Novel CGRP receptor antagonist and application thereof

Abstract

The invention discloses a CGRP receptor antagonist and application thereof. The CGRP receptor antagonist has a structure as shown in a formula I, or pharmaceutically acceptable salt of the structure as shown in the formula I, and an isomer thereof. The invention also provides application of the compound shown in the formula I in preparation of medicines for preventing and / or treating related respiratory diseases such as asthma.

Description

Technical Field

[0001] This application relates to a series of novel compounds with CGRP receptor antagonistic function, which can be used to alleviate and / or treat CGRP receptor-related asthma, chronic obstructive pulmonary disease (COPD), and pulmonary heart disease. Background Technology

[0002] Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide containing 37 amino acids. It is widely distributed in the cardiovascular, respiratory, digestive, and endocrine systems and is an important mediator of the neuro-immune system. CGRP exists in two configurations, α and β, with similar biological effects.

[0003] In vivo, CGRP can bind to its specific receptors to produce various biological effects, primarily including vasodilation and stimulation of airway smooth muscle contraction. Current research on CGRP is increasing. Studies have shown that CGRP degradation produced by endothelin-converting enzyme-1 (ECE-1) can promote airway inflammatory infiltration, thereby stimulating mast cell degranulation and leading to the release of various vasoactive substances. This effect can directly cause vascular permeability problems or airway inflammation. In the lungs, CGRP can promote migration and infiltration at sites of lung inflammation, and in severe cases, it can worsen pulmonary microvascular permeability, leading to lung damage. CGRP can also participate in the cAMP / PKA (Protein Kinase A, PKA) signaling pathway, altering airway immune regulation mechanisms, causing allergic inflammation in the airways, and subsequently triggering asthma attacks. Clinical data also show that blood CGRP levels are significantly elevated in asthma patients, and this elevation is linearly related to the severity of asthma. CGRP can also activate CGRP receptors, thereby inducing endothelial cell proliferation and enhancing the contractile effect on airway smooth muscle. Therefore, overexpression of CGRP and its receptor can increase airway vascular permeability, increase mucus secretion, and lead to severe asthma.

[0004] Currently, research results in both human and animal models indicate that CGRP antagonists can significantly reduce the stimulatory effect of CGRP on airway epithelial cells, demonstrating a marked effect in inhibiting airway inflammation and improving airway structure, thus greatly alleviating asthma symptoms. Significant progress has been made in the research of neuropeptide receptor antagonists, and with ongoing research, the potential for these antagonists to become new drugs is increasing. Summary of the Invention

[0005] This invention provides a novel CGRP receptor antagonist that exhibits significant vasodilatory effects in vivo and significant therapeutic effects on asthma in rats. Unexpectedly, the compound was found to have a significant advantage in improving bioavailability, achieving unexpected technical results.

[0006] This invention relates to a compound of formula I, or a pharmaceutically acceptable salt of formula I, and isomers thereof:

[0007]

[0008] X is CH or N;

[0009] R1 is hydrogen or deuterium;

[0010] R2 is hydrogen, deuterium, hydroxyl, or amino;

[0011] R3 is hydrogen or deuterium;

[0012] R4 is C6-C 12 Aryl, or C3-C 12 heteroaryl; the aforementioned C6-C 12 Aryl, C3-C 12 The heteroaryl group may optionally be substituted with one or more hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, formaldehyde, hydroxymethyl, hydroxyethyl, methanesulfonyl, or ethanesulfonyl groups;

[0013] R5 is hydrogen or deuterium; and R1, R3, and R5 are not all hydrogen at the same time.

[0014] R6 is

[0015] R7 is

[0016] R8 is hydrogen or deuterium;

[0017] R9 is hydrogen,

[0018] Y1 and Y2 are each independently O or NH;

[0019] R a R b Each is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or R. a R b Connected to form a ring;

[0020] R c R dEach is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or R. a R b Connected to form a ring;

[0021] R 10 It is a C1-C6 alkyl, a deuterated C1-C6 alkyl, or a C1-C6 alkoxy;

[0022] R 11 R 12 Each is independently hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C6-C 12 aryl, or R 11 R 12 Linked into a ring; the C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C6-C 12 The aryl group may optionally be substituted with one or more hydrogens, deuteriums, halogens, or trifluoromethyl groups.

[0023] The compound is characterized in that it has the structure of formula II:

[0024]

[0025] The substituents in Formula II are defined as defined in Formula I.

[0026] The compound is characterized in that it has the structure of Formula III:

[0027]

[0028] The substituents in Formula III are defined as defined in Formula I.

[0029] The compound is characterized in that it has the structure of formula IV:

[0030]

[0031] The substituents in Formula IV are defined as defined in Formula I.

[0032] The compound mentioned is selected from:

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] The compound described herein is an antagonist of the calcitonin gene-related peptide (CGRP) receptor.

[0039] A pharmaceutical composition comprising the said compound, or the said compound and its isomers, and a pharmaceutically acceptable additive.

[0040] The compounds and compositions described herein may be used to relieve and / or treat bronchial asthma, chronic obstructive pulmonary disease (COPD), pulmonary heart disease, headache, migraine, and organ pain-related diseases.

[0041] The composition is described in order to relieve and / or treat asthma, chronic obstructive pulmonary disease, pulmonary heart disease, headache, migraine, and organ pain-related diseases, and can be administered to humans or other mammals orally, intranasally, intraorally, through the skin, or by intravenous injection.

[0042] In this invention, for a more detailed understanding of the invention, the terms are defined as follows.

[0043] In this article, "amino" refers to a functional group having one nitrogen atom and 0 to 2 hydrogen atoms.

[0044] In this article, halogens refer to fluorine (F) atoms, chlorine (Cl) atoms, bromine (Br) atoms, or iodine (I) atoms.

[0045] In this article, "C1-C6 alkyl" refers to straight-chain or branched hydrocarbon groups with 1 to 6 carbon atoms. Examples include methyl, ethyl, isopropyl, sec-butyl, tert-butyl, and isopentyl.

[0046] In this article, "C1-C6 alkoxy" refers to a group in which an O or OH group is inserted at any reasonable position in a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, 2-ethoxypropyl, propylene oxide, and propylene glycol methyl ether.

[0047] The "C6-C" in this article 12 "Aryl" refers to a group containing at least one aromatic ring with 6 to 12 carbon atoms. In addition to covalent groups, the rings of polycyclic aryl groups can have different linkages, such as fusion or bridging, and the fused rings can be saturated or unsaturated. Examples include phenyl, diphenylmethyl, α-tetrahydronaphthyl, benzocyclobutene, and indanyl.

[0048] The "C3-C" in this article 12"Heteroaryl" refers to an aromatic heterocyclic group with 3 to 12 carbon atoms and containing at least one atom selected from oxygen (O), nitrogen (N), boron (B), phosphorus (P), or sulfur (S). Examples include furanyl, thiophene, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, and pyridazinyl.

[0049] The compounds containing double bonds in this invention include all configurational isomers (such as cis and trans isomers).

[0050] The compounds of the present invention have asymmetric centers, and therefore the present invention relates to the use of optical isomers and stereoisomers of all such compounds and mixtures thereof.

[0051] The present invention also relates to the use of compounds having tautomers and mixtures thereof.

[0052] The compounds of this invention contain a basic nitrogen atom (heterocyclic or aliphatic amino group, etc.), which is readily oxidized by oxidizing agents such as oxygen in the air or hydrogen peroxide to form N-oxides, thereby generating other compounds of this invention. Therefore, the resulting N-oxide derivatives are considered part of the compounds of this invention.

[0053] The terms “a,” “an,” or similar terms used in this document refer to objects comprising one or more numbers, or mixtures thereof, and are not limited to one or an object.

[0054] In this invention, the term "independently" means that, with more than one variable, the choice of each instance of a substituent from the available variable definitions is independent of the other choices used to define the variables. Therefore, each substituent may be the same as or different from the other substituents.

[0055] In this invention, the term "antagonist" refers to a compound or combination thereof that has a strong affinity for a receptor and can block the binding of an agonist to the receptor, thereby antagonizing or canceling the effect of the agonist.

[0056] In this invention, the term "pharmaceutically acceptable salt of a compound" refers to a complex formed by the combination of the compound with the corresponding acid. This property depends on the characteristics of the compound. The compound is an addition salt of an acid, such as inorganic acid salts like hydrochlorides, sulfates, and hydrobromic acids; organic acid salts like maleates, fumarates, acetates, propionates, malates, tartrates, malonates, succinates, citrates, cinnamates, mandelates, methanesulfonates, p-toluenesulfonates, and salicylates. The term "pharmaceutically acceptable salt of a compound" also refers to an addition salt of a base, such as inorganic base salts like sodium, potassium, ammonium, calcium, and magnesium salts; and organic amine salts like diethylamine, ethylenediamine, meglumine, aminobutanetriol, arginine, lysine, histidine, and piperidine.

[0057] The term "pharmaceutically acceptable additive" in this invention refers to a substance that helps an individual take or absorb the active substance in a pharmaceutical composition and does not cause significant adverse effects on the patient or individual, including disintegrants, fillers, flavoring agents, lubricants, hydroxymethyl cellulose, stabilizers, emulsifiers, colorants, etc.

[0058] The term "relief and / or treatment" in this invention refers to the effect of reducing or even reversing the condition of a subject or individual by administering an effective therapeutic amount of a compound or its composition to the subject or individual in need of treatment.

[0059] In this invention, mammals refer to warm-blooded animals, such as rats, guinea pigs, mice, gerbils, rabbits, dogs, pigs, sheep, monkeys, chickens, ducks, geese, cats, cattle, horses, chimpanzees, etc.

[0060] In this invention, the term "treatment" refers to actions taken to inhibit the progression of an applicable disorder or one or more conditions, or to reverse the symptoms, and also includes adjunctive treatment for conditions.

[0061] The compounds of this invention can be used in the form of salts derived from inorganic or organic acids, depending on the characteristics of the compound, such as enhancing drug stability, water solubility, and achieving satisfactory solubility. They can also be used as adjuncts for separation, purification, and / or resolution. Detailed Implementation

[0062] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0063] Example 1: Synthesis of intermediate T-9

[0064]

[0065] T-2:

[0066] The starting material T-1 (17.5 g, 0.10 mol) was dissolved in dichloromethane (350 mL), and nitrogen was purged for 10 minutes to remove oxygen from the solvent. The temperature was lowered to 0 °C, and Rh-(Rbinapine)(COD)BF4 (0.88 g, 0.86 mmol) was slowly added. After the addition was complete, the air in the reaction system was replaced with deuterium. The reaction was then maintained at 150 psi deuterium pressure at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated to obtain a brown oily substance, which was used directly in the next step.

[0067] T-3:

[0068] Intermediate T-2 (17.9 g, 0.10 mol) was dissolved in dichloromethane (300 mL), and triethylamine (20.2 g, 0.20 mol) was added. The mixture was cooled to 0 °C, and triisopropylsilyl trifluoromethanesulfonate (30.6 g, 0.10 mol) was slowly added. The mixture was then reacted at room temperature for 5 hours. 200 mL of 0.01 M ammonium chloride solution was added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was separated and concentrated. 200 mL of n-hexane was added, and the mixture was concentrated again. The residue was recrystallized from n-heptane / ethyl acetate (1:1, V / V) to give 22.1 g of intermediate T-3 (66%). MS (ESI, m / z): 335.3 [M+H] + H 1 NMR(400MHz):8.68(d,1H),8.17(d,1H),7.73(t,1H),2.21(m,2H),1.99-1.34(m,7H),0.93(d,18H).

[0069] T-5:

[0070] Intermediate T-3 (21.0 g, 62.7 mmol) was dissolved in toluene (300 mL), and 1-bromo-2,3-difluorobenzene (14.5 g, 75.2 mmol), palladium acetate (0.14 g, 0.6 mmol), tritert-butylphosphine tetrafluoroborate (0.17 g, 0.6 mmol), and sodium tert-butoxide (7.2 g, 75.2 mmol) were added. After purging with nitrogen three times, the mixture was heated to 100 °C for 6 hours, cooled to room temperature, and concentrated. 0.01 M ammonium chloride solution (200 mL) and ethyl acetate (200 mL) were added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was concentrated, and the resulting brown oily substance was purified by pre-liquid chromatography to obtain 7.0 g of intermediate T-5 (25%). MS (ESI, m / z): 447.2 [M+H] + H 1 NMR(400MHz):8.68(d,1H),8.17(d,1H),7.73(t,1H),7.19-7.07(m,3H),3. 53(t,1H),2.41-2.20(m,2H),1.93-1.68(m,2H),1.42(m,3H),0.93(d,18H).

[0071] T-6:

[0072] Intermediate T-5 (6.9 g, 15.6 mmol) was dissolved in isopropyl ether (150 mL), purged three times with nitrogen, and cooled to 0 °C. A solution of lithium tri-tert-butoxy-aluminum hydride (1.0 M) (23.4 mL) was slowly added, and the reaction was carried out in an ice bath for 18 hours. A 0.01 M ammonium chloride solution (50 mL) was slowly added, and the mixture was concentrated under reduced pressure. The residue was then extracted twice with 0.01 M ammonium chloride solution (100 mL) using ethyl acetate (100 mL). The organic phase was concentrated, and the resulting brown oily substance was purified by pre-HPLC to yield 3.2 g of intermediate T-6 (46%). MS (ESI, m / z): 449.0 [M+H] + , NMR(400MHz):8.68(d,1H),8.17(d,1H),7.73(t,1H),7.19-7.07(m,3H) ,5.16(d,1H),3.06(m,1H),1.93-1.68(m,4H),1.42(m,3H),0.93(d,18H).

[0073] T-7:

[0074] Intermediate T-6 (3.0 g, 6.7 mmol) was dissolved in DMF (10 mL), and triethylamine (2.5 g, 25.0 mmol) was added. After purging with nitrogen three times, the mixture was cooled to 0 °C, and phosphorus oxychloride (1.0 g, 6.7 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to react at room temperature for 15 hours. Ice water (30 mL) was then slowly added, resulting in the precipitation of a solid. The solid was filtered and dried to obtain 1.9 g of intermediate T-7 (62%). MS (ESI, m / z): 467.1 [M+H] + , NMR(400MHz):8.68(d,1H),8.17(d,1H),7.19-7.07(m,4H),5.02(d,1H),3.41(m,1H),1.93-1.68(m,4H),1.42(m,3H),0.93(d,18H).

[0075] T-8:

[0076] Intermediate T-7 (1.9 g, 4.1 mmol) was dissolved in DMF (7 mL), and potassium carbonate (0.27 g, 2.0 mmol) and sodium azide (0.5 g, 8.2 mmol) were added. After purging with nitrogen three times, the mixture was heated to 90 °C and reacted for 18 hours. The mixture was then cooled to room temperature, and ice water (25 mL) was slowly added. The mixture was extracted twice with ethyl acetate (25 mL). The organic phase was concentrated, and the residue was purified by pre-HPLC to obtain 0.68 g of intermediate T-8 (35%). MS (ESI, m / z): 474.1 [M+H] +, NMR(400MHz):8.57(d,1H),7.91(d,1H),7.03(m,4H),3.01(m,2H),1.95-1.32(m,7H),0.91(d,18H).

[0077] T-9:

[0078] Intermediate T-8 (0.47 g, 1.0 mmol) was dissolved in methanol (10 mL), and palladium on carbon (0.05 g) was added. After three purgings with hydrogen, the mixture was heated to reflux under a hydrogen atmosphere for 3 hours. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated. The residue was separated by column chromatography to give 0.34 g of intermediate T-8 (77%), MS (ESI, m / z): 448.2 [M+H]. + , NMR(400MHz):8.75(brs,2H),8.51(d,1H),7.31(t,1H),7.03(m,3H),4.27(d,1H),3.00(q,1H),1.97-1.37(m,7H),0.95(d,18H).

[0079] Example 2: Synthesis of intermediate T-13

[0080]

[0081] T-12:

[0082] T-10 (3.0 g, 10.0 mmol) was dissolved in dichloromethane (100 mL), and potassium carbonate (2.8 g, 20.0 mmol) and T-11 (3.0 g, 10.0 mmol) were added. The mixture was reacted at room temperature for 20 hours, then ice water (50 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was separated into liquid and liquid phases, and the organic phase was concentrated. The residue was separated by column chromatography, and the solid was added to methanol (100 mL). 0.2 g of palladium on carbon was added, and the mixture was refluxed under a hydrogen atmosphere for 5 hours. The mixture was cooled to room temperature, filtered, concentrated, and the residue was separated by column chromatography to give 1.97 g of intermediate T-12 (62%). MS (ESI, m / z): 319.0 [M+H] + , NMR(400MHz):8.17(d,2H),7.14(t,1H),3.57(m,1H),2.73-2.54(m,4H),1.84(m,4H),1.41(s,9H).

[0083] T-13:

[0084] T-12 (1.59 g, 5.0 mmol) was dissolved in dichloromethane (100 mL), and the mixture was purged with nitrogen for 10 min. Triethylamine (1.01 g, 10.0 mmol) and N,N'-carbonyldiimidazole (0.81 g, 5.0 mmol) were added, and the mixture was reacted at room temperature for 15 h. 0.01 M ammonium chloride solution (100 mL) was added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was separated, concentrated, and the residue was separated by column chromatography to yield 1.13 g of intermediate T-13 (55%). MS (ESI, m / z): 413.1 [M+H] + , NMR(400MHz):8.15(m,3H),7.47(d,1H),7.17(m,2H),3.71-3.48(m,5H),2.01-1.95(m,4H),1.41(s,9H).

[0085] Example 3: Synthesis of compound CG204-1

[0086]

[0087] T-14:

[0088] T-8 (4.73 g, 10.0 mmol) was dissolved in THF (100 mL), cooled to -10 °C, and tetrabutylammonium fluoride (2.61 g, 10.0 mmol) was added. The mixture was reacted at room temperature for 2 hours, and then 0.01 M sodium bicarbonate solution (50 mL) was added. After thorough stirring, the mixture was concentrated, and the residue was separated by column chromatography to obtain 2.09 g of brown solid. The solid was added to dry DMF (35 mL), and T-13 (2.72 g, 6.6 mL) was added. The mixture was cooled to -10℃ and NaHMDS (1.32 mL, 1.0 M) was slowly added under nitrogen protection. After the addition was complete, the temperature was slowly raised to room temperature and reacted for 2 hours. 100 mL of 0.01 M ammonium chloride solution (on ice) was added, followed by 150 mL of ethyl acetate. After thorough stirring, the mixture was separated into layers. The separated organic phase was concentrated, and the residue was separated by column chromatography to yield 1.45 g of intermediate T-14 (22%). MS (ESI, m / z): 662.2 [M+H] + , NMR(400MHz):8.51(d,1H),8.21(d,2H),7.91(d,1H),7.14-7.05(m,5H),3.79-3.30(5H),3.10(m,2H),2.04-1.87(m,8H),1.41(s,9H).

[0089] CG204-1:

[0090] Intermediate T-14 (0.33 g, 0.5 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.05 g) was added, and the mixture was purged with hydrogen three times. The mixture was then heated to reflux under a hydrogen atmosphere for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was added to dichloromethane (10 mL), followed by trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 3 hours, and then 0.01 M sodium bicarbonate solution (10 mL) was added. The mixture was stirred at room temperature for 1 hour, separated, and the organic phase was concentrated. The residue was then used to prepare a liquid phase. 45.5 mg of product CG204-1 (17%) was isolated. MS (ESI, m / z): 536.2 [M+H]+, NMR (400 MHz): 8.51 (d, 1H), 8.08 (d, 1H), 7.99 (t, 2H), 7.31 (t, 1H), 7.18-7.09 (m, 4H), 4.24 (d, 1H), 3.57-3.31 (m, 5H), 3.02 (m, 1H), 2.10-1.79 (m, 8H).

[0091] Example 4: Synthesis of compound CG204-2

[0092]

[0093] T-15:

[0094] CG204-1 (0.54 g, 1.0 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and di-tert-butyl dicarbonate (0.22 g, 1.0 mmol) and triethylamine (0.20 g, 2.0 mmol) were added. The mixture was reacted at room temperature for 5 hours, and then 20 mL of 0.01 M ammonium chloride solution was added. After thorough stirring and standing, the organic phase was separated, concentrated, and the residue was separated by column chromatography to obtain 0.4 g of precipitate. 3g intermediate T-15 (68%), MS (ESI, m / z): 636.3 [M+H]+, NMR (400MHz): 8.48 (d, 1H), 8.07-7.91 (m, 3H), 7.23-7.01 (m, 5H), 5.18 (d, 1H), 3.82-3.31 (m, 6H), 2.07-1.68 (m, 8H), 1.41 (s, 9H).

[0095] CG204-2:

[0096] Intermediate T-15 (0.40 g, 0.63 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% sodium hydride (0.05 g, 1.26 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and dimethyl chloromethyl carbonate (0.12 g, 1.0 mmol) was slowly added. The mixture was reacted at room temperature for 6 hours, and then 15 mL of 0.01 M ammonium chloride solution (ice) and 25 mL of dichloromethane were added. The mixture was stirred thoroughly for 30 minutes and allowed to stand. The organic phase was separated, concentrated, and the residue was added to dichloromethane (20 mL), followed by 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 hours, and then 2 mL of 0.01 M sodium bicarbonate solution (2 mL) was added. 0 mL), stirred at room temperature for 1 hour, separated, concentrated the organic phase, and the resulting residue was preparatively separated to obtain 58.9 mg of product CG204-2 (15%). MS (ESI, m / z): 624.4 [M+H]+, NMR (400 MHz): 8.51 (d, 1H), 8.15 (d, 1H), 8.08 (d, 1H), 7.98 (d, 1H), 7.26-7.17 (m, 5H), 6.03 (s, 2H), 4.21 (d, 1H), 3.81 (s, 3H), 3.75-3.52 (m, 5H), 3.01 (m, 1H), 2.21-1.58 (m, 8H).

[0097] Example 5: Synthesis of compound CG204-3

[0098]

[0099] CG204-3:

[0100] Add methyl chloroformate (0.13 g, 1.0 mmol) to THF (5 mL), cool to 0 °C, add triethylamine (0.10 g, 1.0 mmol) and deuterated methanol (0.1 mL), and after the addition is complete, let it react at room temperature for 4 hours for later use.

[0101] Intermediate T-15 (0.32 g, 0.5 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% sodium hydride (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and the above solution was slowly added. The mixture was reacted at room temperature for 5 hours. 0.01 M ammonium chloride solution (15 mL) on ice was added, followed by dichloromethane (25 mL). The mixture was stirred thoroughly for 30 minutes and allowed to stand. The organic phase was separated and concentrated. The residue was then treated with dichloromethane (20 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 3 hours, followed by 0.01 M sodium bicarbonate solution (20 mL). The mixture was stirred at room temperature for 1 hour. The mixture was separated, and the organic phase was concentrated. The residue was then subjected to preparative HPLC to obtain 34.4 mg of product CG204-3 (11%). MS (ESI, m / z): 627.1 [M+H]+ NMR(400MHz):8.51(d,1H),8.15(d,1H),8.08(d,1H),7.98(d,1H),7.26-7.17(m, 5H),6.03(s,2H),4.21(d,1H),3.75-3.52(m,5H),3.01(m,1H),2.21-1.58(m,8H).

[0102] Example 6: Synthesis of compound CG204-8

[0103]

[0104] CG204-8:

[0105] Intermediate T-15 (0.40 g, 0.63 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% sodium hydride (0.05 g, 1.26 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and methyl tervastatin (0.15 g, 1.0 mmol) was slowly added. The mixture was reacted at room temperature for 6 hours, and then 15 mL of 0.01 M ammonium chloride solution (ice) and 25 mL of dichloromethane were added. The mixture was stirred thoroughly for 30 minutes and allowed to stand. The organic phase was separated and concentrated. The residue was then treated with 20 mL of dichloromethane and 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 hours, and then 20 mL of 0.01 M sodium bicarbonate solution was added. The mixture was stirred at room temperature for 1 hour, separated, and the organic phase was concentrated. The residue was then subjected to prepolymer chromatography to obtain 0.26 g of product CG204-8 (65%). MS (ESI, m / z): 650.1 [M+H] + ,NMR(400MHz):8.51(d,1H),8.15(d,1H),8.08(d,1H),7.98(d,1H),7.26-7.17(m,5H),6 .03(s,2H),4.21(d,1H),3.75-3.52(m,5H),3.01(m,1H),2.21-1.58(m,8H),1.12(s,9H).

[0106] Example 7: Synthesis of compound T-24

[0107]

[0108] T-16:

[0109] Intermediate T-1 (17.5 g, 0.1 mol) was dissolved in dichloromethane (200 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid (20.6 g, 0.12 mol) was added. The mixture was stirred for 30 hours at room temperature. Then, 0.01 M potassium carbonate (200 mL) was added and stirred thoroughly for 30 minutes. The mixture was allowed to stand, the organic phase was separated, and the concentration was achieved. The residue was used directly for the next step.

[0110] T-17:

[0111] Intermediate T-16 (19.1 g, 0.1 mol) was dissolved in dichloromethane (500 mL), cooled to 0 °C, and triphenylphosphine (39.3 g, 0.15 mol) was added. Trifluoroacetic anhydride solution (31.5 g, 0.15 mol) was slowly added dropwise, and the mixture was stirred at room temperature for 20 hours. Sodium bromide (20.6 g, 0.2 mol) was slowly added, and the mixture was stirred rapidly for 5 hours. Ice water (500 mL) was added, and the mixture was stirred for 30 minutes. After standing, the organic phase was separated, concentrated to dryness, and ether (200 mL) was added. The mixture was placed under sonication for 1 hour, cooled to 0 °C, and allowed to stand for 24 hours. After filtration, the solid was added to ether (100 mL), placed under sonication for 1 hour, cooled to 0 °C, and allowed to stand for 24 hours. After filtration and drying, 10.8 g of product T-17 (21%, two-step yield) was obtained. MS (ESI, m / z): 516.3 [M+H] + .

[0112] T-18:

[0113] Intermediate T-17 (10.4 g, 20.0 mmol) was added to deuterated water (30 mL), cooled to 0 °C, and 1,4-diazabicyclo[2.2.2]octane (4.5 g, 40.0 mmol) was added. The mixture was reacted at room temperature for 20 hours, concentrated, and the residue was separated by preparative liquid chromatography to obtain 0.63 g of product T-18 (18%), MS (ESI, m / z): 177.2 [M+H]. + ,NMR(400MHz):8.81(d,1H),7.97(d,1H),2.39(m,4H),1.85(m,2H).

[0114] T-19: Dissolve the starting material T-18 (17.6 g, 0.10 mol) in dichloromethane (350 mL), purge with nitrogen for 10 minutes to remove oxygen from the solvent, cool to 0 °C, and slowly add Rh-(Rbinapine)(COD)BF4 (0.88 g, 0.86 mmol). After the addition is complete, replace the air in the reaction system with deuterium gas, and then maintain the reaction at room temperature for 16 hours at a deuterium pressure of 150 psi. Filter, concentrate the filtrate to obtain a brown oily substance, and use it directly in the next step.

[0115] T-20:

[0116] Intermediate T-19 (18.0 g, 0.10 mol) was dissolved in dichloromethane (300 mL), and triethylamine (20.2 g, 0.20 mol) was added. The mixture was cooled to 0 °C, and triisopropylsilyltrifluoromethanesulfonate (30.6 g, 0.10 mol) was slowly added. The mixture was then reacted at room temperature for 5 hours. 0.01 M ammonium chloride solution (200 mL) was added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was separated and concentrated. Hexane (200 mL) was added, and the mixture was concentrated again. The residue was recrystallized from heptane / ethyl acetate (1:1, V / V) to give a brown solid. The brown solid was dissolved in toluene (300 mL), and 1-bromine was added... -2,3-Difluorobenzene (14.5 g, 75.2 mmol), palladium acetate (0.14 g, 0.6 mmol), tri-tert-butylphosphine tetrafluoroborate (0.17 g, 0.6 mmol), and sodium tert-butoxide (7.2 g, 75.2 mmol) were purged with nitrogen three times and heated to 100 °C for 8 hours. After cooling to room temperature, the mixture was concentrated, and 200 mL of 0.01 M ammonium chloride solution and 200 mL of ethyl acetate were added. After thorough stirring, the mixture separated into layers. The organic phase was concentrated, and the resulting brown oily substance was preparatively separated into 4.5 g of intermediate T-20 (10%). MS (ESI, m / z): 448.3 [M+H] + ,NMR(400MHz):8.71(d,1H),7.76(d,1H),7.23-7.09(m,3H),3.75(t,1H),2.48-2.21(m,2H),1.97-1.79(m,2H),1.43(m,3H),0.96(d,18H).

[0117] T-21:

[0118] Intermediate T-20 (4.5 g, 10.0 mmol) was dissolved in isopropyl ether (150 mL), purged three times with nitrogen, and cooled to 0 °C. A solution of lithium tri-tert-butoxy-aluminum hydride (1.0 M) (20.0 mL) was slowly added, and the reaction was carried out in an ice bath for 18 hours. A 0.01 M ammonium chloride solution (50 mL) was slowly added, and the mixture was concentrated under reduced pressure. The residue was then extracted twice with ethyl acetate (100 mL) in a 0.01 M ammonium chloride solution (100 mL). The resulting brown oily substance was concentrated by mechanical phase, and 1.03 g of intermediate T-21 (23%) was obtained by pre-liquid phase separation. MS (ESI, m / z): 450.1 [M+H]+, NMR (400MHz): 8.71 (d, 1H), 7.76 (d, 1H), 7.23-7.09 (m, 3H), 5.25 (m, 1H), 3.07 (m, 1H), 1.97-1.43 (m, 7H), 0.96 (d, 18H).

[0119] T-22:

[0120] Intermediate T-21 (1.0 g, 2.2 mmol) was dissolved in DMF (10 mL), and triethylamine (0.25 g, 2.5 mmol) was added. After purging with nitrogen three times, the mixture was cooled to 0 °C, and phosphorus oxychloride (1.0 g, 6.7 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to react at room temperature for 15 hours. Ice water (30 mL) was then slowly added, resulting in the precipitation of a solid. The solid was filtered and dried to obtain 0.58 g of intermediate T-22 (56%). MS (ESI, m / z): 468.3 [M+H] + .

[0121] T-23:

[0122] Intermediate T-22 (0.47 g, 1.0 mmol) was dissolved in DMF (5 mL), and potassium carbonate (0.27 g, 2.0 mmol) and sodium azide (0.13 g, 2.0 mmol) were added. After purging with nitrogen three times, the mixture was heated to 90 °C and reacted for 10 hours. The mixture was then cooled to room temperature, and ice water (15 mL) was slowly added. The mixture was extracted twice with ethyl acetate (25 mL). The organic phase was concentrated, and the residue was separated by pre-HPLC to obtain 0.12 g of intermediate T-23 (25%). MS (ESI, m / z): 475.0 [M+H] + .

[0123] T-24:

[0124] Intermediate T-23 (0.12 g, 0.25 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.02 g) was added, and the mixture was purged with hydrogen three times. The mixture was then heated to reflux under a hydrogen atmosphere for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was separated by column chromatography to obtain 62.8 mg of intermediate T-24 (56%). MS (ESI, m / z): 449.4 [M+H]+, NMR (400 MHz): 8.14 (d, 1H), 7.36 (d, 1H), 7.13–7.09 (m, 3H), 4.14 (m, 1H), 3.07 (m, 1H), 1.97–1.43 (m, 7H), 0.96 (d, 18H).

[0125] Example 8: Synthesis of compound CG204-10

[0126]

[0127] T-25:

[0128] T-23 (0.47 g, 1.0 mmol) was dissolved in THF (20 mL), cooled to -10 °C, and tetrabutylammonium fluoride (0.26 g, 1.0 mmol) was added. The mixture was reacted at room temperature for 4 hours, and 0.01 M sodium bicarbonate solution (20 mL) was added. After thorough stirring, the mixture was concentrated, and the residue was separated by column chromatography to obtain 0.32 g of brown solid. The solid was added to dry DMF (10 mL), and T-13 (0.41 g, 1.0 mmol) was added. The mixture was cooled to -10 °C, and NaHMDS (1.50 mL, 1.0 M) was slowly added under nitrogen protection. After the addition was complete, the temperature was slowly raised to room temperature. The reaction was carried out at a warm temperature for 5 hours. Then, 30 mL of 0.01 M ammonium chloride solution (ice) and 50 mL of ethyl acetate were added. After thorough stirring, the mixture was separated into layers. The separated organic phase was concentrated, and the residue was separated by column chromatography to yield 0.22 g of intermediate T-25 (33%). MS (ESI, m / z): 663.3 [M+H]+, NMR (400 MHz): 8.23 ​​(d, 2H), 7.82 (d, 1H), 7.37–7.04 (m, 5H), 3.52–3.31 (m, 5H), 3.04 (m, 2H), 2.18–1.75 (m, 8H), 1.42 (s, 9H).

[0129] CG204-10:

[0130] Intermediate T-25 (0.20 g, 0.3 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.04 g) was added, and the mixture was purged with hydrogen three times. The mixture was then heated to reflux under a hydrogen atmosphere for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was added to dichloromethane (10 mL), followed by trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 3 hours, then 0.01 M sodium bicarbonate solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was separated, and the organic phase was concentrated. The residue was then... 25.6 mg of product CG204-10 (16%) was obtained by preparative liquid chromatography. MS (ESI, m / z): 537.1 [M+H]+, NMR (400 MHz): 8.10 (d, 1H), 7.98 (d, 2H), 7.34 (d, 1H), 7.21-7.08 (m, 4H), 4.21 (d, 1H), 3.65-3.54 (m, 5H), 3.01 (m, 1H), 2.10-1.62 (m, 8H).

[0131] Example 9: Synthesis of compound CG204-11

[0132]

[0133] T-26:

[0134] CG204-10 (0.54 g, 1.0 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and di-tert-butyl dicarbonate (0.22 g, 1.0 mmol) and triethylamine (0.20 g, 2.0 mmol) were added. The mixture was reacted at room temperature for 5 hours, and then 0.01 M ammonium chloride solution (20 mL) was added. After thorough stirring and standing, the organic phase was separated, concentrated, and the residue was separated by column chromatography to obtain 0.45 g of intermediate T. -26(71%), MS(ESI,m / z): 637.1[M+H]+, NMR(400MHz):8.06(d,1H),7.93(d,2H),7.35(d,1H) ,7.17(t,1H),7.07(m,3H),5.17(d,1H),3.83-3.56(m,6H),2.14-1.68(m,8H),1.43(s,9H).

[0135] CG204-11:

[0136] Intermediate T-26 (0.44 g, 0.7 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% sodium hydride (0.06 g, 1.5 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and dimethyl chloromethyl carbonate (0.12 g, 1.0 mmol) was slowly added. The mixture was reacted at room temperature for 6 hours, and then 15 mL of 0.01 M ammonium chloride solution (ice) and 25 mL of dichloromethane were added. The mixture was stirred thoroughly for 30 minutes and allowed to stand. The organic phase was separated, concentrated, and the residue was treated with 20 mL of dichloromethane and 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 hours, and then 20 mL of 0.01 M sodium bicarbonate solution was added. The mixture was stirred at room temperature for 1 hour, separated, and the organic phase was concentrated. The resulting residue was then subjected to preparative HPLC to obtain 56.8 mg of product CG204-11 (13%). MS (ESI, m / z): 625.2 [M+H]+, NMR (400MHz): 8.18 (d, 1H), 8.08 (d, 1H), 7.98 (d, 1H), 7.37 (d, 1H), 7.17 (t, 1H), 7.07 (m, 3H), 6.01 (s, 2H), 4.19 (d, 1H), 3.80 (s, 3H), 3.70-3.38 (m, 5H), 3.00 (m, 1H), 2.17-1.48 (m, 8H).

[0137] Example 10: Synthesis of compound CG204-12

[0138]

[0139] CG204-12:

[0140] Add methyl chloroformate (0.13 g, 1.0 mmol) to THF (5 mL), cool to 0 °C, add triethylamine (0.10 g, 1.0 mmol) and deuterated methanol (0.1 mL), and after the addition is complete, let it react at room temperature for 4 hours for later use.

[0141] Intermediate T-26 (0.32 g, 0.5 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% sodium hydride (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and the above solution was slowly added. The mixture was allowed to react at room temperature for 5 hours. 15 mL of 0.01 M ammonium chloride solution (on ice) was added, followed by 25 mL of dichloromethane. The mixture was stirred thoroughly for 30 minutes and allowed to stand. The organic phase was separated and concentrated. The residue was then added to 20 mL of dichloromethane and 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 hours, followed by 20 mL of 0.01 M sodium bicarbonate solution. The mixture was stirred at room temperature. After 1 hour, the mixture was separated, the organic phase was concentrated, and the residue was preparatively separated to yield 47.1 mg of product CG204-12 (15%). MS (ESI, m / z): 628.0 [M+H]+, NMR (400MHz): 8.17 (d, 1H), 8.08 (d, 1H), 7.94 (d, 1H), 7.37 (d, 1H), 7.17 (t, 1H), 7.08 (m, 3H), 6.07 (s, 2H), 4.19 (d, 1H), 3.68–3.45 (m, 5H), 3.01 (m, 1H), 2.17–1.42 (m, 8H).

[0142] Example 11: Synthesis of Compound T-32

[0143]

[0144] T-27:

[0145] The starting material T-18 (17.6 g, 0.10 mol) was dissolved in dichloromethane (350 mL), and nitrogen was purged for 10 minutes to remove oxygen from the solvent. The temperature was lowered to 0 °C, and Rh-(Rbinapine)(COD)BF4 (0.88 g, 0.86 mmol) was slowly added. After the addition was complete, hydrogen was used to displace the air in the reaction system. The reaction was then maintained at 150 psi hydrogen pressure at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated to obtain a brown oily substance, which was used directly in the next step.

[0146] T-28:

[0147] Intermediate T-27 (17.8 g, 0.10 mol) was dissolved in dichloromethane (300 mL), and triethylamine (20.2 g, 0.20 mol) was added. The mixture was cooled to 0 °C, and triisopropylsilyl trifluoromethanesulfonate (30.6 g, 0.10 mol) was slowly added. The mixture was then reacted at room temperature for 5 hours. 200 mL of 0.01 M ammonium chloride solution was added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was separated and concentrated. 200 mL of n-hexane was added, and the mixture was concentrated again. The residue was recrystallized from n-heptane / ethyl acetate (1:1, V / V) to give a brown solid. The brown solid was dissolved in toluene (300 mL), and 1-bromo-2,3-difluorobenzene (14.5 g, 75.2 mmol), palladium acetate (0.14 g, 0.6 mmol), and tri-tert-butylphosphine tetratetrafluoroborate (0.17 g, 0.6 mmol) were added. 7.2 g (75.2 mmol) of sodium tert-butoxide was purged with nitrogen three times and heated to 100 °C for 8 hours. After cooling to room temperature, the mixture was concentrated, and 200 mL of 0.01 M ammonium chloride solution and 200 mL of ethyl acetate were added. After thorough stirring, the mixture was separated into layers. The organic phase was concentrated, and the resulting brown oily substance was purified by liquid chromatography to obtain 6.7 g of intermediate T-28 (15%). MS (ESI, m / z): 447.1 [M+H]+, NMR (400 MHz): 8.58 (d, 1H), 7.67 (d, 1H), 7.11-7.03 (m, 3H), 4.81 (t, 1H), 3.45 (t, 1H), 2.58-2.17 (m, 2H), 1.94-1.63 (m, 2H), 1.48 (m, 3H), 0.93 (d, 18H).

[0148] T-29:

[0149] Intermediate T-28 (6.5 g, 14.5 mmol) was dissolved in isopropyl ether (150 mL), purged three times with nitrogen, and cooled to 0 °C. A solution of lithium tri-tert-butoxy-aluminum hydride (1.0 M) (20.0 mL) was slowly added, and the reaction was carried out in an ice bath for 16 hours. A 0.01 M ammonium chloride solution (50 mL) was slowly added, and the mixture was concentrated under reduced pressure. The residue was then extracted twice with ethyl acetate (100 mL) using 100 mL of 0.01 M ammonium chloride solution. The organic phase was concentrated, and the resulting brown... The colored oily substance was preparatively separated by liquid chromatography to yield 1.37 g of intermediate T-29 (21%). MS (ESI, m / z): 449.3 [M+H]+, NMR (400 MHz): 8.07 (d, 1H), 7.37 (d, 1H), 7.07 (m, 3H), 5.17 (d, 1H), 4.77 (t, 1H), 3.03 (m, 1H), 1.98–1.48 (m, 4H), 1.43 (m, 3H), 0.93 (d, 18H).

[0150] T-30:

[0151] Intermediate T-29 (1.35 g, 3.0 mmol) was dissolved in DMF (10 mL), and triethylamine (0.60 g, 6.0 mmol) was added. After purging with nitrogen three times, the mixture was cooled to 0 °C, and phosphorus oxychloride (1.0 g, 6.7 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to react at room temperature for 15 hours. Ice water (30 mL) was then slowly added, resulting in the precipitation of a solid. The solid was filtered and dried to obtain 0.77 g of intermediate T-30 (55%). MS (ESI, m / z): 467.3 [M+H] + .

[0152] T-31:

[0153] Intermediate T-30 (0.75 g, 1.6 mmol) was dissolved in DMF (5 mL), and potassium carbonate (0.27 g, 2.0 mmol) and sodium azide (0.13 g, 2.0 mmol) were added. After purging with nitrogen three times, the mixture was heated to 90 °C and reacted for 16 hours. The mixture was then cooled to room temperature, and ice water (15 mL) was slowly added. The mixture was extracted twice with ethyl acetate (25 mL). The organic phase was concentrated, and the residue was purified by pre-HPLC to obtain 0.49 g of intermediate T-31 (65%). MS (ESI, m / z): 474.3 [M+H] + .

[0154] T-32:

[0155] Intermediate T-31 (0.47 g, 1.0 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.04 g) was added, and the mixture was purged with hydrogen three times. The mixture was then heated to reflux under a hydrogen atmosphere for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was separated by column chromatography to obtain 0.31 g of intermediate T-32 (70%). MS (ESI, m / z): 448.1 [M+H]+, NMR (400 MHz): 8.01 (d, 1H), 7.33 (d, 1H), 7.07 (m, 3H), 4.77 (t, 1H), 4.19 (d, 1H), 3.01 (m, 1H), 1.97–1.56 (m, 4H), 1.42 (m, 3H), 0.94 (d, 18H).

[0156] Example 12: Synthesis of compound CG204-19

[0157]

[0158] T-33:

[0159] T-31 (0.47 g, 1.0 mmol) was dissolved in THF (20 mL), cooled to -10 °C, and tetrabutylammonium fluoride (0.26 g, 1.0 mmol) was added. The mixture was reacted at room temperature for 5 hours. Then, 0.01 M sodium bicarbonate solution (20 mL) was added, and the mixture was stirred thoroughly and concentrated. The residue was separated by column chromatography to obtain 0.35 g of brown solid. The solid was added to dry DMF (10 mL), and T-13 (0.41 g, 1.0 mmol) was added. The mixture was cooled to -10 °C, and NaHMDS (1.50 mL, 1.0 M) was slowly added under nitrogen protection. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 10 hours. At that time, 30 mL of 0.01 M ammonium chloride solution was added to ice, followed by 50 mL of ethyl acetate. After thorough stirring, the mixture was separated into layers. The separated organic phase was concentrated, and the residue was separated by column chromatography to yield 0.19 g of intermediate T-33 (29%). MS (ESI, m / z): 662.3 [M+H]+, NMR (400 MHz): 8.17 (d, 2H), 7.87 (d, 1H), 7.25–7.07 (m, 5H), 5.87 (t, 1H), 3.68–3.37 (m, 5H), 3.09 (m, 2H), 1.98–1.54 (m, 8H), 1.42 (s, 9H).

[0160] CG204-19:

[0161] Intermediate T-33 (0.18 g, 0.27 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.04 g) was added, and the mixture was purged with hydrogen three times. The mixture was then heated to reflux under a hydrogen atmosphere for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was added to dichloromethane (10 mL), followed by trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 3 hours, and then 0.01 M sodium bicarbonate solution (10 mL) was added. The mixture was stirred at room temperature for 1 hour, separated, and the organic phase was concentrated. The residue was then used to prepare a liquid phase. 33.2 mg of product CG204-19 (23%) was isolated. MS (ESI, m / z): 536.0 [M+H]+, NMR (400 MHz): 8.07 (d, 1H), 7.97 (d, 2H), 7.37 (d, 1H), 7.18-7.03 (m, 4H), 5.85 (m, 1H), 4.31 (d, 1H), 3.71-3.58 (m, 5H), 3.01 (m, 1H), 2.08-1.62 (m, 8H).

[0162] Example 13: Synthesis of compound CG204-20

[0163]

[0164] T-34:

[0165] CG204-19 (0.27 g, 0.5 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and di-tert-butyl dicarbonate (0.11 g, 0.5 mmol) and triethylamine (0.10 g, 1.0 mmol) were added. The mixture was reacted at room temperature for 5 hours, and then 0.01 M ammonium chloride solution (20 mL) was added. After thorough stirring and standing, the organic phase was separated, concentrated, and the residue was separated by column chromatography to obtain 0.24 g of intermediate T-3. 4(78%), MS(ESI,m / z): 636.2[M+H]+, NMR(400MHz): 8.07(d,1H),7.97(d,2H),7.37(d,1H),7. 18-7.01(m,4H),5.85(m,1H),5.17(d,1H),3.69-3.37(m,6H),2.10-1.73(m,8H),1.43(s,9H).

[0166] CG204-20:

[0167] Intermediate T-34 (0.23 g, 0.36 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% sodium hydride (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and dimethyl chloromethyl carbonate (0.06 g, 0.5 mmol) was slowly added. The mixture was reacted at room temperature for 5 hours, and then 15 mL of 0.01 M ammonium chloride solution (ice) and 25 mL of dichloromethane were added. The mixture was stirred thoroughly for 30 minutes and allowed to stand. The organic phase was separated, concentrated, and the residue was reacted with 20 mL of dichloromethane and 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 hours, and then 20 mL of 0.01 M sodium bicarbonate solution was added. The mixture was stirred for 1 hour, separated, and the organic phase was concentrated. The resulting residue was then subjected to preparative HPLC separation to obtain 33.7 mg of product CG204-20 (15%). MS (ESI, m / z): 624.0 [M+H]+, NMR (400MHz): 8.17 (d, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.34 (d, 1H), 7.18-7.01 (m, 4H), 6.07 (s, 2H), 5.85 (m, 1H), 4.18 (d, 1H), 3.81 (s, 3H), 3.69-3.37 (m, 5H), 3.01 (m, 1H), 2.10-1.73 (m, 8H).

[0168] Example 14: Synthesis of compound CG204-24

[0169]

[0170] T-34:

[0171] CG204-19 (0.27 g, 0.5 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and di-tert-butyl dicarbonate (0.11 g, 0.5 mmol) and triethylamine (0.10 g, 1.0 mmol) were added. The mixture was reacted at room temperature for 5 hours, and then 0.01 M ammonium chloride solution (20 mL) was added. After thorough stirring and standing, the organic phase was separated, concentrated, and the residue was separated by column chromatography to obtain 0.24 g of intermediate T-3. 4(78%), MS(ESI,m / z): 636.2[M+H]+, NMR(400MHz): 8.07(d,1H),7.97(d,2H),7.37(d,1H),7. 18-7.01(m,4H),5.85(m,1H),5.17(d,1H),3.69-3.37(m,6H),2.10-1.73(m,8H),1.43(s,9H).

[0172] CG204-24:

[0173] Intermediate T-34 (0.23 g, 0.36 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and 60% sodium hydride (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes. Chloromethyl acetate (0.05 g, 0.5 mmol) was slowly added, and the mixture was reacted at room temperature for 5 hours. 15 mL of 0.01 M ammonium chloride solution (on ice) was added, followed by 25 mL of dichloromethane. The mixture was stirred thoroughly for 30 minutes, allowed to stand, and the organic phase was separated and concentrated. The residue was then reacted with 20 mL of dichloromethane and 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 hours, followed by 20 mL of 0.01 M sodium bicarbonate solution. The mixture was stirred at room temperature. Stir for 1 hour, separate the liquid and concentrate the organic phase, and the resulting residue was purified by preparative HPLC to obtain 17.59 mg of product CG204-24 (8%). MS (ESI, m / z): 608.1 [M+H]+, NMR (400MHz): 8.17 (d, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.34 (d, 1H), 7.18-7.01 (m, 4H), 6.07 (s, 2H), 5.85 (m, 1H), 4.18 (d, 1H), 3.69-3.37 (m, 5H), 3.01 (m, 1H), 2.23 (s, 3H), 2.10-1.73 (m, 8H).

[0174] Example 15: Synthesis of compound CG204-28

[0175]

[0176] T-35:

[0177] Intermediate T-6 (44.8 g, 0.1 mol) was dissolved in dry toluene (500 mL), p-toluenesulfonic acid (0.86 g, 5.0 mmol) was added, and after purging with nitrogen three times, dihydropyran (8.4 g, 0.1 mol) was slowly added. After the addition was complete, the mixture was reacted at room temperature for 30 hours. The mixture was filtered, and 300 mL of ice-cold 0.01 M sodium bicarbonate solution was added to the filtrate. The mixture was stirred for 30 minutes, allowed to stand, and then separated. The organic phase was concentrated, and the residue was separated by column chromatography to obtain 29.3 g of intermediate. T-35(55%), MS(ESI,m / z): 533.0[M+H]+, NMR(400MHz):8.38(d,1H),8.07(d,1H),7.32(dt,1H),7.07( m,3H),4.86(d,1H),4.57(qt,1H),3.75-3.57(m,2H),3.18(m,1H),1.98-1.42(m,13H),0.96(d,18H).

[0178] T-36:

[0179] T-35 (52.0 g, 97.6 mmol) was dissolved in THF (500 mL), cooled to -10 °C, and tetrabutylammonium fluoride (31.4 g, 120.0 mmol) was added. The mixture was reacted at room temperature for 6 hours, followed by the addition of 0.01 M sodium bicarbonate solution (200 mL). After thorough stirring, the mixture was concentrated, and the residue was separated by column chromatography to yield 22.4 g of intermediate T-36 (61%). MS (ESI, m / z): 377.4 [M+H] + .

[0180] CG204-28:

[0181] T-36 (22.0 g, 58.4 mmol) was dissolved in THF (300 mL), and T-13 (24.1 g, 58.4 mmol) was added. The mixture was cooled to -10 °C, and NaHMDS (87.6 mL, 1.0 M) was slowly added under nitrogen protection. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 15 hours. 200 mL of 0.01 M ammonium chloride solution (on ice) was added, and the mixture was concentrated. The residue was then added to 200 mL of 0.01 M ammonium chloride solution, followed by 200 mL of ethyl acetate. After thorough stirring, the mixture separated into layers. The separated organic phase was concentrated, and the residue was added to 200 mL of dichloromethane and 20 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 5 hours, the organic phase was separated, 0.01M sodium bicarbonate (200mL) was added, and stirring was continued for 1 hour. The organic phase was then separated, concentrated, and the residue was used to prepare 8.1g of product CG204-28 (26%) by liquid chromatography. MS (ESI, m / z): 537.1 [M+H]+, NMR (400MHz): 8.51 (d, 1H), 8.10 (d, 1H), 7.97 (d, 2H), 7.17-7.07 (m, 5H), 5.18 (d, 1H), 3.63-3.43 (m, 5H), 3.07 (m, 1H), 2.09-1.62 (m, 8H).

[0182] Example 16: Synthesis of compound CG204-29

[0183]

[0184] CG204-29:

[0185] CG204-28 (0.27 g, 0.5 mmol) was dissolved in DMF (3 mL), cooled to 0 °C, and 60% sodium hydride (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and dimethyl chloromethyl carbonate (0.06 g, 0.5 mmol) was slowly added. The mixture was allowed to react at room temperature for 5 hours, and then 10 mL of 0.01 M ammonium chloride solution (on ice) and 25 mL of dichloromethane were added. The mixture was stirred thoroughly for 30 minutes, allowed to stand, and the organic phase was separated. The solution was concentrated, and the residue was used to prepare a 53.0 mL solution by liquid chromatography. g product CG204-20 (17%), MS (ESI, m / z): 625.3 [M+H]+, NMR (400MHz): 8.48 (d, 1H), 8.17 (d, 1H), 8.08 (d, 1H), 7.93 (d, 1H), 7.31-7.03 (m, 5H), 6.02 (s, 2H), 5.17 (d, 1H), 3.81 (s, 3H), 3.53-3.42 (m, 5H), 3.07 (m, 1H), 2.00-1.63 (m, 8H).

[0186] Example 17: Synthesis of compound CG204-37

[0187]

[0188] T-37:

[0189] T-14 (6.6 g, 10.0 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 °C, and then slowly added to trifluoroacetic acid (10 mL). The reaction was carried out at room temperature for 2 hours. Then, 0.01 M sodium bicarbonate solution (100 mL) was added, and the mixture was stirred thoroughly and separated. The organic phase was concentrated, and the residue was separated by column chromatography to yield 2.52 g of intermediate T-37 (45%). MS (ESI, m / z): 562.1 [M+H] + .

[0190] CG204-37:

[0191] Intermediate T-37 (0.28 g, 0.5 mmol) was dissolved in DMF (5 mL), and 60% sodium hydroxide (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and dimethyl chlorophosphate (0.09 g, 0.5 mmol) was slowly added. The mixture was reacted at room temperature for 6 hours, and dimethyl chlorophosphate (0.09 g, 0.5 mmol) was added again. The reaction was continued for 12 hours, and 15 mL of 0.01 M ammonium chloride solution (ice) was added. Dichloromethane (25 mL) was added, and the mixture was stirred for 30 minutes until it separated into layers. The organic phase was concentrated to dryness, and the residue was added to methanol (15 mL). Palladium on carbon (0.05 g) was added, and the mixture was purged three times with hydrogen gas. The mixture was heated to reflux for 3 hours under a specific atmosphere, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was then subjected to pre-HPLC separation to obtain 30.3 mg of product CG204-37 (9%). MS (ESI, m / z): 674.1 [M+H]+, NMR (400MHz): 8.48 (d, 1H), 8.17 (d, 1H), 8.08 (d, 1H), 7.93 (d, 1H), 7.31-7.03 (m, 5H), 5.83 (s, 2H), 4.17 (d, 1H), 3.75 (d, 6H), 3.53-3.42 (m, 5H), 3.07 (m, 1H), 2.00-1.63 (m, 8H).

[0192] Example 18: Synthesis of compound CG204-40

[0193]

[0194] T-38:

[0195] T-25 (6.6 g, 10.0 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 °C, and then slowly added to trifluoroacetic acid (10 mL). The reaction was carried out at room temperature for 2 hours. Then, 0.01 M sodium bicarbonate solution (100 mL) was added, and the mixture was stirred thoroughly and separated. The organic phase was concentrated, and the residue was separated by column chromatography to yield 2.92 g of intermediate T-38 (51%). MS (ESI, m / z): 563.3 [M+H] + .

[0196] CG204-40:

[0197] Intermediate T-37 (0.28 g, 0.5 mmol) was dissolved in DMF (5 mL), and 60% sodium hydroxide (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and dimethyl chlorophosphate (0.09 g, 0.5 mmol) was slowly added. The mixture was reacted at room temperature for 6 hours, and dimethyl chlorophosphate (0.09 g, 0.5 mmol) was added again. The reaction was continued for 12 hours, and 15 mL of 0.01 M ammonium chloride solution (ice) was added. Dichloromethane (25 mL) was added, and the mixture was stirred for 30 minutes until it separated into layers. The organic phase was concentrated to dryness, and the residue was added to methanol (15 mL). Palladium on carbon (0.05 g) was added, and the mixture was purged three times with hydrogen gas. The mixture was heated to reflux for 3 hours under a specific atmosphere, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was then subjected to pre-HPLC separation to obtain 16.9 mg of product CG204-40 (5%). MS (ESI, m / z): 675.0 [M+H]+, NMR (400MHz): 8.18 (d, 1H), 8.07 (d, 1H), 7.98 (d, 1H), 7.37 (d, 1H), 7.31-7.03 (m, 4H), 5.83 (s, 2H), 4.17 (d, 1H), 3.75 (d, 6H), 3.53-3.42 (m, 5H), 3.07 (m, 1H), 2.00-1.63 (m, 8H).

[0198] Example 19: Synthesis of compound CG204-43

[0199]

[0200] T-39:

[0201] T-33 (6.6 g, 10.0 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 °C, and then slowly added to trifluoroacetic acid (10 mL). The reaction was carried out at room temperature for 2 hours. Then, 0.01 M sodium bicarbonate solution (100 mL) was added, and the mixture was stirred thoroughly and separated. The organic phase was concentrated, and the residue was separated by column chromatography to yield 3.14 g of intermediate T-39 (56%). MS (ESI, m / z): 562.2 [M+H] +.

[0202] CG204-43:

[0203] Intermediate T-39 (0.28 g, 0.5 mmol) was dissolved in DMF (5 mL), and 60% sodium hydroxide (0.04 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and dimethyl chlorophosphate (0.09 g, 0.5 mmol) was slowly added. The mixture was reacted at room temperature for 6 hours, and dimethyl chlorophosphate (0.09 g, 0.5 mmol) was added again. The reaction was continued for 12 hours, and 15 mL of 0.01 M ammonium chloride solution (ice) was added. Dichloromethane (25 mL) was added, and the mixture was stirred for 30 minutes until it separated into layers. The organic phase was concentrated to dryness, and the residue was added to methanol (15 mL). Palladium on carbon (0.05 g) was added, and the mixture was purged three times with hydrogen before being reacted under a hydrogen atmosphere. The mixture was heated to reflux for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was then subjected to pre-HPLC separation to obtain 33.7 mg of product CG204-43 (10%). MS (ESI, m / z): 674.3 [M+H]+, NMR (400MHz): 8.18 (d, 1H), 8.07 (d, 1H), 7.98 (d, 1H), 7.37 (d, 1H), 7.31-7.03 (m, 4H), 5.83 (m, 3H), 4.17 (d, 1H), 3.75 (d, 6H), 3.53-3.42 (m, 5H), 3.07 (m, 1H), 2.00-1.63 (m, 8H).

[0204] Example 20: Synthesis of compound CG204-44

[0205]

[0206] CG204-44:

[0207] Intermediate T-39 (0.50 g, 0.89 mmol) was dissolved in DMF (5 mL), and 60% sodium hydroxide (0.07 g, 1.78 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, and diethyl chloromethyl phosphate (0.17 g, 0.90 mmol) was slowly added. The mixture was reacted at room temperature for 6 hours, and diethyl chloromethyl phosphate (0.17 g, 0.9 mmol) was added again. The reaction was continued for 12 hours, and 15 mL of 0.01 M ammonium chloride solution (ice) was added. Dichloromethane (25 mL) was added, and the mixture was stirred for 30 minutes until it separated into layers. The organic phase was concentrated to dryness, and the residue was added to methanol (15 mL). Palladium on carbon (0.05 g) was added, and the mixture was purged with hydrogen three times. The mixture was then heated to reflux under a hydrogen atmosphere. The reaction was carried out for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated. The residue was then subjected to preparative liquid chromatography to obtain 106.21 mg of product CG204-44 (17%). MS (ESI, m / z): 702.2 [M+H]+, NMR (400MHz): 8.11 (d, 1H), 8.04 (d, 1H), 7.96 (d, 1H), 7.37 (d, 1H), 7.31-7.03 (m, 4H), 5.92-5.83 (m, 3H), 4.17 (d, 1H), 4.02 (q, 4H), 3.53-3.42 (m, 5H), 3.07 (m, 1H), 2.00-1.63 (m, 8H), 1.18 (t, 6H).

[0208] Example 21: Synthesis of Compound T-46

[0209]

[0210] T-40:

[0211] The starting material T-1 (17.5 g, 0.10 mol) was dissolved in dichloromethane (350 mL), and nitrogen was purged for 10 minutes to remove oxygen from the solvent. The temperature was lowered to 0 °C, and Rh-(Rbinapine)(COD)BF4 (0.88 g, 0.86 mmol) was slowly added. After the addition was complete, hydrogen was used to displace the air in the reaction system. The reaction was then maintained at 150 psi hydrogen pressure at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated to obtain a brown oily substance, which was used directly in the next step.

[0212] T-41:

[0213] Intermediate T-40 (17.7 g, 0.10 mol) was dissolved in dichloromethane (300 mL), and triethylamine (20.2 g, 0.20 mol) was added. The mixture was cooled to 0 °C, and triisopropylsilyl trifluoromethanesulfonate (30.6 g, 0.10 mol) was slowly added. The mixture was then reacted at room temperature for 5 hours. 200 mL of 0.01 M ammonium chloride solution was added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was separated and concentrated. 200 mL of n-hexane was added, and the mixture was concentrated again. The residue was recrystallized from n-heptane / ethyl acetate (1:1, V / V) to give 26.3 g of intermediate T-41 (79%). MS (ESI, m / z): 334.1 [M+H] + H 1 NMR(400MHz):8.88(d,1H),8.47(d,1H),7.53(t,1H),5.01(t,1H),2.41-2.32(m,2H),1.99-1.34(m,7H),0.91(d,18H).

[0214] T-42:

[0215] Intermediate T-41 (26.0 g, 78.03 mmol) was dissolved in toluene (300 mL), and 1-bromo-2,3-difluorobenzene (18.1 g, 93.63 mmol), palladium acetate (0.13 g, 0.8 mmol), tri-tert-butylphosphine tetrafluoroborate (0.23 g, 0.8 mmol), and sodium tert-butoxide (9.0 g, 93.63 mmol) were added. After purging with nitrogen three times, the mixture was heated to 100 °C for 6 hours, cooled to room temperature, and concentrated. 0.01 M ammonium chloride solution (200 mL) and ethyl acetate (200 mL) were added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was concentrated, and the resulting brown oily substance was purified by pre-liquid chromatography to obtain 12.16 g of intermediate T-42 (35%). MS (ESI, m / z): 446.1 [M+H] + H 1 NMR(400MHz):8.78(d,1H),8.37(d,1H),7.71(t,1H),7.19-7.07(m,3H),4.82(t,1 H),3.53(t,1H),2.41-2.20(m,2H),1.93-1.68(m,2H),1.47(m,3H),0.93(d,18H).

[0216] T-43:

[0217] Intermediate T-42 (7.0 g, 15.7 mmol) was dissolved in isopropanol (150 mL), cooled to 0 °C under a nitrogen atmosphere, and sodium borodeuteride (0.72 g, 17.29 mmol) was slowly added. The reaction was carried out in an ice bath for 18 hours. Then, 0.01 M ammonium chloride solution (50 mL) was slowly added, and the mixture was concentrated under reduced pressure. The residue was added to 0.01 M ammonium chloride solution (100 mL), and extracted twice with ethyl acetate (100 mL). The organic phase was concentrated, and the resulting brown oily substance was purified by pre-HPLC to obtain 5.09 g of intermediate T-43 (72%). MS (ESI, m / z): 450.1 [M+H] + , NMR(400MHz):8.38(d,1H),8.07(d,1H),7.13(t,1H),7.10-7.07(m,3H) ,4.82(t,1H),3.06(t,1H),1.93-1.68(m,4H),1.43(m,3H),1.01(d,18H).

[0218] T-44:

[0219] Intermediate T-43 (3.0 g, 6.7 mmol) was dissolved in DMF (10 mL), and triethylamine (2.5 g, 25.0 mmol) was added. After purging with nitrogen three times, the mixture was cooled to 0 °C. Phosphorus oxychloride (1.0 g, 6.7 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to react at room temperature for 15 hours. Ice water (30 mL) was then slowly added, resulting in the precipitation of a solid. The solid was filtered and dried to obtain 1.8 g of intermediate. Bulk T-44 (58%), MS (ESI, m / z): 467.0 [M+H]+, NMR (400MHz): 8.48 (d, 1H), 7.87 (d, 1H), 7.10 -7.07(m,4H),4.98(t,1H),3.41(m,1H),1.93-1.68(m,4H),1.40(m,3H),0.97(d,18H).

[0220] T-45:

[0221] Intermediate T-44 (1.9 g, 4.1 mmol) was dissolved in DMF (7 mL), and potassium carbonate (0.27 g, 2.0 mmol) and sodium azide (0.5 g, 8.2 mmol) were added. After purging with nitrogen three times, the mixture was heated to 90 °C and reacted for 18 hours. The mixture was then cooled to room temperature, and ice water (25 mL) was slowly added. The mixture was extracted twice with ethyl acetate (25 mL). The organic phase was concentrated, and the residue was purified by pre-HPLC to obtain 0.82 g of intermediate T-45 (42%). MS (ESI, m / z): 474.2 [M+H] +, NMR(400MHz):8.37(d,1H),7.82(d,1H),7.03(m,4H),4.81(t,1H),3.01(m,1H),1.95-1.32(m,7H),0.91(d,18H).

[0222] T-46:

[0223] Intermediate T-45 (0.47 g, 1.0 mmol) was dissolved in THF (10 mL), water (1 mL) was added dropwise, the mixture was cooled to 0 °C, and then triphenylphosphine (0.79 g, 3.0 mmol) was added. The reaction was carried out for 2 hours, followed by the addition of EA and thorough stirring. The mixture was separated into liquid and liquid phases, washed with saturated brine, dried and concentrated. The residue was separated by column chromatography to obtain 0.38 g of intermediate T-46 (84%), MS (ESI, m / z): 448.0 [M+H]. + , NMR(400MHz):8.50(d,1H),7.91(d,1H),7.33(t,1H),7.10-7.05(m,3H),4.77(t,1H),3.00(t,1H),1.97-1.37(m,7H),0.95(d,18H).

[0224] Example 22: Synthesis of compound CG204-55

[0225]

[0226] T-47:

[0227] T-45 (4.73 g, 10.0 mmol) was dissolved in THF (100 mL), cooled to -10 °C, and tetrabutylammonium fluoride (2.61 g, 10.0 mmol) was added. The mixture was reacted at room temperature for 2 hours, and then 0.01 M sodium bicarbonate solution (50 mL) was added. After thorough stirring, the mixture was concentrated, and the residue was separated by column chromatography to obtain 2.09 g of brown solid. The solid was added to dry DMF (35 mL), and T-13 (2.72 g, 6.6 mL) was added. The mixture was cooled to -10℃ and NaHMDS (1.32 mL, 1.0 M) was slowly added under nitrogen protection. After the addition was complete, the temperature was slowly raised to room temperature and reacted for 2 hours. 100 mL of 0.01 M ammonium chloride solution (on ice) was added, followed by 150 mL of ethyl acetate. After thorough stirring, the mixture was separated into layers. The separated organic phase was concentrated, and the residue was separated by column chromatography to yield 2.05 g of intermediate T-47 (31%). MS (ESI, m / z): 662.0 [M+H] +, NMR(400MHz):8.51(d,1H),8.21(d,2H),7.91(d,1H),7.14-7.05(m,5H), 5.81(t,1H),3.79-3.30(5H),3.10(t,1H),2.04-1.87(m,8H),1.41(s,9H).

[0228] CG204-1:

[0229] Intermediate T-47 (0.33 g, 0.5 mmol) was dissolved in methanol (10 mL), water (1 mL) was added, and the mixture was cooled to 0 °C. Triphenylphosphine (0.39 g, 1.5 mmol) was added, and the reaction was carried out for 3 hours. EA was added and stirred. The mixture was allowed to stand and separated. The organic phase was washed with saturated brine, dried, and concentrated. The residue was added to dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. 0.01 M sodium bicarbonate solution (10 mL) was added, and the mixture was stirred at room temperature. Stir for 1 hour, separate the liquids, concentrate the organic phase, and the resulting residue was purified by preparative HPLC to obtain 163.25 mg of product CG204-55 (61%). MS (ESI, m / z): 536.1 [M+H]+, NMR (400MHz): 8.47 (d, 1H), 8.05 (m, 3H), 7.24 (m, 5H), 5.75 (t, 1H), 3.57-3.31 (m, 5H), 3.01 (t, 1H), 2.10-1.79 (m, 8H).

[0230] Example 23: Synthesis of compound CG204-58

[0231]

[0232] CG204-58:

[0233] CG204-1 (53.52 mg, 0.1 mmol) was dissolved in anhydrous ethanol (5 mL), cooled to 0 °C, and freshly prepared sulfuric acid ethanol solution (1 mol / L, 0.1 mL) was slowly added. After the addition was complete, the mixture was stirred for 1 hour, resulting in a large amount of solid. After stirring for another 12 hours, the mixture was filtered. The filter cake was washed with anhydrous ethanol and dried to obtain 50.65 mg of white solid CG204-58 (80%). MS (ESI, m / z): 536.2 [M+H]+, NMR (400 MHz): 8.51 (d, 1H), 8.08 (d, 1H), 7.99 (t, 2H), 7.20–7.09 (m, 5H), 4.24 (d, 1H), 3.57–3.31 (m, 5H), 3.02 (m, 1H), 2.10–1.79 (m, 8H).

[0234] Example 24: Synthesis of compound CG204-59

[0235]

[0236] CG204-59:

[0237] CG204-10 (53.52 mg, 0.1 mmol) was dissolved in anhydrous ethanol (5 mL), cooled to 0 °C, and freshly prepared sulfuric acid ethanol solution (1 mol / L, 0.1 mL) was slowly added. After the addition was complete, the mixture was stirred for 1 hour, resulting in a large amount of solid. After stirring for another 12 hours, the mixture was filtered. The filter cake was washed with anhydrous ethanol and dried to obtain 46.30 mg of white solid CG204-59 (73%). MS (ESI, m / z): 537.2 [M+H]+, NMR (400 MHz): 8.10 (d, 1H), 7.98 (d, 2H), 7.34 (d, 1H), 7.21-7.08 (m, 4H), 4.21 (d, 1H), 3.65-3.54 (m, 5H), 3.01 (m, 1H), 2.10-1.62 (m, 8H).

[0238] Example 25: Synthesis of compound CG204-60

[0239]

[0240] CG204-60:

[0241] CG204-19 (53.52 mg, 0.1 mmol) was dissolved in anhydrous ethanol (5 mL), cooled to 0 °C, and freshly prepared sulfuric acid ethanol solution (1 mol / L, 0.1 mL) was slowly added. After the addition was complete, the mixture was stirred for 1 hour, resulting in a large amount of solid. After stirring for another 12 hours, the mixture was filtered. The filter cake was washed with anhydrous ethanol and dried to obtain 46.30 mg of white solid CG204-59 (73%). MS (ESI, m / z): 536.2 [M+H]+, NMR (400 MHz): 8.07 (d, 1H), 7.97 (d, 2H), 7.37 (d, 1H), 7.18–7.03 (m, 4H), 5.85 (m, 1H), 4.31 (d, 1H), 3.71–3.58 (m, 5H), 3.01 (m, 1H), 2.08–1.62 (m, 8H).

[0242] Example 26: Synthesis of compound CG204-61

[0243]

[0244] CG204-61:

[0245] CG204-55 (53.52 mg, 0.1 mmol) was dissolved in anhydrous ethanol (5 mL), cooled to 0 °C, and freshly prepared sulfuric acid ethanol solution (1 mol / L, 0.1 mL) was slowly added. After the addition was complete, the mixture was stirred for 1 hour, resulting in a large amount of solid. After stirring for another 12 hours, the mixture was filtered. The filter cake was washed with anhydrous ethanol and dried to obtain 48.76 mg of white solid CG204-61 (77%). MS (ESI, m / z): 536.1 [M+H]+, NMR (400 MHz): 8.47 (d, 1H), 8.05 (m, 3H), 7.24 (m, 5H), 5.75 (t, 1H), 3.57–3.31 (m, 5H), 3.01 (t, 1H), 2.10–1.79 (m, 8H).

[0246] Example 27: Synthesis of Compound T-52

[0247]

[0248] T-49:

[0249] The raw material T-48 (24.31 g, 0.1 mol) was dissolved in triethyl orthoformate (100 mL), slowly heated to 110 °C, and reacted for 3 hours. The mixture was then cooled to room temperature, diluted with EA, washed with water and saturated brine, dried, and concentrated. The concentrated residue was dissolved in a small amount of EA, and petroleum ether was slowly added, precipitating a large amount of solid. The mixture was filtered, and the filtrate was washed with petroleum ether and dried to obtain 25.56 g of solid T-49 (95%). MS (ESI, m / z): 270.0 [M+H]+, NMR (400 MHz): 8.38 (d, 1H), 7.01 (d, 1H), 1.38 (s, 9H).

[0250] T-50:

[0251] T-49 (13.45 g, 0.05 mol) was dissolved in methanol (100 mL), Pd / C (0.1 g) was added, and the mixture was reacted at room temperature under a deuterium atmosphere for 6 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain T-50, which was used directly in the next step without purification.

[0252] T-51:

[0253] T-50 (2.36 g, 10.0 mmol) was dissolved in dichloromethane (100 mL), potassium carbonate (2.8 g, 20.0 mmol) and T-10 (3.0 g, 10.0 mmol) were added, and the mixture was reacted at room temperature for 20 hours. Ice water (50 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was separated by liquid-liquid chromatography, and the organic phase was concentrated. The residue was separated by column chromatography, and the resulting solid was added to methanol (100 mL). 0.2 g of palladium on carbon was added, and the mixture was refluxed under a hydrogen atmosphere for 5 hours. The mixture was cooled to room temperature, filtered, concentrated, and the residue was separated by column chromatography to give 2.36 g of intermediate T-51 (74%). MS (ESI, m / z): 320.0 [M+H] + , NMR(400MHz):8.13(d,1H),7.14(d,1H),3.55(m,1H),2.73-2.54(m,4H),1.84(m,4H),1.41(s,9H).

[0254] T-52:

[0255] T-51 (1.60 g, 5.0 mmol) was dissolved in dichloromethane (100 mL), and the mixture was purged with nitrogen for 10 min. Triethylamine (1.01 g, 10.0 mmol) and N,N'-carbonyldiimidazole (0.81 g, 5.0 mmol) were added, and the mixture was reacted at room temperature for 15 h. 0.01 M ammonium chloride solution (100 mL) was added, and the mixture was stirred thoroughly until it separated into layers. The organic phase was separated, concentrated, and the residue was separated by column chromatography to yield 1.32 g of intermediate T-13 (64%). MS (ESI, m / z): 414.1 [M+H] + , NMR(400MHz):8.15(m,2H),7.47(d,1H),7.17(m,2H),3.71-3.48(m,5H),2.01-1.95(m,4H),1.41(s,9H).

[0256] Example 28: Synthesis of compound CG204-62

[0257]

[0258] T-54:

[0259] T-53 (2.90 g, 10 mmol) was dissolved in THF (50 mL), and Boc anhydride (2.40 g, 11 mmol) was added at room temperature. The mixture was then heated to 60 °C and reacted for 6 hours. After cooling the system to room temperature, petroleum ether was added, resulting in a large amount of solid. The mixture was filtered, and the filter cake was washed with petroleum ether and dried to obtain 2.55 g of solid T-54 (91%). MS (ESI, m / z): 391.2 [M+H] + .

[0260] CG204-62:

[0261] T-54 (1.95 g, 5 mmol) and T-52 (2.07 g, 5 mmol) were mixed and dissolved in THF (50 mL). The mixture was cooled to -10 °C, and NaHMDS (1.50 mL, 1.0 M) was slowly added under nitrogen protection. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 10 hours. Then, 0.01 M ammonium chloride solution (30 mL) was added on ice, followed by ethyl acetate (50 mL). After thorough stirring, the mixture separated into layers. The separated organic phase was concentrated, and the residue was subjected to column chromatography. 0.99 g of intermediate CG204-62 (37%) was isolated. MS (ESI, m / z): 536.2 [M+H]+, NMR (400 MHz): 8.58 (d, 1H), 8.07 (dd, 2H), 7.23-7.11 (m, 5H), 5.82 (t, 1H), 4.18 (d, 1H), 3.61-3.39 (m, 5H), 3.03 (m, 1H), 2.04-1.68 (m, 8H).

[0262] Example 29: Synthesis of compound CG204-63

[0263]

[0264] CG204-63:

[0265] CG204-62 (53.52 mg, 0.1 mmol) was dissolved in anhydrous ethanol (5 mL), cooled to 0 °C, and freshly prepared sulfuric acid ethanol solution (1 mol / L, 0.1 mL) was slowly added. After the addition was complete, the mixture was stirred for 1 hour, resulting in a large amount of solid. After stirring for another 12 hours, the mixture was filtered. The filter cake was washed with anhydrous ethanol and dried to obtain 51.92 mg of white solid CG204-61 (82%). MS (ESI, m / z): 536.2 [M+H]+, NMR (400 MHz): 8.58 (d, 1H), 8.07 (dd, 2H), 7.23–7.11 (m, 5H), 5.82 (t, 1H), 4.18 (d, 1H), 3.61–3.39 (m, 5H), 3.03 (m, 1H), 2.04–1.68 (m, 8H).

[0266] The following compounds were prepared according to the methods described in the above embodiments:

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] Example 30: Compound Cytotoxicity Test

[0273] MDCK (Madin-Daby Canine Kidney Cells) cell suspension was seeded into 48-well plates at a cell density of approximately 5 × 10⁶ cells / well. 5 Cells were inoculated at a density of 10 cells / mL. The 48-well plates were incubated at 37°C for 24 hours. The original DMEM medium was replaced with fresh DMEM medium, and the appropriate drug solution (0.1M stock solution containing 0.1% DMSO for dissolution) was added to control the final drug concentration per well to 30.0 μM. Three replicates were set up for each drug-treated well. The control group was incubated with the corresponding volume of DMEM medium. The plates were incubated at 37°C for another 60 hours. After incubation in the dark, 20.0 μL of MTT solution was added to each well, and incubation continued for 3.0 hours. Then, 100 μL of DMSO was added to each well, and the absorbance (Optical Density, OD) of each well was measured at 490 nm. Cell viability (%) was calculated.

[0274] Formula 1: Cell viability (%) = (OD of drug-treated group / OD of normal group) × 100%.

[0275] The final calculation results are shown in Table 1:

[0276] Table 1: Cytotoxicity assay of compounds

[0277]

[0278] Analysis of the data in Table 1 shows that the tested compounds at a concentration of 30.0 μM did not exhibit significant toxicity to MDCK cells, with cell viability consistently above 60%. Specifically, the cell viability of MDCK cells in wells CG204-1, CG204-2, CG204-11, CG204-24, CG204-28, CG204-37, CG204-44, CG204-55, CG204-58, CG204-59, CG204-60, CG204-61, CG204-62, and CG204-63 after administration to MDEM culture medium was above 75%, while the cell viability in wells treated with retimegan sulfate was only 46.9%. These results indicate that the tested compounds have a higher expected safety profile as drugs compared to retimegan sulfate.

[0279] Example 31: Vasodilatory effect of the compound on rats

[0280] SD rats weighing 180±20g were anesthetized by intraperitoneal injection of 5.0% chloroacetaldehyde hydrate solution. The aorta was then dissected and placed in Krebs solution at 0–4℃ for 12 hours. After removing the blood, a 4.0cm long vascular ring was cut, one end of which was fixed and then immersed in a constant-temperature Krebs solution at 37.0℃. A mixture of 95% O2 and 5% CO2 was continuously introduced into the ring at a constant pH of 7.4. The other end was connected to a tension transducer, and data was synchronously transmitted to a computer database. The resting tension of the vascular ring was adjusted to 2.0g, and after equilibration, 50mM... After pre-constricting the vascular ring with KC1 solution and rebalancing for 20 minutes, 2.5 μM phenylephrine was added to further constrict the vascular ring. Once the constriction stabilized, 10.0 μM of capsazepine, a selective competitive capsaicin receptor antagonist, was added, and incubation continued for 15 minutes. Then, 10.0 μM of CGRP depletion agent capsaicin was added, and incubation continued for 15 minutes. Finally, 5.0 μM solutions of retinoic acid sulfate (positive control compound), CG204-1, CG204-2, CG204-11, CG204-24, CG204-28, CG204-37, CG204-44, CG204-55, CG204-58, CG204-59, CG204-60, CG204-61, CG204-62, and CG204-63 were added, and incubation continued for 15 minutes. Changes in vascular ring tension were continuously recorded during this period, and the recorded data are shown in Table 2.

[0281] Table 2: Vasodilatory effects of the compounds

[0282] compound concentration Vasodilatory percentage compound concentration Vasodilatory percentage Remepiride sulfate 5.0μM 29％ CG204-1 5.0μM 39％ CG204-55 5.0μM 47％ CG204-2 5.0μM 51％ CG204-58 5.0μM 52％ CG204-11 5.0μM 58％ CG204-59 5.0μM 60％ CG204-24 5.0μM 48％ CG204-60 5.0μM 47％ CG204-28 5.0μM 40％ CG204-61 5.0μM 58％ CG204-37 5.0μM 41％ CG204-62 5.0μM 46％ CG204-44 5.0μM 55％ CG204-63 5.0μM 47％

[0283] Analysis of the data in Table 2 indicates that the tested compounds exert their vasodilatory effect by promoting the release of CGRP. Compared to the positive control group, all compounds in the test group showed better vasodilatory function, with CG204-2, CG204-11, CG204-44, CG204-58, CG204-59, and CG204-61 showing particularly good results. The percentage of vasodilation was greater than 50%, which is more than 1.7 times that of the positive control group, demonstrating excellent vasodilatory function.

[0284] Example 32: Pharmacokinetic Study of the Compound in Rats

[0285] (1) Experimental method: Forty-two male SD rats weighing 180±20g were acclimatized for three days and randomly divided into 14 groups of 3 rats each. The positive control drugs Remipan sulfate, CG204-2, CG204-11, CG204-44, CG204-58, CG204-59 and CG204-61 were administered orally by gavage or intravenously, and were administered once.

[0286] Fasting for at least 12 hours before administration and 4 hours after administration is permitted, but water intake is not restricted throughout the course of treatment. The administration method and dosage are shown in Table 3.

[0287] Table 3: Compound administration routes and dosages

[0288]

[0289] (2) Experimental method: drug preparation

[0290] Preparation of oral gavage administration samples: Weigh appropriate amounts of the test sample and place them in separate reagent bottles. Add an appropriate amount of 1% methylcellulose solution to prepare the administration solution. Prepare and use immediately.

[0291] Preparation of intravenous injection sample: Weigh appropriate amounts of the test sample and place them separately in reagent bottles. Add an appropriate amount of mixed solvent (10% DMSO: 30% PEG400: 60% physiological saline for injection). Prepare the corresponding concentration of the drug solution. Before use, filter the solution through a microporous membrane in a sterile environment and place it in a sterile transfer bottle. Prepare and use immediately.

[0292] (3) Blood collection

[0293] Blood samples were collected at 0h before a single oral gavage administration, and at 0.25h, 1h, 1.5h, 2h, 2.5h, 3h, 5h, 10h, and 24h after administration.

[0294] Blood samples were collected before a single intravenous injection (0h) and at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration.

[0295] (4) Blood sample collection and processing: At each blood collection time point, about 300 μL of venous blood was collected through the rat's eyeball and placed in a heparinized centrifuge tube on an ice bath. After standing for 15 minutes, the tube was centrifuged at 4℃ / 4000 rpm for 10 minutes. 50 μL of plasma was collected, and the concentration of active drug in the plasma was measured. The main pharmacokinetic parameters were calculated based on the measured data.

[0296] The correspondence between the test sample and the analyte is shown in Table 4:

[0297] Table 4: Correspondence between test samples and assay drugs

[0298] Test sample Determination of compounds Remepiride sulfate Remegpam CG204-2 CG204-1 CG204-11 CG204-10 CG204-44 CG204-19 CG204-58 CG204-1 CG204-59 CG204-10 CG204-61 CG204-55

[0299] The calculation results are shown in Tables 5 and 6:

[0300] Table 5: Metabolic studies of compounds administered via gavage

[0301]

[0302] Table 6: Metabolism studies of compounds administered via intravenous injection

[0303]

[0304] Based on the above data analysis, the tested compounds showed the following exposure levels (AUC). last Peak plasma concentration (C) max Both CG204-2 and CG204-58 exhibited superior pharmacokinetic characteristics in terms of mean residence time (MRT). Regarding bioavailability, CG204-2, CG204-58, CG204-59, and CG204-61 showed better performance. Compared to retamipine sulfate, the compounds disclosed in this invention exhibited increased plasma concentrations and prolonged mean residence time, suggesting that the same therapeutic effect can be achieved with a lower dose.

[0305] Through the above detailed description of this patent, those skilled in the art can thoroughly understand the features of this invention, and the improvements made to this invention also fall within the scope of the appended claims.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt of formula I, or an isomer thereof: X is CH or N; R1 is hydrogen or deuterium; R2 is hydrogen, deuterium, hydroxyl, or amino; R3 is hydrogen or deuterium; R4 is C6-C 12 Aryl, or C3-C 12 heteroaryl; the aforementioned C6-C 12 Aryl, C3-C 12 The heteroaryl group may optionally be substituted with one or more hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, formaldehyde, hydroxymethyl, hydroxyethyl, methanesulfonyl, or ethanesulfonyl groups; R5 is hydrogen or deuterium; and R1, R3, and R5 are not all hydrogen at the same time. R6 is R7 is R8 is hydrogen or deuterium; R9 is hydrogen, Y1 and Y2 are each independently O or NH; R a R b Each is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or R. a R b Connected to form a ring; R c R d Each is independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or R. a R b Connected to form a ring; R 10 It is a C1-C6 alkyl, a deuterated C1-C6 alkyl, or a C1-C6 alkoxy; R 11 R 12 Each is independently hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C6-C 12 aryl, or R 11 R 12 Linked into a ring; the C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C6-C 12 The aryl group may optionally be substituted with one or more hydrogens, deuteriums, halogens, or trifluoromethyl groups.

2. The compound according to claim 1, characterized in that... The compound has the structure of Formula II as follows: The substituents in Formula II are defined as defined in Formula I.

3. The compound according to claim 1, characterized in that... The compound has the structure of Formula III as follows: The substituents in Formula III are defined as defined in Formula I.

4. The compound according to claim 1, characterized in that... The compound has the structure of Formula IV: The substituents in Formula IV are defined as defined in Formula I.

5. The compound according to claims 1 to 4, wherein the compound is selected from:

6. The compound according to claims 1 to 5 is a calcitonin gene-related peptide (CGRP) receptor antagonist.

7. A pharmaceutical composition comprising the compound of claims 1 to 5, or the compound and its isomers, and a pharmaceutically acceptable additive.

8. The compounds of claims 1-5 and the composition of claim 7 may be used to relieve and / or treat bronchial asthma, chronic obstructive pulmonary disease (COPD), pulmonary heart disease, headache, migraine, and organ pain-related diseases.

9. The composition of claim 8 relieves and / or treats asthma, chronic obstructive pulmonary disease, pulmonary heart disease, headache, migraine, organ pain-related diseases, and may be administered to humans or other mammals orally, intranasally, intraorally, over the skin, or intravenously.

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