] Example 16

[0176] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-methoxybenzoate

[0177]

[0178] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 19.6%. 1 H NMR (600MHz, DMSO-d6) δ8.78(d,J=9.0Hz,1H),8.60(s,2H),7.94–7.90(m,2H),7.78(dd,J=10.8,8.6Hz,2H),7.31(d,J=8.3Hz,1H),7.06– 7.02(m,2H),6.84(dd,J=9.8,4.5Hz,1H),3.98(s,3H),3.86(dd,J=14.0,9.9Hz,1H),3.83(s,3H),3.55(dd,J=14.0,4.6Hz,1H).Calcd.for C 25 H 20 Cl3N2O4 + [M+H] + 517.0483; found 517.0484.

[0179] Example 17

[0180] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-chlorobenzoate

[0181]

[0182] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 15.2%. 1 H NMR (600MHz, DMSO-d6) δ8.76(d,J=9.0Hz,1H),8.60(s,2H),7.99–7.95(m,2H),7.78(t,J=8.9Hz,2H),7.64–7.59(m,2H),7.31(d ,J=8.3Hz,1H),6.86(dd,J=9.6,4.7Hz,1H),3.98(s,3H),3.87(dd,J=14.0,9.6Hz,1H),3.58(dd,J=14.1,4.7Hz,1H).Calcd.for C 24 H 17 Cl4N2O3 + [M+H] + 520.9988;found520.9981.

[0183] Example 18

[0184] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-acetamidobenzoate

[0185]

[0186] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 16.8%. 1 H NMR(600MHz,Chloroform-d)δ8.74(d,J=8.9Hz,1H),8.45(s,2H),8.00–7.94(m ,2H),7.83(s,1H),7.72(d,J=8.2Hz,1H),7.60(d,J=8.4Hz,2H),7.53(d,J=8.8 Hz,1H),7.08(d,J=8.2Hz,1H),6.89(dd,J=10.2,4.5Hz,1H),4.04(s,3H),3.94 (dd,J=13.8,10.2Hz,1H),3.48(dd,J=13.8,4.6Hz,1H),2.19(s,3H).Calcd.for C 26 H 21 Cl3N3O4+ [M+H] + 544.0592; found 544.0580.

[0187] Example 19

[0188] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-methoxyphenyl)acetate

[0189]

[0190] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 25.2%. 1 H NMR (600MHz, DMSO-d6) δ8.57(s,2H),8.54(d,J=8.9Hz,1H),7.65(d,J=8.9Hz,1H),7.57(d,J=8.2Hz,1H),7.24(d,J=8.3Hz,1H),6.99–6.96(m,2H),6. 80–6.78(m,2H),6.58(dd,J=9.5,5.0Hz,1H),3.97(s,3H),3.72(s,3H),3.6 8(dd,J=13.9,9.5Hz,1H),3.56–3.49(m,2H),3.43–3.41(m,1H).Calcd.for C 26 H 22 Cl3N2O4 + [M+H] + 531.0640;found 531.0615.

[0191] Example 20

[0192] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-chlorophenyl)acetate

[0193]

[0194] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 23.2%. 1H NMR (600MHz, DMSO-d6) δ8.56(s,2H),8.53(d,J=9.0Hz,1H),7.66(d,J=8.9Hz,1H),7.58(d,J=8.2Hz,1H),7.33–7.29(m,2H),7.25(d,J=8.3H z,1H),7.13–7.10(m,2H),6.60(dd,J=9.5,5.0Hz,1H),3.98(s,3H),3.70–3.67(m,1H),3.66–3.60(m,2H),3.42(d,J=9.0Hz,1H).Calcd.for C 25 H 19 Cl4N2O3 + [M+H] + 535.0144; found 535.0142.

[0195] Example 21

[0196] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-trifluoromethylphenyl)acetate

[0197]

[0198] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 28.4%. 1 H NMR(600MHz,Chloroform-d)δ8.46(d,J=9.3Hz,3H),7.53(d,J=7.7Hz,2H),7.47(d,J=7.9Hz,1H),7.42(d,J=8.8Hz,1H),7.21(d,J=7.8Hz,2H),7.0 1(d,J=8.0Hz,1H),6.68(dd,J=10.0,4.4Hz,1H),4.07(s,3H),3.79(dd,J=13.6,9.9Hz,1H),3.61(s,2H),3.39(dd,J=13.6,4.5Hz,1H).Calcd.forC 26 H 19 Cl3F3N2O3 + [M+H] + 569.0408;found 569.0408.

[0199] Example 22

[0200] 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-methylphenyl)acetate

[0201]

[0202] The preparation method is the same as that of Example 5, the product is a white solid, and the yield is 19.5%. 1 H NMR(600MHz,Chloroform-d)δ8.46(d,J=8.9Hz,1H),8.41(s,2H),7.49(d,J=8.2Hz,1H),7.35(d,J=8.9Hz,1H),7.02(dd,J=16.3,8.0Hz,3H),6.95–6. 92(m,2H),6.62(dd,J=9.9,4.8Hz,1H),4.06(s,3H),3.76(dd,J=13.7,10.0 Hz,1H),3.49(s,2H),3.36(dd,J=13.7,4.8Hz,1H),2.33(s,3H).Calcd.for C 26 H 22 Cl3N2O3 + [M+H] + 515.0691; found 515.0683.

[0203] Example 23

[0204] Pharmacological activity experiment part: Study on in vitro enzyme inhibitory activity of quinoline derivatives of the present invention

[0205] Experimental Materials:

[0206] Multifunctional microplate reader (PerkinElmer EnVision), PDE4 protein (Sigma- ), AMP-Glo TM Detection kit (Promega), centrifuge (Thermo Fisher), 384-well assay plate (PerkinElmer)

[0207] Experimental steps:

[0208] Dilute 5× buffer to a working concentration using ddH2O; transfer 100 nL of the compound's DMSO solution to the assay plate using the liquid workstation Echo; dilute PDE4B1 protein to a working concentration using buffer, transfer 5 μL per well to the assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 20 minutes; dilute cAMP to a working concentration using buffer and transfer 5 μL per well to the assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 10 minutes; add 5 μL of the detection reagent AMP-Glo ​​to each well of the assay plate. TM, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes; 10 μL of detection reagent AMP detection solution was added to each well of the test plate, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes; the signal value was read on the microplate reader EnVision. In order to measure the inhibitory activity of each compound on PDE4, at least eight concentrations of each compound were prepared to calculate the IC 50 All experimental data were analyzed using GraphPad Prism version 8.0. Rolipram was used as a positive control to test the IC 50 The value was 44.64 nM. The results are shown in Table 1.

[0209] Table 1: Inhibitory effects of the compounds of the present invention on PDE4

[0210] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> Example 1 0.019 Example 12 1.73 Example 2 0.011 Example 13 1.67 Example 3 298.40 Example 14 11.14 Example 4 2.85 Example 15 7.44 Example 5 0.72 Example 16 1.32 Example 6 1.38 Example 17 7.01 Example 7 1.14 Example 18 14.04 Example 8 0.41 Example 19 0.97 Example 9 3.71 Example 20 3.88 Example 10 6.44 Example 21 2.62 Example 11 2.23 Example 22 2.03

[0211] The test results in Table 1 indicate that the quinoline derivatives of the present invention have good inhibitory activity against PDE4 and represent a series of PDE4 inhibitors with novel structures. They can be used to prevent or treat PDE4-related diseases, particularly inflammatory diseases. They possess potential application prospects and clinical research value.

[0212] Obviously, the above embodiments are merely examples for the purpose of illustrating the present invention and are not intended to limit the embodiments of the present invention. Those skilled in the art may make various modifications and variations to the present invention without departing from the spirit and scope of the present invention. Thus, to the extent such modifications and variations fall within the scope of the claims and their equivalents, the present invention is intended to encompass such modifications and variations.

Claims

1. A quinoline derivative, characterized in that The derivative is a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof; General formula (I) wherein R1 is selected from hydrogen; R2 is selected from methoxy, R3 is selected from halogen; R4 and R5 are independently selected from hydrogen; R6 is selected from one or more halogens; X1, X2, X3, X4 and X5 are each independently selected from -CH- or N, and only one of them is selected from N; Ring B is a pyridyl group, and the pyridine ring of the pyridyl group is substituted by one or more halogens; X is selected from: Wherein, W is CH2, O or NH; Z is (CH2)m, where m=0 or 1, or Z is CR c R d , where R c is selected from H or linear or branched (C1-C4) alkyl, R d is a straight chain or branched (C1-C4) alkyl group; A is selected from phenyl, benzyl, phenylpropyl, thiazolyl, tetrahydrothiophenyl, pyrrolyl, dimethoxyphenyl, trifluoromethylphenyl, methoxyphenyl, chlorophenyl, acetamidophenyl, methoxybenzyl, chlorobenzyl, trifluoromethylbenzyl or methylbenzyl.

2. The quinoline derivative according to claim 1, characterized in that In the general formula (I), X is selected from: Wherein, W is CH2, O or NH; Z is (CH2)m, where m=0 or 1, or Z is CR c R d , where R c H, R d It is -CH3, -CH2CH3 or -CH2CH2CH3.

3. The quinoline derivative according to claim 1, wherein In the general formula (I), X is selected from: Where W is O; Z is (CH2)m, where m=0 or 1, or Z is CR c R d , where R c H, R d It is -CH3, -CH2CH3 or -CH2CH2CH3.

4. A quinoline derivative, characterized in that The derivative is selected from: 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one; 1-(2-chloro-8-(difluoromethoxy)quinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-one; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethan-1-ol; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl acetate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl propionate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl benzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-phenyl acetate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 3-phenylpropanoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 3,4-dimethoxybenzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-(trifluoromethyl)benzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-(trifluoromethyl)benzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-methoxybenzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-chlorobenzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-methylbenzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 4-acetamidobenzoate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-methoxyphenyl)acetate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-chlorophenyl)acetate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-trifluoromethylphenyl)acetate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl 2-(4-methylphenyl)acetate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethylthiazole-2-carboxylate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethylthiophene-2-carboxylate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl tetrahydrothiophene-2-carboxylate; 1-(2-chloro-8-methoxyquinolin-5-yl)-2-(3,5-dichloropyridin-4-yl)ethyl H -pyrrole-2-carboxylate.

5. Use of the quinoline derivative according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating a disease associated with PDE4.

6. Use of the quinoline derivative according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating inflammatory diseases.

7. A pharmaceutical composition, characterized in that The composition comprises the quinoline derivative according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

8. Use of the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing or treating diseases associated with PDE4.

9. Use of the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing or treating inflammatory diseases.

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