Quinoline carboxylic acid compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a quinoline carboxylic acid compound and a preparation method, a pharmaceutical composition and application thereof. The invention provides a compound as shown in a formula (I) or a stereoisomer, a geometric isomer, a tautomer, a deuterated compound, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrugs of the stereoisomer, the geometric isomer, the tautomer, the deuterated compound, the nitrogen oxide, the solvate, the metabolite and the pharmaceutically acceptable salt of the compound as shown in the formula (I), and also provides a preparation method of the compound. The invention also relates to application of the compound in preparation of drugs for thyroid hormone receptor mediated diseases. According to the compound, good THR-beta agonist activity is maintained, selectivity to THR-alpha and druggability of the compound are improved, and certain activity is shown in an in-vivo pharmacological experiment.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to quinoline carboxylic acid compounds, their preparation methods, pharmaceutical compositions and uses. Background Art

[0002] Thyroid hormones (THs) are the endogenous ligands of thyroid hormone receptors (THRs), including 3,5,3'-L-triiodothyronine (T3) and 3,5,3',5'-L-tetraiodothyronine (T4), and mediate the homeostasis of biological growth, development and metabolism. T4 is the general form of TH, secreted and released by the thyroid gland. Once released, T4 is converted into the active form T3 of TH by type I deiodinase (D1) and type II deiodinase (D2), or can also be converted into the inactive 3,3',5'-L-triiodothyronine (reverse T3 / rT3) by type III deiodinase (D3) to maintain the balance of thyroid hormone function.

[0003] THRs are ligand-dependent transcription factors that belong to the nuclear receptor superfamily and are involved in many important physiological functions. THRs contain multiple subtypes, each of which is composed of four domains shared by nuclear hormone receptors and has a high degree of homology. Among them, Rα is important for heart rate regulation, TRα1 is mainly expressed in myocardial and skeletal muscles, osteoclasts and many areas of the brain, and TRα2 is not regulated by T3; TRβ accounts for about 80% of T3-bound THRs and plays an important role in lipid metabolism and the inhibition of thyroid-stimulating hormone (TSH). TRβ1 is dominant in the liver, and TRβ2 plays a key role in regulating the hypothalamus-pituitary-thyroid axis. TRβ1 (hereinafter referred to as THRβ) is the main subtype of THR in the liver and is mainly responsible for lowering cholesterol levels. Thyrotoxicosis characterized by tachycardia, arrhythmia, and muscle atrophy is mainly mediated by TRα1 (hereinafter referred to as THRα), and the side effects of TSH inhibition are mainly mediated by TRβ2 in the pituitary. The beneficial metabolic effects of THRβ activation include lowering low-density lipoprotein (LDL) cholesterol, increasing liver metabolic rate, and reducing body weight. Therefore, thyroid hormone receptor beta (THRβ) has attracted extensive attention as a molecular target for the treatment of dyslipidemia and NASH.

[0004] Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and THRβ are closely related. THRβ improves metabolic disorders by enhancing fatty acid decomposition, thereby reducing liver fat content. THRβ oral agonist Resmetirom is the only FDA-approved drug for the treatment of non-alcoholic fatty liver disease (NASH) with its excellent Phase III clinical data. Therefore, THRβ is currently widely concerned as a very potential target for the treatment of NASH.

[0005] Currently, THRβ agonists have a single structural type, and it is difficult to separate the toxic side effects caused by THRα activation to achieve selectivity. It is necessary to develop THRβ agonists with stronger effects and higher selectivity. Summary of the invention

[0006] In order to achieve the above-mentioned object, the first aspect of the present invention provides a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, deuterated compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I):

[0007]

[0008] Among them, R6, R7, and R8 are each independently located on any substitutable ring atom of the quinoline ring;

[0009] R6 and R8 are each independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, phenyl, C5-C7 heteroaryl, C5-C6 substituted heteroaryl; and R6 and R8 are different or identical substituents;

[0010] R7 is one or more (such as 1, 2, 3, or 4) substituents selected from the group consisting of: H, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, located on the quinoline benzene ring;

[0011] X is selected from the group consisting of: -O-, -CH2-, -C(=O)-, -CH(OH), -S-, -NR9-, -NH(=O)

[0012] R9 is a substituent selected from the group consisting of: H, deuterium, tritium, halogen, C1-C6 alkyl;

[0013] R1, R2, R3, and R4 are each independently selected from the group consisting of: H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR a , -NR b R c , -SR d , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C5-C6 aryl, or 5- to 6-membered heteroaryl;

[0014] R a R b R c R d are each independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, C5-C6 aryl, or 5- to 6-membered heteroaryl.

[0015] Y is -OR 10 -, -CR 10 -, -SR 10 -, -NHC(=O)R 10 -, -C(=O)NHR 10 -- or -NHCHR 10 -; R 10Selected from hydrogen and substituted or unsubstituted C0-C6 alkyl, wherein the substituent of the substituted alkyl is selected from halogen atoms, hydroxyl groups, and Cl-C6 alkoxy groups;

[0016] R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C5-C6 aryl, or 5-6 membered heteroaryl;

[0017] The second aspect of the present invention discloses the use of the above-mentioned compound or its stereoisomer, geometric isomer, tautomer, deuterated compound, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug in the preparation of a drug for preventing, treating or alleviating a disease;

[0018] The disease includes diseases mediated by thyroid hormone receptors,

[0019] The diseases mediated by thyroid hormone receptors are selected from: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer;

[0020] The disease also includes androgenic alopecia or alopecia caused by thyroid abnormalities.

[0021] The third aspect of the present invention discloses a pharmaceutical composition, using the above-mentioned compound or its stereoisomer, geometric isomer, tautomer, deuterated compound, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug as an active ingredient.

[0022] The pharmaceutical composition further includes a pharmaceutically acceptable carrier and / or adjuvant.

[0023] The thyroid hormone receptor in the present invention is the thyroid hormone β receptor.

[0024] The treatment of the disease by the above-mentioned pharmaceutical composition is achieved by administering an effective therapeutic amount of the compound of formula (I) or its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug to a subject.

[0025] The foregoing only outlines certain aspects of the present invention, but is not limited to these aspects. The content of these aspects and other aspects will be described more specifically and completely below.

[0026] The fourth aspect of the present invention discloses a method for synthesizing the compound of general formula (I), including steps such as cyclization, condensation, nucleophilic substitution, reduction, formation of diazonium salt followed by addition, amine ester exchange, hydrolysis, decarboxylation, etc.

[0027]

[0028] Detailed Embodiments

[0029] As used throughout this application, including in the claims, unless otherwise specifically indicated, the following terms have the meanings defined below as used herein.

[0030] The term "C1-C6 alkyl" refers to a saturated branched or straight-chain alkyl group having 1 to 6 carbon atoms, such as (but not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0031] The term "C1-C6 alkoxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy.

[0032] The term "C1-C6 alkylthio" refers to -S-alkyl. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, n-hexylthio, cyclopropylthio, and cyclobutylthio.

[0033] The term "C1-C6 haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0034] The term "C1-C6 mono- or poly-substituted alkyl" refers to one or more hydrogen atoms in the C1-C6 alkyl group as defined above being replaced by substituents selected from the following: OH, halogen, alkyl, dialkylamino, or heterocyclic group, such as morpholinyl, piperidinyl, etc.

[0035] The term "C2-C6 alkenyl" refers to a straight-chain or branched-chain monovalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing more than one carbon-carbon double bond, preferably having 2-4 carbon atoms. Non-limiting examples are vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0036] The term "C2-C6 alkynyl" refers to a straight-chain or branched-chain monovalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing more than one carbon-carbon triple bond, preferably having 2-4 carbon atoms. Non-limiting examples are ethynyl, propynyl, propargyl, etc.

[0037] The term "C3-C8 cycloalkyl" refers to a cyclic saturated monovalent monocyclic or bicyclic hydrocarbon group containing 3 to 8 carbon atoms. Non-limiting examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. The cycloalkyl may optionally be substituted with one, two, or three substituents selected from halogen atoms, hydroxyl groups, and aryl groups.

[0038] The term "3- to 8-membered heterocycloalkyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic system containing 3 to 12 atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, sulfur, oxygen, phosphorus atoms, etc. Among them, the heterocyclic group is non-aromatic and does not contain any aromatic rings, and this ring system has one or more connection points to connect with the rest of the molecule. Non-limiting examples are oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, thioxolanyl, etc. The heterocycloalkyl may optionally be substituted with one, two, or three substituents selected from halogen atoms, hydroxyl groups, and aryl groups.

[0039] The term "aryl" refers to all monocyclic or fused polycyclic aromatic groups of carbon containing 6 to 10 carbon atoms and having a conjugated electron system. Non-limiting examples are phenyl or naphthyl.

[0040] The term "substituted or unsubstituted aryl" means that 0 to 3 hydrogen atoms on the aryl are replaced by substituents selected from the following: aryl, halogen, C1-6 alkyl, nitrile, alkyl, amino, nitro, alkanesulfonyl, ester group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl group.

[0041] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic group, wherein one or more heteroatomic ring members (ring-forming atoms) in at least one ring are each independently selected from oxygen (O), sulfur (S), and nitrogen (N). Examples of heteroaryl include (but are not limited to) 6-membered ring substituents, non-limiting examples being pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 5-membered heteroaryls such as triazolyl, imidazolyl, furyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thienyl, thiazolyl, isothiazolyl, and pyrazolyl; 6 / 5-membered fused ring substituents such as indolyl, indazolyl, benzofuryl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothienyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridyl, purinyl, imidazopyridyl, imidazopyrimidinyl, pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, thiophenopyridyl, triazolopyrimidinyl, triazolopyridyl (e.g., 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl), and anthraniloyl; and 6 / 6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and 1,4-benzoxazinyl.

[0042] The term "substituted or unsubstituted heteroaryl" means that 0 to 3 hydrogen atoms on the heteroaryl are replaced by substituents selected from the following: aryl, halogen, C1-6 alkyl, group, alkyl, amino, nitro, alkanesulfonyl, ester group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenol hydroxyl.

[0043] The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in space within a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0044] The term "optionally" or "optionally" means that the subsequent described event or circumstance may but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example: "alkyl optionally substituted by F" means that it may or may not be substituted by F, and the description includes the cases of being substituted by F and not being substituted by F.

[0045] The term "solvate" refers to a substance formed by a compound of the present invention or its salt and a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0046] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith. Preferably, "pharmaceutically acceptable" as used herein means approved by a federal regulatory agency or a national government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals, particularly in humans.

[0047] The term "cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. A cocrystal is a multi-component crystal, including both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0048] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as other excipients including physiologically / pharmaceutically acceptable carriers, excipients, diluents, binders, fillers, and additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents, or lipid-lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

[0049] The term "effective therapeutic amount" refers to the amount of a compound administered that, to some extent, alleviates one or more symptoms of the disorder being treated.

[0050] The term "pharmaceutically acceptable carrier" refers to a carrier that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic, not biologically or otherwise undesirable, and includes carriers that are pharmaceutically acceptable to animals and humans. "Pharmaceutically acceptable carrier" as used in the specification and claims includes one or more such carriers.

[0051] The term "carrier" refers to a system that does not cause significant irritation to an organism, does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0052] The term "excipient" refers to a substance that is not itself a therapeutic agent and is used as a diluent, adjuvant, binder, and / or vehicle, which is added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate the formation of a unit dosage form of a compound or pharmaceutical composition for administration. As is known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweetening agents. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethyl cellulose (e.g., sodium cross-linked carboxymethyl cellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) diols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0053] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only for illustrating the present invention and not for limiting the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0054]

[0055] 6-(2,6-dichloro-4-nitrophenoxy)quinoline (3)

[0056] Step a: Put raw material 1 (10.0 g, 68.9 mmol, 1 eq) and raw material 2 (14.5 g, 68.9 mmol, 1 eq) into a 250 ml round-bottom flask, and then add potassium carbonate (19.0 g, 137.8 mmol, 2 eq) to the flask. Subsequently, add DMF (80 ml), stir overnight at room temperature (25 °C - 30 °C), and after TLC detects that the reaction is complete, extract with EA (100 ml) and water (200 ml), and extract the organic phase multiple times until there is no ultraviolet in the aqueous phase. Then combine the aqueous phases and back-extract with EA (50 ml). After combining the organic phases, wash the organic phase once with saturated brine. Purify by column chromatography (PE) to obtain 22.0 g of white solid with a yield of 95.3%.

[0057] 3,5-Dichloro-4-(quinolin-6-yloxy)aniline (4)

[0058] Step b: Put intermediate 3 (22.0 g, 65.6 mmol, 1 eq), iron powder (14.7 g, 262.6 mmol, 4 eq), and ammonium chloride (7.0 g, 131.9 mmol, 2 eq) into a 250 ml round-bottom flask, then add 100 ml of a mixed solvent of EtOH:H2O = 3:1, insert a condenser at the mouth of the flask, stir the system at 65 °C overnight, and TLC detects that the reaction is complete. After cooling the system to room temperature, distill under reduced pressure to remove EtOH, extract the remaining aqueous phase with EA (50 ml) 3 times, combine the organic phases, dry with anhydrous sodium sulfate and distill under reduced pressure to obtain a yellow oil. Purify by column chromatography (PE-PE:EA = 10:1) to obtain 18.6 g of white solid with a yield of 92.9%.

[0059] (3,5-Dichloro-4-(quinolin-6-yloxy)phenyl)glycine methyl ester (FW-GY-A1)

[0060] Intermediate 4 (500.0 mg, 1.6 mmol, 1 eq) was placed into a 100 ml two-necked flask. Subsequently, potassium iodide (299.2 mg, 1.8 mmol, 1.1 eq) and potassium carbonate (339.7 mg, 2.5 mmol, 1.5 eq) were also placed into the container. Acetone (10 ml) was added to the system. The system was protected with nitrogen using a three-way stopcock and purged three times. Methyl bromoacetate (1.0 g, 6.6 mmol, 4 eq) was added to the system via a syringe. The mixture was stirred at 60 °C overnight. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, the acetone was removed by distillation under reduced pressure. The residue was dissolved in EA (10 ml), extracted with water three times, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 3:1) afforded 235.0 mg of a white solid in 38.0% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 4.2 Hz, 1H), 8.29 (dd, J = 8.4, 2.0 Hz, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.54 (dd, J = 9.2, 2.9 Hz, 1H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 6.86 (s, 2H), 6.79 (s, 1H), 4.06 (d, J = 6.1 Hz, 2H), 3.72 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.69, 155.54, 149.35, 148.56, 147.69, 144.78 (d, J = 2.5 Hz), 135.66, 131.66, 129.13, 122.42, 121.12, 113.99, 112.66, 108.64, 52.32, 44.72. LC-MS-ESI+:[M+H]+ 376.9.

[0061] Methyl 4-((3,5-dichloro-4-(quinolin-6-yloxy)phenyl)amino)methyl)benzoate (FW-GY-A2)

[0062] The preparation method was the same as that of FW-GY-A1, and 350.0 mg of a pale yellow product was obtained with a yield of 47.1%. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (dd, J = 4.3, 1.7 Hz, 1H), 8.28 (dd, J = 8.5, 1.7 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.59–7.46 (m, 5H), 7.07 (s, 1H), 6.82 (s, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.60, 155.56, 149.30, 147.92, 145.56, 144.71, 135.73, 131.58, 129.94, 129.20, 128.89, 128.01, 127.50, 122.41, 121.12, 113.98, 112.55, 108.67, 52.60, 46.44. LC-MS-ESI+: [M + H]+ 453.0.

[0063] Methyl 2-((3,5-dichloro-4-(quinolin-6-yloxy)phenyl)amino)methyl)benzoate (FW-GY-A3)

[0064] The preparation method was the same as that of FW-GY-A1, and 286.0 mg of a pale yellow solid was obtained with a yield of 38.5%. 1H NMR (400 MHz, DMSO-d6) δ 8.31–8.25 (m, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.66–7.56 (m, 2H), 7.54–7.37 (m, 4H), 7.07 (d, J = 2.8 Hz, 1H), 6.84 (t, J = 6.1 Hz, 1H), 6.81 (s, 2H), 4.66 (d, J = 5.9 Hz, 2H), 3.88 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 167.74, 155.56, 149.35, 148.09, 144.84, 140.66, 135.61, 132.93, 131.66, 130.93, 129.65, 129.20, 129.18, 128.96, 127.76, 126.99, 122.39, 121.07, 112.40, 108.67, 52.69, 45.31. LC-MS-ESI+: [M + H]+ 452.9.

[0065] 3-(3,5-Dichloro-4-(quinolin-6-yloxy)phenyl)amino)-3-oxopropanoic acid (FW-GY-A5)

[0066] The intermediate 4 (200.0 mg, 0.65 mmol, 1 eq) was placed into a 50 ml round-bottom flask. Subsequently, malonic acid (81.8 mg, 0.82 mmol, 1.2 eq), HATU (373.8 mg, 0.98 mmol, 1.5 eq) and HOBT (132.8 mg, 0.98 mmol, 1.5 eq) were similarly placed into the container. DMF (10 ml) was added to the system, and Et3N (199.0 mg, 1.97 mmol, 3 eq) was added under stirring. The mixture was stirred at 50 °C overnight. The reaction was monitored by TLC and found to be complete. Extraction was carried out with EA (30 ml) and water (15 ml), and the organic phase was extracted multiple times until there was no UV in the aqueous phase. The aqueous phases were combined and back-extracted with EA (10 ml). After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) gave 190 mg of a white solid with a yield of 74.1%. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.82 (d, J = 4.5 Hz, 1H), 8.42 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.92 (s, 2H), 7.58 (s, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 3.36 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 160.91, 154.74, 149.62, 144.96, 141.91, 137.58, 135.70, 131.85, 129.68, 129.20, 129.12, 122.50, 121.08, 120.18, 118.28, 108.94. LC-MS-ESI+: [M + H]+ 391.1.

[0067] 4-(3,5-dichloro-4-(quinolin-6-yloxy)phenyl)amino)-4-oxobutanoic acid (FW-GY-A6)

[0068] The preparation method was the same as that of FW-GY-A5 to obtain 202.0 mg of a pale yellow solid with a yield of 76.1%. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.85–8.76 (m, 1H), 8.27 (dd, J = 8.4, 2.1 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.90 (s, 2H), 7.58 (dd, J = 9.2, 2.9 Hz, 1H), 7.49 (ddd, J = 8.3, 4.1, 2.3 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 2.13 (s, 4H). 13C NMR (101 MHz, DMSO-d6) δ 169.52, 154.81, 149.58, 144.94, 141.35, 138.68, 135.69, 131.83, 129.20, 128.93, 122.48, 121.07, 119.75, 108.91, 24.59. LC-MS-ESI+: [M + H]+ 404.8.

[0069] 4-(3,5-Dichloro-4-(quinolin-6-yloxy)phenyl)carbamoyl)benzoic acid (FW-GY-A8)

[0070] The preparation method was the same as that of FW-GY-A5 to obtain 230.0 mg of a pale yellow solid with a yield of 77.4%. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.83 (dd, J = 4.2, 1.7 Hz, 1H), 8.30 (dd, J = 8.4, 1.7 Hz, 1H), 8.17 (s, 2H), 8.16–8.07 (m, 5H), 7.62 (dd, J = 9.2, 2.9 Hz, 1H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.16 (d, J = 2.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 165.86, 154.77, 149.65, 144.97, 142.07, 138.41, 135.73, 131.89, 129.98, 129.21, 128.92, 128.52, 122.53, 121.14, 108.95. LC-MS-ESI+: [M + H]+ 453.1.

[0071] 3-(N-(3,5-Dichloro-4-(quinolin-6-yloxy)phenyl)sulfamoyl)propanoic acid (FW-GY-A9)

[0072] The preparation method was the same as that of FW-GY-A5, and 220.0 mg of a pale yellow solid was obtained with a yield of 76.1%. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (dd, J = 4.2, 1.7 Hz, 1H), 8.28 (dd, J = 8.4, 1.7 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 9.2, 2.9 Hz, 1H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.43 (s, 2H), 7.15 (d, J = 2.9 Hz, 1H), 3.53 (t, J = 7.1 Hz, 2H), 2.73 (t, J = 7.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.02, 154.72, 149.64, 144.95, 141.95, 138.04, 135.69, 131.84, 129.49, 122.52, 121.02, 120.00, 109.01, 47.64, 28.79, 23.02. LC-MS-ESI+: [M+H]+ 441.2.

[0073] (3,5-Dichloro-4-(quinolin-6-yloxy)phenyl)glycine (FW-GY-A4)

[0074] The final product FW-GY-A1 (50.0 mg, 0.13 mmol, 1 eq) and lithium hydroxide (25.4 mg, 1.06 mmol, 8 eq) were placed together in a 25 ml round-bottom flask, and then MeOH (8 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH, and then extracted with EA (30 ml) and water (15 ml). The organic matter was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. It was purified by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) to obtain 41.0 mg of a white solid with a yield of 85.2%. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.50–7.45 (m, 1H), 7.05 (d, J = 2.9 Hz, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 3.53 (s, 2H). LC-MS-ESI+: [M+H]+ 362.7.

[0075]

[0076] Methyl 3,5-dichloro-4-fluorobenzoate (6)

[0077] The raw material 5 (10.0 g, 47.9 mmol, 1 eq) was placed in a 100 ml round-bottom flask, MeOH (40 ml) was added, and the system was stirred at 50 °C. A catalytic amount of concentrated sulfuric acid was slowly added dropwise under stirring. After 0.5 h, the reaction was detected by TLC to be complete. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. It was extracted with EA (100 ml) and water (100 ml), and the organic phase was extracted multiple times until there was no UV in the aqueous phase. After combining the organic phases, the organic phase was washed once with saturated brine. Dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 10.0 g of a white solid with a yield of 93.7%.

[0078] Methyl 3,5-dichloro-4-(quinolin-6-yloxy)benzoate (7)

[0079] The raw material 6 (10.0 g, 44.8 mmol, 1 eq) and the raw material 1 (6.5 g, 44.8 mmol, 1 eq) were placed in a 250 ml round-bottom flask, and potassium carbonate (12.4 g, 89.7 mmol, 2 eq) was added to the flask. Subsequently, DMF (80 ml) was added, and it was stirred overnight at room temperature (25 °C - 30 °C). After the reaction was detected by TLC to be complete. It was extracted with EA (100 ml) and water (200 ml), and the organic phase was extracted multiple times until there was no UV in the aqueous phase. Then the aqueous phases were combined and back-extracted with EA (50 ml). After combining the organic phases, the organic phase was washed once with saturated brine. Purified by column chromatography (PE) to obtain 14.1 g of a white solid with a yield of 90.3%.

[0080] 3,5-Dichloro-4-(quinolin-6-yloxy)benzoic acid (8)

[0081] The intermediate 7 (14 g, 40.2 mmol, 1 eq) and lithium hydroxide (7.7 g, 321.7 mmol, 8 eq) were jointly placed in a 250 ml round-bottom flask, and then MeOH (100 ml) was added. A condenser was inserted at the mouth of the flask, and the system was stirred at 65 °C overnight. The reaction was detected by TLC to be complete. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining material was extracted with EA (100 ml) and water (50 ml). The organic phase was taken, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purified by column chromatography (PE:EA = 5:1) to obtain 11.5 g of a white solid with a yield of 85.6%.

[0082] (3,5-Dichloro-4-(quinolin-6-yloxy)benzoyl)aspartic acid (FW-GY-A7)

[0083] The intermediate 8 (200.0 mg, 0.60 mmol, 1 eq) was placed into a 50 ml round-bottom flask. Subsequently, aspartic acid (95.6 mg, 0.72 mmol, 1.2 eq), HATU (341.4 mg, 0.90 mmol, 1.5 eq) and HOBT (121.3 mg, 0.90 mmol, 1.5 eq) were also placed into the container. DMF (10 ml) was added to the system, and Et3N (181.7 mg, 1.80 mmol, 3 eq) was added under stirring. The mixture was stirred overnight at 50 °C. The reaction was monitored by TLC and found to be complete. Extraction was carried out with EA (30 ml) and water (15 ml), and the organic phase was extracted multiple times until there was no UV absorption in the aqueous phase. The aqueous phases were combined and back-extracted with EA (10 ml). After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained, which was purified by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) to give 185.0 mg of a white solid with a yield of 68.8%. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 7.7 Hz, 1H), 8.83 (dd, J = 4.2, 1.8 Hz, 1H), 8.29 (dd, J = 8.5, 1.7 Hz, 1H), 8.20 (s, 2H), 8.00 (d, J = 8.5 Hz, 1H), 7.58–7.54 (m, 1H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.18 (d, J = 2.9 Hz, 1H), 4.80 (td, J = 8.1, 5.4 Hz, 1H), 2.95–2.88 (m, 1H), 2.82–2.69 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.12, 163.48, 154.24, 149.78, 148.77, 145.01, 135.79, 133.33, 131.97, 129.37, 127.83, 125.02, 122.56, 121.18, 119.64, 110.12, 50.24, 36.10. LC-MS-ESI+:[M+H]+ 448.9.

[0084] 3-(3,5-Dichloro-4-(quinolin-6-yloxy)benzamido)-2,2-dimethylpropanoic acid (FW-GY-A10)

[0085] The preparation method was the same as that of FW-GY-A7, and 190.0 mg of a pale yellow solid was obtained with a yield of 73.3%. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.2, 1.7 Hz, 1H), 8.69 (t, J = 6.2 Hz, 1H), 8.28 (dd, J = 8.4, 1.7 Hz, 1H), 8.17 (s, 2H), 8.09 (d, J = 9.2 Hz, 1H), 7.63 (dd, J = 9.2, 2.9 Hz, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.17 (d, J = 2.9 Hz, 1H), 3.50 (d, J = 6.1 Hz, 2H), 1.16 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 178.18, 172.07, 164.30, 154.27, 149.77, 148.45, 145.00, 135.75, 134.22, 131.95, 129.30 (d, J = 16.6 Hz), 122.56, 121.10, 109.19, 47.52, 43.47, 23.65, 23.00. LC-MS-ESI+: [M+H]+ 433.1.

[0086]

[0087] 4-Methylquinolin-6-ol (10)

[0088] The raw material 9 (5 g, 27.8 mmol, 1 eq) was placed in a 250 ml two-necked flask, and then manganese chloride (175.2 mg, 1.39 mmol, 0.05 eq) was added. THF (50 ml) was added, and the system was protected by nitrogen and purged 3 times. The system was placed in an ice-water bath, and methylmagnesium bromide (27.8 ml, 55.7 mmol, 2 eq) was slowly added dropwise using a constant-pressure dropping funnel under stirring. After the addition was complete, the system was transferred to room temperature and stirred overnight. TLC detected that the reaction was complete. It was extracted with EA (50 ml) and water (30 ml) for 3 times. After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained and purified by column chromatography (PE:EA = 20:1) to obtain 4.1 g of a white solid with a yield of 92.5%.

[0089] Methyl 3,5-dichloro-4-(4-methylquinolin-6-yloxy)benzoate (11)

[0090] Put raw material 6 (3.0 g, 13.5 mmol, 1 eq) and raw material 10 (2.1 g, 13.5 mmol, 1 eq) into a 100 ml round-bottom flask, and then add potassium carbonate (3.7 g, 26.9 mmol, 2 eq) to the flask. Subsequently, add DMF (40 ml), stir overnight at room temperature (25 °C - 30 °C). After the reaction is complete as detected by TLC, extract with EA (100 ml) and water (200 ml), and extract the organic phase multiple times until there is no ultraviolet in the aqueous phase. Then combine the aqueous phases and back-extract with EA (50 ml). After combining the organic phases, wash the organic phase once with saturated brine. Purify by column chromatography (PE) to obtain 3.98 g of white solid with a yield of 81.7%.

[0091] 3,5-Dichloro-4-(4-methylquinolin-6-yloxy)benzoic acid (12)

[0092] Put intermediate 11 (3.98 g, 11.0 mmol, 1 eq) and lithium hydroxide (2.11 g, 87.9 mmol, 8 eq) into a 100 ml round-bottom flask, then add MeOH (40 ml), insert a condenser at the mouth of the flask, stir the system at 65 °C overnight, and detect the reaction is complete by TLC. After cooling the system to room temperature, distill under reduced pressure to remove MeOH. Extract the remaining substance with EA (100 ml) and water (50 ml) for 3 times. Take the organic phase and dry it with anhydrous sodium sulfate, then distill under reduced pressure to obtain a yellow oil. Purify by column chromatography (PE:EA = 5:1) to obtain 2.9 g of white solid with a yield of 74.8%.

[0093] Ethyl 3-(3,5-dichloro-4-((4-methylquinolin-6-yl)oxy)benzamido)propionate (FW-GY-B1)

[0094] Intermediate 12 (200.0 mg, 0.57 mmol, 1 eq) was placed into a 50 ml round-bottom flask. Subsequently, ethyl 3-aminopropionate (80.7 mg, 0.69 mmol, 1.2 eq), HATU (327.6 mg, 0.86 mmol, 1.5 eq) and HOBT (116.4 mg, 0.86 mmol, 1.5 eq) were also placed into the container. DMF (10 ml) was added to the system, and Et3N (173.4 mg, 1.72 mmol, 3 eq) was added under stirring. The mixture was stirred overnight at 50 °C. The reaction was monitored by TLC and found to be complete. Extraction was carried out with EA (30 ml) and water (15 ml), and the organic phase was extracted multiple times until there was no UV absorption in the aqueous phase. The aqueous phases were combined and back-extracted with EA (10 ml). After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained, which was purified by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) to give 177.0 mg of a white solid with a yield of 68.9%. 1H NMR (600 MHz, DMSO-d6) δ 8.87 (t, J = 5.4 Hz, 1H), 8.69 (d, J = 4.3 Hz, 1H), 8.12 (s, 2H), 8.04 (d, J = 9.2 Hz, 1H), 7.42 (dd, J = 9.2, 2.9 Hz, 1H), 7.38 (dd, J = 4.3, 1.1 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.53 (td, J = 6.9, 5.4 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.53 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 170.60, 162.55, 153.08, 148.44, 147.36, 143.65, 142.52, 132.81, 131.46, 128.15 (d, J = 19.8 Hz), 121.98, 118.57, 105.59, 59.42, 35.18, 32.89, 17.51, 13.48. LC-MS-ESI+:[M+H]+ 447.2.

[0095] Diethyl (3,5-dichloro-4-((4-methylquinolin-6-yl)oxy)benzoyl)aspartate (FW-GY-B2)

[0096] The preparation method was the same as that of FW-GY-B1, and 268.0 mg of a pale yellow solid was obtained with a yield of 92.3%. 1H NMR (600 MHz, DMSO-d6) δ 9.22 (d, J = 7.6 Hz, 1H), 8.69 (d, J = 4.3 Hz, 1H), 8.15 (s, 2H), 8.04 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 9.2, 2.8 Hz, 1H), 7.38 (dd, J = 4.3, 1.1 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 4.90–4.79 (m, 1H), 4.20–4.06 (m, 4H), 2.95 (dd, J = 16.4, 6.0 Hz, 1H), 2.85 (dd, J = 16.4, 8.1 Hz, 1H), 2.54 (s, 3H), 1.20 (td, J = 7.1, 3.0 Hz, 6H). 13C NMR (151 MHz, DMSO-d6) δ 169.74, 169.26, 162.57, 153.05, 148.46, 147.74, 143.66, 142.57, 131.97, 131.46, 128.37, 128.28, 127.96, 121.99, 118.60, 105.68, 60.49, 59.82, 49.02, 34.87, 17.54, 13.41 (d, J = 4.5 Hz). LC-MS-ESI+: [M + H]+ 519.0.

[0097] (3,5-Dichloro-4-((4-methylquinolin-6-yl)oxy)benzoyl)aspartic acid (FW-GY-B3)

[0098] The preparation method was the same as that of FW-GY-B1, and 210.0 mg of a pale yellow solid was obtained with a yield of 81.4%. 1H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 4.3 Hz, 0H), 8.18 (s, 1H), 8.04 (d, J = 9.2 Hz, 0H), 7.44 (dd, J = 9.2, 2.8 Hz, 0H), 7.40–7.36 (m, 0H), 7.30 (d, J = 2.8 Hz, 0H), 4.75 (td, J = 7.8, 5.8 Hz, 0H), 2.87 (dd, J = 16.5, 5.9 Hz, 0H), 2.72 (dd, J = 16.6, 8.0 Hz, 0H), 2.54 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 171.61, 171.04, 162.33, 153.06, 148.43, 147.57, 143.63, 142.58, 132.26, 131.44, 128.28, 128.27, 127.95, 121.97, 118.64, 105.60, 49.07, 35.34, 17.55. LC-MS-ESI+: [M + H]+ 462.8.

[0099] ((3,5-Dichloro-4-((4-methylquinolin-6-yl)oxy)benzamido)methyl)phosphonic acid (FW-GY-B4)

[0100] The preparation method was the same as that of FW-GY-B1, and 188.0 mg of a pale yellow solid was obtained with a yield of 76.6%. 1H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 4.3 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.73 (s, 2H), 7.41 (dd, J = 9.2, 2.9 Hz, 1H), 7.38 (d, J = 4.3 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 3.46 (d, J = 7.6 Hz, 2H), 2.55 (s, 3H). LC-MS-ESI+: [M + H]+ 441.0.

[0101]

[0102] 1-Chloro-3-cyclopropyl-2-fluoro-5-nitrobenzene (13)

[0103] Put raw material 2 (5 g, 23.8 mmol, 1 eq), cyclopropylboronic acid (2.45 g, 28.6 mmol, 1.2 eq), palladium acetate (267.3 mg, 1.19 mmol, 0.05 eq), tricyclohexylphosphine tetrafluoroborate (876.8 mg, 2.38 mmol, 0.1 eq) and potassium phosphate (25.3 g, 119.1 mmol, 5 eq) into a 250 ml round-bottom flask, and add a mixed solvent of toluene:water = 20:1 (100 ml) to the system. Protect the system with nitrogen and displace the gas 3 times. Then stir the system at 100 °C overnight. TLC detects that the reaction is complete. Extract with EA (100 ml) and water (150 ml) three times, and finally wash the organic phase with saturated brine once. Dry the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain a pale yellow oil, and purify by column chromatography (PE:EA = 20:1) to obtain 4.5 g of white solid, with a yield of 87.7%.

[0104] 6-(2-Chloro-6-cyclopropyl-4-nitrophenoxy)quinoline (14)

[0105] Put raw material 1 (3.0 g, 20.7 mmol, 1 eq) and intermediate 13 (4.5 g, 20.7 mmol, 1 eq) into a 100 ml round-bottom flask, and then add potassium carbonate (7.0 g, 41.3 mmol, 2 eq) to the flask. Then add DMF (40 ml) and stir overnight at room temperature (25 °C - 30 °C). After TLC detects that the reaction is complete, extract with EA (50 ml) and water (100 ml), and extract the organic phase multiple times until there is no ultraviolet in the aqueous phase. Then combine the aqueous phases and back-extract with EA (50 ml). After combining the organic phases, wash the organic phase with saturated brine once. Purify by column chromatography (PE) to obtain 6.17 g of white solid, with a yield of 87.6%.

[0106] 3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)aniline (15)

[0107] Put intermediate 14 (6 g, 17.6 mmol, 1 eq), iron powder (3.93 g, 70.43 mmol, 4 eq), and ammonium chloride (1.9 g, 35.2 mmol, 2 eq) into a 100 ml round-bottom flask, and then add 50 ml of a mixed solvent of EtOH:H2O = 3:1. Insert a condenser at the bottle mouth and stir the system at 65 °C overnight. TLC detects that the reaction is complete. After cooling the system to room temperature, distill under reduced pressure to remove EtOH. Extract the remaining aqueous phase with EA (50 ml) three times, combine the organic phases, dry with anhydrous sodium sulfate and distill under reduced pressure to obtain a yellow oil. Purify by column chromatography (PE-PE:EA = 10:1) to obtain 5.12 g of white solid, with a yield of 93.4%.

[0108] (3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)phenyl)glycine methyl ester (FW-GY-C3)

[0109] Intermediate 15 (200.0 mg, 0.64 mmol, 1 eq) was placed into a 50 ml two-necked flask. Subsequently, potassium iodide (117.5 mg, 0.71 mmol, 1.1 eq) and potassium carbonate (133.4 mg, 0.97 mmol, 1.5 eq) were also placed into the container. Acetone (10 ml) was added to the system. The system was protected with nitrogen using a three-way valve and purged 3 times. Methyl bromoacetate (393.8 mg, 2.57 mmol, 4 eq) was added to the system via a syringe. The mixture was stirred at 60 °C overnight. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, the acetone was removed by distillation under reduced pressure. The residue was dissolved in EA (10 ml), extracted with water 3 times, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 3:1) afforded 180.0 mg of a white solid with a yield of 61.0%. 1H NMR (600 MHz, DMSO-d6) δ 8.76 (dd, J = 4.2, 1.8 Hz, 1H), 8.24 (dd, J = 8.5, 1.8 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.52 (dd, J = 9.2, 2.9 Hz, 1H), 7.44 (dd, J = 8.4, 4.2 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.24–6.19 (m, 2H), 3.98 (d, J = 6.2 Hz, 2H), 3.69 (s, 2H), 1.85–1.77 (m, 1H), 0.77–0.73 (m, 2H), 0.64–0.58 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 170.96, 155.33, 147.95, 146.09, 143.56, 138.17, 137.96, 134.38, 130.40, 128.17, 126.32, 121.21, 120.21, 109.46, 107.53, 106.84, 51.11, 43.90, 9.54, 7.78. LC-MS-ESI+:[M+H]+ 383.9.

[0110] (3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)phenyl)alanine methyl ester (FW-GY-C5)

[0111] The preparation method was the same as that of FW-GY-C3, and 178.0 mg of a pale yellow solid was obtained with a yield of 72.3%. 1H NMR (600 MHz, DMSO-d6) δ 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.28–8.19 (m, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.57 (d, J = 2.7 Hz, 1H), 6.26 (d, J = 8.2 Hz, 1H), 6.17 (d, J = 2.7 Hz, 1H), 4.22–4.09 (m, 1H), 3.67 (s, 3H), 1.81 (tt, J = 8.5, 5.2 Hz, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.77 (ddd, J = 8.6, 3.5, 1.4 Hz, 2H), 0.64–0.49 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.94, 155.31, 147.96, 145.56, 143.57, 138.25, 137.99, 134.39, 130.41, 128.17, 126.34, 121.21, 120.19, 109.68, 107.56, 106.81, 51.29, 50.31, 17.48, 9.48, 7.82 (d, J = 6.1 Hz). LC-MS-ESI+: [M + H]+ 397.0.

[0112] 3-((3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)phenyl)amino)-3-oxopropanoic acid (FW-GY-C1)

[0113] Intermediate 15 (200.0 mg, 0.64 mmol, 1 eq) was placed in a 50 ml round-bottom flask. Subsequently, malonic acid (80.4 mg, 0.77 mmol, 1.2 eq), HATU (367.0 mg, 0.97 mmol, 1.5 eq), and HOBT (130.4 mg, 0.97 mmol, 1.5 eq) were similarly placed in the container. DMF (10 ml) was added to the system, and Et3N (195.4 mg, 1.93 mmol, 3 eq) was added under stirring. The mixture was stirred at 50 °C overnight. The reaction was monitored by TLC and found to be complete. Extraction was carried out with EA (30 ml) and water (15 ml), and the organic phase was extracted multiple times until there was no UV in the aqueous phase. The aqueous phases were combined and back-extracted with EA (10 ml). After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained and purified by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) to give 170.0 mg of a white solid with a yield of 66.8%. 1H NMR (600 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.78 (dd, J = 4.2, 1.7 Hz, 1H), 8.28–8.21 (m, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 9.2, 2.9 Hz, 1H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 2.9 Hz, 1H), 3.33 (s, 2H), 1.90 (tt, J = 8.4, 5.1 Hz, 1H), 0.89–0.78 (m, 2H), 0.70–0.51 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 168.00, 154.64, 148.17, 143.65, 142.72, 138.34, 137.20, 134.49, 130.56, 128.16, 125.99, 121.29, 120.17, 116.94, 113.71, 107.73, 23.42, 9.48, 8.01. LC-MS-ESI+:[M+H]+ 397.2.

[0114] 4-((3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)phenyl)amino)-4-oxobutanoic acid (FW-GY-C2)

[0115] The preparation method was the same as that of FW-GY-C1, and 175.0 mg of a pale yellow solid was obtained with a yield of 66.2%. 1H NMR (600 MHz, DMSO-d6) δ 8.80 (dd, J = 4.2, 1.7 Hz, 1H), 8.31 (dd, J = 8.5, 1.7 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.58 (dd, J = 9.2, 2.8 Hz, 1H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 2.9 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 2.80 (s, 4H), 1.97 (tt, J = 8.5, 5.2 Hz, 1H), 0.92–0.81 (m, 2H), 0.68–0.61 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 176.06, 154.17, 148.39, 147.07, 143.74, 138.86, 134.60, 130.79, 130.46, 128.13, 126.17, 125.60, 122.80, 121.38, 120.09, 107.98, 27.91, 9.58, 8.17. LC-MS-ESI+: [M+H]+ 410.3.

[0116] (3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)phenyl)glycine (FW-GY-C4)

[0117] The end product FW-GY-C3 (100 mg, 0.26 mmol, 1 eq) and lithium hydroxide (50.0 mg, 2.09 mmol, 8 eq) were placed together in a 100 ml round-bottom flask, and then MeOH (10 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining material was extracted with EA (10 ml) and water (5 ml) three times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 81 mg of a white solid with a yield of 84.1%. 1H NMR (600 MHz, DMSO-d6) δ 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.24 (dd, J = 8.4, 1.7 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.52 (dd, J = 9.2, 2.8 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.58 (d, J = 2.7 Hz, 1H), 6.20 (d, J = 2.7 Hz, 1H), 3.85 (s, 2H), 1.81 (tt, J = 8.5, 5.2 Hz, 1H), 0.80–0.71 (m, 2H), 0.64–0.57 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 171.79, 155.36, 147.93, 146.21, 143.55, 138.09, 137.79, 134.38, 130.38, 128.18, 126.25, 121.21, 120.22, 109.40, 107.52, 106.83, 44.12, 9.54, 7.73. LC-MS-ESI+: [M+H]+ 369.2.

[0118] (3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)phenyl)alanine (FW-GY-C6)

[0119] The preparation method is the same as that of FW-GY-C4, with the raw material being the final product FW-GY-C5. 77 mg of light yellow solid was obtained, and the yield was 79.8%. 1H NMR (600 MHz, DMSO-d6) δ 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.26–8.20 (m, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 2.6 Hz, 1H), 6.19 (d, J = 2.7 Hz, 1H), 4.00 (p, J = 7.0, 6.5 Hz, 1H), 1.81 (tt, J = 8.5, 5.2 Hz, 1H), 1.38 (d, J = 6.9 Hz, 3H), 0.81–0.71 (m, 2H), 0.62–0.51 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 174.98, 155.34, 147.95, 145.78, 143.56, 138.14, 137.81, 134.39, 130.39, 128.18, 126.26, 121.21, 120.20, 109.57, 107.55, 106.93, 50.40, 17.48, 9.50, 7.79, 7.71. LC-MS-ESI+:[M+H]+ 382.0

[0120]

[0121] Methyl 3-chloro-5-cyclopropyl-4-fluorobenzoate (16)

[0122] Put the intermediate 6 (5 g, 22.42 mmol, 1 eq), cyclopropylboronic acid (2.31 g, 26.9 mmol, 1.2 eq), palladium acetate (251.7 mg, 1.12 mmol, 0.05 eq), tricyclohexylphosphine tetrafluoroborate (825.6 mg, 2.24 mmol, 0.1 eq) and potassium phosphate (23.8 g, 112.1 mmol, 5 eq) into a 250 ml round-bottom flask, and add a mixed solvent of toluene:water = 20:1 (100 ml) to the system. Protect the system with nitrogen and displace the gas 3 times. Then stir the system at 100 °C overnight. TLC detected that the reaction was complete. Extract with EA (100 ml) and water (150 ml) for 3 times, and finally wash the organic phase with saturated brine once. Dry the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain a light yellow oil, and purify by column chromatography (PE:EA = 20:1) to obtain 4.33 g of white solid, with a yield of 84.5%.

[0123] Methyl 3-chloro-5-cyclopropyl-4-(quinolin-6-yloxy)benzoate (17)

[0124] Intermediate 16 (3.0 g, 13.12 mmol, 1 eq) and starting material 1 (1.9 g, 13.12 mmol, 1 eq) were placed into a 100 ml round-bottom flask, and potassium carbonate (3.6 g, 26.24 mmol, 2 eq) was further added to the flask. Subsequently, DMF (40 ml) was added, and the mixture was stirred overnight at room temperature (25 °C - 30 °C). After the reaction was complete as detected by TLC, extraction was carried out with EA (50 ml) and water (100 ml), and the organic phase was extracted multiple times until there was no UV in the aqueous phase. Then the aqueous phases were combined and back-extracted with EA (50 ml). After combining the organic phases, the organic phase was washed once with saturated brine. Purification by column chromatography (PE) gave 4.05 g of a white solid with a yield of 87.2%.

[0125] 3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)benzoic acid (18)

[0126] Intermediate 16 (4 g, 11.3 mmol, 1 eq) and lithium hydroxide (2.17 g, 90.5 mmol, 8 eq) were placed together into a 50 ml round-bottom flask, and then MeOH (30 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. After the reaction was complete as detected by TLC, the system was cooled to room temperature and then distilled under reduced pressure to remove MeOH. The remaining material was extracted with EA (30 ml) and water (15 ml) three times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 3.51 g of a white solid with a yield of 91.4%.

[0127] Ethyl 3-(3-chloro-5-cyclopropyl-4-(quinolin-6-yloxy)benzamido)propionate (FW-GY-C7)

[0128] Intermediate 18 (200.0 mg, 0.59 mmol, 1 eq) was placed in a 50 ml round-bottom flask. Subsequently, ethyl 3-aminopropionate (82.8 mg, 0.71 mmol, 1.2 eq), HATU (335.7 mg, 0.88 mmol, 1.5 eq) and HOBT (119.3 mg, 0.88 mmol, 1.5 eq) were also placed into the container. DMF (10 ml) was added to the system, and Et3N (178.7 mg, 1.77 mmol, 3 eq) was added under stirring. The mixture was stirred overnight at 50 °C. The reaction was monitored by TLC and found to be complete. The mixture was extracted with EA (30 ml) and water (15 ml), and the organic phase was extracted multiple times until there was no UV absorption in the aqueous phase. The aqueous phases were combined and back-extracted with EA (10 ml). After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained, which was purified by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) to give 212.0 mg of a white solid with a yield of 83.2%. 1H NMR (600 MHz, DMSO-d6) δ 8.75 (t, J = 5.5 Hz, 1H), 8.67 (d, J = 4.3 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.41 (dd, J = 9.1, 2.8 Hz, 1H), 7.36 (dd, J = 4.4, 1.1 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.51 (td, J = 6.9, 5.4 Hz, 2H), 3.33 (s, 3H), 2.61 (t, J = 6.9 Hz, 2H), 1.97 (tt, J = 8.5, 5.2 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H), 0.91–0.83 (m, 2H), 0.82–0.74 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 170.69, 163.80, 154.01, 149.59, 148.11, 143.43, 142.23, 138.72, 132.18, 131.30, 127.97, 126.46, 126.01, 122.52, 121.87, 118.91, 105.24, 59.39, 33.07, 17.48, 13.48, 9.67, 8.31. LC-MS-ESI+:[M+H]+ 439.2.

[0129] Methyl 3-(3-chloro-5-cyclopropyl-4-(quinolin-6-yloxy)benzamido)-2,2-dimethylpropionate (FW-GY-C9)

[0130] The preparation method was the same as that of FW-GY-C7, and 231 mg of pale yellow solid was obtained with a yield of 86.6%. 1H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 4.3 Hz, 1H), 8.59 (t, J = 6.3 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 9.1, 2.8 Hz, 1H), 7.36 (dd, J = 4.4, 1.1 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 3.45 (d, J = 6.3 Hz, 1H), 1.97 (tt, J = 8.4, 5.2 Hz, 1H), 1.16 (s, 3H), 0.91–0.84 (m, 1H), 0.81–0.74 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 175.52, 164.42, 154.00, 149.57, 148.11, 143.42, 142.25, 138.62, 132.42, 131.27, 127.98, 126.37, 126.10, 122.78, 121.86, 118.84, 105.35, 51.27, 46.57, 42.72, 22.39, 17.51, 9.68, 8.26. LC-MS-ESI+: [M + H]+ 452.8.

[0131] 3-(3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)benzamido)propanoic acid (FW-GY-C8)

[0132] The end product FW-GY-C7 (100 mg, 0.23 mmol, 1 eq) and lithium hydroxide (43.65 mg, 1.82 mmol, 8 eq) were placed together in a 50 ml round-bottom flask, and then MeOH (10 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining material was extracted with EA (10 ml) and water (5 ml) three times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 76 mg of a white solid with a yield of 81.2%. 1H NMR (600 MHz, DMSO-d6) δ 8.73 (t, J = 5.5 Hz, 1H), 8.67 (d, J = 4.3 Hz, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.41 (dd, J = 9.2, 2.8 Hz, 1H), 7.37–7.35 (m, 1H), 7.23 (d, J = 2.8 Hz, 1H), 3.48 (td, J = 6.9, 5.3 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 1.96 (tt, J = 8.4, 5.2 Hz, 1H), 0.90–0.85 (m, 2H), 0.81–0.74 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 172.27, 170.82, 163.73, 154.00, 149.54, 148.10, 143.41, 142.24, 138.69, 132.21, 131.28, 127.97, 126.43, 126.01, 122.52, 121.86, 118.90, 105.25, 21.91, 17.50, 9.66, 8.29. LC-MS-ESI+:[M+H]+ 411.2.

[0133] 3-(3-Chloro-5-cyclopropyl-4-(quinolin-6-yloxy)benzamido)-2,2-dimethylpropanoic acid (FW-GY-C10)

[0134] The preparation method was the same as that of FW-GY-C8, with the raw material being the end product FW-GY-C9. 77 mg of pale yellow solid was obtained, and the yield was 79.5%. 1H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 4.3 Hz, 1H), 8.56 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.95–7.90 (m, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 9.2, 2.8 Hz, 1H), 7.36 (d, J = 4.3 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 3.44 (d, J = 6.1 Hz, 2H), 1.96 (td, J = 8.5, 4.2 Hz, 1H), 1.12 (s, 7H), 0.86 (qd, J = 6.0, 4.1, 3.6 Hz, 2H), 0.81–0.73 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 164.34, 154.02, 149.51, 148.09, 143.41, 142.25, 138.57, 132.56, 131.26, 127.98, 126.33, 126.11, 122.79, 121.86, 118.86, 105.32, 42.38, 22.66, 21.91, 17.51, 9.69, 8.24. LC-MS-ESI+: [M+H]+ 439.2.

[0135]

[0136] 6-(2-Chloro-6-cyclopropyl-4-nitrophenoxy)-4-methylquinoline (19)

[0137] Intermediate 10 (3.0 g, 18.9 mmol, 1 eq) and Intermediate 13 (4.1 g, 18.9 mmol, 1 eq) were placed in a 100 ml round-bottom flask, and potassium carbonate (5.2 g, 37.7 mmol, 2 eq) was added to the flask. Subsequently, DMF (20 ml) was added, and the mixture was stirred overnight at room temperature (25 °C - 30 °C). After the reaction was complete as detected by TLC, extraction was carried out with EA (50 ml) and water (25 ml), and the organic phase was extracted multiple times until there was no UV in the aqueous phase. Then the aqueous phases were combined and back-extracted with EA (20 ml). After combining the organic phases, the organic phase was washed once with saturated brine. Purification by column chromatography (PE) gave 6.34 g of white solid with a yield of 94.8%.

[0138] 3-Chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)aniline (20 / FW-GY-D16)

[0139] Intermediate 19 (6.0 g, 16.9 mmol, 1 eq), iron powder (3.8 g, 67.7 mmol, 4 eq), ammonium chloride (1.8 g, 33.8 mmol, 2 eq) were placed together in a 250 ml round-bottom flask, and then 100 ml of a mixed solvent of EtOH:H2O = 3:1 was added. A condenser was inserted into the bottle mouth, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove EtOH. The remaining aqueous phase was extracted 3 times with EA (50 ml). The organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE - PE:EA = 10:1) gave 5.12 g of a white solid with a yield of 93.2%. 1H NMR (600 MHz, DMSO-d6) δ 8.66–8.60 (m, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.39 (ddd, J = 9.1, 2.8, 1.0 Hz, 1H), 7.33 (d, J = 4.3 Hz, 1H), 7.19 (d, J = 2.9 Hz, 1H), 6.60 (dd, J = 2.6, 0.9 Hz, 1H), 6.18 (d, J = 2.5 Hz, 1H), 5.30 (s, 1H), 2.50 (s, 1H), 1.87–1.77 (m, 1H), 0.79–0.72 (m, 1H), 0.57 (dd, J = 5.3, 1.9 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 155.40, 147.62, 146.80, 143.22, 141.89, 138.20, 137.36, 130.92, 128.02, 126.05, 121.69, 119.10, 111.29, 107.98, 104.65, 17.51, 9.42, 7.86. LC-MS-ESI+:[M+H]+ 325.3.

[0140] Methyl (3-chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)phenyl)alaninate (FW-GY-D1)

[0141] Intermediate 20 (200.0 mg, 0.62 mmol, 1 eq) was placed into a 50 ml two-necked flask. Subsequently, potassium iodide (112.4 mg, 0.68 mmol, 1.1 eq) and potassium carbonate (127.7 mg, 0.92 mmol, 1.5 eq) were also placed into the container. Acetone (10 ml) was added to the system, and the system was protected with nitrogen using a three-way valve, and the gas was replaced 3 times. Methyl 2-bromopropionate (411.3 mg, 2.46 mmol, 4 eq) was added to the system via a syringe. The mixture was stirred at 60 °C overnight. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, it was distilled under reduced pressure to remove acetone. The remaining material was dissolved in EA (10 ml), extracted with water 3 times, washed once with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 3:1) gave 192.0 mg of a white solid with a yield of 78.6%. 1H NMR (600 MHz, DMSO-d6) δ 8.63 (d, J = 4.3 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.35 (dd, J = 9.2, 2.7 Hz, 1H), 7.33 (d, J = 4.2 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 6.57 (d, J = 2.6 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 6.16 (d, J = 2.7 Hz, 1H), 4.17 (p, J = 7.2 Hz, 1H), 3.66 (s, 3H), 3.32 (d, J = 1.1 Hz, 5H), 1.83 (tt, J = 8.3, 5.1 Hz, 1H), 1.38 (d, J = 6.9 Hz, 3H), 0.81–0.73 (m, 2H), 0.65–0.50 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.92, 155.23, 147.68, 145.59, 143.21, 141.91, 138.37, 137.96, 130.95, 127.99, 126.34, 121.70, 118.92, 109.75, 106.67, 104.80, 51.25, 50.34, 17.47, 17.42, 9.51, 8.01, 7.92. LC-MS-ESI+: [M + H]+ 411.1.

[0142] (3-Chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-D3)

[0143] The preparation method was the same as that of FW-GY-D1, and 188.0 mg of a pale yellow solid was obtained with a yield of 79.8%. 1H NMR (600 MHz, DMSO-d6) δ 8.65 (d, J = 4.3 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.38–7.30 (m, 2H), 7.26 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 3.0 Hz, 1H), 6.09 (d, J = 3.1 Hz, 1H), 4.28 (s, 4H), 3.68 (s, 6H), 2.52 (s, 4H), 1.86 (tt, J = 8.5, 5.2 Hz, 1H), 0.81–0.73 (m, 2H), 0.67–0.59 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 170.19, 155.06, 147.63, 145.65, 143.01, 142.26, 138.64, 138.29, 130.82, 128.04, 126.61, 121.73, 118.82, 109.94, 106.45, 105.13, 51.85, 51.19, 17.55, 9.80, 8.04. LC-MS-ESI+: [M + H]+ 396.9.

[0144] 3-((3-Chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)phenyl)amino)-3-oxopropanoic acid (FW-GY-D5)

[0145] Intermediate 20 (200.0 mg, 0.62 mmol, 1 eq) was placed into a 50 ml round-bottom flask. Subsequently, malonic acid (76.9 mg, 0.74 mmol, 1.2 eq), HATU (351.2 mg, 0.92 mmol, 1.5 eq) and HOBT (124.8 mg, 0.92 mmol, 1.5 eq) were also placed into the container. DMF (10 ml) was added to the system, and Et3N (186.9 mg, 1.85 mmol, 3 eq) was added under stirring. The mixture was stirred overnight at 50 °C. The reaction was monitored by TLC and found to be complete. Extraction was carried out with EA (30 ml) and water (15 ml), and the organic phase was extracted multiple times until there was no UV absorption in the aqueous phase. The aqueous phases were combined and back-extracted with EA (10 ml). After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) gave 163.0 mg of a white solid with a yield of 64.4%. 1H NMR (600 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.65 (d, J = 4.3 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 9.2, 2.8 Hz, 1H), 7.35 (d, J = 4.2 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 2.06 (s, 3H), 1.91 (tt, J = 8.5, 5.2 Hz, 1H), 0.87–0.81 (m, 2H), 0.63–0.57 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 168.02, 154.57, 147.90, 143.32, 142.65, 142.09, 138.48, 137.19, 131.13, 127.97, 126.01, 121.79, 118.92, 116.87, 113.51, 104.94, 39.45, 23.42, 17.49, 9.52, 8.17. LC-MS-ESI+:[M + H]+ 411.2.

[0146] 4-((3-Chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)phenyl)amino)-4-oxobutanoic acid (FW-GY-D6)

[0147] The preparation method was the same as that of FW-GY-D5, and 182.0 mg of a pale yellow solid was obtained with a yield of 69.6%. 1H NMR (600 MHz, DMSO-d6) δ 8.65 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.41 (dd, J = 9.2, 2.9 Hz, 1H), 7.35 (dd, J = 4.3, 1.1 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 2.59–2.54 (m, 1H), 2.50 (s, 1H), 1.92 (tt, J = 8.4, 5.1 Hz, 1H), 0.90–0.81 (m, 1H), 0.65–0.56 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 173.18, 169.91, 161.72, 154.60, 147.90, 143.33, 142.62, 142.13, 138.53, 137.19, 131.14, 127.99, 126.06, 123.74, 121.80, 118.99, 116.81, 113.43, 109.13, 104.92, 17.52, 8.19. LC-MS-ESI+: [M + H]+ 425.2.

[0148] Methyl 3-(N-(3-chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)phenyl)sulfamoyl)propionate (FW-GY-D11)

[0149] The preparation method was the same as that of FW-GY-D5, and 223.0 mg of pale yellow solid was obtained with a yield of 76.25%. 1H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.66 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.40 (dd, J = 9.2, 2.8 Hz, 1H), 7.35 (d, J = 4.3 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 2.6 Hz, 1H), 3.62 (s, 3H), 3.48 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H), 2.52 (s, 3H), 1.92 (tt, J = 8.5, 5.1 Hz, 1H), 0.89–0.83 (m, 2H), 0.66–0.58 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 169.89, 154.45, 147.95, 143.69, 143.33, 142.23, 139.30, 135.93, 131.13, 128.01, 126.72, 121.82, 118.85, 117.37, 114.28, 105.14, 51.29, 45.99, 27.39, 17.45, 9.64, 8.27. LC-MS-ESI+: [M + H]+ 474.9.

[0150] Methyl 5-((3-chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)phenyl)amino)-5-oxopentanoate (FW-GY-D13)

[0151] The preparation method was the same as that of FW-GY-D5, and 201.0 mg of a pale yellow solid was obtained with a yield of 72.1%. 1H NMR (600 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.66 (d, J = 4.3 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.43–7.39 (m, 1H), 7.34 (dd, J = 4.4, 1.2 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 3.62 (d, J = 0.9 Hz, 3H), 2.51 (s, 3H), 2.44–2.36 (m, 4H), 1.97–1.91 (m, 1H), 1.90–1.84 (m, 2H), 0.88–0.82 (m, 2H), 0.65–0.59 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 172.48, 170.38, 154.64, 147.90, 143.35, 142.73, 142.16, 138.52, 137.17, 131.16, 128.03, 126.08, 121.81, 119.00, 117.02, 113.65, 104.99, 50.72, 34.74, 32.03, 19.68, 17.53, 9.59, 8.20. LC-MS-ESI+: [M + H]+ 453.0.

[0152] (3-Chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)phenyl)alanine (FW-GY-D2)

[0153] The end product FW-GY-D1 (100 mg, 0.24 mmol, 1 eq) and lithium hydroxide (46.6 mg, 1.95 mmol, 8 eq) were placed together in a 50 ml round-bottom flask, and then MeOH (10 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining substance was extracted with EA (10 ml) and water (5 ml) three times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 78.0 mg of a white solid with a yield of 80.8%. 1H NMR (600 MHz, DMSO-d6) δ 8.63 (d, J = 4.3 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.35 (dd, J = 9.2, 2.8 Hz, 1H), 7.33–7.32 (m, 1H), 7.20 (d, J = 2.8 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1H), 6.18 (d, J = 2.7 Hz, 1H), 3.94 (q, J = 6.9 Hz, 1H), 2.50 (dd, J = 3.8, 2.0 Hz, 13H), 1.82 (tt, J = 9.1, 5.4 Hz, 1H), 0.81–0.70 (m, 2H), 0.63–0.52 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 170.83, 155.29, 147.64, 145.90, 143.20, 141.92, 138.20, 137.61, 130.91, 128.00, 126.24, 121.67, 118.92, 109.52, 106.81, 104.80, 21.90, 17.59, 17.50, 9.53, 7.91, 7.84. LC-MS-ESI+: [M+H]+ 397.1.

[0154] (3-Chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-D4)

[0155] The preparation method was the same as that of FW-GY-D2, with the raw material being the end product FW-GY-D3. 69.0 mg of a pale yellow solid was obtained, and the yield was 71.5%. 1H NMR (600 MHz, DMSO-d6) δ 8.63 (d, J = 4.3 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 2.8 Hz, 1H), 7.33 (d, J = 4.3 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 6.19 (d, J = 2.7 Hz, 1H), 3.72 (s, 1H), 2.03–1.94 (m, 1H), 0.80–0.72 (m, 2H), 0.64–0.58 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 155.33, 147.63, 146.29, 143.20, 141.91, 138.17, 137.55, 130.91, 128.01, 126.25, 121.68, 118.97, 109.29, 107.94, 106.63, 104.76, 17.52, 9.58, 7.86, 7.83. LC-MS-ESI+: [M+H]+ 383.2.

[0156] 3-(N-(3-chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)phenyl)sulfamoyl)propanoic acid (FW-GY-D12)

[0157] The preparation method was the same as that of FW-GY-D2, with the raw material being the end product FW-GY-D11. 86.0 mg of a pale yellow solid was obtained, and the yield was 88.6%. 1H NMR (600 MHz, DMSO-d6) δ 8.66 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2, 2.8 Hz, 1H), 7.35 (d, J = 4.3 Hz, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 3.41 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.52 (s, 5H), 1.93–1.90 (m, 2H), 0.89–0.78 (m, 2H), 0.63 (dt, J = 6.6, 3.2 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 171.05, 154.47, 147.95, 143.34, 142.22, 139.25, 136.25, 131.14, 128.01, 126.67, 121.81, 118.82, 117.48, 114.40, 105.17, 46.50, 28.09, 21.91, 17.48, 9.65, 8.26. LC-MS-ESI+: [M + H]+ 461.1.

[0158] 5-((3-Chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)phenyl)amino)-5-oxopentanoic acid (FW-GY-D14)

[0159] The preparation method was the same as that of FW-GY-D2, with the raw material being the end product FW-GY-D13. 86.0 mg of a pale yellow solid was obtained, and the yield was 88.8%. 1H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.65 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 9.1, 2.8 Hz, 1H), 7.36–7.33 (m, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 2.50 (s, 1H), 2.41 (t, J = 7.4 Hz, 1H), 2.24 (t, J = 7.4 Hz, 1H), 1.93–1.89 (m, 1H), 1.82 (p, J = 7.5 Hz, 1H), 0.90–0.79 (m, 1H), 0.65–0.58 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 174.39, 172.22, 171.07, 170.91, 154.64, 147.89, 143.31, 142.53, 142.13, 138.35, 137.42, 131.12, 127.99, 125.88, 121.80, 119.03, 116.94, 113.71, 104.89, 21.91, 17.52, 9.57, 8.14. LC-MS-ESI+: [M+H]+ 439.1.

[0160]

[0161] Methyl 3-chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)benzoate (21)

[0162] Intermediate 16 (3.0 g, 13.1 mmol, 1 eq) and Intermediate 10 (2.1 g, 13.1 mmol, 1 eq) were placed in a 100 ml round-bottom flask, and potassium carbonate (3.6 g, 26.2 mmol, 2 eq) was added to the flask. Subsequently, DMF (40 ml) was added, and the mixture was stirred overnight at room temperature (25 °C - 30 °C). After TLC detection showed that the reaction was complete, extraction was carried out with EA (100 ml) and water (200 ml). The organic phase was extracted multiple times until there was no UV in the aqueous phase. Then the aqueous phase was combined and back-extracted with EA (50 ml). After combining the organic phases, the organic phase was washed once with saturated brine. Purification by column chromatography (PE) gave 4.08 g of a white solid with a yield of 84.5%.

[0163] 3-Chloro-5-cyclopropyl-4-(4-methylquinolin-6-yl)oxy)benzoic acid (22)

[0164] Intermediate 21 (4.0 g, 10.9 mmol, 1 eq) and lithium hydroxide (2.08 g, 87 mmol, 8 eq) were placed together in a 100 ml round-bottom flask, and then MeOH (40 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining substance was extracted with EA (100 ml) and water (50 ml) three times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 3.12 g of a white solid with a yield of 81.1%.

[0165] Ethyl 3-(3-chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)benzamido)propionate (FW-GY-D7)

[0166] Intermediate 22 (200.0 mg, 0.57 mmol, 1 eq) was placed in a 50 ml round-bottom flask. Subsequently, ethyl 3-aminopropionate (79.5 mg, 0.68 mmol, 1.2 eq), HATU (322.4 mg, 0.85 mmol, 1.5 eq) and HOBT (114.6 mg, 0.85 mmol, 1.5 eq) were also placed into the container. DMF (10 ml) was added to the system, and Et3N (171.6 mg, 1.70 mmol, 3 eq) was added under stirring. The mixture was stirred overnight at 50 °C. The reaction was monitored by TLC and found to be complete. Extraction was carried out with EA (30 ml) and water (15 ml), and the organic phase was extracted multiple times until there was no UV absorption in the aqueous phase. The aqueous phases were combined and back-extracted with EA (10 ml). After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a pale yellow oil was obtained, which was purified by column chromatography (PE:EA - PE:EA = 10:1 - 5:1) to give 196.0 mg of a white solid with a yield of 74.3%. 1H NMR (600 MHz, DMSO-d6) δ 8.76 (t, J = 5.5 Hz, 1H), 8.67 (d, J = 4.3 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 7.36 (d, J = 4.3 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 1H), 3.52 (q, J = 6.7 Hz, 1H), 2.61 (t, J = 6.9 Hz, 1H), 2.50 (s, 1H), 1.98 (tt, J = 8.5, 5.2 Hz, 1H), 1.19 (t, J = 7.1 Hz, 1H), 0.87 (dt, J = 8.5, 3.2 Hz, 1H), 0.80–0.76 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 170.70, 163.83, 154.03, 149.61, 148.12, 143.45, 142.24, 138.73, 132.20, 131.30, 127.99, 126.48, 126.03, 122.54, 121.88, 118.93, 105.25, 59.41, 35.10, 33.09, 17.49, 13.49, 9.68, 8.31. LC-MS-ESI+:[M+H]+ 453.1.

[0167] Methyl 3-(3-chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)benzamido)-2,2-dimethylpropionate (FW-GY-D9)

[0168] Prepared in the same method as FW-GY-D7, 180.0 mg of pale yellow solid was obtained with a yield of 68.2%. 1H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 4.3 Hz, 1H), 8.59 (t, J = 6.3 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 9.2, 2.8 Hz, 1H), 7.36 (dd, J = 4.3, 1.1 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 3.62 (s, 1H), 3.45 (d, J = 6.3 Hz, 1H), 2.51 (s, 1H), 1.97 (tt, J = 8.4, 5.2 Hz, 1H), 1.16 (s, 2H), 0.91–0.84 (m, 1H), 0.81–0.75 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 175.52, 164.42, 154.00, 149.57, 148.11, 143.42, 142.25, 138.62, 132.42, 131.27, 127.98, 126.37, 126.10, 122.78, 121.86, 118.84, 105.35, 51.27, 46.57, 42.72, 39.45, 22.39, 17.51, 9.68, 8.26. LC-MS-ESI+: [M + H]+ 467.2.

[0169] Methyl 1-(3-chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)benzoyl)azetidine-3-carboxylate (FW-GY-D15)

[0170] The preparation method was the same as that of FW-GY-D7, and 181.0 mg of a pale yellow solid was obtained with a yield of 71.0%. 1H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 9.2, 2.8 Hz, 1H), 7.36 (d, J = 4.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 4.56 (t, J = 8.8 Hz, 1H), 4.43 (t, J = 7.3 Hz, 1H), 4.25 (t, J = 9.6 Hz, 1H), 4.14 (t, J = 8.1 Hz, 1H), 3.69 (s, 1H), 3.60 (tt, J = 9.3, 6.0 Hz, 1H), 2.52 (s, 2H), 1.97 (tt, J = 8.5, 5.1 Hz, 1H), 0.86 (dt, J = 8.7, 3.1 Hz, 1H), 0.79–0.73 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 171.97, 166.51, 153.97, 149.38, 148.13, 143.41, 142.27, 139.00, 131.26, 130.89, 127.99, 126.65, 126.22, 122.92, 121.87, 118.75, 105.47, 54.38, 51.46, 50.32, 31.37, 17.48, 9.62, 8.41. LC-MS-ESI+: [M+H]+ 450.8.

[0171] 3-(3-Chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)benzamido)propanoic acid (FW-GY-D8)

[0172] The end product FW-GY-D7 (100 mg, 0.22 mmol, 1 eq) and lithium hydroxide (42.3 mg, 1.77 mmol, 8 eq) were placed together in a 50 ml round-bottom flask, and then MeOH (10 ml) was added. A condenser was inserted into the bottle mouth, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining substance was extracted with EA (10 ml) and water (5 ml) for 3 times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 71.0 mg of a white solid with a yield of 75.7%. 1H NMR (600 MHz, DMSO-d6) δ 8.75 (t, J = 5.4 Hz, 1H), 8.67 (d, J = 4.3 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 7.36 (d, J = 4.3 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 3.50 (td, J = 6.9, 5.3 Hz, 1H), 2.56 (t, J = 7.0 Hz, 1H), 2.51 (s, 1H), 1.98 (tt, J = 8.5, 5.2 Hz, 1H), 0.87 (dt, J = 8.4, 3.2 Hz, 1H), 0.81–0.76 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 172.33, 163.77, 154.04, 149.58, 148.10, 143.44, 142.26, 138.71, 132.25, 131.29, 128.00, 126.47, 126.05, 122.55, 121.87, 118.93, 105.28, 35.20, 33.13, 17.51, 9.69, 8.31. LC-MS-ESI+:[M+H]+ 424.7.

[0173] 3-(3-Chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)benzamido)-2,2-dimethylpropanoic acid (FW-GY-D10)

[0174] The preparation method was the same as that of FW-GY-D7, with the raw material being the final product FW-GY-D9. 71.0 mg of light yellow solid was obtained, and the yield was 75.4%. 1H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 4.3 Hz, 1H), 8.53 (t, J = 6.3 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.41 (dd, J = 9.2, 2.8 Hz, 1H), 7.36 (d, J = 4.3 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 3.46 (d, J = 6.2 Hz, 2H), 2.51 (s, 5H), 1.97 (tt, J = 8.4, 5.2 Hz, 1H), 1.14 (s, 6H), 0.91–0.83 (m, 2H), 0.80–0.75 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 177.11, 164.42, 154.02, 149.53, 148.10, 143.42, 142.25, 138.59, 132.52, 131.27, 127.99, 126.34, 126.15, 122.80, 121.86, 118.86, 105.33, 46.24, 42.43, 22.57, 21.91, 17.52, 9.69, 8.25. LC-MS-ESI+: [M + H]+ 453.0.

[0175] (3-Chloro-5-cyclopropyl-4-((4-methylquinolin-6-yl)oxy)benzoyl)aspartic acid (FW-GY-D17)

[0176] The preparation method was the same as that of FW-GY-D7, and 152.0 mg of a pale yellow solid was obtained with a yield of 57.4%. 1H NMR (600 MHz, DMSO-d6) δ 8.96 (d, J = 7.8 Hz, 1H), 8.67 (d, J = 4.3 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.43 (dd, J = 9.2, 2.8 Hz, 1H), 7.37–7.34 (m, 1H), 7.23 (d, J = 2.8 Hz, 1H), 2.88 (dd, J = 16.5, 5.8 Hz, 1H), 2.76–2.66 (m, 1H), 2.51 (s, 4H), 2.03–1.94 (m, 1H), 0.91–0.84 (m, 2H), 0.82–0.75 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 171.77, 171.11, 163.55, 153.97, 149.84, 148.11, 143.42, 142.29, 138.78, 131.60, 131.28, 127.97, 126.52, 126.19, 122.81, 121.86, 118.96, 105.25, 48.96, 17.53, 9.72, 8.27, 8.23. LC-MS-ESI+: [M + H]+ 469.1.

[0177]

[0178] 2-Chloro-6-(2-chloro-6-cyclopropyl-4-nitrophenoxy)quinoline (25a)

[0179] The raw material 23a (3.0 g, 16.7 mmol, 1 eq) and the intermediate 13 (3.6 g, 16.7 mmol, 1 eq) were placed in a 100 ml round-bottom flask, and potassium carbonate (4.62 g, 33.4 mmol, 2 eq) was added to the flask. Subsequently, DMF (40 ml) was added, and the mixture was stirred overnight at room temperature (25 °C - 30 °C). After the reaction was complete as detected by TLC, extraction was carried out with EA (50 ml) and water (100 ml), and the organic phase was extracted multiple times until there was no ultraviolet in the aqueous phase. Then the aqueous phase was combined and back-extracted with EA (50 ml). After combining the organic phases, the organic phase was washed once with saturated brine. Purification by column chromatography (PE) gave 6.08 g of a white solid with a yield of 97.0%.

[0180] 3-Chloro-4-((2-chloroquinolin-6-yl)oxy)-5-cyclopropylaniline (26a)

[0181] Intermediate 25a (6 g, 16.0 mmol, 1 eq), iron powder (3.57 g, 64.0 mmol, 4 eq), and ammonium chloride (1.7 g, 32.0 mmol, 2 eq) were placed together in a 100 ml round-bottom flask. Then, 50 ml of a mixed solvent of EtOH:H2O = 3:1 was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, it was distilled under reduced pressure to remove EtOH. The remaining aqueous phase was extracted 3 times with EA (50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE-PE:EA = 10:1) gave 5.23 g of a white solid with a yield of 94.7%.

[0182] (3-Chloro-4-((2-chloroquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine methyl ester (FW-GY-E5)

[0183] Intermediate 26a (200.0 mg, 0.58 mmol, 1 eq) was placed in a 50 ml two-necked flask. Subsequently, potassium iodide (105.8 mg, 0.64 mmol, 1.1 eq) and potassium carbonate (120.1 mg, 0.87 mmol, 1.5 eq) were also placed into the container. Acetone (10 ml) was added to the system, and the system was protected with nitrogen using a three-way stopcock, with the gas being replaced three times. Methyl bromoacetate (354.5 mg, 2.32 mmol, 4 eq) was added to the system via a syringe. The mixture was stirred at 60 °C overnight. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, it was distilled under reduced pressure to remove acetone. The remaining material was dissolved in EA (10 ml), extracted with water three times, washed once with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 3:1) gave 179.0 mg of a white solid with a yield of 76.6%. 1H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.11 (d, J = 2.7 Hz, 1H), 3.91 (s, 2H), 3.82 (s, 3H), 1.88 (tt, J = 8.5, 5.2 Hz, 1H), 0.78 (dt, J = 8.5, 3.3 Hz, 2H), 0.64–0.57 (m, 2H). 13C NMR (151 MHz, Chloroform-d) δ 171.18, 156.74, 148.53, 145.21, 144.15, 140.88, 139.64, 137.85, 130.28, 128.54, 127.78, 122.59, 121.99, 111.11, 108.57, 108.54, 52.46, 45.63, 10.44, 8.38. LC-MS-ESI+:[M + H]+ 417.2.

[0184] (4-((4-Bromoquinolin-6-yl)oxy)-3-chloro-5-cyclopropylphenyl)glycine methyl ester (FW-GY-E8)

[0185] The preparation method was the same as that of FW-GY-E5, and 155.0 mg of a pale yellow solid was obtained with a yield of 67.4%. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 4.7 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 4.6 Hz, 1H), 7.63 (dd, J = 9.2, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 6.64 (d, J = 2.7 Hz, 1H), 6.23 (d, J = 2.8 Hz, 1H), 4.01 (d, J = 4.9 Hz, 1H), 3.70 (s, 1H), 1.83 (tt, J = 8.4, 5.2 Hz, 1H), 0.81–0.74 (m, 1H), 0.67–0.58 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.01, 157.83, 148.94, 147.39, 145.24, 139.22, 138.76, 132.54, 131.97, 128.54, 127.23, 126.25, 122.44, 110.61, 107.93, 107.50, 52.22, 45.00, 10.67, 8.96. LC-MS-ESI+:[M+H]+ 460.9.

[0186] (3-Chloro-5-cyclopropyl-4-((3-fluoroquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-E10)

[0187] The preparation method was the same as that of FW-GY-E5, and 160.0 mg of a pale yellow solid was obtained with a yield of 68.0%. 1H NMR (400 MHz, Chloroform-d) δ 8.70 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.61 (dd, J = 9.1, 2.7 Hz, 1H), 7.49 (dd, J = 9.2, 2.7 Hz, 1H), 6.90 (d, J = 2.7 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 3.95 (d, J = 5.4 Hz, 2H), 3.86 (s, 3H), 1.92 (td, J = 8.6, 4.3 Hz, 1H), 0.88–0.78 (m, 2H), 0.68–0.60 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 171.24, 157.39, 155.58, 145.22, 140.86, 139.69, 139.42, 139.15, 131.31, 128.55, 120.38, 117.67, 117.50, 111.12, 108.56, 107.96, 52.56, 45.67, 10.45, 8.48. LC-MS-ESI+: [M+H]+ 401.0.

[0188] (4-((3-Bromoquinolin-7-yl)oxy)-3-chloro-5-cyclopropylphenyl)glycine methyl ester (FW-GY-E13)

[0189] The preparation method was the same as that of FW-GY-E5, and 163.0 mg of a pale yellow solid was obtained with a yield of 70.9%. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.50 (dd, J = 9.0, 2.6 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 6.25 (t, J = 6.3 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 4.00 (d, J = 6.3 Hz, 1H), 3.70 (s, 1H), 1.88–1.72 (m, 1H), 0.82–0.73 (m, 1H), 0.63–0.57 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.02, 159.84, 151.99, 147.56, 147.41, 139.21, 138.70, 137.79, 129.95, 127.26, 125.30, 119.91, 115.15, 110.56, 109.96, 107.84, 52.22, 44.99, 10.54, 8.98. LC-MS-ESI+: [M + H]+ 461.2.

[0190] (3-Chloro-5-cyclopropyl-4-((2-methyl-1H-indol-5-yl)oxy)phenyl)glycine methyl ester (FW-GY-E15)

[0191] The preparation method was the same as that of FW-GY-E5, and 160.0 mg of a pale yellow solid was obtained with a yield of 67.48%. 1H NMR (400 MHz, DMSO-d6) δ 7.20–7.08 (m, 1H), 6.66–6.60 (m, 1H), 6.54 (dd, J = 5.1, 2.7 Hz, 1H), 6.50–6.42 (m, 1H), 6.18–6.07 (m, 2H), 4.03–3.91 (m, 3H), 3.70–3.67 (m, 4H), 3.35 (s, 4H), 1.86 (td, J = 8.5, 4.4 Hz, 1H), 0.81–0.73 (m, 1H), 0.58 (tt, J = 6.4, 3.9 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.15, 172.04, 152.54, 146.49, 139.76, 137.06, 132.22, 129.45, 127.95, 111.46, 110.42, 109.41, 107.49, 103.09, 99.47, 52.18, 45.07, 13.95, 10.59, 9.16. LC-MS-ESI+: [M + H]+ 385.3.

[0192] (3-Chloro-4-((2-chloroquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine (FW-GY-E6)

[0193] The end product FW-GY-E5 (100 mg, 0.24 mmol, 1 eq) and lithium hydroxide (45.9 mg, 1.92 mmol, 8 eq) were placed together in a 50 ml round-bottom flask, and then MeOH (10 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining substance was extracted with EA (10 ml) and water (5 ml) three times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 91.0 mg of a white solid with a yield of 94.2%. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 9.3, 2.8 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.22 (d, J = 2.8 Hz, 1H), 3.87 (s, 1H), 1.81 (dq, J = 8.6, 4.5, 3.5 Hz, 1H), 0.82–0.74 (m, 2H), 0.67–0.58 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.88, 156.96, 148.27, 147.39, 143.96, 139.51, 139.12, 138.78, 130.41, 128.27, 127.29, 123.23, 122.50, 110.53, 109.00, 108.01, 45.15, 10.67, 8.80. LC-MS-ESI+:[M+H]+ 403.1.

[0194] (3-Chloro-4-((4-chloroquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine (FW-GY-E7)

[0195] The preparation method was the same as that of FW-GY-E6, and 90.0 mg of light yellow solid was obtained with a yield of 93.13%. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 4.7 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 4.7 Hz, 1H), 7.64 (dd, J = 9.3, 2.8 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 6.23 (d, J = 2.7 Hz, 1H), 3.88 (s, 2H), 1.82 (td, J = 8.5, 4.5 Hz, 1H), 0.82–0.74 (m, 2H), 0.64–0.59 (m, 2H). LC-MS-ESI+: [M + H]+ 403.3.

[0196] (4-((4-Bromoquinolin-6-yl)oxy)-3-chloro-5-cyclopropylphenyl)glycine (FW-GY-E9)

[0197] The preparation method was the same as that of FW-GY-E6, with the raw material being the final product FW-GY-E8, and 87.0 mg of light yellow solid was obtained with a yield of 89.7%. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 4.6 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 4.7 Hz, 1H), 7.64 (dd, J = 9.2, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 6.24 (d, J = 2.7 Hz, 1H), 3.88 (s, 2H), 1.90–1.75 (m, 1H), 0.83–0.74 (m, 2H), 0.68–0.54 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.88, 157.85, 148.95, 147.51, 145.22, 139.14, 138.56, 132.54, 131.99, 128.54, 127.16, 126.25, 122.47, 110.53, 107.88, 107.45, 45.12, 10.66, 8.96. LC-MS-ESI+: [M + H]+ 447.0.

[0198] (3-Chloro-5-cyclopropyl-4-((3-fluoroquinolin-6-yl)oxy)phenyl)glycine (FW-GY-E11)

[0199] The preparation method was the same as that of FW-GY-E6. Using the final product FW-GY-E10 as the raw material, 73.0 mg of light yellow solid was obtained, and the yield was 75.6%. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 2.8 Hz, 1H), 8.19 (dd, J = 10.0, 3.0 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.52 (dd, J = 9.2, 2.8 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.22 (d, J = 2.7 Hz, 1H), 3.82 (s, 2H), 1.80 (td, J = 8.6, 4.3 Hz, 1H), 0.77 (dt, J = 8.5, 3.1 Hz, 2H), 0.66–0.58 (m, 2H). LC-MS-ESI+: [M + H]+ 387.1.

[0200] (4-((3-Bromoquinolin-7-yl)oxy)-3-chloro-5-cyclopropylphenyl)glycine (FW-GY-E14)

[0201] The preparation method was the same as that of FW-GY-E6. Using the final product FW-GY-E13 as the raw material, 73.0 mg of light yellow solid was obtained, and the yield was 75.3%. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.50 (dd, J = 9.0, 2.6 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 6.22 (d, J = 2.7 Hz, 1H), 3.87 (s, 2H), 1.81 (tt, J = 8.4, 5.2 Hz, 1H), 0.77 (dt, J = 8.6, 3.2 Hz, 2H), 0.67–0.52 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.86, 159.87, 151.99, 147.55, 139.13, 138.53, 137.77, 129.94, 127.19, 125.28, 119.92, 115.14, 110.50, 109.95, 107.82, 45.18, 14.60, 10.53, 8.96. LC-MS-ESI+: [M + H]+ 446.8.

[0202] (3-Chloro-5-cyclopropyl-4-((2-methyl-1H-indol-5-yl)oxy)phenyl)glycine (FW-GY-E16)

[0203] The preparation method is the same as that of FW-GY-E6. The raw material is the end product FW-GY-E15, and 76.0 mg of light yellow solid is obtained with a yield of 78.9%. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 8.6 Hz, 1H), 6.64 (dd, J = 8.6, 2.5 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 6.12 (d, J = 2.8 Hz, 1H), 6.00 (s, 1H), 3.86 (d, J = 13.1 Hz, 4H), 2.36 (d, J = 8.1 Hz, 5H), 1.86 (td, J = 8.4, 4.3 Hz, 1H), 0.82–0.76 (m, 3H), 0.59 (dt, J = 5.3, 3.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 173.02, 152.56, 146.64, 140.06, 139.70, 137.05, 132.20, 129.44, 111.47, 111.01, 110.36, 109.42, 107.44, 103.06, 99.47, 45.21, 13.96, 10.57, 9.15. LC-MS-ESI+: [M + H]+ 371.2.

[0204] 2-Methylquinolin-6-ol (24a)

[0205] The raw material 23a (0.5 g, 2.8 mmol, 1 eq) was placed in a 25 ml two-necked flask, and then manganese chloride (17.5 mg, 0.14 mmol, 0.05 eq) was added. THF (50 ml) was added, and the system was protected with nitrogen and purged 3 times. The system was placed in an ice-water bath, and methylmagnesium bromide (2.78 ml, 5.6 mmol, 2 eq) was slowly added dropwise using a constant-pressure dropping funnel under stirring. After the addition was complete, the system was transferred to room temperature and stirred overnight. TLC detected that the reaction was complete. It was extracted with EA (50 ml) and water (30 ml) for 3 times. After combining the organic phases, the organic phase was washed once with saturated brine. After distillation under reduced pressure, a light yellow oil was obtained and purified by column chromatography (PE:EA = 20:1) to obtain 423 mg of white solid with a yield of 95.5%.

[0206] 4-Ethylquinolin-6-ol (24b)

[0207] The preparation method is the same as that of 24a, and 390.0 mg of white solid is obtained with a yield of 80.9%

[0208] 4-Phenylquinolin-6-ol (24c)

[0209] The preparation method was the same as that of 24a, and 562.0 mg of white solid was obtained with a yield of 91.2%.

[0210] 4-Cyclopropylquinolin-6-ol (24d)

[0211] The preparation method was the same as that of 24a, and 462.0 mg of white solid was obtained with a yield of 89.6%.

[0212] 2-Ethylquinolin-6-ol (24e)

[0213] The preparation method was the same as that of 24a, and 462.0 mg of white solid was obtained with a yield of 95.8%.

[0214] 2-Cyclohexylquinolin-6-ol (24f)

[0215] The preparation method was the same as that of 24a, and 515.0 mg of white solid was obtained with a yield of 81.4%.

[0216] 2-Phenylquinolin-6-ol (24g)

[0217] The preparation method was the same as that of 24a, and 513.0 mg of white solid was obtained with a yield of 83.3%.

[0218] 2-Isopropylquinolin-6-ol (24h)

[0219] The preparation method was the same as that of 24a, and 501.0 mg of white solid was obtained with a yield of 96.1%.

[0220] 6-(2-Chloro-6-cyclopropyl-4-nitrophenoxy)-2-methylquinoline (27a)

[0221] Put the raw material 24a (0.3 g, 1.9 mmol, 1 eq) and the intermediate 13 (406.3 mg, 1.9 mmol, 1 eq) into a 100 ml round-bottom flask, and then add potassium carbonate (520.9 mg, 3.8 mmol, 2 eq) to the flask. Subsequently, add DMF (10 ml), stir overnight at room temperature (25 °C - 30 °C). After the reaction is complete by TLC detection, extract with EA (5 ml) and water (10 ml), and extract the organic phase multiple times until there is no UV in the aqueous phase. Then combine the aqueous phases and back-extract with EA (5 ml). After combining the organic phases, wash the organic phase once with saturated brine. Purify by column chromatography (PE) to obtain 602.0 mg of white solid with a yield of 90.2%.

[0222] 3-Chloro-5-cyclopropyl-4-((2-methylquinolin-6-yl)oxy)aniline (28a)

[0223] Intermediate 25a (500 mg, 1.41 mmol, 1 eq), iron powder (314.8 mg, 5.6 mmol, 4 eq), and ammonium chloride (150.8 g, 2.82 mmol, 2 eq) were placed together in a 50 ml round-bottom flask, and then 50 ml of a mixed solvent of EtOH:H2O = 3:1 was added. A condenser was inserted into the bottle mouth, and the system was stirred overnight at 65 °C. The reaction was monitored by TLC and found to be complete. After the system was cooled to room temperature, it was distilled under reduced pressure to remove EtOH. The remaining aqueous phase was extracted 3 times with EA (50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE-PE:EA = 10:1) gave 386.0 mg of a white solid with a yield of 84.3%.

[0224] (3-Chloro-5-cyclopropyl-4-((2-methylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-E1)

[0225] Intermediate 28a (200.0 mg, 0.62 mmol, 1 eq) was placed into a 50 ml two-necked flask. Subsequently, potassium iodide (112.4 mg, 0.68 mmol, 1.1 eq) and potassium carbonate (127.7 mg, 0.92 mmol, 1.5 eq) were also placed into the container. Acetone (10 ml) was added to the system, and the system was protected with nitrogen using a three-way stopcock, with the gas being exchanged three times. Methyl bromoacetate (376.8 mg, 2.46 mmol, 4 eq) was added to the system via a syringe. The mixture was stirred at 60 °C overnight. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, the acetone was removed by distillation under reduced pressure. The remaining material was dissolved in EA (10 ml), extracted with water three times, washed once with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 3:1) gave 176.0 mg of a white solid with a yield of 74.7%. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.46 (dd, J = 9.2, 2.8 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.26–6.16 (m, 1H), 3.99 (d, J = 6.2 Hz, 1H), 3.70 (s, 2H), 2.62 (s, 2H), 1.82 (td, J = 8.4, 4.4 Hz, 1H), 0.76 (dt, J = 8.5, 3.2 Hz, 1H), 0.64–0.56 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.08, 157.11, 155.87, 147.12, 144.14, 139.30, 139.18, 135.68, 130.65, 127.47, 127.39, 122.99, 120.95, 110.55, 108.60, 107.90, 52.22, 45.01, 25.08, 10.65, 8.90. LC-MS-ESI+: [M + H]+ 396.9.

[0226] (3-Chloro-5-cyclopropyl-4-((4-ethylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-E3)

[0227] The preparation method was the same as that of FW-GY-E1, and 188.0 mg of a pale yellow solid was obtained with a yield of 80.3%. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 4.5 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.62 (dd, J = 9.2, 2.8 Hz, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.36 (d, J = 2.7 Hz, 1H), 4.02 (s, 2H), 3.07 (q, J = 7.5 Hz, 2H), 1.99 (tt, J = 8.8, 5.1 Hz, 1H), 1.40–1.37 (m, 1H), 0.97–0.88 (m, 2H), 0.82–0.72 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 173.02, 156.86, 148.41, 147.53, 139.47, 138.89, 131.49, 130.79, 128.44, 127.49, 121.04, 120.96, 110.67, 107.93, 105.56, 45.30, 29.67, 25.11, 14.15, 10.76, 9.15. LC-MS-ESI+: [M + H]+ 397.1.

[0228] (3-Chloro-5-cyclopropyl-4-((4-phenylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-E4)

[0229] The preparation method was the same as that of FW-GY-E1, and 163.0 mg of a pale yellow solid was obtained with a yield of 70.9%. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.51–7.48 (m, 6H), 7.44 (d, J = 4.4 Hz, 2H), 7.09 (d, J = 2.8 Hz, 1H), 6.49 (d, J = 2.7 Hz, 1H), 6.09 (d, J = 2.7 Hz, 1H), 3.70–3.64 (m, 2H), 1.86–1.75 (m, 1H), 0.82–0.76 (m, 2H), 0.61–0.52 (m, 2H). LC-MS-ESI+: [M + H]+ 444.9.

[0230] 2-(3-Chloro-5-cyclopropyl-4-((4-cyclopropylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (FW-GY-E12)

[0231] The preparation method is the same as that of MGL-3196. Using 24d as the raw material, 115.0 mg of pale yellow solid was obtained, and the yield was 50.3%. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 2.6 Hz, 2H), 7.45 (dd, J = 9.2, 2.8 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.16 (d, J = 4.6 Hz, 1H), 2.33–2.23 (m, 1H), 2.07–1.95 (m, 1H), 1.11–1.02 (m, 2H), 0.93–0.84 (m, 2H), 0.82–0.77 (m, 2H), 0.75–0.70 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 155.31, 149.37, 148.54, 147.86, 144.51, 139.84, 139.62, 132.41, 129.53, 126.99, 125.31, 122.61, 122.15, 119.92, 118.12, 114.78, 106.47, 29.51, 12.07, 10.84, 9.42, 9.11, 8.34. LC-MS-ESI+: [M + H]+ 472.1.

[0232] (3-Chloro-5-cyclopropyl-4-((2-ethylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-E18)

[0233] The preparation method was the same as that of FW-GY-E1, and 183.0 mg of a pale yellow solid was obtained with a yield of 78.1%. 1H NMR (600 MHz, Chloroform-d) δ 8.56 (d, J = 9.3 Hz, 1H), 8.42 (d, J = 8.6 Hz, 1H), 7.74 (dd, J = 9.4, 2.8 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 6.12 (d, J = 2.8 Hz, 1H), 3.91 (s, 2H), 3.83 (s, 3H), 3.33 (q, J = 7.6 Hz, 3H), 1.83 (tt, J = 8.5, 5.2 Hz, 1H), 1.48 (t, J = 7.7 Hz, 3H), 0.82–0.77 (m, 2H), 0.62–0.57 (m, 2H). 13C NMR (151 MHz, Chloroform-d) δ 171.10, 159.81, 158.37, 145.62, 143.03, 140.20, 139.41, 135.37, 128.54, 128.26, 125.78, 124.06, 121.64, 111.14, 108.69, 108.64, 52.51, 45.53, 27.52, 13.63, 10.36, 8.37. LC-MS-ESI+: [M + H]+ 411.2.

[0234] (3-Chloro-4-((2-cyclohexylquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine methyl ester (FW-GY-E20)

[0235] The preparation method was the same as that of FW-GY-E1, and 198.0 mg of a pale yellow solid was obtained with a yield of 86.3%. 1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 9.2, 2.8 Hz, 1H), 7.27 (s, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.10 (d, J = 2.8 Hz, 1H), 4.31 (t, J = 5.5 Hz, 1H), 3.91 (d, J = 5.4 Hz, 2H), 2.94–2.80 (m, 1H), 1.99 (d, J = 12.6 Hz, 2H), 1.95–1.83 (m, 3H), 1.53–1.21 (m, 4H), 0.83–0.75 (m, 2H), 0.66–0.55 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 171.29, 164.90, 155.78, 145.01, 141.21, 139.84, 135.43, 130.67, 128.72, 127.69, 120.70, 119.87, 111.11, 108.54, 108.34, 52.53, 47.49, 45.72, 32.97, 29.76, 26.61, 26.15, 10.48, 8.48. LC-MS-ESI+: [M + H]+ 465.2.

[0236] (3-Chloro-5-cyclopropyl-4-((2-phenylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-E21)

[0237] The preparation method was the same as that of FW-GY-E1, and 143.0 mg of a pale yellow solid was obtained with a yield of 62.2%. LC-MS-ESI+: [M + H]+ 459.0.

[0238] (3-Chloro-5-cyclopropyl-4-((2-isopropylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-E23)

[0239] The preparation method was the same as that of FW-GY-E1, and 90.0 mg of pale yellow solid was obtained with a yield of 79.0%. 1H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 9.2, 2.7 Hz, 1H), 7.24 (s, 1H), 6.87 (d, J = 2.7 Hz, 1H), 6.51 (d, J = 2.7 Hz, 1H), 6.09 (d, J = 2.7 Hz, 1H), 3.89 (d, J = 4.8 Hz, 2H), 3.80 (s, 3H), 3.20 (p, J = 6.9 Hz, 1H), 1.89 (tt, J = 8.8, 5.3 Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H), 0.79–0.73 (m, 2H), 0.61–0.54 (m, 2H). 13C NMR (151 MHz, Chloroform-d) δ 171.23, 165.65, 155.79, 145.00, 144.06, 141.22, 139.79, 135.47, 130.63, 128.69, 127.62, 120.65, 119.40, 111.11, 108.54, 108.35, 52.44, 45.69, 37.10, 22.60, 10.46, 8.38. LC-MS-ESI+: [M+H]+ 425.2.

[0240] (3-Chloro-5-cyclopropyl-4-((2-methylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-E2)

[0241] The end product FW-GY-E1 (100 mg, 0.24 mmol, 1 eq) and lithium hydroxide (48.3 mg, 1.92 mmol, 8 eq) were placed together in a 50 ml round-bottom flask, and then MeOH (10 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining material was extracted with EA (10 ml) and water (5 ml) three times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 76.0 mg of a white solid with a yield of 78.8%. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 7.15 (s, 1H), 6.61 (dd, J = 6.0, 2.6 Hz, 1H), 6.22 (dd, J = 6.0, 2.6 Hz, 1H), 3.87 (s, 2H), 1.81 (tt, J = 8.9, 5.1 Hz, 1H), 0.79–0.71 (m, 2H), 0.62 (dt, J = 5.3, 2.9 Hz, 2H). LC-MS-ESI+: [M+H]+ 383.1.

[0242] (3-Chloro-5-cyclopropyl-4-((2-ethylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-E19)

[0243] The preparation method was the same as that of FW-GY-E2, with the raw material being the end product FW-GY-E18. 89.0 mg of a pale yellow solid was obtained, and the yield was 92.2%. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 9.2 Hz, 2H), 7.81 (t, J = 9.5 Hz, 3H), 7.29 (d, J = 2.9 Hz, 2H), 6.62 (d, J = 2.7 Hz, 1H), 6.25 (d, J = 2.7 Hz, 1H), 3.88 (s, 2H), 3.18–3.03 (m, 3H), 1.85–1.74 (m, 1H), 1.42–1.35 (m, 5H), 0.80–0.72 (m, 2H), 0.67–0.57 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.89, 160.88, 158.49, 157.44, 147.56, 139.02, 138.53, 137.01, 128.55, 127.17, 126.99, 122.98, 119.28, 110.54, 109.34, 108.10, 45.11, 13.86, 10.68, 8.74. LC-MS-ESI+: [M+H]+ 397.1.

[0244] (3-Chloro-5-cyclopropyl-4-((2-phenylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-E22)

[0245] The preparation method is the same as that of FW-GY-E2, with the raw material being the end product FW-GY-E21, and 81.0 mg of pale yellow solid is obtained, with a yield of 83.6%. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.8 Hz, 1H), 8.27–8.23 (m, 2H), 8.09 (d, J = 8.9 Hz, 2H), 7.63–7.43 (m, 4H), 7.08 (d, J = 2.8 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 6.25–6.20 (m, 1H), 3.88 (s, 2H), 1.84 (td, J = 8.5, 4.3 Hz, 1H), 0.78 (dt, J = 8.4, 3.1 Hz, 2H), 0.68–0.58 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.93, 156.55, 154.75, 147.32, 144.42, 139.21, 138.93, 136.69, 131.67, 129.89, 129.81, 129.33, 128.35, 127.47, 127.38, 121.67, 119.63, 110.52, 108.57, 107.94, 45.16, 10.68, 8.87. LC-MS-ESI+: [M+H]+ 444.9.

[0246] (3-Chloro-5-cyclopropyl-4-((2-isopropylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-E24)

[0247] The preparation method was the same as that of FW-GY-E2, with the raw material being the end product FW-GY-E23. 79.0 mg of light yellow solid was obtained, and the yield was 81.7%. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 9.2, 2.9 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 3.85 (s, 2H), 3.17 (hept, J = 7.0 Hz, 1H), 1.82 (tt, J = 8.6, 5.2 Hz, 1H), 1.31 (d, J = 6.9 Hz, 7H), 0.83–0.73 (m, 2H), 0.66–0.54 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.93, 165.49, 155.95, 147.27, 143.91, 139.22, 138.94, 135.96, 130.96, 127.82, 127.41, 120.85, 120.81, 110.47, 108.53, 107.89, 45.31, 36.59, 22.83, 10.65, 8.86. LC-MS-ESI+: [M+H]+ 411.2.

[0248]

[0249] 4-Ethyl-6-methoxyquinolin-2-ol (31)

[0250] The raw material 29 (20.0 g, 162.4 mmol, 1 eq) and the raw material 30 (92.72 ml, 649.6 mmol, 4 eq) were placed into a 500 ml round-bottom flask and stirred at 160 °C for 2 hours. By TLC detection, most of the reaction occurred but it was not complete. Without any treatment, the system was cooled to 60 °C, and then concentrated H2SO4 (40 ml) was slowly added dropwise under stirring conditions. The ratio was 1 g of raw material 29: 2 ml of H2SO4, and the mixture was stirred overnight at 100 °C. By TLC detection, the reaction of the new spots was complete. The reaction solution was slowly added dropwise into the sodium bicarbonate solution prepared with ice water until the pH was neutral. It was extracted with DCM (200 ml) three times. After combining the organic phases, it was washed with saturated brine, then dried over anhydrous sodium sulfate, and distilled under reduced pressure. Purification by column chromatography (PE:EA = 20:1) gave 19.3 g of white solid, and the yield was 53.7%.

[0251] 2-Chloro-4-ethyl-6-methoxyquinoline (32)

[0252] Dissolve intermediate 31 (5 g, 24.6 mmol, 1 eq) in phosphorus oxychloride (33.78 ml, 369.0 mmol, 15 eq), stir at 80 °C for 2 h, and monitor the reaction completion by TLC. Slowly add the reaction solution dropwise to water, stir in water for 0.5 h, then extract with EA (50 ml) three times. Combine the organic phases, wash the organic phase with saturated brine once more, dry over anhydrous sodium sulfate, and distill under reduced pressure. Purify by column chromatography (PE:EA = 5:1) to obtain 4.1 g of a white solid with a yield of 75.2%.

[0253] 4-Ethyl-6-methoxy-2-(4-(trifluoromethyl)phenyl)quinoline (33a)

[0254] Put intermediate 32 (500 mg, 2.26 mmol, 1 eq) into a 50 ml two-necked flask. Subsequently, add p-trifluoromethylboronic acid (556.9 mg, 2.93 mmol, 1.3 eq), tetrakis(triphenylphosphine)palladium (130.3 mg, 0.11 mmol, 0.05 eq), and potassium carbonate (717.2 mg, 6.77 mmol, 3 eq) into the container as well. Add a mixed solvent of 1,4-Dioxane:H2O = 4:1 (20 ml) to the system, protect the system with nitrogen using a three-way valve, and change the gas three times. Stir overnight at 100 °C. Monitor the reaction completion by TLC. After cooling the system to room temperature, distill under reduced pressure to remove 1,4-Dioxane. Dissolve the remaining substance in EA (20 ml), extract with water three times, wash with saturated brine once, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain a yellow oil. Purify by column chromatography (PE:EA = 5:1) to obtain 613.0 mg of a white solid with a yield of 82.0%.

[0255] 2-(4-Chlorophenyl)-4-ethyl-6-methoxyquinoline (33b)

[0256] The preparation method is the same as that of 33a to obtain 592.0 mg of a white solid with a yield of 88.1%

[0257] 4-Ethyl-2-isopropyl-6-methoxyquinoline (33c)

[0258] The preparation method is the same as that of 33a to obtain 463.0 mg of a white solid with a yield of 89.5%

[0259] 4-Ethyl-2-ethyl-6-methoxyquinoline (33d)

[0260] The preparation method is the same as that of 33a to obtain 426 mg of a white solid with a yield of 82.4%

[0261] 2-(4-(tert-Butyl)phenyl)-4-ethyl-6-methoxyquinoline (33e)

[0262] The preparation method was the same as that of 33a, and 598.0 mg of white solid was obtained with a yield of 83.0%.

[0263] 4-Ethyl-2-(3-fluoro-4-methylphenyl)-6-methoxyquinoline (33f)

[0264] The preparation method was the same as that of 33a, and 567.0 mg of white solid was obtained with a yield of 85.1%.

[0265] 2-(2-Chloro-4-methylphenyl)-4-ethyl-6-methoxyquinoline (33g)

[0266] The preparation method was the same as that of 33a, and 603.0 mg of white solid was obtained with a yield of 85.7%.

[0267] 2-(3,5-Difluorophenyl)-4-ethyl-6-methoxyquinoline (33h)

[0268] The preparation method was the same as that of 33a, and 541.0 mg of white solid was obtained with a yield of 80.1%.

[0269] 4-Ethyl-6-methoxy-2-(2,4,5-trifluorophenyl)quinoline (33i)

[0270] The preparation method was the same as that of 33a, and 555.0 mg of white solid was obtained with a yield of 77.5%.

[0271] 2-(3,5-Difluorophenyl)-4-ethyl-6-methoxyquinoline (33j)

[0272] It was consistent with intermediate 32. For convenience in the following, it was numbered as 33j again.

[0273] 4-Ethyl-2-(4-(trifluoromethyl)phenyl)quinolin-6-ol (34a)

[0274] Put intermediate 33a (500 mg, 1.68 mmol, 1 eq) into a 50 ml two-necked flask, dissolve it in DCM (15 ml), protect the system with nitrogen through a three-way valve, and change the gas 3 times. Stir the 2M boron tribromide solution (2.52 ml, 5.04 mmol, 3 eq) at room temperature overnight. TLC detected that the reaction was complete. Slowly dropwise add saturated sodium bicarbonate solution into the system until the solution showed neutrality, shake, stand still, and separate the liquid. Extract the organic phase with water 3 times, wash it once with saturated brine, dry it with anhydrous sodium sulfate, and distill it under reduced pressure to obtain a yellow oil. Purify it by column chromatography (PE:EA = 20:1) to obtain 446.0 mg of white solid with a yield of 93.6%.

[0275] 6-(2-Chloro-6-cyclopropyl-4-nitrophenoxy)-4-ethyl-2-(4-(trifluoromethyl)phenyl)quinoline (35a)

[0276] The raw material 34a (0.3 g, 0.95 mmol, 1 eq) and the intermediate 13 (203.8 mg, 0.95 mmol, 1 eq) were placed into a 100 ml round-bottom flask, and potassium carbonate (261.3 mg, 1.9 mmol, 2 eq) was further added to the flask. Subsequently, DMF (10 ml) was added, and the mixture was stirred overnight at room temperature (25 °C - 30 °C). After the reaction was detected to be complete by TLC, extraction was carried out with EA (5 ml) and water (10 ml), and the organic phase was extracted multiple times until there was no ultraviolet in the aqueous phase. Then the aqueous phases were combined and back-extracted with EA (5 ml). After combining the organic phases, the organic phase was washed once with saturated brine. Purification by column chromatography (PE) gave 431.0 mg of a white solid with a yield of 88.9%.

[0277] 3-chloro-5-cyclopropyl-4-((4-ethyl-2-(4-(trifluoromethyl)phenyl)quinolin-6-yl)oxy)aniline (36a)

[0278] The intermediate 35a (300 mg, 0.58 mmol, 1 eq), iron powder (130.6 mg, 2.34 mmol, 4 eq), and ammonium chloride (62.6 mg, 1.17 mmol, 2 eq) were jointly placed into a 50 ml round-bottom flask, and 20 ml of a mixed solvent of EtOH:H2O = 3:1 was further added. A condenser was inserted at the mouth of the flask, and the system was stirred overnight at 65 °C. After the reaction was detected to be complete by TLC, the system was cooled to room temperature and then distilled under reduced pressure to remove EtOH. The remaining aqueous phase was extracted 3 times with EA (20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE - PE:EA = 10:1) gave 243.0 mg of a white solid with a yield of 86.0%.

[0279] (3-chloro-4-((2-chloro-4-ethylquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine methyl ester (FW-GY-F1)

[0280] Intermediate 33j (200.0 mg, 0.54 mmol, 1 eq) was placed into a 50 ml two-necked flask. Subsequently, potassium iodide (97.8 mg, 0.59 mmol, 1.1 eq) and potassium carbonate (111.1 mg, 0.80 mmol, 1.5 eq) were also placed into the container. Acetone (10 ml) was added to the system, and the system was protected with nitrogen using a three-way stopcock, and the gas was replaced three times. Methyl bromoacetate (409.8 mg, 2.68 mmol, 4 eq) was added to the system via a syringe. The mixture was stirred at 60 °C overnight. The reaction was monitored by TLC and found to be complete. After cooling the system to room temperature, it was distilled under reduced pressure to remove acetone. The remaining material was dissolved in EA (10 ml), extracted with water three times, washed once with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA - PE:EA = 10:1 - 3:1) gave 176.0 mg of a white solid with a yield of 73.8%. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 9.2 Hz, 1H), 7.46 (dd, J = 9.2, 2.8 Hz, 1H), 7.41 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 4.00 (d, J = 6.3 Hz, 2H), 3.69 (s, 3H), 2.98–2.83 (m, 2H), 1.84 (ddd, J = 8.4, 5.2, 3.2 Hz, 1H), 1.24 (t, J = 7.5 Hz, 3H), 0.82–0.72 (m, 2H), 0.66–0.57 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 170.91, 155.81, 151.94, 147.37, 146.22, 142.82, 138.25, 137.75, 130.10, 126.27, 126.14, 120.28, 120.26, 109.50, 106.73, 104.79, 51.08, 43.92, 23.72, 12.73, 9.51, 7.90. LC-MS-ESI+:[M+H]+ 445.1.

[0281] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-(4-(trifluoromethyl)phenyl)quinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-F3)

[0282] The preparation method was the same as that of FW-GY-F1. The raw material was intermediate 33a, and 171.0 mg of light yellow solid was obtained with a yield of 74.4%. 1H NMR (600 MHz, DMSO-d6) δ 8.46 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 9.2, 2.7 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 6.24–6.20 (m, 1H), 3.99 (d, J = 6.3 Hz, 1H), 3.68 (s, 2H), 2.97 (q, J = 7.5 Hz, 1H), 1.90–1.82 (m, 1H), 1.29 (t, J = 7.5 Hz, 2H), 0.81–0.75 (m, 1H), 0.63–0.58 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 170.93, 155.79, 151.92, 148.98, 146.17, 143.36, 142.08, 138.29, 137.86, 131.57, 127.08, 126.32, 125.05 (d, J = 3.9 Hz), 119.86, 117.38, 109.50, 106.72, 104.20, 51.08, 43.93, 24.19, 13.20, 9.53, 7.91. LC-MS-ESI+: [M + H]+ 555.2.

[0283] (3-Chloro-4-((2-(4-chlorophenyl)-4-ethylquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine methyl ester (FW-GY-F5)

[0284] The preparation method was the same as that of FW-GY-F1, using intermediate 33b as the raw material, and 153.0 mg of light yellow solid was obtained with a yield of 65.9%. 1H NMR (600 MHz, DMSO-d6) δ 8.30–8.24 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.43 (dd, J = 9.2, 2.8 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 6.28–6.14 (m, 1H), 3.99 (d, J = 6.4 Hz, 1H), 3.68 (s, 2H), 2.94 (q, J = 7.5 Hz, 1H), 1.92–1.77 (m, 1H), 1.28 (t, J = 7.5 Hz, 2H), 0.81–0.73 (m, 1H), 0.60 (dd, J = 5.2, 2.0 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 170.93, 155.54, 152.24, 148.74, 146.14, 143.33, 138.30, 137.90, 137.05, 133.48, 131.36, 128.17, 128.10, 126.34, 126.25, 119.68, 116.99, 109.49, 106.70, 104.20, 51.08, 43.93, 24.17, 13.20, 9.53, 7.92. LC-MS-ESI+: [M+H]+ 521.3.

[0285] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-isopropylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-F7)

[0286] The preparation method was the same as that of FW-GY-F1. Using intermediate 33c as the raw material, 162.0 mg of light yellow solid was obtained, with a yield of 68.1%. 1H NMR (600 MHz, DMSO-d6) δ 7.94 (d, J = 9.1 Hz, 1H), 7.35 (dd, J = 9.1, 2.8 Hz, 1H), 7.29 (s, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.22–6.15 (m, 1H), 3.98 (d, J = 6.1 Hz, 1H), 3.68 (s, 1H), 3.14 (p, J = 6.9 Hz, 1H), 2.85 (q, J = 7.5 Hz, 1H), 1.30 (d, J = 7.0 Hz, 2H), 1.22 (t, J = 7.5 Hz, 1H), 0.81–0.72 (m, 1H), 0.63–0.56 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 170.94, 164.15, 154.86, 146.06, 138.34, 137.99, 128.12, 126.39, 125.71, 118.85, 118.24, 111.55, 109.48, 106.67, 104.17, 51.07, 43.94, 35.37, 30.54, 29.22, 23.96, 21.69, 13.11, 9.51, 7.92. LC-MS-ESI+: [M + H]+ 452.9.

[0287] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-ethylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-F9)

[0288] The preparation method was the same as that of FW-GY-F1, with the raw material being intermediate 33d, and 170.0 mg of light yellow solid was obtained, with a yield of 71.0%. 1H NMR (600 MHz, DMSO-d6) δ 7.92 (d, J = 9.1 Hz, 1H), 7.34 (dd, J = 9.1, 2.8 Hz, 1H), 7.25 (s, 1H), 7.14 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.25–6.14 (m, 2H), 3.98 (d, J = 6.1 Hz, 2H), 3.68 (s, 3H), 2.94–2.78 (m, 5H), 1.84 (tt, J = 8.4, 5.2 Hz, 1H), 1.29 (t, J = 7.6 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H), 0.80–0.72 (m, 2H), 0.63–0.55 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 170.94, 160.59, 154.78, 147.49, 146.05, 142.99, 138.35, 138.03, 130.40, 126.39, 125.52, 119.40, 118.80, 109.48, 106.65, 104.16, 51.07, 43.94, 30.46, 23.80, 13.02, 9.51, 7.93. LC-MS-ESI+: [M+H]+ 439.2.

[0289] (4-((2-(4-(tert-Butyl)phenyl)-4-ethylquinolin-6-yl)oxy)-3-chloro-5-cyclopropylphenyl)glycine methyl ester (FW-GY-F11)

[0290] The preparation method is the same as that of FW-GY-F1. The raw material is intermediate 33e, and 193.0 mg of light yellow solid is obtained with a yield of 83.7%. 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.39 (dd, J = 9.2, 2.8 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 6.11 (d, J = 2.8 Hz, 1H), 4.32 (t, J = 5.5 Hz, 1H), 3.92 (d, J = 5.4 Hz, 2H), 2.97 (q, J = 7.5 Hz, 2H), 1.95 (tt, J = 8.5, 5.3 Hz, 1H), 1.36 (d, J = 7.8 Hz, 12H), 0.85–0.74 (m, 2H), 0.69–0.51 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 171.27, 156.06, 155.63, 152.05, 149.02, 145.04, 144.76, 141.19, 139.90, 137.47, 132.08, 128.72, 127.22, 127.13, 125.77, 120.06, 118.00, 111.19, 108.51, 105.18, 52.51, 45.78, 34.75, 31.37, 25.42, 13.77, 10.52, 8.59, 1.08. LC-MS-ESI+: [M+H]+ 543.3.

[0291] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-(3-fluoro-4-methylphenyl)quinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-F13)

[0292] The preparation method was the same as that of FW-GY-F1, using intermediate 33f as the raw material, and 185.0 mg of light yellow solid was obtained with a yield of 79.7%. 1H NMR (400 MHz, Chloroform-d) δ 8.20–8.09 (m, 1H), 7.92–7.78 (m, 2H), 7.67 (d, J = 4.4 Hz, 1H), 7.49–7.42 (m, 1H), 7.38–7.30 (m, 1H), 7.28–7.24 (m, 1H), 6.62–6.55 (m, 1H), 6.20–6.13 (m, 1H), 4.01–3.91 (m, 2H), 3.91–3.83 (m, 3H), 3.08–2.95 (m, 2H), 2.39 (q, J = 2.0 Hz, 3H), 2.04–1.93 (m, 1H), 1.46–1.36 (m, 3H), 0.90–0.80 (m, 2H), 0.72–0.62 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 171.25, 163.00, 160.57, 156.27, 154.11, 149.32, 145.07, 144.63, 141.12, 139.83, 132.10, 131.68 (d, J = 5.4 Hz), 128.67, 127.42, 125.61 (d, J = 17.6 Hz), 122.51, 120.29, 117.55, 113.80 (d, J = 23.5 Hz), 111.17, 108.50, 105.18, 52.50, 45.74, 25.45, 14.55, 13.77, 10.51, 8.56. LC-MS-ESI+: [M+H]+ 519.2.

[0293] (3-Chloro-4-((2-(2-chloro-4-methylphenyl)-4-ethylquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine methyl ester (FW-GY-F15)

[0294] The preparation method is the same as that of FW-GY-F1. Using 33 g of the intermediate as the raw material, 201.0 mg of a pale yellow solid was obtained, with a yield of 87.0%. 1H NMR (400 MHz, Chloroform-d) δ 8.19–8.10 (m, 1H), 7.61–7.52 (m, 2H), 7.47–7.40 (m, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.30 (s, 1H), 7.21 (d, J = 7.4 Hz, 1H), 6.60–6.54 (m, 1H), 6.14 (d, J = 5.3 Hz, 1H), 3.98–3.91 (m, 2H), 3.90–3.81 (m, 3H), 3.04–2.93 (m, 2H), 2.42 (d, J = 7.8 Hz, 3H), 2.02–1.92 (m, 1H), 1.34–1.26 (m, 2H), 0.87–0.82 (m, 1H), 0.70–0.60 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 171.25, 156.42, 155.44, 148.01, 145.08, 144.45, 141.07, 139.94, 139.89, 137.10, 132.07, 131.43, 130.47, 128.69, 127.99, 127.30, 121.65, 120.08, 111.19, 108.49, 105.12, 52.51, 45.76, 25.17, 21.03, 13.52, 10.49, 8.61, 1.07. LC-MS-ESI+: [M+H]+ 535.2.

[0295] (3-Chloro-5-cyclopropyl-4-((2-(3,5-difluorophenyl)-4-ethylquinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-F17)

[0296] The preparation method was the same as that of FW-GY-F1. The raw material was intermediate 33h, and 184.0 mg of light yellow solid was obtained with a yield of 79.3%. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (t, J = 8.2 Hz, 1H), 7.76–7.68 (m, 1H), 7.67–7.62 (m, 1H), 7.52–7.44 (m, 1H), 7.32 (s, 1H), 6.99–6.85 (m, 1H), 6.64–6.54 (m, 1H), 6.24–6.11 (m, 1H), 4.02–3.92 (m, 1H), 3.09–2.95 (m, 1H), 2.03–1.93 (m, 1H), 1.66–1.63 (m, 1H), 1.46–1.37 (m, 2H), 0.93–0.78 (m, 1H), 0.71–0.61 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ 171.26, 164.68 (d, J = 12.2 Hz), 162.28, 156.69, 152.69, 149.80, 145.15, 144.56, 141.05, 139.83, 132.32, 128.66, 127.81, 120.70, 117.38, 111.21, 110.15 (d, J = 26.0 Hz), 108.55, 105.17, 104.10 (t, J = 25.4 Hz), 52.54, 45.76, 25.51, 13.78, 10.53, 8.58. LC-MS-ESI+: [M + H]+ 522.9.

[0297] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-(2,4,5-trifluorophenyl)quinolin-6-yl)oxy)phenyl)glycine methyl ester (FW-GY-F19)

[0298] The preparation method was the same as that of FW-GY-F1, with the raw material being intermediate 33i, and 180.0 mg of pale yellow solid was obtained, with a yield of 78.0%. 1H NMR (400 MHz, DMSO-d6) δ 8.16–7.98 (m, 1H), 7.48 (dd, J = 9.2, 2.8 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 6.64 (d, J = 2.7 Hz, 1H), 6.30–6.17 (m, 1H), 4.01 (d, J = 6.3 Hz, 1H), 3.70 (s, 1H), 2.95 (q, J = 7.4 Hz, 1H), 1.87 (tt, J = 8.4, 5.2 Hz, 1H), 1.32–1.24 (m, 3H), 0.85–0.72 (m, 1H), 0.71–0.51 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.04, 157.02, 149.75, 149.52, 147.29, 144.41, 139.38, 138.92, 132.58, 127.41, 121.17, 121.08, 121.03, 119.11, 118.89, 110.60, 107.83, 107.76, 107.54, 107.46, 107.25, 105.22, 52.20, 45.03, 25.12, 14.10, 10.64, 9.02. LC-MS-ESI+: [M+H]+ 541.1.

[0299] (3-Chloro-4-((2-chloro-4-ethylquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine (FW-GY-F2)

[0300] The end product FW-GY-F1 (100 mg, 0.24 mmol, 1 eq) and lithium hydroxide (45.9 mg, 1.92 mmol, 8 eq) were placed together in a 50 ml round-bottom flask, and then MeOH (10 ml) was added. A condenser was inserted into the mouth of the flask, and the system was stirred overnight at 65 °C. The reaction was detected to be complete by TLC. After the system was cooled to room temperature, it was distilled under reduced pressure to remove MeOH. The remaining substance was extracted with EA (10 ml) and water (5 ml) for 3 times. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a yellow oil. Purification by column chromatography (PE:EA = 5:1) gave 76.0 mg of a white solid with a yield of 78.6%. 1H NMR (600 MHz, DMSO-d6) δ 7.95 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 9.2, 2.8 Hz, 1H), 7.40 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 3.86 (s, 2H), 2.89 (d, J = 7.5 Hz, 2H), 1.82 (s, 1H), 1.22 (t, J = 7.4 Hz, 4H), 0.80–0.74 (m, 2H), 0.60 (dd, J = 5.3, 2.1 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 171.75, 155.84, 151.94, 147.36, 146.33, 142.81, 138.18, 137.60, 130.09, 126.21, 126.15, 120.27, 109.44, 106.73, 104.79, 44.06, 23.72, 12.73, 9.51, 7.86. LC-MS-ESI+:[M+H]+ 431.1.

[0301] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-(4-(trifluoromethyl)phenyl)quinolin-6-yl)oxy)phenyl)glycine (FW-GY-F4)

[0302] The preparation method was the same as that of FW-GY-F2, with the raw material being intermediate FW-GY-F3, and 82.0 mg of pale yellow solid was obtained, with a yield of 84.2%. 1H NMR (600 MHz, DMSO-d6) δ 8.46 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.46 (dd, J = 9.2, 2.7 Hz, 1H), 7.24 (d, J = 2.7 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 6.22 (d, J = 2.6 Hz, 1H), 3.87 (s, 1H), 2.97 (q, J = 7.5 Hz, 1H), 1.91–1.79 (m, 1H), 1.30 (t, J = 7.5 Hz, 2H), 0.83–0.74 (m, 1H), 0.64–0.58 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 171.77, 155.84, 151.92, 148.99, 146.29, 143.37, 142.09, 138.22, 137.72, 131.57, 127.09, 125.06 (t, J = 3.8 Hz), 119.87, 117.36, 109.45, 106.73, 104.21, 44.10, 24.20, 13.21, 9.55, 7.88. LC-MS-ESI+: [M+H]+ 541.2.

[0303] (3-Chloro-4-((2-(4-chlorophenyl)-4-ethylquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine (FW-GY-F6)

[0304] The preparation method was the same as that of FW-GY-F2. Using intermediate FW-GY-F5 as the raw material, 88.0 mg of pale yellow solid was obtained, with a yield of 90.6%. 1H NMR (600 MHz, DMSO-d6) δ 8.29–8.25 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.45–7.41 (m, 1H), 7.21 (d, J = 2.8 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 3.87 (s, 1H), 2.95 (q, J = 7.5 Hz, 1H), 1.89–1.80 (m, 1H), 1.28 (t, J = 7.5 Hz, 2H), 0.80–0.75 (m, 1H), 0.61 (dd, J = 5.2, 2.0 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 171.76, 155.57, 152.23, 148.75, 146.25, 143.33, 138.23, 137.76, 137.06, 133.48, 131.35, 128.17, 128.09, 126.28, 126.26, 119.68, 116.96, 109.43, 106.71, 104.21, 44.09, 24.18, 13.21, 9.54, 7.88. LC-MS-ESI+: [M + H]+ 406.9.

[0305] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-isopropylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-F8)

[0306] The preparation method was the same as that of FW-GY-F2. Using intermediate FW-GY-F7 as the raw material, 81.0 mg of pale yellow solid was obtained, with a yield of 83.8%. LC-MS-ESI+: [M + H]+ 439.2.

[0307] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-ethylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-F10)

[0308] The preparation method was the same as that of FW-GY-F2, with the raw material being intermediate FW-GY-F9, and 76.0 mg of light yellow solid was obtained, with a yield of 78.7%. 1H NMR (600 MHz, DMSO-d6) δ 8.02 (d, J = 9.5 Hz, 1H), 7.48–7.35 (m, 2H), 7.23 (s, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.20 (d, J = 2.8 Hz, 1H), 3.86 (s, 2H), 2.97–2.85 (m, 4H), 1.86–1.79 (m, 1H), 1.35–1.28 (m, 3H), 1.26–1.21 (m, 4H), 0.76 (d, J = 7.8 Hz, 2H), 0.60 (d, J = 5.4 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 171.74, 160.14, 155.29, 146.26, 138.19, 137.70, 126.25, 125.73, 119.69, 117.24, 113.88, 109.42, 106.72, 104.54, 44.06, 24.04, 12.93, 9.52, 7.84. LC-MS-ESI+: [M+H]+ 425.2.

[0309] (4-((2-(4-(tert-Butyl)phenyl)-4-ethylquinolin-6-yl)oxy)-3-chloro-5-cyclopropylphenyl)glycine (FW-GY-F12)

[0310] The preparation method was the same as that of FW-GY-F2, with the raw material being intermediate FW-GY-F11. 85.0 mg of pale yellow solid was obtained, and the yield was 87.2%. 1H NMR (400 MHz, DMSO-d6) δ 8.20–8.11 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.91 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 6.22 (d, J = 2.7 Hz, 1H), 5.77 (s, 1H), 3.87 (s, 1H), 3.19 (s, 1H), 2.95 (q, J = 7.5 Hz, 1H), 1.91–1.82 (m, 1H), 1.36 (s, 5H), 1.30 (t, J = 7.5 Hz, 1H), 0.82–0.76 (m, 1H), 0.66–0.59 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.87, 170.85, 156.39, 154.67, 152.31, 149.41, 147.33, 144.52, 139.36, 138.87, 136.71, 132.35, 127.41, 127.23, 127.16, 126.02, 120.49, 118.16, 110.51, 107.77, 105.31, 60.27, 31.57, 21.27, 14.59, 10.64, 9.01. LC-MS-ESI+: [M+H]+ 529.3.

[0311] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-(3-fluoro-4-methylphenyl)quinolin-6-yl)oxy)phenyl)glycine (FW-GY-F14)

[0312] The preparation method was the same as that of FW-GY-F2, with the raw material being intermediate FW-GY-F13. 86.0 mg of light yellow solid was obtained, and the yield was 88.4%. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 1H), 8.04–8.02 (m, 1H), 7.99 (d, J = 13.5 Hz, 2H), 7.50–7.38 (m, 2H), 7.22 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 6.22 (d, J = 2.7 Hz, 1H), 3.88 (s, 2H), 2.95 (q, J = 7.5 Hz, 2H), 2.33 (d, J = 1.8 Hz, 3H), 1.91–1.81 (m, 1H), 1.29 (t, J = 7.6 Hz, 3H), 0.84–0.72 (m, 2H), 0.66–0.59 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.88, 162.86, 160.45, 156.63, 153.19, 149.78, 147.36, 144.37, 139.34, 139.27, 138.84, 132.45, 127.40, 125.86 (d, J = 17.1 Hz), 123.08, 120.73, 118.08, 113.51 (d, J = 23.4 Hz), 110.51, 107.78, 105.30, 45.22, 25.29, 14.62, 14.60, 14.36, 10.64, 9.01. LC-MS-ESI+: [M+H]+ 505.2.

[0313] (3-Chloro-4-((2-(2-chloro-4-methylphenyl)-4-ethylquinolin-6-yl)oxy)-5-cyclopropylphenyl)glycine (FW-GY-F16)

[0314] The preparation method was the same as that of FW-GY-F2, with the raw material being intermediate FW-GY-F15. 78.0 mg of light yellow solid was obtained, and the yield was 80.1%. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 9.1 Hz, 1H), 7.58–7.54 (m, 2H), 7.47–7.43 (m, 2H), 7.33–7.28 (m, 1H), 7.24 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 6.23 (d, J = 2.7 Hz, 1H), 3.86 (s, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.40 (s, 3H), 1.87 (td, J = 8.5, 4.2 Hz, 1H), 1.25–1.23 (m, 2H), 0.86–0.76 (m, 2H), 0.67–0.59 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.88, 156.78, 155.24, 148.31, 147.38, 144.31, 140.64, 139.35, 138.76, 136.98, 132.37, 131.99, 131.47, 130.57, 128.56, 127.38, 127.10, 121.94, 120.57, 110.52, 107.79, 105.18, 45.31, 24.96, 20.93, 14.04, 10.63, 9.02. LC-MS-ESI+: [M + H]+ 521.2.

[0315] (3-Chloro-5-cyclopropyl-4-((2-(3,5-difluorophenyl)-4-ethylquinolin-6-yl)oxy)phenyl)glycine (FW-GY-F18)

[0316] The preparation method was the same as that of FW-GY-F2. The raw material was intermediate FW-GY-F17, and 76.0 mg of light yellow solid was obtained with a yield of 78.1%. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 9.2 Hz, 1H), 8.05 (s, 1H), 8.03–7.97 (m, 2H), 7.47 (dd, J = 9.2, 2.8 Hz, 1H), 7.41–7.33 (m, 1H), 7.23 (d, J = 2.8 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 6.23 (d, J = 2.7 Hz, 1H), 3.88 (s, 2H), 2.96 (q, J = 7.5 Hz, 2H), 1.86 (td, J = 8.5, 4.2 Hz, 1H), 1.30 (t, J = 7.5 Hz, 3H), 0.79 (dt, J = 8.8, 3.2 Hz, 2H), 0.66–0.58 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.88, 164.62 (d, J = 13.3 Hz), 162.18 (d, J = 13.1 Hz), 156.99, 151.84, 150.19, 147.39, 144.23, 143.28–143.01 (m), 139.31, 138.78, 132.67, 127.79, 127.36, 121.01, 118.33, 110.37 (d, J = 27.9 Hz), 107.80, 105.28, 105.24–104.66 (m), 45.18, 25.31, 14.34, 10.64, 9.00. LC-MS-ESI+: [M+H]+ 509.2.

[0317] (3-Chloro-5-cyclopropyl-4-((4-ethyl-2-(2,4,5-trifluorophenyl)quinolin-6-yl)oxy)phenyl)glycine (FW-GY-F20)

[0318] The preparation method was the same as that of FW-GY-F2, with the raw material being intermediate FW-GY-F19, and 75.0 mg of light yellow solid was obtained, with a yield of 77.0%. 1H NMR (400 MHz, DMSO-d6) δ 8.15–8.02 (m, 1H), 7.80–7.68 (m, 1H), 7.47 (ddd, J = 12.1, 9.2, 2.8 Hz, 1H), 7.23 (dd, J = 7.7, 2.8 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 6.23 (d, J = 2.5 Hz, 1H), 3.88 (s, 1H), 3.02–2.87 (m, 1H), 1.87 (tt, J = 8.4, 5.1 Hz, 1H), 1.30–1.25 (m, 5H), 0.83–0.74 (m, 1H), 0.69–0.55 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.87, 157.05, 149.72, 149.51, 149.20, 147.40, 144.40, 139.29, 138.76, 132.57, 127.35, 127.13, 121.03, 119.05, 118.88, 110.53, 107.83, 107.49 (d, J = 8.2 Hz), 105.22, 57.23, 45.22, 32.04, 29.93, 25.13, 14.11 (d, J = 4.3 Hz), 10.65, 8.97. LC-MS-ESI+: [M + H]+ 527.2.

[0319] Biological test experiment

[0320] At the molecular level, the binding ability of the compound to THRβ / THRα was determined by the AlphaScreen detection method. First, recombinant GST-THRβ / GST-THRα fusion proteins were constructed separately, and then the reaction of the compound with the receptor was carried out in a 384-well plate. The reaction of the mixture of recombinant protein, agonist, co-regulator, receptor beads and donor beads was carried out in a buffer containing: 50 mM Tris-HCl (pH 7.4), 50 mM NaCl, 0.1% BSA, 1 mM DTT. If the compound could bind to the receptor protein, the relative positions of the receptor beads and the donor beads changed, and then fluorescence of a specific wavelength would be emitted. We detected the fluorescence signal intensity at a wavelength of 570 nm by a fluorescence detector Envision to characterize the binding activity of the compound to THRβ. And the compound EC 50 .

[0321]

[0322]

[0323]

[0324]

[0325] EC 50 : A: 0 - 100 nM, B: 100 - 500 nM, C: 500 - 1000 nM, D: > 1000 nM

[0326] Selectivity: -: 0 - 1, +: 1 - 10, ++: 10 - 100, +++: > 100

[0327] NT: Not detected

[0328] In vitro cell - level agonist activity evaluation

[0329] When detecting its binding at the cell level, use the FH - THRa / β expression plasmid, pal - luciferase reporter plasmid and RL - TK plasmid. After co - transfecting the three into 293T cells, inoculate the cells into a 96 - well flat - bottomed microplate and culture the cells for 24 h to ensure plasmid expression. Add the TRa / β agonist to be tested. After 18 h, use the Dual - Luciferase Reporter Assay System to detect. Use firefly luciferase as the reporter gene and Renilla luciferase as the internal reference gene. Detect the bioluminescence intensity through the Envision fluorescence detector, and the activation efficiency of the compound on the TRa / β receptor can be reflected.

[0330]

[0331] EC 50 : A: 0 - 100 nM, B: 100 - 500 nM, C: 500 - 1000 nM, D: > 1000 nM

[0332] Selectivity: -: 0 - 1, +: 1 - 10, ++: 10 - 100, +++: > 100

[0333] As described above, it is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. A compound having a structure represented by formula (I), or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof: in, R6, R7, and R8 are each independently located on any substitutable ring atom of the quinoline ring; R6 and R8 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C5-C7 heteroaryl, C5-C6 substituted heteroaryl; and R6 and R8 are different or the same substituents; R7 is one or more (such as 1, 2, 3 or 4) substituents located on the quinoline benzene ring selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl; X is selected from the group consisting of -O-, -CH2-, -C(=O)-, -CH(OH), -S-, -NR9-, -NH(=O); R9 is a substituent selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl; R1, R2, R3 and R4 are each independently selected from the group consisting of H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR a 、-NR b R c 、-SR d , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; R a , R b , R c , R d Each is independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl or 5-6 membered heteroaryl; Y is -OR 10 -、-CR 10 -、-SR 10 -、-NHC(=O)R 10 -、-C(=O)NHR 10 --or-NHCHR 10 -; R 10 is selected from hydrogen and substituted or unsubstituted C0-C6 alkyl, wherein the substituted substituent is selected from halogen atoms, hydroxyl groups and Cl-C6 alkoxy groups; R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl.

2. The compound of claim 1, or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof, characterized in that: R1, R2, R3 and R4 are each independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl; R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; R6 is selected from the following group: C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C5-C7 heteroaryl; and the phenyl or heteroaryl may optionally have 1-3 substituents selected from the following group: hydrogen, deuterium, tritium, halogen, -CN, -OH, oxo, -ORa, -NRbRc, -C(=O)Rc, -C(=O)ORa, -C(=O)NRbRc, C1-C6 alkyl, C1-C6 haloalkyl; R8 is selected from the following group: hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl.

3. The compound of claim 1, or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof, characterized in that: The compound of formula I has the structure shown in the following formula Ia:

4. The compound of claim 1, or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof, characterized in that: The compound of formula I also has a structure shown in the following formula Ib or Ic:

5. A compound having a structure represented by formula (II), or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof: in, R6, R7, and R8 are each independently located on any substitutable ring atom of the isoquinoline ring; R6 and R8 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C5-C7 heteroaryl, C5-C6 substituted heteroaryl; and R6 and R8 are different or the same substituents; R7 is one or more (such as 1, 2, 3 or 4) substituents located on the quinoline benzene ring selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl; X is selected from the following group: -O-, -CH2-, -C(=O)-, -CH(OH), -S-, -NR9-, -NH(=O) R9 is a substituent selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl; R1, R2, R3 and R4 are each independently selected from the group consisting of H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR a 、-NR b R c 、-SR d , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; R a , R b , R c , R d Each is independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl or 5-6 membered heteroaryl. Y is -OR 10 -、-CR 10 -、-SR 10 -、-NHC(=O)R 10 -、-C(=O)NHR 10 --or-NHCHR 10 -; R 10 Selected from Hydrogen and substituted or unsubstituted C0-C6 alkyl, wherein the substituted substituent is selected from halogen atoms, hydroxyl groups and Cl-C6 alkoxy groups; R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl.

6. A compound having a structure represented by formula (III), or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof: in, R7 is independently located on any substitutable ring atom of the indole ring; R6 and R8 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C5-C7 heteroaryl, C5-C6 substituted heteroaryl; and R6 and R8 are different or the same substituents; R7 is one or more (such as 1, 2, 3 or 4) substituents located on the quinoline benzene ring selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl; X is selected from the following group: -O-, -CH2-, -C(=O)-, -CH(OH), -S-, -NR9-, -NH(=O) R9 is a substituent selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl; R1, R2, R3 and R4 are each independently selected from the group consisting of H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR a 、-NR b R c 、-SR d , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; R a , R b , R c , R d Each is independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl or 5-6 membered heteroaryl. Y is -OR a 、-NR b R c , -CR 10 -、-SR 10 -、-NHC(=O)R 10 -、-C(=O)NHR 10 --or-NHCHR 10 -; R 10 is selected from hydrogen and substituted or unsubstituted C0-C6 alkyl, wherein the substituted substituent is selected from halogen atoms, hydroxyl groups and Cl-C6 alkoxy groups; R5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl; R 11 It is selected from hydrogen, deuterium and substituted or unsubstituted C0-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aryl, or 5-6 membered heteroaryl, and the substituted substituent is selected from halogen atoms, hydroxyl and Cl-C6 alkoxy.

7. The compound of claim 1, comprising a stereoisomer, a deuterated compound, a solvate, a metabolite, a pharmaceutically acceptable salt, a cocrystal or a prodrug thereof: The specific compounds are as follows:

8. Use of the compound according to any one of claims 1 to 7 or its stereoisomers, geometric isomers, tautomers, deuterated compounds, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs in the preparation of drugs for preventing, treating or alleviating diseases; The diseases include thyroid hormone receptor mediated diseases, The thyroid hormone receptor-mediated disease is selected from: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer; Such diseases also include androgenic alopecia or hair loss caused by thyroid abnormalities.

9. A pharmaceutical composition, characterized in that The active ingredient is a compound according to any one of claims 1 to 7 or a stereoisomer, geometric isomer, tautomer, deuterated compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or adjuvant.

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