(1, 1, 1-trichloro-2) carbamate derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a (1, 1, 1-trichloro-2) carbamate derivative as well as a preparation method and application thereof. The (1, 1, 1-trichloro-2) carbamate derivative is a compound as shown in a general formula (I), an optical isomer or a pharmaceutically acceptable salt thereof, X is selected from the following structure: Y is A selected from C1-C12 alkylene of a straight chain or a branched chain,-(CH2CH2O) n-,-(CH2) mNH-and-(CH2) p-4-7-membered nitrogen-containing lipid heterocycle. The compound synthesized by the invention is in targeted combination with Cdc20 and Hsp90 at the same time, realizes a double-target synergistic effect, shows remarkable tumor inhibition activity, and particularly has a good application prospect in the aspect of treating malignant melanoma and malignant melanoma generating drug resistance to Vemrafenib.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a (1,1,1-trichloro-2)carbamate derivative, its preparation method and application. Background Technology

[0002] Malignant melanoma (MM) is a highly malignant skin tumor characterized by rapid growth, aggressiveness, and early metastasis. In recent years, with the discovery of driver gene mutations such as BRAF, NRAS, and KIT, targeted therapy has become an important treatment for MM. Among these, targeting BRAF... V600E Mutant vemurafenib, as the first approved BRAF inhibitor, has significantly prolonged progression-free survival and overall survival in clinical practice. However, despite its significant initial efficacy, the vast majority of patients develop acquired resistance within 6 to 8 months after treatment, leading to disease relapse and severely limiting the sustainability of efficacy and its clinical application value.

[0003] Cell division cycle 20 (Cdc20) is a crucial protein regulating cell mitosis. It promotes late-stage cell progression by activating the APC / C complex and is upregulated in various tumors. Overactivation of Cdc20 can induce aneuploidy, inhibit apoptosis, and promote tumorigenesis and development. Previous studies have shown that Cdc20 inhibitors can effectively suppress the growth of drug-resistant tumors by upregulating the apoptosis regulator Bim.

[0004] Heat shock protein 90 (Hsp90) is an important molecular chaperone protein that is widely involved in the proper folding and stability of various tumor-associated proteins, including p53, Cyclin B1, Akt, and B-Raf. Hsp90 inhibitors disrupt its chaperone function, inducing the degradation of client proteins and thereby disrupting tumor cells' dependence on key signaling pathways. They have shown promising therapeutic potential, particularly in vemurafenib-resistant melanoma models.

[0005] However, existing Cdc20 inhibitors and Hsp90 inhibitors are mostly single-target drugs, which have problems such as limited efficacy, high toxicity and side effects, and difficulty in overcoming complex drug resistance mechanisms. For example, the existing technology CN 111606891 A proposes a (1,1,1-trichloro-2)carbamate derivative, with the general structural formula shown in formulas (I-III):

[0006]

[0007] However, it can only act as a Cdc20 inhibitor and cannot inhibit Hsp90. Summary of the Invention

[0008] The purpose of this invention is to provide a (1,1,1-trichloro-2)carbamate derivative that simultaneously inhibits Cdc20 and Hsp90, its preparation method, and its application.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A (1,1,1-trichloro-2)carbamate derivative, which is a compound of general formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0011]

[0012] Wherein, X is selected from the following structures:

[0013]

[0014] The Y is A is selected from straight-chain or branched C1-C12 alkylene groups, -(CH2CH2O). n -、-(CH2) m NH-, -(CH2) p -4-7 nitrogen-containing lipid heterocycles;

[0015] n is an integer from 1 to 8; m is an integer from 1 to 8; p is an integer from 1 to 4; q is an integer from 1 to 4;

[0016] B is

[0017] C is -(CH2) q -C≡C-; q is an integer from 1 to 4;

[0018] R1, R2, and R3 are independently selected from hydrogen, C1-C3 alkyl, halogen, and aniline;

[0019] R6, R7, R8, R 10 Independently selected from hydrogen and C1-C4 alkyl groups;

[0020] R4 and R5 are independently selected from hydrogen, C1-C3 alkyl, halogen, and amino.

[0021] R9 is selected from hydrogen, C1-C3 alkyl, and amide groups.

[0022] According to embodiments of the present invention, the present invention can be further optimized, and the optimized technical solution is as follows:

[0023] In one preferred embodiment, A is selected from linear or branched C1-C8 alkylene groups.

[0024] In one preferred embodiment, n is an integer from 1 to 6.

[0025] In one preferred embodiment, m is an integer from 1 to 5.

[0026] In one preferred embodiment, p is an integer from 1 to 3.

[0027] In one preferred embodiment, q is an integer from 1 to 3.

[0028] In one preferred embodiment, A is selected from -(CH2). p -Azacyclobutane, -(CH2) p -azacyclopentane, -(CH2) p -Zycyclohexane.

[0029] In one preferred embodiment, R2 is selected from hydrogen and C1-C3 alkyl groups.

[0030] In one preferred embodiment, R3 is selected from hydrogen, halogen, and C1-C3 alkyl.

[0031] In one preferred embodiment, the (1,1,1-trichloro-2)carbamate derivative is a compound of general formula (II), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0032]

[0033] Wherein, A is selected from straight-chain or branched C1-C12 alkylene groups, -(CH2CH2O). n -、-(CH2) m NH-, -(CH2) p -4-7 nitrogen-containing lipid heterocycles;

[0034] n is an integer from 1 to 8; m is an integer from 1 to 8; p is an integer from 1 to 4;

[0035] R1, R2, and R3 are independently selected from hydrogen, C1-C3 alkyl, halogen, and aniline.

[0036] In one preferred embodiment, the (1,1,1-trichloro-2)carbamate derivative is a compound, optical isomer, or pharmaceutically acceptable salt thereof represented by the following formula:

[0037]

[0038]

[0039] In one preferred embodiment, the pharmaceutically acceptable salt is a sodium salt, potassium salt, ammonium salt, lithium salt, magnesium salt, or calcium salt.

[0040] In one preferred embodiment, the compound comprises the present invention's structural formula labeled with various isotopes, such as 3H, 2H, 13C, 14C, and 18F.

[0041] Based on the same inventive concept, this invention also claims a method for preparing the (1,1,1-trichloro-2)carbamate derivative, comprising the following steps:

[0042] S1. Acylation of the amino group of raw material 1 to obtain intermediate 2; iodination at position 7 of the ring of intermediate 2 to obtain intermediate 3; nucleophilic substitution of intermediate 3 to obtain intermediate 4; removal of amide protection from intermediate 4 to obtain intermediate 5; Sonogashira coupling of intermediate 5 to obtain intermediate 6; azide reaction of intermediate 6 to obtain intermediate 7.

[0043]

[0044] S2, raw material 8 is dehydrated and condensed to obtain intermediate 9; intermediate 9 is ammonified with chloride to obtain intermediate 10; raw material 11 is reacted with p-nitrophenyl chloroformate to obtain intermediate 12, which is further reacted with intermediate 10 to obtain intermediate 13;

[0045]

[0046] S3, intermediate 13 and intermediate 7 undergo a Click reaction to obtain the (1,1,1-trichloro-2)carbamate derivative;

[0047]

[0048] Based on the same inventive concept, this invention also claims another method for preparing the (1,1,1-trichloro-2)carbamate derivative, comprising the following steps:

[0049] S1. Acylation of the amino group of raw material 1 to obtain intermediate 2; iodination at position 7 of the ring of intermediate 2 to obtain intermediate 3; nucleophilic substitution of intermediate 3 to obtain intermediate 4; removal of amide protection from intermediate 4 to obtain intermediate 5; Sonogashira coupling of intermediate 5 to obtain intermediate 6; azide reaction of intermediate 6 to obtain intermediate 7.

[0050]

[0051] S4. Raw material 8 is dehydrated and condensed to obtain intermediate 9; intermediate 9 is ammonified with chloride to obtain intermediate 10; raw material 14 reacts with p-nitrophenyl chloroformate to obtain intermediate 15; intermediate 15 reacts with intermediate 10 to obtain intermediate 16; intermediate 16 is deprotected by the Boc protecting group and then undergoes a substitution reaction to generate intermediate 13.

[0052]

[0053] S3, intermediate 13 and intermediate 7 undergo a Click reaction to obtain the (1,1,1-trichloro-2)carbamate derivative;

[0054]

[0055] Based on the same inventive concept, the present invention also claims the use of the (1,1,1-trichloro-2)carbamate derivative in the preparation of a Cdc20 / Hsp90 dual-target inhibitor.

[0056] Based on the same inventive concept, the present invention also claims the use of the (1,1,1-trichloro-2)carbamate derivative in the preparation of a medicament for treating malignant melanoma.

[0057] Based on the same inventive concept, the present invention also claims the use of the (1,1,1-trichloro-2)carbamate derivative in the preparation of a medicament for treating vemurafenib-resistant malignant melanoma.

[0058] In one preferred embodiment, the medicament for treating malignant melanoma further includes other pharmaceutically available active ingredients.

[0059] In one preferred embodiment, the other pharmaceutically available active ingredient is vemurafenib.

[0060] Based on the same inventive concept, the present invention also claims a pharmaceutical composition comprising the (1,1,1-trichloro-2)carbamate derivative and a pharmaceutically acceptable carrier or excipient.

[0061] In one preferred embodiment, the pharmaceutical composition further includes other pharmaceutically available active ingredients.

[0062] In one preferred embodiment, the other pharmaceutically available active ingredient is vemurafenib.

[0063] In one preferred embodiment, pharmaceutically acceptable excipients include one or more of solvents, diluents, liquid excipients, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants.

[0064] In one preferred embodiment, the dosage form of the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray.

[0065] In one preferred embodiment, the pharmaceutical composition can be administered by any suitable means, and can be given to humans or other animals orally, rectally, parenterally, intracerebrospinal, vaginally, intraperitoneally, or locally, depending on the severity of the disease.

[0066] Compared with the prior art, the beneficial effects of the present invention are:

[0067] 1. The compound synthesized in this invention simultaneously targets and binds to Cdc20 and Hsp90, achieving a dual-target synergistic effect and enhancing the therapeutic effect;

[0068] 2. The compounds synthesized in this invention exhibit significant tumor-suppressive activity, and show promising application prospects, especially in the treatment of malignant melanoma and malignant melanoma resistant to vemurafenib. Attached Figure Description

[0069] Figure 1 This refers to the binding affinity between the compound in Example 24 of this invention and Cdc20 and Hsp90; wherein, Figure 1 A is the equilibrium dissociation constant K between Apcin and Cdc20. D Value curve graph; Figure 1 B is the equilibrium dissociation constant K between 18h and Cdc20. D Value curve graph; Figure 1 C is the equilibrium dissociation constant K between 18l and Cdc20. D Value curve graph; Figure 1 D is the equilibrium dissociation constant K between 18h and Hsp90. D Value curve graph; Figure 1 E is the equilibrium dissociation constant K between 18l and Hsp90. D Value curve graph.

[0070] Figure 2 This is a pharmacodynamic study of the compound in Example 25 of this invention on A375 cells and a vemurafenib-resistant A375 cell subcutaneous xenograft model; wherein, Figure 2 A is a tumor tissue diagram at the end of the experiment in the A375 cell subcutaneous xenograft tumor model. Figure 2 B is a graph showing the change in tumor volume in mice during treatment in the A375 cell subcutaneous xenograft tumor model. Figure 2 C is a dot plot of tumor tissue weight at the end of the experiment in the A375 cell subcutaneous xenograft tumor model. Figure 2 D represents the tumor growth inhibition rate in each group of the A375 cell subcutaneous xenograft tumor model. Figure 2 E is a tumor tissue diagram at the end of the experiment in a vemurafenib-resistant A375 cell subcutaneous xenograft model. Figure 2 F is a graph showing the change in tumor volume in mice during treatment in a vemurafenib-resistant A375 cell subcutaneous xenograft tumor model. Figure 2 G is a dot plot of tumor tissue weight at the end of the experiment in a vemurafenib-resistant A375 cell subcutaneous xenograft tumor model. Figure 2 H represents the tumor growth inhibition rate in each group of the vemurafenib-resistant A375 cell subcutaneous xenograft model. Detailed Implementation

[0071] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0072] In this invention, "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0073] When "alkyl" in this invention is used as a group or part of a group, it refers to a straight-chain or branched aliphatic hydrocarbon group. Preferably, alkyl groups are C1-C14 alkyl groups; more preferably, C1-C10 alkyl groups; and most preferably, C1-C4 alkyl groups, unless otherwise specified. Examples of straight-chain or branched C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl.

[0074] Examples of straight-chain or branched C1-C4 alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, 2-propyl.

[0075] "Alicyclic heterocyclic rings" refer to carbon rings that are saturated or partially saturated, including monocyclic, fused, or spirocyclic rings. Rings consisting of 3-9 carbon atoms are preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0076] "Alicyclic heterocycle" refers to a group formed by replacing one or more (preferably 1, 2, or 3) carbon atoms in a "cycloalkyl" group as defined above with oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur atoms (preferably oxygen, sulfur, or nitrogen). It preferably contains 1-3 heteroatoms. The preferred ring is a 3-14 membered ring (i.e., a 3-14 membered heterocyclic alkyl), and more preferably a 4-7 membered ring (i.e., a 4-7 membered heterocyclic alkyl). Heterocyclic alkyl groups include, but are not limited to: pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, dihydropyrazolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, oxocyclopropyl, azirropropyl, or 2-pyrazolinyl, as well as lactams, lactones, cyclic imines, and cyclic anhydrides. Heterocyclic alkyl groups may be substituted with one or more substituents.

[0077] A spirocyclic group is a shared atom that has at least one atom that is a bicyclic atom.

[0078] The compounds of this invention can be used alone or in combination with one or more other drugs; or in combination with surgery or radiotherapy; or formulated into a specific dosage form with pharmaceutically acceptable carriers, diluents, or excipients for administration. The specific dosage form depends on the route of administration.

[0079] Compounds represented by general formula (I) can be synthesized using the synthetic routes and methods discussed below. The raw materials used are readily available. However, the synthetic routes and methods used in this invention can be widely applied to the synthesis of similar compounds, requiring only a change in the starting materials. For example, the synthesis of compounds not described in detail in the examples herein can be achieved by simply replacing the starting materials with those of the corresponding target compound, and, based on common chemical knowledge, slightly altering the reaction conditions if necessary.

[0080] The reagents for each specific embodiment can be prepared using the reaction pathways or synthetic flowcharts described below. The preparation of specific compounds in each embodiment is detailed in the following examples. However, those skilled in the art will recognize that the described chemical reactions are applicable to the preparation of many other compounds in different embodiments. For example, the synthesis of non-example compounds can be successfully carried out with modifications readily apparent to those skilled in the art, or by changing to other suitable reagents known in the art. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1981. Other reactions disclosed herein or known in the art may be considered suitable for the preparation of other compounds in each embodiment.

[0081] The reagents that can be used to synthesize compounds can be obtained or prepared according to techniques known in this art.

[0082] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius.

[0083] All starting materials and reagents were commercially available. Suppliers included, but were not limited to, Aldrich Chemical Company and Lancaster Synthesis Ltd. Commercially available materials and reagents were used directly without further purification unless otherwise specified.

[0084] Glassware was dried in an oven and / or heated. The reaction was tracked on glass silica gel-60F254 plates (0.25 mm) (TLC). Analytical thin-layer chromatography was performed with appropriate solvent ratios (v / v). The reaction endpoint was defined as the depletion of the starting material on TLC.

[0085] Typically, the subsequent treatment involves doubling the volume of the reaction solution using the solvent used in the reaction, followed by three extractions with 25% of the total volume of extraction solvent, unless otherwise specified. The product extract is dehydrated with anhydrous sodium sulfate, filtered, and then evaporated under reduced pressure on a rotary evaporator, taking care to remove the solvent under vacuum. Finally, the target compound is obtained by rapid column chromatography (J. Org. Chem., 1978; 43: 2923).

[0086] 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Chloroform (7.25 ppm) or tetramethylsilane (0.00 ppm) was used as the reference standard. Other commonly used NMR solvents may also be used if necessary. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0087] Mass spectrometry was performed using LC / MS, with ionization methods including ESI or APCI. All melting points were uncorrected.

[0088] The examples below are merely illustrative of the synthetic methods for the specific compounds invented. There are no limitations on the synthetic methods used. Compounds not listed below can also be prepared using the same synthetic routes and methods, by selecting appropriate starting materials and making minor adjustments to the reaction conditions where necessary.

[0089] The preparation method of the compound of the present invention is as follows:

[0090] The preparation of intermediate 9 of the S1 and Hsp90 ligands is carried out according to Scheme 1: after acylation of the amino group of starting material 1 to obtain intermediate 2, intermediate 3 is obtained by iodination at the 7-position of the ring; intermediate 3 undergoes nucleophilic substitution with chloromethylpyridine to obtain intermediate 4, and the amide protection is removed to obtain intermediate 5; intermediate 5 is coupled with 3-butynediol p-toluenesulfonic acid via Sonogashira coupling to obtain intermediate 6, and further undergoes azidation to obtain intermediate 7.

[0091]

[0092] Option 1: Preparation of Intermediate 7. The reaction reagents and conditions are as follows:

[0093] (i) Trimethylacetyl chloride (PivCl) and pyridine, reacted overnight at room temperature;

[0094] (ii) N-iodosuccinimide (NIS), tetrahydrofuran (THF), room temperature, 1 hour;

[0095] (iii) Chloromethylpyridine, potassium carbonate (K2CO3), dimethylformamide (DMF), room temperature, 24 hours;

[0096] (iv) Zinc chloride (ZnCl2), ethanol-water (EtOH-H2O), 80℃, 20 hours;

[0097] (v) 3-Butynyl p-toluenesulfonate, triphenylphosphine (PPh3), palladium on carbon (Pd / C), cuprous iodide (CuI), potassium carbonate (K2CO3), DMF-water, 75°C, 3 hours;

[0098] (vi) Sodium azide (NaN3), DMF, 60℃, 3 hours.

[0099] The preparation of intermediate 10 of S2 and Cdc20 ligands was carried out according to Scheme 2: after the dehydration condensation of raw material 8 with hydrated chloral to obtain intermediate 9, intermediate 10 was obtained by ammoniation with chloride.

[0100]

[0101] Option 2: Preparation of Intermediate 10. The reaction reagents and conditions are as follows:

[0102] (i) Chloral hydrate, 90°C, reaction for 4 hours;

[0103] (ii) ① Thionyl chloride (SOCl2), dichloromethane (DCM), room temperature, reaction for 3 hours; ② Ammonia water (NH3·H2O), 0℃.

[0104] The preparation of S3, Cdc20 / Hsp90 dual-targeting compound 18 was carried out according to Scheme 3: Starting materials 11a-n reacted with p-nitrophenyl chloroformate to obtain intermediates 12a-n, which were further reacted with intermediates 10a or 10b to obtain intermediates 13a-n. Starting material 14o-u reacted with p-nitrophenyl chloroformate to obtain intermediate 15o-u, which was further reacted with intermediate 10b to obtain intermediate 16o-u; intermediate 16o-u was deprotected with dilute hydrochloric acid and then reacted with 3-bromopropyne to generate intermediate 13o-u. Intermediate 13a-u was subjected to a Click reaction with intermediate 7 obtained from Scheme 1 to obtain the target compound 18a-u of the example.

[0105]

[0106] Option 3: Preparation of Cdc20 / Hsp90 dual-targeting compound 18. The reaction reagents and conditions are as follows:

[0107] (i) p-Nitrophenyl chloroformate, triethylamine (Et3N), dichloromethane (DCM), room temperature, reaction for 4 hours;

[0108] (ii) Intermediate 10,3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), dimethylformamide (DMF), N,N-diisopropylethylamine (DIPEA), reacted at 40°C for 8 hours;

[0109] (iii) Methanol (MeOH), hydrochloric acid (HCl), 40℃, reaction for 4 hours;

[0110] (iv) 3-Bromopropyne, triethylamine (Et3N), dimethylformamide (DMF), room temperature, reaction for 1.5 hours;

[0111] (v) Intermediate 13, sodium ascorbate, copper sulfate pentahydrate (CuSO4·5H2O), dioxane-water (dioxane-H2O), 50℃, reaction for 30 minutes.

[0112] The preparation process of the intermediate product is as follows:

[0113] Preparation of intermediate 2 (N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropionamide): Starting material 1 (29.66 mmol) was added to pyridine (30 mL) and dissolved. Trimethylacetyl chloride (PivCl, 88.98 mmol) was then added, and the mixture was stirred overnight at room temperature for approximately 9 hours. The reaction was detected by thin-layer chromatography using MeOH / CH2Cl2 (1:30) as the developing solvent. The mixture was concentrated by rotary evaporation. A 1:4 mixture of NH3 / MeOH was added, and the mixture was stirred at room temperature for 30 min. The resulting mixture was washed with water (3 × 20 mL) and filtered under reduced pressure to give a yellow solid compound in 80% yield. 1 H NMR (500MHz, DMSO-d6) δ12.34(s,1H),10.05(s,1H),7.55(dd,J=3.6,2.3Hz,1H),6.53(dd,J=3.5,1.8Hz,1H),1.23(s,9H).

[0114] Preparation of intermediate 3 (N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropionamide): Intermediate 2 (7.91 mmol) and N-iodosuccinimide (NIS, 9.51 mmol) were dissolved in THF (25 mL) and stirred under N2 protection at room temperature. After 1 h, the reaction was detected by thin-layer chromatography with EtOAc / PE (1:2) as the developing solvent. The mixture was diluted with water (50 mL), and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The dichloromethane layers were combined and dried over anhydrous sodium sulfate. The filtrate was filtered under reduced pressure and concentrated by rotary evaporation. Then, methanol (20 mL) was added, and the mixture was filtered under reduced pressure and washed with methanol (3 × 10 mL) to give a white solid compound in 61% yield. 1 H NMR (500MHz, DMSO-d6) δ12.71 (s, 1H), 10.13 (s, 1H), 7.78 (d, J = 2.4Hz, 1H), 1.23 (s, 9H).

[0115] Preparation of intermediate 4 (N-[4-chloro-5-iodo-7-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-2,2-dimethylpropionamide): Intermediate 3 (2.64 mmol), chloromethylpyridine (2.90 mmol), and potassium carbonate (7.96 mmol) were dissolved in DMF (8 mL) and stirred at room temperature. After 24 h, the reaction was detected by thin-layer chromatography, with EtOAc / PE (1:2) as the developing solvent. The mixture was diluted with water (50 mL) and extracted from the aqueous layer with dichloromethane (3 × 30 mL). The dichloromethane layer was dried over anhydrous sodium sulfate. After filtration under reduced pressure, the solution was concentrated by rotary evaporation. Purification was performed using a 200-300 mesh silica gel column with EtOAc / PE (1:4) as the mobile phase to give a white powder compound in 80% yield. 1 H NMR (500MHz, DMSO-d6) δ10.14(s,1H),8.05(s,1H),7.72(s,1H),5.46(s,2H),3.73(s,3H),2.32(s,3H),2.15(s,3H),1.20(s,9H).

[0116] Preparation of intermediate 5 (4-chloro-5-iodo-7-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine): Intermediate 5 (2.84 mmol) was dissolved in H₂O / EtOH (1:20, 21 mL), and then zinc chloride (14.23 mmol) was added. The mixture was refluxed at 80 °C. After 20 h, the reaction was monitored by thin-layer chromatography using EtOAc / PE (1:2) as the developing solvent. The mixture was diluted with water (50 mL) and stirred. After filtration under reduced pressure, a white solid compound was given in 88% yield. 1 H NMR (500MHz, DMSO-d6) δ8.06(s,1H),7.26(s,1H),6.73(s,2H),5.28(s,2H),3.72(s,3H),2.25(s,3H),2.16(s,3H).

[0117] Preparation of intermediate 6 (4-[2-amino-4-chloro-7-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]but-3-yn-1-yl 4-methylbenzenesulfonate): Intermediate 5 (1.13 mmol), cuprous iodide (0.12 mmol), PPh3 (0.46 mmol), Pd-C (10%), and potassium carbonate (1.24 mmol) were dissolved in H2O / DMF (1:3, 16 mL). After degassing under N2 protection, the mixture was reacted at 75 °C, and then 3-butynediol p-toluenesulfonate (1.69 mmol) dissolved in DMF (2 mL) was slowly added dropwise. After 3 h, the reaction was detected by thin-layer chromatography using EtOAc / PE (1:1) as the developing solvent. Dilute with water (50 mL) and extract with EtOAc (3 × 20 mL). Assemble the EtOAc layers, dry on anhydrous sodium sulfate, and filter under reduced pressure. Concentrate the filtrate by rotary evaporation to obtain the crude product. Purify by 200-300 mesh silica gel column chromatography with EtOAc / PE (1:2) as the mobile phase to give a white solid compound in 60% yield. 1 H NMR(500MHz,DMSO-d6)δ8.08(s,1H),7.79(d,J=8.3Hz,2H),7.41(d,J=8.0Hz,2H),7.27(s,1H),6.73(s,2H),5 .30(s,2H),4.13(t,J=6.1Hz,2H),3.73(s,3H),2.77(t,J=6.1Hz,2H),2.32(s,3H),2.26(s,3H),2.16(s,3H).

[0118] Preparation of intermediate 7 (5-(4-azidobut-1-yn-1-yl)-4-chloro-7-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine}): Intermediate 6 (0.91 mmol) was dissolved in DMF (8 mL), and then sodium azide (2.74 mmol) was added. The reaction was carried out at 60 °C. After 3 h, the mixture was monitored by thin-layer chromatography. The developing solvent was EtOAc / PE (1:1). The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 20 mL). The EtOAc layers were assembled, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The mixture was concentrated by rotary evaporation to give the crude product. Purification was carried out using a 200-300 mesh silica gel column with EtOAc / PE (1:2) as the mobile phase to give a white solid compound in 97% yield. 1H NMR(500MHz,DMSO-d6)δ8.06(s,1H),7.28(s,1H),6.72(s,2H),5.28(s,2H),3.7 3(s,3H),3.50(t,J=6.5Hz,2H),2.72(t,J=6.5Hz,2H),2.25(s,3H),2.16(s,3H).

[0119] Preparation of intermediate 10b (2,2,2-trichloro-N-(pyrimidin-2-yl)ethane-1,1-diamine): Chloral hydrate (937.11 mmol) was dissolved and stirred at 60 °C, then 2-aminopyrimidine (8b, 126.18 mmol) was added, and the temperature was raised to 90 °C and refluxed. After 4 h, the reaction was detected by thin-layer chromatography with EtOAc / PE (1:1) as the developing solvent. The mixture was concentrated by rotary evaporation, ethyl acetate (50 mL) was added, sonicated, and filtered under reduced pressure to obtain intermediate 9b as a white solid. Intermediate 9b (40.90 mmol) was dissolved in dichloromethane (100 mL), then thionyl chloride (122.7 mmol) was slowly added, and the mixture was stirred at room temperature. After 3 h, the reaction was detected by thin-layer chromatography with EtOAc / PE (1:1) as the developing solvent. Thionyl chloride was removed by rotary evaporation and concentration, followed by the addition of dichloromethane (50 mL) to obtain a white suspension. The suspension was slowly added to ammonia water (100 mL) in an ice-water bath while stirring the mixture. After addition, thin-layer chromatography was performed using EtOAc / PE (1:1) as the developing solvent. The mixture was diluted with water (50 mL), and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The organic layer was dried over anhydrous sodium sulfate. After vacuum dilution and concentration, rotary evaporation, and filtration, intermediate 10b was obtained as a white solid in 92% yield. 1 H NMR (500MHz, DMSO-d6) δ 8.37 (d, J = 4.8 Hz, 2H), 7.51 (d, J = 9.0 Hz, 1H), 6.73 (t, J = 4.8 Hz, 1H), 5.68 (q, J = 7.8 Hz, 1H), 2.73 (d, J = 7.6 Hz, 2H).

[0120] Intermediate 10a (6-chloro-N) 2 -(1-Amino-2,2,2-trichloroethyl)-N 4 Preparation of (-phenylpyrimidine-2,4-diamine): Following the preparation method of 10b (reaction carried out at the same molar ratio, hereinafter the same), 8a was used as the starting material. White solid, yield 52%. 1H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 7.64 (s, 2H), 7.31 (t, J=7.7Hz, 2H), 7.03 (t, J= 7.4Hz, 1H), 6.13 (s, 1H), 5.76 (s, 1H), 5.57 (d, J = 8.7Hz, 1H), 2.72 (d, J = 8.3Hz, 2H).

[0121] Preparation of intermediate 13a (but-3-yn-1-yl(2,2,2-trichloro-1-{[4-chloro-6-(anilino)pyrimidin-2-yl]amino}ethyl)carbamate): Starting material 11a (6.94 mmol) was dissolved in dichloromethane (15 mL), and then Et3N (1 mL, 7.19 mmol) was added. The mixture was stirred at room temperature. p-Nitrophenyl chloroformate (7.45 mmol) dissolved in dichloromethane (2 mL) was slowly added to the mixture. After 4 h, the reaction was detected by thin-layer chromatography using EtOAc / PE (1:2) as the developing solvent. The mixture was diluted with water (50 mL), and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The dichloromethane layer was dried over anhydrous sodium sulfate. After filtration under reduced pressure, the solution was concentrated by rotary evaporation to obtain a yellow oily intermediate 12a. Intermediate 12a (5.50 mmol), intermediate 10a (4.14 mmol), and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt, 6.18 mmol) were dissolved in DMF (40 mL) and DIPEA (1.5 mL, 8.61 mmol). The reaction was carried out at 40 °C for 8 h, and the reaction was monitored by thin-layer chromatography using EtOAc / PE (1:1) as the developing solvent. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 20 mL). The EtOAc layers were assembled, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The mixture was concentrated by rotary evaporation to give the crude product. Purification was performed using a 200-300 mesh silica gel column with EtOAc / PE (1:10) as the mobile phase to give compound 13a. It was a white solid in 63% yield. 1 H NMR (500MHz, DMSO-d6) δ9.66(s,1H),7.90(s,1H),7.67(d,J=8.0Hz,2H),7.32(t,J=7.7Hz,2H),7.05(t,J=7.4 Hz,1H),6.61(d,J=54.8Hz,1H),6.21(s,1H),4.09(t,J=6.6Hz,2H),2.85(t,J=2.8Hz,1H),2.77–2.51(m,2H).

[0122] The preparation of the following intermediates follows the same method as described in 13a, except for the different types of raw materials. For example, the molar ratio of the raw materials is the same, and the preparation process is identical.

[0123] Preparation of intermediate 13b (pentano-4-yn-1-yl(2,2,2-trichloro-1-{[4-chloro-6-(anilino)pyrimidin-2-yl]amino}ethyl)carbamate): obtained from 11b using the same method as 13a. White solid, yield 59%. 1 HNMR(500MHz,DMSO-d6)δ9.65(s,1H),7.81(s,1H),7.67(d,J=7.9Hz,2H),7.38(s,1H),7.32(t,J=7.8Hz,2H),7.04(t, J=7.4Hz,1H),6.66(s,1H),6.21(s,1H),4.08(t,J=6.5Hz,2H),2.80(t,1H),2.22(d,J=7.7Hz,2H),1.83–1.66(m,2H).

[0124] Preparation of intermediate 13c (hexane-5-yn-1-yl(2,2,2-trichloro-1-{[4-chloro-6-(anilino)pyrimidin-2-yl]amino}ethyl)carbamate): obtained from 11c using the same method as 13a. White solid, yield 66%. 1 HNMR(400MHz,DMSO-d6)δ9.61(s,1H),7.81(s,1H),7.67(d,J=7.4Hz,2H),7.39–7.30(m,3H),6.16(s,1H),6.00(s,1 H), 4.39 (t, J = 6.4Hz, 2H), 2.81 (t, J = 2.7Hz, 1H), 2.25 (td, J = 7.0, 2.7Hz, 2H), 1.88–1.79 (m, 2H), 1.65–1.55 (m, 2H).

[0125] Preparation of intermediate 13d (hept-6-yn-1-yl(2,2,2-trichloro-1-{[4-chloro-6-(anilino)pyrimidin-2-yl]amino}ethyl)carbamate): Obtained using 11d as a starting material, following the preparation method of 13a. White solid, yield 61%. 1HNMR(400MHz, DMSO-d6)δ9.62(s,1H),7.90(d,J=7.9Hz,1H),7.69(s,2H),7.33(d,J=6.1Hz,3H),6.17–6.16(m,1H),6 .00(s,1H),4.36(t,J=6.5Hz,2H),2.76(t,J=2.8Hz,1H),2.21–2.16(m,2H),1.76(t,J=6.8Hz,2H),1.54–1.46(m,4H).

[0126] Preparation of intermediate 13e (but-3-yn-1-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Following the preparation method of 13a, using 11e as the starting material, the intermediate was reacted with intermediate 10b to obtain the product. It was a white solid, with a yield of 71%. 1 H NMR (500MHz, DMSO-d6) δ8.44(d,J=4.7Hz,2H),7.97(d,J=8.9Hz,1H),7.10(d,J=9.6Hz,1H),6.84(t, J=4.8Hz,1H),6.68(t,J=9.2Hz,1H),4.08(t,J=6.5Hz,2H),2.86(t,J=2.6Hz,1H),2.49–2.46(m,2H).

[0127] Preparation of intermediate 13f (pentan-4-yn-1-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11f as a starting material, following the preparation method for 13e. White solid, yield 65%. 1 H NMR (500MHz, DMSO-d6) δ8.44(d,J=4.9Hz,2H),7.91(d,J=9.0Hz,1H),7.21(d,J=9.6Hz,1H),6.84(t,J=4.8Hz,1H), 6.71(t,J=9.3Hz,1H), 4.09(t,J=6.4Hz,2H), 2.79(t,J=2.6Hz,1H), 2.24(dt,J=7.2,3.6Hz,2H), 1.78–1.73(m,2H).

[0128] Preparation of intermediate 13g (hexane-5-yn-1-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained from 11g of intermediate using the same method as 13e. White solid, yield 63%. 1H NMR(500MHz,Chloroform-d)δ8.40(d,J=4.9Hz,2H),6.82(t,1H),6.74(t,J=4.9Hz,1H),5.95(d,1H),5.60(d,1H),4. 16(dd,J=12.7,6.3Hz,2H),2.22(td,J=7.0,2.6Hz,2H),1.95(t,J=2.6Hz,1H),1.81–1.72(m,2H),1.65–1.57(m,2H).

[0129] Preparation of intermediate 13h (hepta-6-yn-1-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11h as the starting material, following the preparation method of 13e. White solid, yield 56%. 1 H NMR(500MHz,Chloroform-d)δ8.39(d,J=4.9Hz,2H),6.83(t,J=9.7Hz,1H),6.74(t,J=4.8Hz,1H),5.91(d,1H),5.60(d,1H),4.15(tq,J =10.9,5.9,3.9Hz,2H),2.19(td,J=6.9,2.7Hz,2H),1.94(t,J=2.7Hz,1H),1.65(p,J=6.8Hz,2H),1.58–1.51(m,2H),1.51–1.42(m,2H).

[0130] Preparation of intermediate 13i (oct-7-yn-1-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11i as the starting material, following the preparation method for 13e. White solid, yield 62%. 1 H NMR(500MHz,Chloroform-d)δ8.39(d,J=4.8Hz,2H),6.82(t,1H),6.74(t,J=4.8Hz,1H),5.89(d,1H),5.59(d,1H),4.19– 4.08(m,2H),2.18(td,J=7.0,2.6Hz,2H),1.94(t,J=2.6Hz,1H),1.69–1.61(m,2H),1.57–1.47(m,2H),1.47–1.31(m,4H).

[0131] Preparation of intermediate 13j (non-8-yn-1-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11j as the starting material, following the preparation method of 13e. White solid, yield 53%. 1H NMR(500MHz,Chloroform-d)δ8.39(d,J=4.9Hz,2H),6.82(t,1H),6.74(t,J=4.8Hz,1H),5.91(d,J=9.6Hz,1H),5.65–5.54(d,1H),4.19–4.08( m,2H),2.18(td,J=7.1,2.6Hz,2H),1.94(t,J=2.7Hz,1H),1.62(q,J=6.9Hz,2H),1.51(p,J=7.1Hz,2H),1.44–1.36(m,2H),1.36–1.28(m,4H).

[0132] Preparation of intermediate 13k (2-(prop-2-yn-1-oxy)ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11k as the starting material, following the preparation method for 13e. White solid, yield 61%. 1 H NMR(500MHz,Chloroform-d)δ8.38(d,J=4.8Hz,2H),6.82(t,J=9.5Hz,1H),6.72(t,J=4.8Hz,1 H), 6.03–5.95 (m, 2H), 4.31 (t, 2H), 4.18 (d, J = 2.4Hz, 2H), 3.73 (t, 2H), 2.43 (t, J = 2.4Hz, 1H).

[0133] Preparation of intermediate 13l (2-(2-(prop-2-yn-1-oxy)ethoxy)ethyl (2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11l as a starting material, following the preparation method of 13e. White solid, yield 45%. 1 H NMR(500MHz,Chloroform-d)δ8.38(d,J=4.8Hz,2H),6.82(t,J=9.6Hz,1H),6.72(t,J=4.8Hz,1H),5.91(d,J=9.7Hz, 1H), 5.82 (d, J=14.2, 9.8Hz, 1H), 4.31–4.28 (m, 2H), 4.18 (d, J=2.4Hz, 2H), 3.71–3.66 (m, 6H), 2.43 (t, J=2.4Hz, 1H).

[0134] Preparation of intermediate 13m (2-[2-[2-(prop-2-yn-1-oxy)ethoxy]ethoxy]ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11m as a starting material, following the preparation method for 13e. White solid, yield 41%.1 H NMR(500MHz,Chloroform-d)δ8.41(d,J=4.7Hz,2H),6.84(t,1H),6.77(t,1H),5.95(d, 1H), 5.81 (d, 1H), 4.30 (t, J = 3.4Hz, 5H), 4.21 (d, 2H), 3.71–3.70 (m, 10H), 2.43 (t, 1H).

[0135] Preparation of intermediate 13n (3,6,9,12-tetraoxopentadecane-14-yn-1-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 11n as the starting material, following the preparation method for 13e. White solid, yield 44%. 1 H NMR(500MHz,Chloroform-d)δ8.37(d,J=4.9Hz,2H),6.82(t,J=9.6Hz,1H),6.70(t,J=4.8Hz,1H),6.13–6 .02(m,2H),4.27(dd,J=5.8,3.4Hz,2H),4.19(d,J=2.4Hz,2H),3.72–3.62(m,14H),2.43(t,J=2.4Hz,1H).

[0136] Preparation of intermediate 13o (2-(prop-2-yn-1-ylamino)ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Following the preparation method of 13o, intermediate 16o was obtained from 14o as the starting material. Intermediate 16o (2.33 mmol) was dissolved in MeOH (20 mL), and then HCl (10 mL, 4 mol / L) was added, and the reaction was carried out at 40 °C. After 4 h, the reaction was monitored by TLC, with CH2Cl2 / MeOH (10:1) as the developing solvent. The pH was adjusted to 7.0-8.0 with NaHCO3. After rotary evaporation and concentration, EtOAc (10 mL) was added, followed by sonication and filtration under reduced pressure. The filtrate was concentrated by rotary evaporation to obtain a white solid intermediate 17o. 3-Bromopropyne (1.89 mmol) and Et3N (2.28 mmol) were dissolved in DMF (5 mL), and then intermediate 17o (1.52 mmol) was added and stirred at room temperature. After 1.5 h, the reaction was monitored by TLC with CH2Cl2 / MeOH (1:10) as the developing solvent. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The EtOAc layers were combined, dried over anhydrous Na2SO4, and filtered under reduced pressure. The mixture was concentrated by rotary evaporation to give the crude product. It was purified by 200-300 mesh silica gel column chromatography with MeOH / CH2Cl2 (1:20) as the mobile phase to give intermediate 13o. The purified product was a pale yellow oily compound with an overall yield (based on starting material 14o) of 20%. 1 HNMR(500MHz,Chloroform-d)δ8.39(d,J=4.9Hz,2H),6.82–6.71(m,2H),5.95(d,J=9.9Hz,2H ), 4.27 (t, J = 5.3Hz, 2H), 3.47 (d, J = 2.5Hz, 2H), 2.99 (d, J = 5.3Hz, 2H), 2.24 (t, J = 2.4Hz, 1H).

[0137] Preparation of intermediate 13p (3-(prop-2-yn-1-ylamino)propyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 14p as the starting material, following the same method as for 13o. A pale yellow oily compound, with an overall yield (based on 14p) of 26%. 1 H NMR (400MHz, DMSO-d6) δ8.44(d,2H),7.85(d,J=9.3Hz,1H),7.16(d,J=10.4Hz,1H),6.87–6.80(m,1 H), 6.68 (t, 1H), 4.13–4.04 (m, 4H), 3.31 (s, 2H), 2.61 (t, J = 7.0Hz, 1H), 1.70 (dd, J = 8.4, 5.1Hz, 2H).

[0138] Preparation of intermediate 13q (4-(prop-2-yn-1-ylamino)butyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 14q as the starting material, following the same method as for 13o. A pale yellow oily compound, with an overall yield (based on 14q) of 22%. 1 H NMR(400MHz, DMSO-d6)δ8.43(d,J=4.8Hz,2H),7.92–7.80(m,1H),7.19(d,J=11.2Hz,1H),6.84(dd, J=6.0,3.7Hz,1H),6.69(td,J=9.5,4.9Hz,1H),4.12–3.94(m,2H),3.30(s,2H),1.83–1.33(m,4H).

[0139] Preparation of intermediate 13r ([(1-(prop-2-yn-1-yl)azacyclobutane-3-yl]methyl](2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 14r as the starting material, following the same method as for 13o. A pale yellow oily compound was obtained in 22% of the total yield (based on 14r). 1 H NMR(400MHz,Chloroform-d)δ8.38(d,J=4.8Hz,2H),6.81–6.71(m,2H),5.90(d,J=9.7Hz,2H),4.26(d,J=6.6Hz,2H),3 .45(t,J=7.6Hz,2H), 3.26(d,J=2.5Hz,2H), 3.17(t,J=6.7Hz,2H), 2.76(tt,J=7.8,5.6Hz,1H), 2.27(t,J=2.4Hz,1H).

[0140] Preparation of intermediate 13S (2-[1-(prop-2-yn-1-yl)azacyclobutan-3-yl]ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 14S as the starting material, following the same method as for 13O. A pale yellow oily compound, with an overall yield (based on 14S) of 19%. 1H NMR(400MHz,Chloroform-d)δ8.38(d,J=4.9Hz,2H),6.82–6.68(m,2H),6.07(d,J=9.7Hz,1H),5.95(d,J=9.5Hz,1H), 4.23(t,J=7.0Hz,2H), 4.14(t,J=7.2Hz,3H), 3.87–3.57(m,2H), 2.80(dd,J=13.2,6.7Hz,1H), 1.96(q,J=6.9Hz,2H).

[0141] Preparation of intermediate 13t ((1-(prop-2-yn-1-yl)piperidin-4-yl)methylcarbamate): Obtained using 14t as the starting material, following the same method as 13o. A pale yellow oily compound, with a total yield (based on 14t) of 17%. 1 H NMR(400MHz,Chloroform-d)δ8.38(d,J=4.9Hz,2H),6.83–6.72(m,2H),5.89(d,J=9.6Hz,1H),5.64(d,J=7.5Hz,1H),4.03(t,J=6.2Hz ,1H),3.32(d,J=2.5Hz,2H),2.90(s,2H),2.35–2.12(m,4H),1.73(d,J=13.2Hz,2H),1.69–1.58(m,1H),1.38(td,J=12.0,8.3Hz,2H).

[0142] Preparation of intermediate 13u (2-[1-(prop-2-yn-1-yl)piperidin-4-yl]ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate): Obtained using 14u as a starting material, following the same method as for 13o. A pale yellow oily compound, with a total yield (based on 14u) of 15%. 1 H NMR(400MHz,Chloroform-d)δ8.39(d,J=4.8Hz,2H),6.87–6.69(m,2H),5.81(d,J=9.7Hz,1H),5.58(d,1H),4.26–4.12(m,2H), 3.35–3.29(m,2H),2.89(d,J=11.2Hz,1H),2.29–2.15(m,3H),2.04(s,4H),1.59(q,J=6.5Hz,2H),1.37(dd,J=8.1,4.9Hz,2H).

[0143] Example 1

[0144] Preparation of 2-(1-[4-(2-amino-4-chloro-7-{(4-methoxy-3,5-dimethylpyridin-2-yl)methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl]-1H-1,2,3-triazol-4-yl)ethyl(2,2,2-trichloro-1-{(4-chloro-6-(phenylamino)pyrimidin-2-yl)amino}ethyl)carbamate (18a)

[0145]

[0146] Intermediate 13a (0.76 mmol), intermediate 7 (0.73 mmol), CuSO4·5H2O (0.15 mmol), and sodium L-ascorbate (0.38 mmol) were dissolved in H2O / dioxane (1:2, 13 mL) and reacted at 50 °C. After 30 minutes, the reaction was monitored by TLC with MeOH / CH2Cl2 (1:10) as the developing solvent. The mixture was rotary evaporated, EtOAc (10 mL) was added, sonicated, and filtered under reduced pressure. The filtrate was concentrated by rotary evaporation. Purification was performed using a 200-300 mesh silica gel column with MeOH / CH2Cl2 (1:50) as the mobile phase to give compound 18a as a white solid. The product was a pale yellow solid with a yield of 23% and a purity of 96.41%. 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.05(s,1H),7.99(s,1H),7.83(s,1H),7.66(d,J=8 .0Hz,2H),7.38(s,1H),7.31(t,J=7.7Hz,2H),7.24(s,1H),7.03(t,J=7.3Hz,1H),6.68( s,2H),6.61(s,1H),6.21(s,1H),5.26(s,2H),4.50(t,J=6.8Hz,2H),4.27(t,J=6.8Hz,2 H),3.72(s,3H),3.01(t,J=6.8Hz,2H),2.95(t,J=6.8Hz,2H),2.24(s,3H),2.15(s,3H). 13C NMR(126MHz,DMSO-d6)δ163.91,162.07,160.63,160.01,158.65,155.57,153 .85,153.79,152.12,149.16,146.11,139.73,131.77,129.22,125.58,123.9 6,123.32,123.20,122.44,120.69,107.86,102.84,95.13,88.01,75.69,70. 26,64.34,60.30,48.63,46.83,25.73,21.30,13.33,10.73.ESI-MS:m / z[M+H] + calcd for C 36 H 35 Cl5N 13 O3 + ,872.1428;found:872.1439.

[0147] Example 2

[0148] Preparation of 3-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]propyl(2,2,2-trichloro-1-{(4-chloro-6-(phenylamino)pyrimidin-2-yl)amino}ethyl)carbamate (18b)

[0149]

[0150] Following the preparation method of 18a, and using 13b and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 32% and a purity of 95.28%. 1H NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.05(s,1H),7.92(s,1H),7.87(s,1H),7.69(d,J=7.7Hz, 2H),7.41(d,1H),7.32(t,J=7.7Hz,2H),7.24(s,1H),7.03(t,J=7.4Hz,1H),6.69(d,J=7.5Hz, 2H),6.61(s,1H),6.23(s,1H),5.27(s,2H),4.51(t,J=6.7Hz,2H),4.14-4.02(m,2H),3.71(s, 3H),3.02(t,J=6.7Hz,2H),2.68(t,J=7.8Hz,2H),2.23(s,3H),2.14(s,3H),1.96-1.85(m,2H). 13 C NMR (126MHz, DMSO-d6) δ163.92,161.92,160.67,160.01,158.61,155.77,153. 81,153.76,152.17,149.14,146.28,139.69,131.71,129.20,125.60,124.00,1 23.29,123.20,122.49,120.68,107.91,102.90,95.20,88.09,75.66,70.32,64 .80,60.27,48.59,46.83,28.78,21.98,21.32,13.31,10.72.ESI-MS:m / z[M+H] + calcd for C 37 H 37 Cl5N 13 O3 + ,886.1585;found:886.1600.

[0151] Example 3

[0152] Preparation of 4-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]butyl(2,2,2-trichloro-1-{(4-chloro-6-(phenylamino)pyrimidin-2-yl)amino}ethyl)carbamate (18c)

[0153]

[0154] Following the preparation method of 18a, and using 13c and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 26% and a purity of 95.86%. 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.05(s,1H),7.89(s,1H),7.76(s,1H),7.67(d,J=8.0H z,2H),7.46(s,1H),7.31(t,J=7.8Hz,2H),7.23(s,1H),7.03(t,J=7.4Hz,1H),6.69(s,2H), 6.50(s,1H),6.21(s,1H),5.26(s,2H),4.49(t,J=6.8Hz,2H),4.05-3.96(m,2H),3.71(s,3H ),3.01(t,J=6.8Hz,2H),2.61(t,J=7.6Hz,2H),2.23(s,3H),2.15(s,3H),1.69-1.49(m,4H). 13 C NMR(126MHz,DMSO-d6)δ163.83,161.84,160.65,160.01,158.65,155.74,153.84 ,153.78,152.12,149.24,146.81,139.71,131.75,129.21,125.53,123.89,123. 29,123.19,122.40,120.66,107.85,102.90,95.13,88.09,75.66,70.34,65.12, 60.27,48.52,46.87,28.42,25.76,25.04,21.34,13.32,10.71.ESI-MS:m / z[M+H] + calcd for C 38 H 39 Cl5N 13 O3 + ,900.1741;found:900.1746.

[0155] Example 4

[0156] Preparation of 5-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]pentyl(2,2,2-trichloro-1-{(4-chloro-6-(phenylamino)pyrimidin-2-yl)amino}ethyl)carbamate (18d)

[0157]

[0158] Following the preparation method of 18a, and using 13d and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 19% and a purity of 97.54%. 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.05(s,1H),7.88(s,1H),7.73(s,1H),7.67(d,J=8.1H z,2H),7.39(s,1H),7.31(t,J=7.8Hz,2H),7.23(s,1H),7.03(t,J=7.5Hz,1H),6.69(s,2H), 6.58(s,1H),6.21(s,1H),5.26(s,2H),4.50(t,J=6.6Hz,2H),3.97(t,2H),3.71(s,3H),3.0 1(t,2H),2.72-2.52(m,2H),2.23(s,3H),2.15(s,3H),1.72-1.41(m,4H),1.36-1.26(m,2H). 13 C NMR(126MHz,DMSO-d6)δ163.82,161.93,160.65,160.01,158.62,155.75,153.85, 153.78,152.12,149.26,147.01,139.77,131.74,129.21,125.52,123.88,123.29, 123.21,122.34,120.66,107.85,104.94,95.13,88.10,75.66,70.30,65.33,60.27 ,48.50,46.88,29.04,28.64,25.41,25.36,21.34,13.32,10.71.ESI-MS:m / z[M+H] + calcd for C 39 H 41 Cl5N 13 O3 + ,914.1898;found:914.1904.

[0159] Example 5

[0160] Preparation of 2-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18e)

[0161]

[0162] Following the preparation method of 18a, and using 13e and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 16% and a purity of 95.18%. 1 H NMR(400MHz,DMSO-d6)δ8.42(d,J=4.8Hz,2H),8.09(s,1H),8.03-7.95(m,1H),7 .89(d,J=9.1Hz,1H),7.25(s,1H),7.14(d,J=10.0Hz,1H),6.87-6.79(m,1H),6. 76-6.67(m,3H),5.28(s,2H),4.51(t,J=6.8Hz,2H),4.26(t,J=7.0Hz,2H),3.73 (s,3H),3.01(t,J=6.7Hz,2H),2.95(t,J=7.2Hz,2H),2.25(s,3H),2.16(s,3H). 13 CNMR(126MHz,DMSO-d6)δ164.00,160.92,160.02,158.83,155.62,153.79,153.70,152.12,149.03,147.03,131.78,125.80,124.30,1 23.23,113.39,107.91,103.11,95.15,88.04,75.70,70.06,64.30,60.33,48.63,46.89,25.73,21.31,13.37,10.77.ESI-MS:m / z[M+H] + calcd for C 30 H 31 Cl4N 12 O3 + ,747.1396;found:747.1414.

[0163] Example 6

[0164] Preparation of 3-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]propyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18f)

[0165]

[0166] Following the preparation method of 18a, and using 13f and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 23% and a purity of 96.36%. 1 H NMR(400MHz,DMSO-d6)δ8.42(d,J=4.8Hz,2H),8.04(s,1H),7.94(s,1H),7.91- 7.84(m,1H),7.25(s,1H),7.21-7.13(m,1H),6.82(s,1H),6.72-6.67(m,3H),5. 28(s,2H),4.50(t,J=6.7Hz,2H),4.04(d,J=7.3Hz,2H),3.72(s,3H),3.03(t,J= 6.5Hz,2H),2.68(t,J=7.8Hz,2H),2.25(s,3H),2.16(s,3H),1.92-1.84(m,2H). 13 C NMR (126MHz, DMSO-d6) δ163.80,160.96,160.00,158.80,155.82,153.97,153.75,152.11,149.01,146.34,131.75,125.78,124.61,122.6 3,113.40,107.99,103.15,95.18,88.13,75.64,70.07,64.75,60.31,48.58,46.97,28.78,21.98,21.29,13.38,10.80.ESI-MS:m / z[M+H] + calcd for C 31 H 33 Cl4N 12 O3 + ,761.1553;found:761.1571.

[0167] Example 7

[0168] Preparation of 4-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]butyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18 g)

[0169]

[0170] Following the preparation method of 18a, using the same molar ratio, and with 13g and 7 as raw materials, a pale yellow solid was obtained, yield 25%, purity: 96.12%. 1 H NMR(500MHz,DMSO-d6)δ8.42(d,J=4.8Hz,2H),8.09(s,1H),7.90(s,1H),7.84(d,J =9.0Hz,1H),7.26(s,1H),7.15(d,J=9.5Hz,1H),6.83(t,J=4.9Hz,1H),6.73-6.66( m,3H),5.29(s,2H),4.50(t,J=6.7Hz,2H),4.06-3.94(m,2H),3.75(s,3H),3.01(t ,J=6.7Hz,2H),2.61(t,J=7.2Hz,2H),2.24(s,3H),2.17(s,3H),1.67-1.53(m,4H). 13 C NMR (126MHz, DMSO-d6) δ163.82,160.94,160.02,158.84,155.80,153.86,153.79,152.12,149.26,146.82,131.77,125.52,123.88,122.41,1 13.35,107.85,103.19,95.12,88.10,75.66,70.05,65.07,60.28,48. 52,46.88,28.44,25.77,25.05,21.34,13.32,10.71.ESI-MS:m / z[M+H] + calcd for C 32 H 35 Cl4N 12 O3 + ,775.1709;found:775.1720.

[0171] Example 8

[0172] Preparation of 5-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]pentyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18h)

[0173]

[0174] Following the preparation method of 18a, and using 13h and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 18% and a purity of 95.53%. 1 H NMR(500MHz,DMSO-d6)δ8.42(d,J=4.8Hz,2H),8.05(s,1H),7.89(s,1H),7.83(d,J=9.2Hz, 1H),7.24(s,1H),7.16(d,J=9.3Hz,1H),6.82(t,J=4.8Hz,1H),6.73-6.65(m,3H),5.26(s,2 H),4.50(t,J=6.7Hz,2H),3.97(d,J=7.1Hz,2H),3.71(s,3H),3.01(t,J=6.7Hz,2H),2.58( t,J=7.5Hz,2H),2.23(s,3H),2.15(s,3H),1.55(dq,J=14.4,7.1Hz,4H),1.34-1.30(m,2H). 13 C NMR(126MHz,DMSO-d6)δ163.84,160.93,160.00,158.79,155.81,153.81 ,153.77,152.13,149.20,147.02,131.77,125.57,123.91,122.38,113. 34,107.85,103.15,95.13,88.13,75.64,70.01,65.26,60.28,48.52,46 .85,29.03,28.64,25.40,25.36,21.33,13.32,10.70.ESI-MS:m / z[M+H] + calcd forC 33 H 37 Cl4N 12 O3 + ,789.1866;found:789.1875.

[0175] Example 9

[0176] Preparation of 6-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]hexyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18i)

[0177]

[0178] It was prepared using the same method as 18a, with 13i and 7 as raw materials. It is a pale yellow solid, 50% yield, with a purity of 95.31%. 1 H NMR(500MHz,DMSO-d6)δ8.42(d,J=4.9Hz,2H),8.10(s,1H),7.90(s,1H),7.82(d,J=9.0Hz, 1H),7.25(s,1H),7.15(d,J=9.6Hz,1H),6.82(t,J=4.8Hz,1H),6.72-6.66(m,3H),5.28(s,2 H),4.50(t,J=6.7Hz,2H),4.02-3.90(m,2H),3.74(s,3H),3.02(t,J=6.7Hz,2H),2.57(t,J= 7.5Hz,2H),2.24(s,3H),2.17(s,3H),1.51(dq,J=27.1,7.0,6.2Hz,4H),1.30-1.25(m,4H). 13 C NMR(126MHz,DMSO-d6)δ163.82,160.94,160.01,158.78,155.80,153.85, 153.78,152.13,149.26,147.08,131.74,125.52,123.89,122.35,113.34, 107.86,103.19,95.14,88.12,75.67,70.06,65.30,60.28,48.50,46.88, 29.30,28.80,28.62,25.49,25.39,21.34,13.32,10.71.ESI-MS:m / z[M+H] + calcd for C 34 H 39 Cl4N 12 O3 + ,803.2022;found:803.2029.

[0179] Example 10

[0180] Preparation of 7-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]heptyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18j)

[0181]

[0182] Following the preparation method of 18a, and using 13j and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 41% and a purity of 95.56%. 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=4.8Hz,2H),8.05(s,1H),7.89(s,1H),7.81(d,J=8.8Hz, 1H),7.24(s,1H),7.14(d,J=11.2Hz,1H),6.82(t,J=4.8Hz,1H),6.71-6.66(m,3H),5.26(s, 2H),4.51(t,J=6.7Hz,2H),3.98(t,J=5.5Hz,2H),3.71(s,3H),3.02(t,J=6.7Hz,2H),2.57( t,J=7.5Hz,2H),2.24(s,3H),2.15(s,3H),1.52(dq,J=13.7,7.3Hz,4H),1.26-1.21(m,6H). 13 C NMR(126MHz,DMSO-d6)δ163.82,160.94,160.01,158.78,155.80,153.85,15 3.77,152.14,149.26,147.13,131.73,125.53,123.90,122.36,113.34,107 .86,103.20,95.15,88.11,75.68,70.05,65.33,60.28,48.50,46.88,29.29 ,28.91,28.87,28.82,25.64,25.44,21.36,13.32,10.72.ESI-MS:m / z[M+H] + calcdfor C 35 H 41 Cl4N 12 O3 + ,817.2179;found:817.2199.

[0183] Example 11

[0184] Preparation of 2-{[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]methoxy}ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18k)

[0185]

[0186] Following the preparation method of 18a, and using 13K and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 42% and a purity of 96.42%. 1 H NMR(400MHz,DMSO-d6)δ8.42(d,J=4.8Hz,2H),8.15(s,1H),8.05(s,1H),8.00(d,J =9.0Hz,1H),7.24(s,1H),7.09(d,J=9.5Hz,1H),6.83(t,J=4.8Hz,1H),6.71-6.65 (m,3H),5.27(s,2H),4.55(t,J=6.6Hz,2H),4.53(s,2H),4.11(t,J=5.0Hz,2H),3. 72(s,3H),3.61(t,J=4.6Hz,2H),3.04(t,J=6.7Hz,2H),2.24(s,3H),2.15(s,3H). 13 C NMR (126MHz, DMSO-d6) δ163.82,160.90,160.02,158.82,155.66,153.85,153.80,152.12,149.26,144.02,131.82,125.52,124.48,123.8 7,113.39,107.85,103.09,95.08,87.97,75.73,70.09,68.14,64.64,63.92,60.28,48.66,46.88,21.32,13.32,10.71.ESI-MS:m / z[M+H] + calcd for C 31 H 33 Cl4N 12 O4 + ,777.1502;found:777.1514.

[0187] Example 12

[0188] Preparation of 2-(2-{[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]methoxy}ethoxy)ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18l)

[0189]

[0190] Following the preparation method of 18a, and using 13l and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 42% and a purity of 99.47%. 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=4.3Hz,2H),8.15(s,1H),8.07(s,1H),7.99(d,J=8.9Hz ,1H),7.25(s,1H),7.09(d,J=9.6Hz,1H),6.82(t,J=4.7Hz,1H),6.73-6.66(m,3H),5.28( s,2H),4.56(t,J=6.7Hz,2H),4.50(s,2H),4.11(q,J=4.8Hz,2H),3.72(s,3H),3.55(d,J= 4.8Hz,2H),3.49(td,J=5.1,2.8Hz,4H),3.04(t,J=6.7Hz,2H),2.25(s,3H),2.15(s,3H). 13 C NMR (126MHz, DMSO-d6) δ164.67,160.89,160.02,158.83,155.70,153.80,153.17,152.17,148.30,144.22,131.68,126.09,124.50,113.39,107 .89,103.08,95.27,88.09,75.66,70.06,70.02,69.29,68.98,64.72,63 .96,60.48,55.38,48.63,46.55,21.32,13.47,10.83.ESI-MS:m / z[M+H] + calcd for C 33 H 37 Cl4N 12 O5 + ,821.1764;found:821.1767.

[0191] Example 13

[0192] Preparation of 2-(2-(2-{[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]methoxy}ethoxy}ethoxy)ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18m)

[0193]

[0194] Following the preparation method of 18a, and using 13m and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 54% and a purity of 97.04%. 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=4.1Hz,2H),8.15(s,1H),8.09(s,1H),7.99(d,J=8.9 Hz,1H),7.25(s,1H),7.10(d,J=9.6Hz,1H),6.83(t,J=4.7Hz,1H),6.74-6.66(m,3H),5 .28(s,2H),4.56(t,J=6.7Hz,2H),4.51(s,2H),4.12(q,J=4.9Hz,2H),3.72(s,3H),3.5 6(t,J=4.7Hz,2H),3.53-3.39(m,8H),3.04(t,J=6.7Hz,2H),2.25(s,3H),2.15(s,3H). 13 C NMR(126MHz,DMSO-d6)δ163.83,160.91,160.00,158.79,155.69,153.83,15 3.70,152.15,149.24,144.35,131.81,124.48,123.61,123.18,113.41,107 .93,103.11,95.13,88.01,75.73,70.18,70.15,70.10,69.34,68.98,64.74 ,64.00,60.28,48.65,32.00,29.90,21.34,13.34,10.78.ESI-MS:m / z[M+H] + calcd forC 35 H 41 Cl4N 12 O6 + ,865.2026;found:865.2033.

[0195] Example 14

[0196] Preparation of 1-[1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl]-2,5,8,11-tetraoxotridecane-13-yl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18n)

[0197]

[0198] Following the preparation method of 18a, and using 13n and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 44% and a purity of 95.46%. 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=4.8Hz,2H),8.15(s,1H),8.06(s,1H),7.99(d,J =8.9Hz,1H),7.25(s,1H),7.09(d,J=9.6Hz,1H),6.83(t,J=4.8Hz,1H),6.74-6.64( m,3H),5.27(s,2H),4.60-4.49(m,4H),4.12(d,J=5.8Hz,2H),3.72(s,3H),3.57(t, J=4.7Hz,2H),3.54-3.37(m,12H),3.04(t,J=6.7Hz,2H),2.24(s,3H),2.15(s,3H). 13 C NMR(126MHz,DMSO-d6)δ163.82,160.91,160.01,158.81,155.69,153.81,153.7 8,152.14,149.26,144.30,131.81,124.45,123.61,123.18,113.40,107.87,10 3.12,95.10,87.98,75.75,70.21,70.18,70.17,70.16,70.11,70.10,69.34,68 .98,64.74,64.01,60.28,48.65,46.91,21.34,13.33,10.73.ESI-MS:m / z[M+H] + calcd forC 37 H 45 Cl4N 12 O7 + ,909.2288;found:909.2298.

[0199] Example 15

[0200] Preparation of 2-{[(1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl)methyl]amino}ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18o)

[0201]

[0202] Following the preparation method of 18a, and using 13o and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 39% and a purity of 98.29%. 1 H NMR(500MHz,DMSO-d6)δ8.42(d,J=4.6Hz,2H),8.05(s,2H),7.94-7.77(m,1H),7.34-7.12(m,2H),6.82(t,J=4.8Hz,1H),6.75-6.60(m,4H), 5.27(s,2H),4.54(d,J=26.0Hz,2H),4.19-3.86(m,2H),3.86-3.61(m ,5H),3.11-2.96(m,2H),2.99-2.57(m,2H),2.24(s,3H),2.15(s,3H). 13 C NMR (126MHz, DMSO-d6) δ163.82,160.95,160.02,158.82,155.79,153.86,153.81,152.13,149.25,140.74,131.84,125.53,123.88,123.6 2,113.35,107.86,103.08,95.08,88.17,75.74,70.09,62.97,60.29,49.06,46.90,32.01,29.90,21.29,13.33,10.72.ESI-MS:m / z[M+H] + calcd for C 31 H 34 Cl4N 13 O3 + ,776.1662;found:776.1662.

[0203] Example 16

[0204] Preparation of 3-{[(1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl)methyl]amino}propyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18p)

[0205]

[0206] Following the preparation method of 18a, and using 13p and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 45% and a purity of 98.21%. 1 H NMR(500MHz,DMSO-d6)δ8.42(d,J=4.8Hz,2H),8.05(s,2H),7.83(d,J=8.8Hz,1H ),7.25(s,1H),7.15(t,J=7.8Hz,1H),6.83(t,J=4.8Hz,1H),6.78-6.57(m,4H), 5.26(s,2H),4.60-4.50(m,2H),4.11-3.98(m,2H),3.82(s,2H),3.72(s,3H),3. 07-2.99(m,2H),2.75-2.58(m,2H),2.24(s,3H),2.15(s,3H),1.78-1.66(m,2H). 13 C NMR(126MHz,DMSO-d6)δ163.82,160.93,160.02,158.82,155.76,153.86,153.80,152.13,149.25,141.06,131.83,125.53,123.86,123.19,1 13.36,107.86,103.70,95.08,88.04,75.72,70.04,64.69,60.29,48. 61,46.88,33.67,32.01,29.90,21.37,13.33,10.71.ESI-MS:m / z[M+H] + calcd for C 32 H 36 Cl4N 13 O3 + ,790.1818;found:790.1825.

[0207] Example 17

[0208] Preparation of 4-{[(1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl)methyl]amino}butyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18q)

[0209]

[0210] Following the preparation method of 18a, and using 13q and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 51% and a purity of 98.62%. 1 H NMR(500MHz,DMSO-d6)δ8.42(d,J=4.3Hz,2H),8.26(s,1H),8.04(s,1H),7.89(d,J= 8.9Hz,1H),7.28(s,1H),7.22(d,J=9.4Hz,1H),6.83(t,J=4.9Hz,1H),6.71-6.67(m ,4H),5.27(s,2H),4.61(t,J=6.8Hz,2H),4.15(s,2H),4.05-3.94(m,2H),3.72(s,3 H),3.05(t,J=6.9Hz,2H),2.86(s,2H),2.25(s,3H),2.16(s,3H),1.65-1.49(m,4H). 13 C NMR(126MHz,DMSO-d6)δ163.82,160.93,160.01,159.48,158.80,155.74 ,153.86,153.80,152.12,149.22,139.77,131.91,125.63,125.54,123. 86,113.35,107.86,103.18,95.01,87.87,75.82,70.05,64.79,60.30,4 8.85,46.88,41.55,26.13,22.95,21.37,13.33,10.72.ESI-MS:m / z[M+H] + calcd for C 33 H 38 Cl4N 13 O3 + ,804.1975; found:804.1987.

[0211] Example 18

[0212] Preparation of (1-{[(1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl)methyl]amino}azacyclobut-3-yl)methyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18r)

[0213]

[0214] Following the preparation method of 18a, and using 13r and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 21% and a purity of 98.19%. 1 H NMR(500MHz,DMSO-d6)δ8.43(d,J=4.7Hz,2H),8.26(d,J=14.2Hz,1H),8.13 -7.95(m,2H),7.37-7.20(m,2H),6.83(t,J=4.7Hz,1H),6.73-6.68(m,3H), 5.27(s,2H),4.70-4.49(m,2H),4.22-4.08(m,2H),4.05-3.91(m,1H),3.71 (d,J=3.7Hz,7H),3.05(s,2H),2.94-2.58(m,2H),2.24(s,3H),2.15(s,3H). 13 C NMR(126MHz,DMSO-d6)δ163.81,160.93,160.01,158.80,155.76,153.86,153.79,152.13,149.25,140.71,131.82,125.53,123.87,123.18,1 13.37,107.85,103.10,95.09,88.03,75.73,70.08,66.76,60.28,48. 59,46.90,34.24,32.00,29.90,21.29,13.32,10.71.ESI-MS:m / z[M+H] + calcd for C 33 H 36 Cl4N 13 O3 + ,802.1818;found:802.1832.

[0215] Example 19

[0216] Preparation of 2-{1-[(1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl)methyl]amino}azacyclobut-3-ylethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18S)

[0217]

[0218] Following the preparation method of 18a, and using 13s and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 3% and a purity of 96.47%. 1 H NMR (500MHz, DMSO-d6) δ8.42(d,J=4.7Hz,2H),8.14-7.91(m,3H),7.25(d,J=6.9Hz,1H),6.83(t,J=4.8Hz,1H),6.73-6.59(m,4H),5.26(d,J=4.8Hz,2 H),4.53(t,J=6.8Hz,2H),3.99-3.87(m,3H),3.72(d,J=3.3Hz,7H),3.51( s,2H),3.02(t,J=6.8Hz,2H),2.24(s,3H),2.15(s,3H),1.76-1.70(m,2H). 13 C NMR(126MHz,DMSO-d6)δ163.81,160.93,160.01,158.80,155.70,153.85 ,153.80,152.13,149.25,140.75,131.82,125.52,123.86,123.19,113. 36,107.83,103.12,95.08,75.74,70.26,70.06,63.87,60.29,48.65,46 .98,34.85,34.25,32.01,29.90,21.36,13.33,10.71.ESI-MS:m / z[M+H] + calcd for C 34 H 38 Cl4N 13 O3 + ,816.1975;found:816.1988.

[0219] Example 20

[0220] Preparation of (1-{[(1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl)methyl]amino}piperidin-4-yl)methyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18t)

[0221]

[0222] Following the preparation method of 18a, and using 13t and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 10% and a purity of 99.03%. 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=4.8Hz,2H),8.05(s,2H),7.86-7.79(m,1H),7.21(d,J=1 4.1Hz,2H),6.82(t,J=4.8Hz,1H),6.72-6.66(m,3H),5.26(s,2H),4.54(t,J=6.8Hz,2H),3. 81(d,J=11.1Hz,2H),3.71(s,3H),3.68(s,2H),3.05(d,J=6.5Hz,2H),2.83(dt,J=14.3,7.1 Hz,2H),2.23(s,3H),2.15(s,3H),2.04-1.88(m,2H),1.55-1.45(m,3H),1.18-1.08(m,2H). 13 C NMR(101MHz,DMSO-d6)δ163.80,160.94,160.00,158.80,155.80,153.84,153.75,152.13,149.23,131.75,125.50,123.92,123.19,113.35,107 .86,103.13,95.09,88.03,75.74,70.03,63.55,60.27,52.53,48.60,46 .90,35.32,32.00,29.89,28.57,21.33,13.33,10.71.ESI-MS:m / z[M+H] + calcd for C 35 H 40 Cl4N 13 O3 + ,830.2131;found:830.2134.

[0223] Example 21

[0224] Preparation of 2-{1-[(1-{4-(2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}but-3-yn-1-yl}-1H-1,2,3-triazol-4-yl)methyl]amino}piperidin-4-yl]ethyl(2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl)carbamate (18u)

[0225]

[0226] Following the preparation method of 18a, and using 13u and 7 as raw materials in the same molar ratio, a pale yellow solid was obtained with a yield of 8% and a purity of 95.32%. 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=4.8Hz,2H),8.05(s,2H),7.80(d,J=9.0Hz,1H),7.23( s,1H),7.17-7.12(m,1H),6.83(t,J=4.8Hz,1H),6.72-6.66(m,3H),5.26(s,2H),4.59-4 .49(m,2H),4.06-3.96(m,3H),3.71(s,3H),3.55(s,2H),3.03(t,J=6.3Hz,2H),2.89-2. 71(m,2H),2.23(s,3H),2.15(s,3H),1.52-1.37(m,4H),1.23(s,2H),1.12-0.97(m,2H). 13 C NMR(101MHz,DMSO-d6)δ163.79,160.92,160.00,158.82,155.79,153.84, 153.81,153.77,152.11,149.22,140.71,131.78,125.55,123.63,123.18, 113.37,107.86,103.16,95.05,88.01,75.79,70.02,63.21,60.28,48.62, 46.87,34.85,34.25,32.01,29.89,21.35,13.33,10.70.ESI-MS:m / z[M+H] + calcd for C 36 H 42 Cl4N 13 O3 + ,844.2288;found:844.2285.

[0227] Example 22

[0228] Preparation of 5-(4-(4-butyl-1H-1,2,3-triazol-1-yl)but-1-yn-1-yl)-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (18z)

[0229]

[0230] It was prepared according to the method of 18a, using 1-hexyne and 7 as raw materials. It is a pale yellow solid, with a yield of 7% and a purity of 99.17%. 1 H NMR (500MHz, DMSO-d6) δ8.05(s,1H),7.90(s,1H),7.23(s,1H),6.70(s,2H),5.27(s,2H),4.50(t,J=6.7Hz,2H),3.72(s,3H),3.02(t,J= 6.7Hz,2H),2.59(t,J=7.6Hz,2H),2.24(s,3H),2.16(s,3H),1.54(p,J=7.6Hz,2H),1.29(dt,J=15.0,7.5Hz,2H),0.83(t,J=7.4Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ163.83,159.99,153.83,152.10,149.21,147.09,131.74,130.28,125.54,123.89,122.38,1 07.82,95.12,88.13,75.66,60.29,48.48,46.86,31.53,25.13,22.06,21.34,14.08,13.33,10.71.ESI-MS:m / z[M+H] + calcd for C 25 H 30 ClN8O + :493.2231; found:493.2237.

[0231] Example 23

[0232] The inhibitory activity of the compound on the proliferation of human malignant melanoma A375 cells and vemurafenib-resistant A375 cells (A375R) was detected.

[0233] 1. Experimental Methods

[0234] Cells were seeded at a density of 3000 cells per well in 96-well plates. After 12 hours of cell adhesion, the original culture medium was aspirated, and different proportions of compounds diluted with the culture medium were added. Cells were cultured for another 48 hours. Subsequently, 100 μL of 10% CCK-8 working solution (diluted with basal medium, from TargetMol, China) was added to each well, and incubated for 1 to 3 hours. Cytation was used. TM A multi-functional cell imaging plate reader (BioTek, USA) was used to measure absorbance at 450 nm. The IC50 of the compound was determined. 50 The value was calculated by fitting the dose-response curve.

[0235] 2. Experimental Results

[0236] Table 1. Inhibitory activity of compounds on the proliferation of A375 cells

[0237] Compound numbering <![CDATA[IC 50 (A375,μM)]]> Compound numbering <![CDATA[IC 50 (A375,μM)]]> 18a 1.119±0.161 18m 0.254±0.128 18b 2.817±0.149 18n 0.205±0.052 18c 1.284±0.692 18o 0.687±0.339 18d 3.522±0.379 18p 1.077±0.054 18e 0.374±0.160 18q 0.714±0.122 18f 0.510±0.029 18r 2.781±0.193 18g 0.317±0.017 18s 4.617±0.212 18h 0.089±0.033 18t 0.672±0.193 18i 0.141±0.039 18u 0.799±0.331 18j 0.209±0.079 Apcin 120.359±11.175 18k 0.104±0.050 18z 4.892±0.798 18l 0.025±0.007

[0238] The specific structures of the reference compounds in the table are as follows:

[0239]

[0240] As shown in Table 1, the compounds described in the examples exhibit inhibitory activity against human malignant melanoma A375 cells, with compound IC... 50 The values ​​were lower than those of Cdc20 reference compound Apcin and Hsp90 reference compound 18z, among which compounds 18h and 18l exhibited superior biological activity.

[0241] Table 2. Inhibitory activity of compounds against the proliferation of vemurafenib-resistant A375R cells.

[0242] Compound numbering <![CDATA[IC 50 (A375,μM)]]> <![CDATA[IC 50 (A375R,μM)]]> Drug resistance index (RI) 18h 0.089 0.007 0.079 18l 0.025 0.004 0.160 Vimorin 0.383 43 112.27

[0243] Vemurafenib has an inhibitory effect on the proliferation of wild-type A375 cell lines, and its IC50 value is [not specified]. 50 The value was 0.383 μM. However, in the vemurafenib-resistant A375R cell line, its IC50 value was 0.383 μM. 50 The concentration was 43 μM, and the resistance index (RI) was 112.30, indicating that the cell line had developed resistance to vemurafenib. In contrast, compounds 18h and 18l had lower IC50 values ​​in A375R cells. 50 The values ​​were 0.007 μM and 0.004 μM, respectively, with resistance indices of 0.079 and 0.160, respectively. Both compounds exhibited higher inhibitory activity in A375R cells than their corresponding values ​​in wild-type A375 cells. Similarly, other compounds of the present invention, 18a-18u, showed higher inhibitory activity in A375R cells than their corresponding values ​​in wild-type A375 cells, and their resistance indices were significantly lower than those of vemurafenib.

[0244] Example 24

[0245] Detecting the binding affinity between the compound and Cdc20 and Hsp90

[0246] 1. Experimental Methods

[0247] The equilibrium dissociation constants (Ki) between the compound and the proteins Cdc20 (CUSABIO, China) and Hsp90 (CUSABIO, China) were determined using surface plasmon resonance (SPR) technology. D The experiment was conducted at Biacore. TM Experiments were performed at 25°C on a 1K instrument (equipped with a CM5 sensor chip, GE Healthcare). The sensor chip was first activated with 40 mM EDC and 10 mM NHS, followed by coupling Cdc20 protein (acetate buffer, pH 4.5) or Hsp90 protein (acetate buffer, pH 4.5) to the sensor surface. Assay samples were prepared using flow buffer (PBS, 0.1% sodium dodecyl sulfate (SDS), 5% DMSO, 0.05% Tween 20). During the experiment, samples and calibration solutions (4.5% DMSO + 95.5% PBST (1×PBS + 0.05% Tween 20) and 5.8% DMSO + 94.2% PBST) were simultaneously injected into the sensor chip channels at different concentrations. Experimental data were analyzed using Biacore. TM The 1K analysis software collects data and performs analysis using a steady-state one-to-one model.

[0248] 2. Experimental Results

[0249] The results are as follows Figure 1 As shown in the figure, Figure 1 A is the equilibrium dissociation constant K between Apcin and Cdc20. D Value curve graph; Figure 1 B is the equilibrium dissociation constant K between 18h and Cdc20. D Value curve graph; Figure 1 C is the equilibrium dissociation constant K between 18l and Cdc20. D Value curve graph; Figure 1 D is the equilibrium dissociation constant K between 18h and Hsp90. D Value curve graph; Figure 1 E is the equilibrium dissociation constant K between 18l and Hsp90. D Value curve graph.

[0250] The results show that compounds 18h and 18l have different K values ​​compared to Cdc20. D The effective molecular weights (M) were 63.7 μM and 16.2 μM, respectively, both stronger than Apcin (K).D (141 μM); K of compounds 18h, 18l and Hsp90 D The values ​​were 0.412 μM and 0.241 μM, respectively.

[0251] Similarly, the other compounds of the present invention, 18a-18u, also have good affinity for Cdc20 (both stronger than Apcin) and Hsp90, and are all dual-target compounds.

[0252] 3. Experimental Conclusions

[0253] The compounds of this invention have the ability to simultaneously bind Cdc20 and Hsp90.

[0254] Example 25

[0255] Pharmacodynamic studies of the compound on A375 cells and vemurafenib-resistant A375 cell subcutaneous xenograft tumor models

[0256] 1. Experimental Methods

[0257] Subcutaneous xenograft models of human malignant melanoma cells A375 and vemurafenib-resistant A375 were constructed using 42 and 20 BALB / c nude mice, respectively. The A375 model was randomly divided into 7 groups: control, Apcin 20 mg / kg, BIIB021 20 mg / kg, combination therapy (Apcin and BIIB021, 20 mg / kg each), vemurafenib 20 mg / kg, low-dose compound 18L 10 mg / kg, and high-dose compound 18L 20 mg / kg, with 6 mice in each group. The vemurafenib-resistant model was randomly divided into 4 groups: control, vemurafenib 20 mg / kg, compound 18L 20 mg / kg, and combination therapy (vemurafenib and compound 18L, 20 mg / kg each), with 5 mice in each group. The two models were conducted independently at different time points, without simultaneous administration. All mice were administered the drug via intraperitoneal injection once daily. During the experiment, mouse weight and the length and width of the transplanted tumor were measured every two days, and tumor volume was calculated (volume = length × width × width / 2). At the end of the experiment, both models were administered the drug for 15 days; all mice were sacrificed according to animal ethics requirements, subcutaneous tumor tissue was harvested, weighed, photographed, and the tumor growth inhibition rate (TGI) was calculated. All experimental data were presented as bar charts using GraphPad Prism software.

[0258] 2. Experimental Results

[0259] The results are as follows Figure 2 As shown in the figure, Figure 2A is a tumor tissue diagram at the end of the experiment in the A375 cell subcutaneous xenograft tumor model. Figure 2 B is a graph showing the change in tumor volume in mice during treatment in the A375 cell subcutaneous xenograft tumor model. Figure 2 C is a dot plot of tumor tissue weight at the end of the experiment in the A375 cell subcutaneous xenograft tumor model. Figure 2 D represents the tumor growth inhibition rate in each group of the A375 cell subcutaneous xenograft tumor model. Figure 2 E is a tumor tissue diagram at the end of the experiment in a vemurafenib-resistant A375 cell subcutaneous xenograft model. Figure 2 F is a graph showing the change in tumor volume in mice during treatment in a vemurafenib-resistant A375 cell subcutaneous xenograft tumor model. Figure 2 G is a dot plot of tumor tissue weight at the end of the experiment in a vemurafenib-resistant A375 cell subcutaneous xenograft tumor model. Figure 2 H represents the tumor growth inhibition rate in each group of the vemurafenib-resistant A375 cell subcutaneous xenograft model. The structure of the reference compound used in the animal experiments is as follows:

[0260]

[0261] The results showed that in the A375 cell subcutaneous xenograft model, the combination of Apcin and BIIB021 significantly inhibited tumor growth, with a tumor growth inhibition rate (TGI) of 52%, comparable to that of the vemurafenib group; while the compound 18l of the present invention, when administered alone at 20 mg / kg, had a TGI of 68%, which was higher than that of the combination of Apcin and BIIB021 and vemurafenib.

[0262] In a vemurafenib-resistant A375 cell subcutaneous xenograft model, the tumor growth inhibition rate (TGI) of vemurafenib decreased from 60% in the A375 model to 23%. In contrast, the TGI of compound 18l increased from 68% in the A375 model to 82%, while the TGI of the combination of compound 18l and vemurafenib reached 89%, which was slightly higher than that of compound 18l alone, but significantly higher than that of vemurafenib alone. This indicates that the compounds of the present invention are beneficial in enhancing the therapeutic effect of vemurafenib on resistant A375 cells.

[0263] 3. Experimental Conclusions

[0264] The compounds of this invention have significant therapeutic effects on malignant melanoma and vemurafenib-resistant malignant melanoma.

[0265] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is impossible to exhaustively list all possible implementations here. All obvious variations or modifications derived from the technical solutions of this invention are still within the scope of protection of this invention.

Claims

1. A (1,1,1-trichloro-2)carbamate derivative, characterized in that, It is a compound, optical isomer or its pharmaceutically acceptable salt shown in general formula (I): Wherein, the X is selected from the following structure: said Y is A is selected from linear or branched C1-C12 alkylene, -(CH2CH20) n - -(CH2) m NH-, -(CH2) p -4-7 membered nitrogen-containing heteroalicyclic ring; n is an integer of 1-8; m is an integer of 1-8; p is an integer of 1-4; q is an integer of 1-4; B is C is -(CH2) q -C≡C-; q is an integer from 1 to 4; R1, R2, R3 are independently selected from hydrogen, C1-C3 alkyl, halogen, anilino; R6, R7, R8, R 10 independently selected from hydrogen, C1-C4alkyl; R4, R5 are independently selected from hydrogen, C1-C3 alkyl, halogen, amino; R9 is selected from hydrogen, C1-C3 alkyl, amido.

2. The (1,1,1-trichloro-2)carbamate derivative according to claim 1, characterized in that, A is selected from linear or branched C1-C8 alkylene; n is an integer of 1-6; m is an integer of 1-5; p is an integer of 1-3; q is an integer of 1-3.

3. The (1,1,1-trichloro-2)carbamate derivative according to claim 1, characterized in that, A is selected from -(CH2) p - azetidine, -(CH2) p - azetidine, -(CH2) p - azetidine, -(CH2) 4. The (1,1,1-trichloro-2)carbamate derivative according to claim 1, characterized in that, The (1,1,1-trichloro-2) carbamic acid derivative is a compound, optical isomer or its pharmaceutically acceptable salt shown in general formula (II): wherein A is selected from linear or branched C1-C12 alkylene, -(CH2CH20) n - -(CH2) m NH-, -(CH2) p - a 4-7 membered nitrogen-containing aliphatic heterocycle; n is an integer of 1-8; m is an integer of 1-8; p is an integer of 1-4; R1, R2, R3 are independently selected from hydrogen, C1-C3 alkyl, halogen, anilino.

5. The (1,1,1-trichloro-2)carbamate derivative according to claim 1, characterized in that, The (1,1,1-trichloro-2) carbamic acid derivative is a compound, optical isomer or its pharmaceutically acceptable salt shown in the following formula:

6. The (1,1,1-trichloro-2)carbamate derivative according to any one of claims 1 to 5, characterized in that, The pharmaceutically acceptable salt is sodium salt, potassium salt, ammonium salt, lithium salt, magnesium salt, calcium salt.

7. Process for the preparation of (1,1,1-trichloro-2)carbamate derivatives according to any one of claims 1 to 6, characterized in that, It comprises the following steps: S1, the amino group of raw material 1 is acylated to obtain intermediate 2; the 7 position on the ring of intermediate 2 is obtained by iodination to obtain intermediate 3; nucleophilic substitution is carried out on intermediate 3 to obtain intermediate 4; the amide protection of intermediate 4 is removed to obtain intermediate 5; Sonogashira coupling is carried out on intermediate 5 to obtain intermediate 6; Intermediate 6 is subjected to azidation reaction to obtain intermediate 7; S2, raw material 8 is subjected to dehydration condensation to obtain intermediate 9; intermediate 9 is subjected to chlorination and amination to obtain intermediate 10; raw material 11 is reacted with p-nitrophenyl chloroformate to obtain intermediate 12, which is further reacted with intermediate 10 to obtain intermediate 13; S3, click reaction is carried out between intermediate 13 and intermediate 7 to obtain the (1,1,1-trichloro-2) carbamic acid derivative; 8. Process for the preparation of (1,1,1-trichloro-2)carbamate derivatives according to any one of claims 1 to 6, characterized in that, It comprises the following steps: S1, the amino group of raw material 1 is acylated to obtain intermediate 2; the 7 position on the ring of intermediate 2 is obtained by iodination to obtain intermediate 3; nucleophilic substitution is carried out on intermediate 3 to obtain intermediate 4; the amide protection of intermediate 4 is removed to obtain intermediate 5; Sonogashira coupling is carried out on intermediate 5 to obtain intermediate 6; Intermediate 6 is subjected to azidation reaction to obtain intermediate 7; S4, raw material 8 is subjected to dehydration condensation to obtain intermediate 9; intermediate 9 is subjected to chlorination and amination to obtain intermediate 10; raw material 14 is reacted with p-nitrophenyl chloroformate to obtain intermediate 15; intermediate 15 is reacted with intermediate 10 to obtain intermediate 16; after removing the Boc protecting group of intermediate 16, substitution reaction is carried out to obtain intermediate 13; S3, click reaction is carried out between intermediate 13 and intermediate 7 to obtain the (1,1,1-trichloro-2) carbamic acid derivative; 9. Use of the (1,1,1-trichloro-2) carbamate derivative according to any one of claims 1-6 for the preparation of a Cdc20 / Hsp90 dual targeting inhibitor.

10. Use of the (1,1,1-trichloro-2) carbamate derivative according to any one of claims 1-6 for the preparation of a medicament for the treatment or co-treatment of malignant melanoma or vemurafenib-resistant malignant melanoma.

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