Amide compound, pharmaceutical composition thereof, and use thereof

Abstract

The present application relates to an amide compound, a pharmaceutical composition thereof, and use thereof. The amide compound is selected from a compound of formula (I), a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof, an atropisomer thereof, and a pharmaceutically acceptable salt thereof. The present application develops a series of novel amide compounds. The amide compound has excellent anti-HIV activity and the ability to inhibit HIV capsid protein binding, and is suitable for intravenous administration, oral administration, and subcutaneous administration. The amide compound has a long half-life and high drug exposure in vivo, and thus possesses the potential to develop long-acting drugs. Also, the amide compound has good metabolic stability, low or medium penetrability and a high protein binding rate in cells, no significant inhibitory effects on various CYP enzymes, and high safety. The amide compound is promising for use against HIV infection.

Description

Amide compounds and their pharmaceutical compositions and applications

[0001] This application claims priority to Chinese patent applications filed on January 14, 2025, with application number 202510056910X and entitled "An amide compound and its use thereof", and filed on November 19, 2024, with application number 2024116561052 and entitled "An amide compound and its use thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of chemical and pharmaceutical technology, such as amide compounds, pharmaceutical compositions thereof, and applications. Background Technology

[0003] Since AIDS (Acquired Immunodeficiency Syndrome) was first reported in 1981, this serious infectious immune system disease caused by HIV infection has posed a severe challenge to global public health due to its high mortality rate and complex pathological mechanisms.

[0004] HIV, with its unique mode of invasion, gradually weakens the body's immune defenses, making infected individuals susceptible to various infections and malignant tumors. Targeting several key steps in the HIV life cycle, such as viral entry into host cells and fusion, viral replication, integration, assembly, budding, and maturation, researchers worldwide have, for over forty years, designed drugs to inhibit key viral enzymes or interfere with viral replication at each stage of the HIV life cycle. These drugs effectively suppress viral load and slow disease progression.

[0005] Marketed anti-HIV drugs mainly include: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, entry inhibitors, and capsid inhibitors. According to HIV treatment guidelines worldwide, first-line and second-line treatment regimens often involve a combination of two core nucleoside inhibitors with a third-line drug, which can be a non-nucleoside inhibitor, a protein inhibitor, or an integrase inhibitor.

[0006] Despite significant progress in HIV treatment over the past few decades, numerous serious challenges remain in current research and clinical practice. Existing antiretroviral therapies effectively suppress viral replication but cannot completely eliminate the viral reservoir latent in host cells. Once treatment is discontinued, these latent viruses can reactivate, leading to viral rebound. Therefore, long-term or lifelong medication is necessary, and clinical observations have shown that long-term use of anti-HIV drugs is accompanied by various complications such as metabolic syndrome, cardiovascular disease, and liver and kidney damage.

[0007] More importantly, due to HIV's extremely high mutation rate, almost all marketed HIV drugs have been found to exhibit varying degrees of drug resistance (Top Antivir Med, 2025, 33(2) 457-473). Drug resistance not only leads to a decline in the efficacy of existing drug treatments but also increases the difficulty and cost of treatment. Lenacapavir, the first drug developed by Gilead Sciences targeting the viral capsid protein, offers a new option for HIV treatment and prevention due to its unique mechanism of action, high resistance barrier, and once-every-six-month dosing regimen. Therefore, it is necessary to develop highly effective HIV drugs with low side effects to improve medication adherence and reduce the risk of drug resistance. Summary of the Invention

[0008] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of the claims.

[0009] This application provides amide compounds, pharmaceutical compositions thereof, and applications, specifically providing an amide compound, a pharmaceutical composition comprising the amide compound, and its use in the preparation of an HIV capsid protein inhibitor and in the preparation of a medicament for the prevention and / or treatment of HIV infection.

[0010] In a first aspect, this application provides an amide compound selected from compounds of formula (I), their tautomers, their meso compounds, their racemic compounds, their enantiomers, their diastereomers, their transisomers, or their pharmaceutically acceptable salts.

[0011] In formula (I),

[0012] Each R1 is independently selected from hydrogen or halogen;

[0013] Each R2 is independently selected from hydrogen or halogen;

[0014] R3 is selected from hydrogen, C1-C6 alkyl, and halo-C1-C6 alkyl; each of the aforementioned alkyl groups may be surrounded by 1-3 R groups. a replace;

[0015] R4 is selected from hydrogen, C1-C6 alkyl, and halo-C1-C6 alkyl; each of the aforementioned alkyl groups may be surrounded by 1-3 R4 groups. a replace;

[0016] R5 or R6 are each independently selected from hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; each of the aforementioned alkyl groups may be surrounded by 1-3 R groups. a replace;

[0017] R5 and R6 are independent of each other, or R5 and R6 are connected together and together with the atoms they are connected to form a 3-6 membered cycloalkyl group;

[0018] R7 is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and halogenated C1-C6 alkyl; each of the aforementioned alkyl groups may be surrounded by 1-3 R groups. a replace;

[0019] R8 and R8' are each independently selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halosubstituted C1-C6 alkyl, amino-substituted alkyl, and amino; the aforementioned alkyl and amino groups may be substituted with 1-3 R's. a replace;

[0020] R9 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, or 3-5 membered cycloalkyl; each of the aforementioned alkyl or cycloalkyl groups may be surrounded by 1-3 Rs. a replace;

[0021] Each R a Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, or 3-10 membered cycloalkyl containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, or cycloalkyl group may optionally be surrounded by 1-3 R atoms. c replace;

[0022] Each R c Each is independently selected from hydrogen, deuterium, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl or halo-C3-C6 cycloalkyl;

[0023] R 10 R 11 R 12 Each is independently selected from hydrogen or C1-C6 alkyl groups;

[0024] R 13 R 14 Each is independently selected from hydrogen or C1-C6 alkyl groups;

[0025] R 15 R 16 R 17 R 18 Selected from hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl;

[0026] Where X is NR', R' is selected from hydrogen or C1-C6 alkyl, and R7, R8' and R8 are independent of each other;

[0027] Or X is O, and the compound shown in formula (I) satisfies any one or at least a combination of two of the following conditions:

[0028] (1) R8' is selected from hydrogen or C1-C6 alkyl, R7 is connected to R8 and together with the atoms they are respectively connected to form a 3-12 membered cycloalkyl group, wherein the 3-12 membered cycloalkyl group is optionally surrounded by 1-3 R a replace;

[0029] (2) R8' is connected to R8 and together with the atoms they are connected to, forms a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally surrounded by 1-3 R... a replace;

[0030] (3) R8' is simultaneously connected to both R7 and R8 and together with the atoms connected to them respectively, forms a 5-10 membered bridged cycloalkyl group, wherein the 5-10 membered bridged cycloalkyl group is optionally surrounded by 1-3 R atoms. a replace;

[0031] (4) R9 is attached to -NH- and forms a 5-6 membered heterocyclic group together with the adjacent S atom;

[0032] (5)R 11 With R 12 They connect and together with the atoms they are attached to, form 3-4 membered cycloalkyl groups;

[0033] Each n is independently selected from 0, 1, 2 or 3;

[0034] Each k is independently selected from 0, 1, 2, 3, 4, or 5.

[0035] In the above text, "C1-C6 alkyl" refers to alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms; "3-10 membered cycloalkyl" refers to 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered cycloalkyl groups; "1-3 R" refers to alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms. a "Refers to 1 R" a 2 R a Or 3 Rs a "C1-C6 alkoxy" means that the number of carbon atoms in the alkoxy group can be 1, 2, 3, 4, 5, or 6; "C3-C6 cycloalkyl" means that the number of carbon atoms in the cycloalkyl group can be 3, 4, 5, or 6; "C2-C6 alkenyl" means that the number of carbon atoms in the alkenyl group can be 2, 3, 4, 5, or 6; "C2-C6 alkynyl" means that the number of carbon atoms in the alkynyl group can be 2, 3, 4, 5, or 6.

[0036] This application develops a series of novel amide compounds with excellent anti-HIV activity and the ability to inhibit HIV capsid protein binding. These compounds are suitable for intravenous, oral, and subcutaneous administration, exhibiting a long half-life and high blood drug exposure in vivo, demonstrating potential for developing long-acting drugs. Furthermore, these amide compounds exhibit good metabolic stability, displaying low to moderate permeability in cells, high protein binding rates, and no significant inhibitory effect on various CYP enzymes, demonstrating high safety. Therefore, their use in anti-HIV infection treatment shows promise.

[0037] In one embodiment, X is O, and the compound shown in formula (I) is the compound shown in formula (Ia);

[0038] Wherein, ring A is a heterocyclic group containing 1-3 heteroatoms and 4-8 ring atoms; the heterocyclic group may optionally be surrounded by 1-3 R atoms. a replace;

[0039] In equation (Ia), R1, R2, R3, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R a n and k are as defined above.

[0040] In one implementation, wherein: Selected from

[0041] In one embodiment, R7 is selected from hydrogen, methyl, or ethyl.

[0042] In one implementation, wherein: Selected from

[0043] In one implementation, X is O, where -NH-S(O)2-R9 is... And / or, R 11 With R 12 They connect and together with the atoms they are attached to, form a cyclopropyl group.

[0044] In one embodiment, X is NH, wherein R7, R8', and R8 are each independently selected from methyl or ethyl, and R9 is selected from methyl or cyclopropyl.

[0045] In one implementation, each R1 is independently selected from hydrogen or fluorine.

[0046] In one implementation, each R2 is independently selected from hydrogen or chlorine.

[0047] In one implementation, R3 is selected from -CH2CF3 or -CH2CHF2.

[0048] In one implementation, R4 is selected from -CF3 or -CHF2.

[0049] In one implementation, R5 is hydrogen and R6 is hydrogen.

[0050] Or, structure yes m is selected from 0, 1, or 2.

[0051] In one implementation, R 11 For hydrogen, R 12 It is hydrogen.

[0052] In one implementation, R 13 For hydrogen, R 14 It is hydrogen.

[0053] In one implementation, R 15 For hydrogen, R 16 For hydrogen, R 17 For hydrogen, R 18 It is hydrogen.

[0054] In some embodiments, the compound represented by formula (I) is selected from any of the following structures:

[0055] In some embodiments, the compound represented by formula (I) is selected from any of the following structures:

[0056] In some embodiments, the structure of the compound shown in formula (I) is as follows:

[0057] In some embodiments, the compound represented by formula (I) is selected from any of the following structures:

[0058] In a second aspect, this application provides a pharmaceutical composition comprising the amide compound described in the first aspect, as well as a pharmaceutically acceptable carrier and / or excipients.

[0059] Thirdly, this application provides the use of the amide compound described in the first aspect or the pharmaceutical composition described in the second aspect in the preparation of HIV capsid protein inhibitors.

[0060] Fourthly, this application provides the use of the amide compound described in the first aspect or the pharmaceutical composition described in the second aspect in the preparation of a medicament for the prevention and / or treatment of HIV infection.

[0061] In one embodiment, the medicament further comprises a therapeutically effective amount of other therapeutic agents, said other therapeutic agents including any one or a combination of at least two of the following: compounds that inhibit HIV protease, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, viral capsid polymerization inhibitors, or non-catalytic site HIV integrase site inhibitors.

[0062] The compounds provided in this application have significant inhibitory activity against viruses, particularly HIV, and have potential advantages in drug development, including evaluation of drug absorption, distribution, metabolism and excretion, as well as safety and efficacy.

[0063] Terms and related explanations used in this application:

[0064] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0065] The term "isomer" includes enantiomers, diastereomers, and geometric (or conformational) isomers of a given structure. For example, this application includes R and S configurations for each asymmetry center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers.

[0066] The term "optional" or "optionally" means that an event or condition described subsequently may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, ethyl "optional" is defined by 1-3 R a Substitution refers to the fact that the ethyl group can be unsubstituted -CH2CH3 or monosubstituted -CH2CH2R. a -CHR a CH3, polysubstituted -CHR a CH2R a -CHR a CH(R a )2、-C(R a )2CH2R aEtc. Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is spatially impossible and / or cannot be synthesized.

[0067] The term "pharmaceutically acceptable salt" refers to salts such as their acid addition salts and / or base salts. Suitable acid addition salts are formed from acids, which form non-toxic salts, such as hydrochlorides / chlorides. Suitable base salts are formed from bases, which form non-toxic salts, such as calcium and sodium salts. Hemisalts of acids and bases can also be formed, such as hemisulfates and hemicalcium salts.

[0068] The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, excipient, or medium that does not impair the pharmacological activity of the compound formulated with it.

[0069] The term "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0070] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the alkyl group is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0071] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, optionally 3 to 12 carbon atoms, further optionally 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms), and most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0072] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0073] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0074] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0075] The term “deuterated alkoxy” refers to an alkoxy group that is replaced by one or more deuterium atoms, where the alkoxy group is as defined above.

[0076] The term "hydroxyl group" refers to the -OH group.

[0077] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0078] The term "cyano" refers to -CN.

[0079] The term "nitro" refers to -NO2.

[0080] The term "amino" refers to -NH3.

[0081] The term "treatment" means administering the compound or pharmaceutical composition described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0082] (i) Suppress the disease or disease state, that is, curb its development;

[0083] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0084] The term "prevention" means administering the compound or pharmaceutical composition described in this application to prevent a disease or one or more symptoms associated with said disease, and includes: preventing the occurrence of a disease or disease state in the body, particularly when the body is susceptible to the disease state but has not yet been diagnosed with it. In this application, prevention of HIV infection includes pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). PrEP refers to a biological prevention method in which an uninfected person, facing a high risk of HIV infection, administers the compound or pharmaceutical composition described in this application to reduce the likelihood of infection. Post-exposure prophylaxis (PEP) refers to a method in which an uninfected person, after engaging in HIV-infected behavior with an HIV-infected person or an individual with an unknown HIV status, administers the compound or pharmaceutical composition described in this application to prevent HIV infection.

[0085] The term "therapeutic effective amount" means the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content herein.

[0086] The compounds of this application may exist in specific geometric or stereoisomer forms. This application envisions all such compounds, including tautomers, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, transisomers, racemic mixtures thereof, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0087] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of this application, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0088] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0089] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0090] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0091] For example, when the pharmaceutical composition is for oral administration, it can be formulated by mixing the active compound, including the compound of this application, with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0092] For example, when the pharmaceutical composition is to be administered parenterally, it can be formulated into a suitable unit dosage form of sterile solution, suspension or lyophilized product.

[0093] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Optional embodiments include, but are not limited to, the embodiments of this application.

[0094] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. To obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments. Compared with the prior art, this application has the following beneficial effects:

[0095] This application develops a series of novel amide compounds with excellent anti-HIV activity and the ability to inhibit HIV capsid protein binding. These compounds are suitable for intravenous, oral, and subcutaneous administration, exhibiting a long half-life and high blood drug exposure in vivo, demonstrating potential for developing long-acting drugs. Furthermore, these amide compounds exhibit good metabolic stability, displaying low to moderate permeability in cells, high protein binding rates, and no significant inhibitory effect on various CYP enzymes, demonstrating high safety. Therefore, their use in anti-HIV infection treatment shows promise.

[0096] After reading and understanding the detailed description, other aspects can be understood. Detailed Implementation

[0097] The technical solution of this application will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely to help understand this application and should not be regarded as specific limitations on this application.

[0098] Preparation Examples: Common chemical reagents and consumables were purchased from commercially available sources. Abbreviations: THF: Tetrahydrofuran; DCM: Dichloromethane; DMF: N,N-Dimethylformamide; DMSO: Dimethyl sulfoxide; TEA: Triethylamine; EA: Ethyl acetate; DIPEA: N,N-Diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; MTBE: Methyl tert-butyl ether; PE: Petroleum ether; DMAP: 4-Dimethylaminopyridine; TLC: Thin-layer chromatography.

[0099] Example 1 Synthesis of N-(1S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (1)

[0100] tert-Butyl(S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (intermediate 1.7)

[0101] N-(4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)methylsulfonamide (intermediate 1.9)

[0102] 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (intermediate 1.12)

[0103] 2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (intermediate 1.13)

[0104] Intermediate 1.7 was prepared according to the preparation method disclosed in WO2019035973A1; intermediates 1.9, 1.12 and 1.13 were prepared according to the preparation method disclosed in WO2019161280A1.

[0105] Step 1: Sulfolane (10.00 g, 83.22 mmol, 1.0 eq.) and isopropyl chloroformate (11.22 g, 91.55 mmol, 1.1 eq.) were added to a four-necked flask. THF (200 mL) was added, and the mixture was cooled to -78 °C under nitrogen protection. LiHMDS (1 M / THF) (167 mL, 1.1 eq.) was added dropwise, and the mixture was gradually heated to room temperature for 2 h. The reaction was quenched with 1 N hydrochloric acid (250 mL), and the mixture was extracted with EA. The organic phases were combined, dried, and evaporated to dryness. The mixture was then subjected to sand column chromatography (PE:EA = 3:1) to obtain 1.2 (6.86 g, yield 40.00%). MS (m / z) = 207.23 [M+H] + .

[0106] Step 2: Compound 1.2 (6.86 g, 33.259 mmol, 1 eq.) and iodomethane (5.20 g, 36.636 mmol, 1.102 eq.) were dissolved in THF (500 mL). After the system temperature was lowered to -78 °C, LiHMDS (1 M) (37 mL, 1.1 eq.) was added dropwise using a constant pressure dropping funnel. The reaction was stirred at -78 °C for 1 h, then raised to room temperature and stirred for 24 h. The system was cooled, quenched with 1 N HCl (64 mL), extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, prepared as sinter, and subjected to column chromatography (PE:EA = 3:1) to obtain compound 1.3 (5.86 g, 26.602 mmol, yield 79.98%). MS (m / z) = 221.28 [M+H] + .

[0107] Step 3: Compound 1.3 (5.86 g, 26.602 mmol, 1 eq.) was dissolved in THF (60 mL) under nitrogen protection. Lithium aluminum hydride (1.22 g, 32.105 mmol, 1.207 eq.) was added in portions under ice bath conditions, and the reaction was carried out at 0 °C for 12 h. The reaction was quenched with 15% NaOH aqueous solution. After the addition was complete, a small amount of anhydrous magnesium sulfate was added to the system for drying. The mixture was filtered, and the filter cake was washed with a small amount of THF. The filtrate was prepared into sand and subjected to column chromatography (PE:EA = 3:1) to obtain compound 1.4 (3.66 g, 22.287 mmol, 83.78%, 1 eq.). MS (m / z) = 165.23 [M+H] + .

[0108] Step 4: Compound 1.4 (3.99 g, 24.296 mmol, 1 eq.) was dissolved in DCM (40 mL), and Dess-Martin reagent (11.34 g, 26.745 mmol, 1.101 eq.) was added in portions under ice bath conditions. The reaction was carried out at room temperature for 12 h. The system was filtered, extracted with DCM, and the filtrate was washed with saturated brine, dried, prepared into sintered precipitate, and subjected to column chromatography (PE:EA = 2:1) to give compound 1.5 (1.68 g, 10.357 mmol, yield 42.63%). MS (m / z) = 163.23 [M+H] + .

[0109] Step 5: Compound 1.5 (1.68 g, 10.357 mmol, 1 eq.) was dissolved in methanol (20 mL), and K₂CO₃ (4.30 g, 31.113 mmol, 3.004 eq.) was added. The mixture was cooled to 0 °C in an ice bath, and dimethyl (1-diazo-2-propanone)phosphonate (2.99 g, 15.564 mmol, 1.503 eq.) was added dropwise. The reaction was carried out at 20 °C for 12 h. The system was directly extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, prepared as sintered sand, and subjected to column chromatography (PE:EA = 4:1) to give compound 1.6 (860 mg, 5.436 mmol, yield 52.48%). MS (m / z) = 159.23 [M+H] + .

[0110] Step 6: Intermediate 1.7 (1.74 g, 3.535 mmol, 1 eq.) and compound 1.6 (672 mg, 4.247 mmol, 1.201 eq.) were dissolved in DMF (20 mL). Triethylamine (1.08 g, 10.673 mmol, 3.019 eq.), bis(triphenylphosphine)palladium(II) dichloride (125 mg, 178.088 μmol, 0.05037 eq.), and CuI (34 mg, 178.525 μmol, 0.05049 eq.) were added, and the mixture was reacted at room temperature for 12 h. The system was poured into three volumes of ice water, extracted with EA, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous magnesium sulfate, prepared as sintered sand, and subjected to column chromatography (PE:EA = 3:1 to 2:1) to give compound 1.8 (1.74 g, 3.056 mmol, yield 86.43%). MS(m / z) = 570.46 [M+H] + .

[0111] Step 7: Compound 1.8 (0.600 g, 1.054 mmol, 1 eq.) was dissolved in dioxane (10 mL) and water (2 mL). Intermediate 1.9 (573 mg, 1.263 mmol, 1.199 eq.), KHCO3 (320 mg, 3.196 mmol, 3.034 eq.), and Pd(dppf)Cl2 (40 mg, 54.667 μmol, 0.05188 eq.) were added. The mixture was purged with nitrogen several times and heated to 65 °C for 12 h. The supernatant was collected, prepared as a slurry, and subjected to column chromatography (PE:EA = 5:1 to 2:1) to obtain compound 1.10 (0.25 g, 306.276 μmol, yield 29.07%). MS (m / z) = 817.26 [M+H] + .

[0112] Step 8: Compound 1.10 (0.250 g, 306.276 μmol, 1 eq.) was dissolved in DCM (1 mL), and TFA (0.6 mL) was added dropwise. The mixture was reacted at 20 °C for 2 h. The system was then diluted with DCM (10 mL), and the solution was added dropwise to an aqueous sodium bicarbonate solution to adjust the pH to 7–8. The mixture was separated, and the aqueous phase was extracted with DCM (10 mL). The organic phases were combined, washed with saturated brine, and dried by rotary evaporation to obtain compound 1.11 (0.200 g, 279.275 μmol, yield 91.18%). MS (m / z) = 717.26 [M+H] + .

[0113] Step 9: Compound 1.11 (0.200 g, 279.275 μmol, 1 eq.) and intermediate 1.12 (78 mg, 276.433 μmol, 0.9898 eq.) were dissolved in DMF (2 mL), HATU (117 mg, 307.709 μmol, 1.102 eq.) and DIPEA (75 mg, 580.307 μmol, 2.078 eq.) were added, and the mixture was reacted at 20 °C for 1 h. The system was then poured into ice water (10 mL), and EA was added for extraction. The organic phase was washed with water and saturated brine, dried, evaporated to dryness, prepared as sand, and subjected to column chromatography (PE:EA = 2:1 to 1:1). The crude product was prepared by thick-plate chromatography (DCM:methanol = 50:1) to obtain compound 1 (0.040 g, yield 14.61%). 1H NMR (400MHz, DMSO) δ10.02(s,1H),9.24-9.29(m,1H),7.72-7.82(m,2H),7.30-7. 34(m,1H),7.01-7.06(m,1H),6.82-6.90(m,1H),6.47-6.48(m,2H),4.90-4.96(m ,1H),4.49-4.72(m,3H),3.96(m,1H),3.38(m,2H),3.16(s,3H),2.98(m,2H),2.5 0-2.62(m,2H),2.30(m,3H),1.68(s,3H),1.41(m,1H),1.24(m,1H),0.97(m,1H). MS(m / z)=978[MH] + .

[0114] Example 2 Synthesis of N-(1S)-1-(3-(4-chloro-3-(methylsulfonyl)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(S-methylsulfonylimino)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (2)

[0115] 4-Chloro-7-(4,4,5,5-Tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine (Intermediate 2.8)

[0116] Intermediate 2.8 was prepared according to the preparation method of WO2019161280 A1.

[0117] Step 1: Compound 2.1 (45.00 g, 287.9 ​​mmol, 1 eq.) was added to a 100 mL single-necked flask. Concentrated hydrochloric acid (153 mL) was slowly added dropwise under ice bath conditions. The mixture was brought to room temperature and stirred for 15 hours. After cooling to 0 °C, MTBE (150 mL) was added. The mixture was separated, and the aqueous phase was extracted with MTBE. The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and subjected to column chromatography to obtain compound 2.2 (35.60 g, yield 70.76%). MS (m / z) = 175.50 [M+H] + .

[0118] Step 2: In a 100 mL single-necked flask, add magnesium powder (19.040 g, 783.2 mmol, 2.01 eq.) and THF (220 mL), then add a THF solution of compound 2.2 (68.00 g, 389.1 mmol, 1 eq.) (330 mL). Initiate the reaction by slight heating, then stir for 30 min. The mixture is then added at 0 °C to a THF solution of methyl methyl thiosulfonate (98.60 g, 781.30 mmol, 2.008 eq.). The reaction is carried out at room temperature for 3 h. The mixture is quenched with 1 N dilute hydrochloric acid, extracted with MTBE, and the aqueous phase is quenched with dilute hydrochloric acid. The organic phases are combined, dried, and evaporated to dryness. Column chromatography (n-pentane) is performed to give compound 2.3 (57.00 g, 305.8 mmol, yield 78.59%). MS (m / z) = 187.39 [M+H] + .

[0119] Step 3: Compound 2.3 (57.00 g, 305.812 mmol, 1 eq.) was dissolved in methanol (820 mL), and water (35 mL) and potassium carbonate (21.20 g, 153.394 mmol, 0.5016 eq.) were added dropwise. After the addition was complete, the mixture was reacted at 20 °C for 2 hours. Ice water (1300 mL) was added to the system, followed by n-pentane (500 mL). The mixture was separated, and the aqueous phase was extracted with n-pentane. The organic phase was washed with saturated brine, dried, and evaporated to dryness in a water bath at 5–10 °C to obtain compound 2.4 (27.00 g, yield 77.31%). MS (m / z) = 115.50 [M+H] + .

[0120] Step 4: Compound 2.5 (1.50 g, yield 48%) was prepared according to the synthetic method of compound 1.8 in Example 1. MS (m / z) = 175.50 [M+H] + .

[0121] Step 5: Compound 2.5 (1.00 g, 1.903 mmol, 1 eq.) was dissolved in dioxane hydrochloride (20 mL) and methanol (10 mL), and reacted at 20 °C for 15 h. The mixture was then evaporated to dryness, and THF was distilled off to give compound 2.6 (0.800 g, 1.881 mmol, yield 98.83%). MS (m / z) = 426.33 [M+H] + .

[0122] Step Six: Compound 2.7 (1.30 g, 83% yield) was prepared according to the method in Step Nine of Example 1. MS (m / z) = 690.48 [M+H] + .

[0123] Step 7: Dissolve compound 2.7 (1.30 g, 1.320 mmol, 70% purity, 1 eq.) and intermediate 2.8 (780 mg, 2.077 mmol, 1.574 eq.) in dioxane (126 mL) and water (21 mL), then add K2CO3 (550 mg, 3.980 mmol, 3.015 eq.) and Pd(dppf)Cl2 (260 mg, 355.335 μmol, 2.692 e.g.). -1 The mixture was purged with nitrogen and stirred at room temperature for 1 h, then heated to 80 °C for 3 h. TLC confirmed complete reaction. The system was directly converted to sand and subjected to column chromatography (PE:EA = 5:1–2:1) to give compound 2.9 (1.30 g, 1.515 mmol, 100% yield). MS (m / z) = 859.19 [M+H]. + .

[0124] Step 8: Dissolve compound 2.9 (1.30 g, 1.515 mmol) in 2-methyltetrahydrofuran (15 mL), add TEA (920 mg, 9.092 mmol, 1.3 mL, 6.002 eq.), add methanesulfonic anhydride (3 eq.) under nitrogen protection in an ice bath, and after the addition is complete, react at 20 °C for 2 h. The reaction is confirmed to be complete by TLC. The reaction was quenched with ice water, the mixture was separated, the organic phase was washed with brine, dried, and evaporated to dryness. A solution of sodium hydroxide (186 mg, 4.650 mmol, 3.004 eq.) in water (5 mL) was added dropwise to 10 mL of ethanol, and the mixture was reacted at 20 °C for 2 hours. Acetic acid (300 mg) and DCM (50 mL) were added to the mixture, and after thorough stirring, the mixture was separated, the organic phase was washed with water (20 mL), washed with saturated brine, dried, and evaporated to dryness. Column chromatography (PE:acetone = 2:1) was performed to give compound 2.10 (1.30 g, 1.388 mmol, yield 89.71%). MS (m / z) = 937.28 [M+H] + .

[0125] Step 9: Compound 2.10 (1.30 g, 1.388 mmol, 1 eq.) was dissolved in methanol (25 mL), and ammonium carbamate (185 mg, 2.370 mmol, 1.707 eq.) was added. Then, iodobenzene diacetate (920 mg, 2.856 mmol, 2.057 eq.) was added under ice bath conditions. The reaction was carried out at 20 °C for 3 h. The system was directly evaporated to dryness and then subjected to column chromatography (PE:acetone = 2:1). After concentration, the mixture was pulped (PE:MTBE approximately 5:1) and filtered to obtain compound 2 (0.250 g, yield 18.61%). 1H NMR (400MHz, DMSO) δ10.01(s,1H),9.25(m,1H),7.72-7.80(m,2H),7.31(m,1H),7.01-7.02(m,1H),6.47(m,2H),4.90-4.95(m,1H),4.50-4. 73(m,4H),4.17(m,1H),3.97-4.01(m,1H),3.16(s,3H),3.11(s,3H),3 .01(m,2H),2.50-2.62(m,2H),1.71(s,6H),1.43(m,1H),0.97(m,1H). MS(m / z)=965[MH] + .

[0126] Example 3 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (3)

[0127] Step 1: Dissolve compound 3.1 (20.00 g, 149.035 mmol, 1.0 eq.) in acetone (120 mL), add K2CO3 (20.80 g, 150.500 mmol, 1.0 eq.), add compound 3.2 (23.47 g, 149.076 mmol, 1.0 eq.), and heat to 55 °C for 12 h under nitrogen protection. After the reaction is complete as monitored by NMR, the system is cooled to room temperature, filtered, and the filter cake is washed with acetone (100 mL). The filtrate is then evaporated to dryness. The resulting liquid is transferred to a 500 mL four-necked flask with DMF (80 mL). Under nitrogen protection, the temperature is lowered to -30 to -20 °C, and potassium tert-butoxide (20.07 g, 178.861 mmol, 1.2 eq.) dissolved in DMF (60 mL) is slowly added dropwise. After the addition is complete, the system is allowed to heat to room temperature for 1 h. The system temperature was then lowered to 0°C, and quenched by slow dropwise addition of 2M HCl (190 mL). PE (80 mL) and EA (80 mL) were then added for extraction. The organic phase was washed with water (100 mL × 2), followed by washing with saturated brine (150 mL). After drying with anhydrous magnesium sulfate, the mixture was filtered, concentrated, prepared into slurry, and subjected to column chromatography to obtain crude compound 3.3 (25.97 g, 100% yield). MS (m / z) = 174.26 [M + H] + .

[0128] Step 2: Compound 3.3 (14.20 g, 81.487 mmol, 1.0 eq.), acetonitrile (140 mL), and acetic acid (28 mL) were added to a 500 mL single-necked flask. 30% hydrogen peroxide (22.17 g, 195.560 mmol, 2.4 eq.) was slowly added dropwise under ice bath conditions. The reaction was carried out at 90 °C for 12 hours. The system was cooled to room temperature, and sodium sulfite (4.1 g) was added under ice bath conditions. The reaction was quenched with water (100 mL), and extracted with EA (100 mL). The organic phase was washed with saturated sodium bicarbonate, dried, and subjected to column chromatography (PE:EA = 4:1) to give compound 3.4 (12.28 g, yield 73.0%). MS (m / z) = 206 [M+H] + .

[0129] Step 3: Compound 3.4 (12.28 g, 59.537 mmol, 1 eq.) was added to a 500 mL four-necked flask and dissolved in THF (120 mL). Under nitrogen protection, lithium aluminum hydride (2.72 g, 71.579 mmol, 1.202 eq.) was slowly added in portions to 0 °C in an ice bath. After the addition was complete, the system was slowly heated to 20 °C and reacted for 12 hours. Water (2.72 mL), 15% NaOH solution (2.72 mL), and water (8.16 mL) were added dropwise to quench the reaction. After the addition was complete, a small amount of anhydrous magnesium sulfate was added to the system for drying. The mixture was filtered, and the filter cake was washed with tetrahydrofuran (50 mL). The filtrate was prepared into sand and subjected to column chromatography (PE:EA = 2:1 to 1:2) to obtain compound 3.5 (7.33 g, yield 74.97%). MS (m / z) = 164 [M+H]. + .

[0130] Step 4: Compound 3.5 was added to a 250 mL single-necked flask and dissolved in DCM (80 mL). DIPEA (23.08 g, 178.580 mmol, 4.001 eq.) and DMSO (34.88 g, 446.418 mmol, 10.002 eq.) were added. Pyridine sulfur trioxide (21.32 g, 133.953 mmol, 3.001 eq.) was added at 0 °C, and the reaction was carried out at 20 °C for 12 h. The system was washed with water and citric acid, the pH was adjusted to weakly acidic, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and prepared as slurry. Column chromatography (PE:EA = 3:1) yielded compound 3.6 (2.00 g, yield 27.62%). MS (m / z) = 162 [M+H] + .

[0131] Step 5: Compound 3.6 (2.00 g, 12.330 mmol, 1 eq.) was added to a 100 mL single-necked flask and dissolved in methanol (20 mL). K₂CO₃ (5.12 g, 37.046 mmol, 3.005 eq.) was then added. Under nitrogen protection, the temperature was lowered to 0 °C, and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.59 g, 18.493 mmol, 1.5 eq.) was added. After the addition was complete, the system was gradually heated to 20 °C and reacted for 12 hours. EA (30 mL) was added to the system, and extraction was performed with saturated brine (30 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and prepared as a precipitate. Column chromatography (PE:EA = 4:1–2:1) yielded compound 3.7 (1.50 g, yield 76.88%). MS (m / z) = 158 [M+H]. + .

[0132] Step 6: Add compound 3.7 (1.50 g, 9.481 mmol, 1.0 eq.) and intermediate 1.7 (4.67 g, 9.489 mmol, 1.001 eq.) to a 50 mL single-necked flask and dissolve them in DMF (15 mL). Then add triethylamine (2.88 g, 28.462 mmol, 1.70 mL, 3.002 eq.), tetrakis(triphenylphosphine)palladium (548 mg, 474.225 μmol, 0.05 eq.), and CuI (110 mg, 577.579 μmol, 0.06 eq.) in sequence. Replace with nitrogen and react at 35 °C for 12 h. The system was poured into ice water (45 mL), extracted with EA (50 mL), washed with organic brine (50 mL), dried over anhydrous magnesium sulfate, prepared as sinter, and subjected to column chromatography (PE:EA = 3:1–2:1) to obtain the racemic mixture (4.15 g, yield 76.86%). MS (m / z) = 569.45 [M+H] + .

[0133] The racemic mixture was prepared chirally (separation conditions: ChiralPak IC, 250 × 50 mm ID, 10 μm; mobile phase: A: CO2, B: methanol, flow rate: 150 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to give compound 3.9 (1.72 g, yield 82.89%). MS (m / z) = 569.45 [M+H] + Compound 3.10 (1.75 g, yield 84.33%) MS (m / z) = 569.45 [M+H] + .

[0134] Step 7: Add compound 3.10 (1.75 g, 3.073 mmol, 1 eq.) to a 250 mL single-necked flask, followed by DCM (20 mL) and dioxane hydrochloride (40 mL). React at 20 °C for 1 h. The system was then concentrated and evaporated to dryness to obtain crude 3.10.1 (1.44 g, 100% yield). MS (m / z) = 469.34 [M+H] + .

[0135] Step 8: Compound 3.10.1 (1.44 g, 3.068 mmol, 1 eq.) was added to DMF (20 mL) in a 100 mL single-necked flask. Compound 1.12 (866 mg, 3.069 mmol, 1.0 eq.) and DIPEA (1.19 g, 9.208 mmol, 3.001 eq.) were added. Finally, HATU (1.40 g, 3.682 mmol, 1.2 eq.) was added under nitrogen protection and in an ice bath. The reaction was then carried out at 20 °C for 12 h. The system was poured into ice water (60 mL), extracted with EA (60 mL), washed with water (60 mL) and saturated brine (60 mL), dried, evaporated to dryness, prepared as sinter, and subjected to column chromatography (PE:EA = 3:1 to 2:1) to obtain 3.10.2 (1.53 g, yield 68%). MS(m / z) = 733.49 [M+H] + .

[0136] Step Nine: Add compound 3.10.2 (200 mg, 272.668 μmol, 1 eq.) and intermediate 1.9 (161 mg, 354.883 μmol, 1.302 eq.) to a 50 mL single-necked flask, dissolved in 1,4-dioxane (10 mL) and water (2 mL). Then add KHCO3 (82 mg, 819.058 μmol, 3.004 eq.) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 27.333 μmol, 1.002 eq.) sequentially. -1 The mixture was purged with nitrogen and heated to 70°C for 15 hours. The resulting slurry was prepared by column chromatography (PE:EA = 4:1–2:1–3:2), concentrated, and then evaporated to dryness. Heptane, MTBE, and EA were added to form a slurry, which was then filtered and dried. Compound 3 (18 mg, yield 6.7%) was obtained. 1H NMR (400MHz, DMSO-d6) δ = 9.99 (s, 1H), 9.23 (m, 1H), 7.81 (m, 2H), 7.31 (m, 1H) ,7.03(m,1H),6.83(m,1H),6.48(m,2H),4.94(m,1H),4.71(m,1H),4.62(m,2H ),4.00(m,1H),3.20-3.14(m,2H),3.08(m,3H),2.90(m,2H),2.60(m,2H),2.3 3-2.20(m,4H),1.69(m,3H),1.41(m,1H),0.97(m,1H), MS(m / z)=980.29[M+H] + .

[0137] Example 4 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (4)

[0138] The preparation method of compound 3.9 is described in Example 3.

[0139] Step 1: Following the synthetic method for compound 3.10.1, crude compound 3.9.1 was obtained (1.42 g, 100% yield). MS (m / z) = 469.34 [M+H] + .

[0140] Step 2: Following the synthetic method for compound 3.10.2, compound 3.9.2 was obtained (1.70 g, yield 76.9%). MS (m / z) = 733.49 [M+H] + .

[0141] Step 3: Following the synthesis method of compound 3, compound 4 (48 mg, yield 17.9%) was obtained. 1HNMR (400MHz, DMSO-d6) δ=10.00(s,1H),9.26(d,J=8.1Hz,1H),7.81(d,J=8.1Hz,1H),7.73(d,J=7.8Hz ,2H),7.33(d,J=7.8Hz,1H),7.03(m,1H),6.89(d,J=7.6Hz,1H),6.48(m,2H),4.92(d,J=16.4Hz,1H),4. 71(d,J=16.4Hz,1H),4.64-4.55(m,1H),4.55-4.46(m,1H),4.01-3.91(m,1H),3.17(s,3H),3.05-2.91 (m,2H),2.60(m,2H),2.30-2.20(m,4H),1.69(s,3H),1.45-1.36(m,1H),0.95(m,1H),MS(m / z)=978[MH] - .

[0142] Example 5 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((2-methyl-1,1-tetrahydro-2H-thiopyran-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (5)

[0143] Step 1: Compound 5.1 (10.00 g, 74.518 mmol, 1 eq.) was added to a 250 mL single-necked flask and dissolved in acetone (50 mL). K₂CO₃ (10.40 g, 75.250 mmol, 1.01 eq.) was added, followed by compound 5.2 (12.78 g, 74.535 mmol, 1.0 eq.). The mixture was heated to 55 °C under nitrogen protection and reacted for 15 hours. The reaction was monitored by NMR until completion. The system was cooled to room temperature, filtered, and the filter cake was washed with acetone (50 mL). The filtrate was evaporated to dryness. The resulting liquid was transferred to a 500 mL four-necked flask with DMF (40 mL). Under nitrogen protection, the temperature was lowered to -30 to -20 °C, and t-BuOK (10.04 g, 89.475 mmol, 1.201 eq.) dissolved in DMF (30 mL) was slowly added dropwise. After the addition was complete, the system was heated to 20 °C and reacted for 1 hour. The system temperature was lowered to 0℃, quenched with 2M HCl (95mL), and then extracted with PE (40mL) and EA (40mL). The organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and prepared as sintered precipitate. Column chromatography (PE:EA = 1:0–20:1) yielded compound 5.3 (8.60g, yield 61.29%). MS (m / z) = 188.28 [M+H] + .

[0144] Step 2: Compound 5.3 (8.60 g, 45.675 mmol, 1 eq.) was added to a 250 mL single-necked flask and dissolved in acetonitrile (90 mL). Then, acetic acid (18 mL) was added, followed by the addition of hydrogen peroxide (30%) (12.43 g, 109.644 mmol, 30% purity, 2.40 eq.) under ice bath conditions. The reaction was carried out at 90 °C for 12 hours. The system was cooled to room temperature, and sodium sulfite (2.3 g) and water (100 mL) were added under ice bath conditions. Extraction was performed using EA, followed by washing with saturated sodium bicarbonate solution of the organic phase. The mixture was dried over anhydrous magnesium sulfate, filtered, concentrated, and prepared as sintered precipitate. Column chromatography (PE:EA = 4:1 to 1:1) yielded compound 5.4 (8.16 g, yield 81.09%). MS (m / z) = 220.28 [M+H] + .

[0145] Step 3: Compound 5.4 (8.16 g, 37.043 mmol, 1 eq.) was dissolved in THF (80 mL) in a 250 mL four-necked flask. Under nitrogen protection, the system temperature was lowered to 0 °C, and lithium aluminum hydride (1.69 g, 44.474 mmol, 1.20 eq.) was slowly added. After the addition was complete, the system was slowly heated to 20 °C and reacted for 12 hours. The reaction was quenched by adding water (1.69 mL), 15% NaOH solution (1.69 mL), and water (5.07 mL) dropwise in an ice bath. After the addition was complete, a small amount of anhydrous magnesium sulfate was added to the system for drying. The mixture was filtered, and the filter cake was washed with tetrahydrofuran (50 mL). The filtrate was prepared as slurry. Column chromatography (PE:EA = 1:1 to 1:2) was performed to give compound 5.5 (6.35 g, yield 96.16%). MS (m / z) = 178.24 [M+H] + .

[0146] Step 4: Compound 5.5 (6.35 g, 35.624 mmol, 1 eq.) was added to a 250 mL single-necked flask and dissolved in DCM (65 mL). Dess-Martin reagent (16.62 g, 39.185 mmol, 1.1 eq.) was added in portions under ice bath conditions, and the system was gradually heated to 20 °C and reacted for 12 hours. The system was filtered through a diatomaceous earth liner, and the filter cake was washed with DCM (60 mL), concentrated, and prepared as slurry. Column chromatography (PE:EA = 3:1–2:1) yielded compound 5.6 (3.00 g, yield 47.78%). MS (m / z) = 176.23 [M+H] + .

[0147] Step 5: Compound 5.6 (3.00 g, 17.023 mmol, 1 eq.) was added to a 100 mL single-necked flask and dissolved in methanol (30 mL). K₂CO₃ (7.06 g, 51.083 mmol, 3.00 eq.) was then added, followed by dimethyl (1-diazo-2-oxopropyl)phosphonate (4.96 g, 25.551 mmol, 1.50 eq.) under ice bath conditions. After addition, the reaction was carried out at 20 °C for 12 hours. The system was filtered, the filter cake was washed with methanol (30 mL), concentrated, extracted with EA (30 mL), washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and prepared as sintered precipitate. Column chromatography (PE:EA = 3:1–2:1) yielded compound 5.7 (2.62 g, yield 89.35%). MS (m / z) = 172.24 [M+H] + .

[0148] Step 6: Add compound 5.7 (385 mg, 2.235 mmol, 1.101 eq.) and intermediate 1.7 (1.00 g, 2.032 mmol, 1.001 eq.) to a 50 mL single-necked flask, dissolve in DMF (10 mL), and then add triethylamine (617 mg, 6.098 mmol, 3.004 eq.), tetrakis(triphenylphosphine)palladium (118 mg, 102.114 μmol, 0.05 eq.), and CuI (24 mg, 126.017 μmol, 0.06 eq.) sequentially. Replace with nitrogen and react at 35 °C for 12 hours. The system was poured into ice water (30 mL), extracted with EA (30 mL), washed with organic brine (30 mL), dried over anhydrous magnesium sulfate, prepared as sinter, and subjected to column chromatography (PE:EA = 3:1–2:1) to give compound 5.8 (1.19 g, 100% yield). MS (m / z) = 583.48 [M+H] + .

[0149] Step 7: Compound 5.8 (1.19 g, 2.039 mmol, 1 eq.) was added to a 250 mL single-necked flask, followed by DCM (20 mL) and dioxane hydrochloride (40 mL). The reaction was carried out at 20 °C for 1 h. The system was then concentrated and evaporated to dryness to obtain crude compound 5.9 (985 mg, 100% yield). MS (m / z) = 483.36 [M+H] + .

[0150] Step 8: Compound 5.9 (986 mg, 2.040 mmol, 1 eq.) dissolved in DMF (20 mL) was added to a 100 mL single-necked flask. Compound 1.12 (576 mg, 2.041 mmol, 1.001 eq.) and DIPEA (792 mg, 6.128 mmol, 3.004 eq.) were added. Finally, HATU (931 mg, 2.449 mmol, 1.2 eq.) was added under nitrogen protection and in an ice bath. The reaction was carried out at 20 °C for 12 hours. The system was poured into ice water (60 mL), extracted with EA (60 mL), washed with water (60 mL) and saturated brine (60 mL), dried, evaporated to dryness, prepared as sintered sand, and subjected to column chromatography (PE:EA = 3:1 to 2:1) to obtain compound 5.10 (1.22 g, yield 80%). MS (m / z) = 747.52 [M+H]. + .

[0151] Step 9: Compound 5.10 (200 mg, 267.551 μmol, 1 eq.) and intermediate 1.9 (158 mg, 348.270 μmol, 1.302 eq.) were added to a 50 mL single-necked flask and dissolved in 1,4-dioxane (10 mL) and water (2 mL). KHCO3 (81 mg, 809.070 μmol, 3.024 eq.) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 26.821 μmol, 0.1 eq.) were added sequentially. The mixture was purged with nitrogen and heated to 70 °C for 15 h. The mixture was then prepared as a slurry, subjected to column chromatography (PE:EA = 4:1–2:1–3:2), concentrated, and then slurried with n-heptane, MTBE, and EA. The slurry was filtered and dried. Compound 5 (46 mg, yield 17.29%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ = 10.00 (s, 1H), 9.24 (m, 1H), 7.85-7.79 (m, 2H), 7.33-7.35 (m, 1H), 7.03-7.05 (m, 1H), 6.95 -6.81(m,1H),6.49(m,2H),4.98-4.85(m,1H),4.73(m,1H),4.66-4.45(m,1H),4.31(m,1H),4.04-3.92(m,1H),3.57-3.40(m,2H),3.25 -3.20(m,1H),3.17(m,3H),3.08(m,2H),2.63-2.58(m,1H),2.22(m,1H)2.10(m,2H),1. 97-1.88(m,2H),1.66(m,1H),1.41(m,3H),1.25(m,1H),0.96(s,1H), MS(m / z)=993[MH] - .

[0152] Example 6 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((2-methyl-1,1-dioxomorpholino-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (6)

[0153] Intermediate 6.1 was prepared according to the preparation method disclosed in WO2019035973A1.

[0154] Step 1: Compounds 1.12 (1.00 g, 2.55 mmol, 1.0 eq.), 6.1 (0.79 g, 2.55 mmol, 1.0 eq.), HATU (1.45 g, 3.81 mmol, 1.5 eq.), and DIPEA (0.98 g, 27.65 mmol, 3.0 eq.) were added to a single-necked flask, and DMF (10 mL) was added. The mixture was reacted at 25 °C for 14 h under nitrogen protection. Water (50 mL) was added to the system, and the mixture was extracted with EA. The organic phases were combined, dried, evaporated to dryness, prepared as slurry, and subjected to column chromatography (PE:EA = 1:1) to obtain compound 6.2 (1.60 g, yield 95.59%). MS (m / z) = 657 [M+H] + .

[0155] Step 2: Compound 6.3 (50.00 g, 369.86 mmol, 1.0 eq.) and TEA (74.85 g, 739.70 mmol, 2.0 eq.) were dissolved in THF (500 mL), and Boc anhydride (88.79 g, 406.82 mmol, 1.1 eq.) was slowly added dropwise. The reaction was carried out at 30 °C for 14 hours, evaporated to dryness, and water (1 L) was added. The mixture was stirred, filtered, and dried to obtain compound 6.4 (84.00 g, yield 96.51%). MS (m / z) = 236 [M+H] + .

[0156] Step 3: Compound 6.4 (20.00 g, 84.99 mmol, 1.0 eq.) was dissolved in THF (200 mL), cooled to -68 °C, and LiHMDS (1 M / THF) (212 mL, 2.5 eq.) was added and stirred for 1 hr. Then, a THF solution of isopropyl chloroformate (12.50 g, 101.99 mmol, 1.2 eq.) was added, and the reaction was carried out at -68 °C for 1.5 hr. LiHMDS (1 M / THF) (84 mL, 1.0 eq.) was added dropwise, and the reaction was carried out at -68 °C for 1.5 hr. The reaction was quenched with 1 N hydrochloric acid (250 mL), extracted with EA, the organic phases were combined, dried, and evaporated to dryness. The mixture was then subjected to sand column chromatography (PE:EA = 5:1) to obtain compound 6.5 (9.50 g, yield 34.77%). MS (m / z) = 322 [M+H] + .

[0157] Step 4: Compound 6.5 (6.86 g, 21.15 mmol, 1 eq.) and iodomethane (3.33 g, 23.27 mmol, 1.102 eq.) were dissolved in THF (700 mL). After the system temperature was lowered to -78 °C, LiHMDS (1 M) (21 mL, 1.1 eq.) was added dropwise using a constant pressure dropping funnel. The reaction was stirred at -78 °C for 1 hr, then heated to room temperature and stirred for 24 hr. The system was cooled, quenched with 1 N HCl, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and prepared as a granulation material. Column chromatography (PE:EA = 5:1) was performed to give compound 6.6 (6.50 g, yield 79.98%). MS (m / z) = 336 [M+H] + .

[0158] Step 5: Compound 6.6 (5.50 g, 16.39 mmol, 1 eq.) was dissolved in THF (60 mL) under nitrogen protection. Lithium aluminum hydride (618 mg, 16.28 mmol, 1.0 eq.) was added in portions under ice bath conditions, and the reaction was carried out at 0 °C for 12 hours. The reaction was quenched with 15% NaOH aqueous solution. After the addition was complete, a small amount of anhydrous magnesium sulfate was added to the system for drying. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. The filtrate was prepared into sand and subjected to column chromatography (PE:EA = 1:1) to give compound 6.7 (3.50 g, yield 76.48%). MS (m / z) = 280 [M+H] + .

[0159] Step Six: Compound 6.7 (3.50 g, 12.52 mmol, 1 eq.) was dissolved in DCM (40 mL). DMSO (9.78 g, 125.17 mmol, 10 eq.), DIPEA (6.47 g, 50.06 mmol, 4.0 eq.), and pyridine sulfur trioxide (5.98 g, 37.57 mmol, 3.0 eq.) were added in portions under ice bath conditions. The reaction was carried out at 0 °C for 1 hour, then at room temperature for 3 hours. The system was extracted with water, washed with saturated brine, dried, prepared as sintered sand, and subjected to column chromatography (PE:EA = 3:1) to give compound 6.8 (2.90 g, yield 83.45%). MS (m / z) = 278 [M+H]. + .

[0160] Step 7: Compound 6.8 (2.90 g, 10.45 mmol, 1 eq.) was dissolved in methanol (30 mL), and K₂CO₃ (4.33 g, 31.33 mmol, 3.004 eq.) was added. The mixture was cooled to 0 °C in an ice bath, and dimethyl (1-diazo-2-propanone)phosphonate (3.04 g, 15.66 mmol, 1.50 eq.) was added dropwise. The reaction was carried out at 20 °C for 12 hours. The system was directly extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, prepared as sintered sand, and subjected to column chromatography (PE:EA = 3:1) to give compound 6.9 (2.5 g, yield 87.46%). MS (m / z) = 274 [M+H] + .

[0161] Step 8: Compound 6.9 (499 mg, 1.82 mmol, 1.201 eq.) was dissolved in DMF (20 mL), and triethylamine (465 mg, 4.59 mmol, 3.019 eq.), bis(triphenylphosphine)palladium(II) dichloride (53 mg, 75.50 μmol, 0.05 eq.), and CuI (14 mg, 75.50 μmol, 0.05 eq.) were added. The reaction was carried out at room temperature for 12 h. The system was poured into three volumes of ice water, extracted with EA, and the organic phases were combined and washed with brine. The mixture was dried over anhydrous magnesium sulfate, prepared as sintered glass, and subjected to column chromatography (PE:EA = 3:1 to 2:1) to give compound 6.10 (0.85 mg, yield 65.72%). MS (m / z) = 549 [M+H] + .

[0162] Step 9: Compound 6.10 (0.85 g, 1.054 mmol, 1 eq.) was dissolved in dioxane (85 mL) and water (15 mL). Intermediate 2.8 (562 mg, 1.5 mmol, 1.5 eq.), potassium carbonate (414 mg, 2.99 mmol, 3.034 eq.), and Pd(dppf)Cl2 (180 mg, 250 μmol, 0.05 eq.) were added. The mixture was purged with nitrogen and heated to 80 °C for 12 h. The supernatant was collected and subjected to column chromatography (PE:EA = 5:1–2:1) to obtain compound 6.11 (720 mg, yield 70.65%). MS (m / z) = 1018 [M+H] + .

[0163] Step 10: Compound 6.11 (0.72 g, 707 μmol, 1 eq.) was dissolved in DCM (10 mL), and TEA (859 mg, 8.48 mmol, 12 eq.) and methanesulfonic anhydride (738 mg, 4.24 mmol, 6.0 eq.) were added dropwise. The mixture was reacted at 20 °C for 24 h, extracted with water, washed with saturated brine, and dried by rotary evaporation to obtain compound 6.12 (0.83 g, yield 99.99%). MS (m / z) = 1174 [M+H] + .

[0164] Step 11: Dissolve compound 6.12 (0.83 g, 707 mmol, 27 mmol, 1 eq.) in ethanol (10 mL), add an aqueous solution of sodium hydroxide (84 mg, 2.10 mmol, 3.0 eq.) (2 mL), react at 20 °C for 0.5 h, evaporate to dryness, prepare slag, and perform column chromatography (PE:acetone = 4:1) to obtain compound 6.13 (320 mg, yield 41.30%).

[0165] Step 12: Compound 6.13 (123 mg, 0.128 mmol, 1 eq.) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at 20 °C for 2 h. The system was evaporated to dryness, and saturated sodium bicarbonate solution and EA were added for extraction. The organic phase was dried to prepare sand, and column chromatography (PE:acetone = 2:1) was performed to obtain compound 6 (16 mg, yield 14.31%).

[0166] 1 H NMR (400MHz, DMSO-d6) δ = 10.16 (s, 1H), 9.25-9.30 (m, 1H), 7.83-7.89 (m, 2H), 7.29-7.35 (m, 1H), 7.01-7 .06(m,1H),6.91.6.92(m,0.5H),6.79-6.81(m,0.5H),6.47-6.49(m,2H),4.89-4.96(m,1H),4.68-4.72( m,1H),4.51-4.62(m,2H),3.96-4.00(m,1H),3.57-3.40(m,1H),3.22-3.66(m,3H),3.16(m,3H),3.11(m, 1H),2.91-3.20(m,3H),2.59-2.60(m,2H)1.62(m,3H),1.39-1.41(m,1H),0.97(s,1H).MS(m / z)=993[MH] - .

[0167] Example 7 Synthesis of N-((1S)-1-((4R)-4-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-1-(3-methyl-3-(S-methylsulfonylimino)but-1-yn-1-yl)-6,7-dihydro-5H-cyclopentane[c]pyridin-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (7)

[0168] Intermediate 10.1 was prepared according to the method disclosed in WO2021104413 A1.

[0169] Step 1: Using intermediate 10.1 as the starting material, and following the synthesis method of compound 2, compound 7 (60 mg, yield 16.56%) was obtained. 1 H NMR(400MHz,MeOD)δ10.00(s,1H),9.13-9.15(m,1H),7.33-7.34(m,1H),7.00(m,1H),6.91-6.9 3(m,1H),6.38-6.39(m,2H),4.93-4.97(m,1H),4.68-4.73(m,1H),4.50(m,2H),4.15(s,1H),4.0 0(m,1H),3.60(m,2H),3.32(s,3H),3.20(m,4H),2.90(m,2H),2.75-2.87(m,1H),2.50(m,2H),2. 32(m,2H),2.06(m,1H),1.85(m,1H),1.60(m,4H)1.45(m,1H),1.09(m,1H), MS(m / z)=1029[M+Na] + .

[0170] Example 8 N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-((S)-S-methylsulfonylimino)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (8.1) and N Synthesis of -((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-((R)-S-methylsulfonylimino)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (8.2)

[0171] Compounds 8.1 and 8.2 of Example 8 were prepared by chiral resolution of compound (2) of Example 2. The corresponding components were collected and concentrated under reduced pressure to obtain title compounds 8.1 and 8.2. The chiral resolution method is as follows:

[0172] Column: Chiralpak IG-3 100×4.6mm ID, 3μm

[0173] Mobile phase: A: CO2, B: Isopropanol (0.05% DEA)

[0174] Gradient: B: Increase from 5% to 40% over 5 minutes, hold at 40% for 2.5 minutes, then hold at 5% for 2.5 minutes.

[0175] Flow rate: 2.5 mL / min

[0176] Column temperature: 35℃

[0177] ABPR: 1500psi

[0178] Compound 8.1: 1H NMR (400MHz, DMSO) δ10.01(s,1H),9.25(m,1H),7.72-7.80(m,2H),7.31(m,1H),7.01-7.02(m,1H),6.47(m,2H),4.90-4.95(m,1H),4.50-4. 73(m,4H),4.17(m,1H),3.97-4.01(m,1H),3.16(s,3H),3.11(s,3H),3 .01(m,2H),2.50-2.62(m,2H),1.71(s,6H),1.43(m,1H),0.97(m,1H). MS(m / z)=989.49[M+Na] + .

[0179] Compound 8.2: 1 H NMR (400MHz, DMSO) δ10.01(s,1H),9.25(m,1H),7.72-7.80(m,2H),7.31(m,1H),7.01-7.02(m,1H),6.47(m,2H),4.90-4.95(m,1H),4.50-4. 73(m,4H),4.17(m,1H),3.97-4.01(m,1H),3.16(s,3H),3.11(s,3H),3 .01(m,2H),2.50-2.62(m,2H),1.71(s,6H),1.43(m,1H),0.97(m,1H). MS(m / z)=989.49[M+Na] + .

[0180] Example 9 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((2,5-dimethyl-1,1-dioxazoline-5-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (9)

[0181] Step 1: Add compound 9.1 (22.00 g, 181.581 mmol, 1 eq.) to a 2 L single-necked flask, dissolve in acetonitrile (770 mL), and add 18-crown-6 (39.36 g, 148.914 mmol, 8.20 eq.). -1The reaction mixture was prepared by reacting K₂CO₃ (100.38 g, 726.307 mmol, 4.0 eq.) and methyl iodoform (103.10 g, 726.373 mmol, 4.0 eq.) at 40 °C for 15 h under nitrogen protection. The system was directly filtered, the filter cake was washed with acetonitrile, and the filtrate was directly used to prepare sintered sand. Column chromatography (PE:EA = 3:1–1:2) gave compound 9.2 (22.42 g, yield 91.33%). MS (m / z) = 135.18 [M+H]. + .

[0182] Step 2: Compound 9.2 (21.38 g, 158.154 mmol, 1 eq.) and isopropyl chloroformate (21.32 g, 173.970 mmol, 1.1 eq.) were added to a 500 mL four-necked flask and dissolved in THF (500 mL). Under nitrogen protection, the mixture was cooled to approximately -78 °C using an ethanol dry ice bath. LiHMDS (1 M) (395 mL, 2.5 eq.) was slowly added dropwise using a constant pressure dropping funnel, maintaining the temperature below -70 °C during the addition. The system reacted at -78 °C to -60 °C for 3 hours. The system was then cooled to between -60 °C and -40 °C, and quenched by slowly adding 4N HCl (60 mL). An appropriate amount of anhydrous magnesium sulfate was added for drying. The mixture was stirred briefly, filtered, and then directly prepared as sintered precipitate. Column chromatography (PE:EA = 3:1 to 2:1) was performed to obtain compound 9.3 (28.59 g, yield 81.69%). MS(m / z) = 221.27[M+H] + .

[0183] Step 3: Compound 9.3 (27.49 g, 124.235 mmol, 1 eq.) was added to a 5 L four-necked flask. Iodomethane (19.41 g, 136.750 mmol, 1.101 eq.) dissolved in THF (2034 mL). After the system temperature was lowered to -78 °C, LiHMDS (1 M) (150 mL, 1.1 eq.) was slowly added dropwise using a constant pressure dropping funnel. The reaction was stirred at -78 °C for 1 h, then slowly raised to room temperature and stirred for 15 h. The system was cooled, quenched with 1 N HCl (25 mL), extracted with EA, washed with saturated brine, dried over anhydrous magnesium sulfate, and prepared as sintered silicate. Column chromatography (PE:EA = 5:1 to 3:1) yielded compound 9.4 (19.78 g, yield 67.67%). MS (m / z) = 235.30 [M+H] + .

[0184] Step 4: Following the synthetic method for compound 3.5, compound 9.5 was obtained (13.19 g, yield 87.54%). MS (m / z) = 179.23 [M+H] + .

[0185] Step 5: Compound 9.5 (13.19 g, 73.590 mmol, 1 eq.) was dissolved in DCM (130 mL) in a 500 mL single-necked flask. Under nitrogen protection and in an ice bath, Dess-Martin reagent (34.39 g, 81.082 mmol, 1.102 eq.) was slowly added in portions. The reaction was carried out at room temperature for 12 h. The system was directly filtered, and the filter cake was washed with DCM (60 mL). The filtrate was directly evaporated to dryness, prepared as sinter, and subjected to column chromatography (PE:EA = 2:1) to obtain compound 9.6 (12.55 g, yield 96.23%). MS (m / z) = 177.22 [M+H] + .

[0186] Step Six: Following the synthetic method for compound 3.7, compound 9.7 was obtained (8.54 g, yield 69.61%). MS (m / z) = 173.23 [M+H] + .

[0187] Step 7: Following the synthetic method for compound 5.8, compound 9.8 was obtained (2.20 g, yield 92.63%). MS (m / z) = 584.47 [M+H] + .

[0188] Step 8: Following the synthetic method for compound 5.9, crude compound 9.9 was obtained (1.82 g, 100% yield) MS (m / z) = 484.35 [M+H] + .

[0189] Step 9: Following the synthetic method for compound 5.10, compound 9.10 was obtained (342 mg, yield 86.58%). MS (m / z) = 748.50 [M+H] + .

[0190] Step 10: Add compound 9.10 (298 mg, 398.125 μmol, 100% purity, 1 eq.) and intermediate 2.8 (300 mg, 798.763 μmol, 2.006 eq.) to a 100 mL single-necked flask, dissolved in 1,4-dioxane (10 mL), water (2 mL), potassium carbonate (169 mg, 1.223 mmol, 3.071 eq.), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine-palladium(II) (57 mg, 80.282 μmol, 2.016 eq.). -1 The mixture was purged with nitrogen and heated to 80°C for 15 hours. The system was then directly converted to sand, and column chromatography (PE:EA = 10:1–2:1) yielded compound 9.11 (160 mg, yield 43.83%). MS (m / z) = 917.21 [M+H]. + .

[0191] Step 11: Compound 9.11 (160 mg, 174.441 μmol, 1 eq.) was added to a 100 mL single-necked flask, dissolved in DCM (5 mL), followed by triethylamine (106 mg, 1.048 mmol, 6.005 eq.). Methanesulfonic anhydride (60 mg, 523.789 μmol, 3.003 eq.) was added under ice bath conditions, and the mixture was then heated to 20 °C and reacted for 1 hour. The system was extracted with ice water (5 mL), and the organic phase was directly evaporated to dryness to give compound 9.12 (138 mg, yield 73.79%). MS (m / z) = 1073.39 [M+H] + .

[0192] Step 12: Compound 9.12 (138 mg, 128.564 μmol, 1 eq.) was added to a 50 mL single-necked flask and dissolved in ethanol (2 mL) and 2N NaOH solution (0.2 mL, 3 eq.). The reaction was carried out at 20 °C for 1 hour. Acetic acid (6 mg) was added to the system, followed by DCM (10 mL). The mixture was extracted, separated, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and prepared as a slurry. Column chromatography (PE:EA = 5:1 to 2:1) was performed. After the solvent was evaporated to dryness, n-heptane and EA were added to form a slurry, which was then filtered and dried. Compound 9 (35 mg, yield 27.35%) was obtained. 1 H NMR (400MHz, DMSO) δ10.00-10.03(s,1H),9.22-9.27(m,1H),7.80-7.88(m,1H),7.73(m,1H),7.71(m ,1H),7.32(m,1H),7.03(m,1H),6.82-6.90(m,1H),6.46-6.48(m,2H),4.91-4.95(m,1H),4.89(m,1H ),4.68-4.72(m,1H),4.02-4.04(m,1H),3.31-3.33(s,3H),3.00(m,2H),2.68-2.75(m,3H),2.48-2. 49(m,1H),1.73(m,3H),1.45(m,1H),1.25(m,3H),0.86-0.88(m,1H),0.84(m,2H), MS(m / z)=996[M+H] + .

[0193] Example 10 Synthesis of N-((S)-1-(S)-4-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-1-(((R)-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)-6,7-dihydro-5H-cyclopentane[c]pyridin-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (10)

[0194] Intermediate 10.1 was prepared according to the preparation method disclosed in WO2021104413A1.

[0195] Step 1: Using intermediate 10.1 as the starting material, the racemic mixture was obtained following the synthetic method of compound 1.8. Compound 10.2 was then prepared chirally (3.50 g, 30% yield). MS (m / z) = 610.52 [M+H] + The chiral decomposition method is as follows:

[0196] Instrument: Waters 200 preparative SFC (QC-R-LC-07)

[0197] Column: ChiralPak IC, 250×50mm ID, 10μm

[0198] Mobile phase: A: CO2, B: Methanol

[0199] Gradient: B: 40%

[0200] Flow rate: 150 mL / min

[0201] Back pressure: 100 bar

[0202] Column temperature: 35℃

[0203] Wavelength: 210nm

[0204] Cycle time: Approximately 4 minutes

[0205] Sample preparation: The compound was dissolved in approximately 500 mL of methanol.

[0206] Injection: 6mL / time

[0207] Step 2: Using intermediate 10.1 as the starting material, the racemic mixture was obtained by following the synthetic method of compound 1.8. Compound 10.3 (3.50 g, yield 30%) was then prepared chirally. MS (m / z) = 610.52 [M+H] +The chiral decomposition method is as follows:

[0208] Instrument: Waters 200 preparative SFC (QC-R-LC-07)

[0209] Column: ChiralPak IC, 250×50mm ID, 10μm

[0210] Mobile phase: A: CO2, B: Methanol

[0211] Gradient: B 40%

[0212] Flow rate: 150 mL / min

[0213] Back pressure: 100 bar

[0214] Column temperature: 35℃

[0215] Wavelength: 210nm

[0216] Cycle time: Approximately 4 minutes

[0217] Sample preparation: The compound was dissolved in approximately 500 mL of methanol.

[0218] Step 3: Using compound 10.2 instead of compound 2.7 as the starting material, the synthesis of compound 2.9 was performed according to the same method as for compound 2.9, yielding title compound 10.2.1 (700 mg, yield 36%). MS (m / z) = 779.30 [M+H] + .

[0219] Step 4: Using compound 10.2.1 instead of compound 6.11 as the starting material, the synthesis of compound 6.12 was performed according to the synthetic method described for compound 6.12, yielding title compound 10.2.1.1 (800 mg, yield 95.50%). MS (m / z) = 935.41 [M+H] + .

[0220] Step 5: Using compound 10.2.1.1 instead of compound 1.10 as the starting material, and following the synthetic method for compound 1.11, compound 10.2.1.2 was synthesized to obtain compound 10.2.1.2 (745 mg, 99% yield). MS (m / z) = 835.25 [M+H] + .

[0221] Step Six: Compound 10.2.1.2 (0.745 g, 855.579 μmol, 1 eq.) was dissolved in DMF (18 mL), and DIPEA (520 mg, 4.023 mmol, 0.7 mL, 4.703 eq.), compound 1.12 (320 mg, 1.134 mmol, 1.326 eq.), and HATU (420 mg, 1.105 mmol, 1.291 eq.) were added. The reaction was carried out under nitrogen protection at room temperature (20 °C) for 2 h. Then, 2N sodium hydroxide (4.3 mL) was added to the system, and the reaction was carried out at room temperature (20 °C) for 1 h. The reaction was confirmed to be complete by LCMS. Ice water (30 mL) and EA (30 mL) were added to the system. After thorough stirring, the mixture was separated. The aqueous phase was extracted once with EA, and the organic phase was washed with water and saturated brine. The mixture was dried, evaporated to dryness, and prepared into sand. Column chromatography (PE:EA = 10:1 to 5:1) was performed to obtain the title compound 10 (660 mg, yield 75.602%). 1 H NMR(400MHz,MeOD)δ7.20-7.22(d,1H),6.78(m,1H),6.49-6.51(m,1H),6.28-6.29(m, 2H),4.76-4.90(m,3H),4.60-4.63(m,2H),4.00-4.03(m,1H),3.42(m,1H),3.32(m,4H ),3.14(m,2H),3.02-3.04(m,1H),2.90(m,1H),2.75-2.87(m,1H),2.10-2.70(m,8H), 2.20(m,1H),2.06(m,1H),1.79(s,3H),1.45(m,1H),1.12(m,1H), MS(m / z)=1020[M+H] + .

[0222] Example 11 Synthesis of N-(S)-1-((S)-4-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-1-(((S)-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)-6,7-dihydro-5H-cyclopentane[c]pyridin-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (11)

[0223] Following the synthetic method of compound 10, intermediate 10.2.1 was replaced with compound 10.2.2 as the starting material to synthesize title compound 11 (20 mg, yield 8.3%). 1H NMR(400MHz,MeOD)δ7.25-7.27(m,2H),6.64-6.73(m,3H),4.90(m,2H),4.63(m,2H),3.97-4.11(m ,2H),3.17-3.34(m,9H),2.23-2.64(m,10H),1.78(s,3H),1.42(m,1H),1.25(m,1H),1.10(m,1H). MS(m / z)=1042[M+Na] + .

[0224] Example 12 Synthesis of N-(((S)-1-((R)-4-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-1-(((S)-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)-6,7-dihydro-5H-cyclopentane[c]pyridin-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (12)

[0225] Compounds 10.3.1 and 10.3.2 were obtained by referring to the synthetic methods of compounds 10.2.1 and 10.2.2.

[0226] Following the synthetic method of compound 10, intermediate 10.2.1 was replaced with compound 10.3.1 as the starting material to synthesize title compound 12 (660 mg, yield 75.6%). 1 H NMR(400MHz,MeOD)δ7.20-7.22(d,1H),6.78(m,1H),6.49-6.51(m,1H),6.28-6.29(m, 2H),4.76-4.90(m,3H),4.60-4.63(m,1H),4.00-4.03(m,1H),3.42(m,1H),3.32(s,3H ),3.14(m,2H),3.02-3.04(m,1H),2.90(m,1H),2.75-2.87(m,1H),2.10-2.70(m,7H), 2.20(m,1H),2.06(m,1H),1.79(s,6H),1.45(m,1H),1.12(m,1H), MS(m / z)=1042[M+Na] + .

[0227] Example 13 Synthesis of N-((S)-1-((R)-4-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-1-(((R)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)-6,7-dihydro-5H-cyclopentane[c]pyridin-3-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (13)

[0228] Following the synthetic method of compound 10, intermediate 10.2.1 was replaced with compound 10.3.2 as the starting material to synthesize title compound 13 (540 mg, yield 76.2%). 1 H NMR(400MHz,MeOD)δ7.26-7.18(m,2H),6.66-6.73(m,3H),4.90(m,2H),4.63(m,3H),3.97-4.11(m,2H),3.17 -3.34(m,7H),2.23-2.64(m,10H),1.78(s,3H),1.42(m,1H),1.26(m,1H),1.11(m,1H), MS(m / z)=1042[M+Na] + .

[0229] Example 14 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-2,5-dimethyl-1,1-dioxazoline-5-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (14)

[0230] Intermediate 9.9 was prepared chirally (separation conditions: ChiralPak IC, 250×50mm ID, 10μm; mobile phase: A for CO2 and B for (Methanol:ACN=1:1), flow rate: 150mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to give compound 9.9.1 (2.64 g, yield 91.66%), MS (m / z) = 584.47 [M+H). +Compound 9.9.2 (2.70 g, yield 93.75%), MS (m / z) = 584.47 [M+H] + .

[0231] Step 1: Following the synthetic method for compound 5.9, crude compound 14.1 was obtained (2.18 g, 100% yield). MS (m / z) = 484.35 [M+H] + .

[0232] Step 2: Following the synthetic method for compound 5.10, compound 14.2 was obtained (407 mg, yield 52.72%). MS (m / z) = 748.50 [M+H] + .

[0233] Step 3: Following the synthetic method for compound 9.11, compound 14.3 was obtained (210 mg, yield 42.16%). MS (m / z) = 917.21 [M+H] + .

[0234] Step 4: Following the synthetic method for compound 9.12, crude compound 14.4 was obtained (244 mg, 100% yield). MS (m / z) = 1073.39 [M+H] + .

[0235] Step 5: Following the synthesis method of compound 9, compound 14 (74 mg, yield 32.74%) was obtained. 1 HNMR(400MHz,DMSO)δ10.05(s,1H),9.24-9.27(m,1H),7.80-7.82(m,1H),7.71-7.73(m,1H),7.31 -7.33(m,1H),6.90(m,1H),6.88(m,1H),6.46-6.49(m,2H),4.94(m,1H),4.89(m,1H),4.68-4.72(m ,1H),4.59-4.61(m,1H),4.51(m,1H),3.96(m,1H),3.30-3.34(m,3H),3.16(m,2H),3.08(m,2H),2. 75(m,3H),2.68(m,1H),2.50-2.51(m,2H),1.73(m,3H),1.41(m,1H),0.90(m,1H)MS(m / z)=993[MH] - .

[0236] Example 15 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-2,5-dimethyl-1,1-dioxazoline-5-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (15)

[0237] Intermediate 9.9 was prepared chirally (separation conditions: ChiralPak IC, 250×50mm ID, 10μm; mobile phase: A for CO2 and B for (Methanol:ACN = 1:1), flow rate: 150mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to give compound 9.9.1 (2.64 g, yield 91.66%), MS (m / z) = 584.47 [M+H). + ; and compound 9.9.2 (2.70 g, yield 93.75%), MS (m / z) = 584.47 [M+H] + .

[0238] Step 1: Following the synthetic method for compound 5.9, crude compound 15.1 was obtained (2.23 g, 100% yield). MS (m / z) = 484.35 [M+H] + .

[0239] Step 2: Following the synthetic method for compound 5.10, compound 15.2 (395 mg, yield 51.16%) was obtained. MS (m / z) = 748.50 [M+H] + .

[0240] Step 3: Following the synthetic method for compound 9.11, compound 15.3 (190 mg, yield 39.25%) was obtained. MS (m / z) = 917.21 [M+H] + .

[0241] Step 4: Following the synthetic method for compound 9.12, crude compound 15.4 was obtained (222 mg, 100% yield). MS (m / z) = 1073.39 [M+H] + .

[0242] Step 5: Following the synthetic method of compound 9, title compound 15 (32 mg, yield 25.19%) was obtained. 1H NMR(400MHz,DMSO)δ9.99(s,1H),9.22-9.24(m,1H),7.80-7.82(m,1H),7.71-7.73(m,1H),7.71(m ,1H),7.30-7.32(m,1H),7.02-7.03(m,1H),6.82-6.84(m,1H),6.46-6.48(m,2H),4.91-4.95(m,1H ),4.89(m,1H),4.68-4.72(m,1H),3.99(m,1H),3.16(m,3H),3.10(m,2H),3.08(m,2H),2.75(m,3H ),2.66(m,1H),2.55(m,1H),1.73(m,3H),1.51(m,1H),1.26(m,2H),0.86(m,1H), MS(m / z)=993[MH] - .

[0243] Example 16 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((5-methyl-1,1-dioxoisothiazoline-5-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (16)

[0244] Step 1: Compound 16.1 (5.00 g, 41.268 mmol, 1 eq.) was added to a 250 mL single-necked flask and dissolved in DMF (50 mL). Under nitrogen protection and in an ice bath, NaH (1.49 g, 62.089 mmol, 1.505 eq.) was slowly added. After 10 min, Boc anhydride (13.51 g, 61.901 mmol, 1.5 eq.) was added, and the system was slowly heated to 20 °C and reacted for 15 h. The system was then poured into ice water (150 mL), extracted with EA, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and prepared as a precipitate. Column chromatography (PE:EA = 3:1–2:1) yielded compound 16.2 (6.63 g, yield 72.60%). MS (m / z) = 221.27 [M+H] + .

[0245] Step 2: Following the synthetic method for compound 9.3, compound 16.3 was obtained (9.20 g, 90% yield). MS (m / z) = 307.36 [M+H] + .

[0246] Step 3: Following the synthetic method for compound 9.4, compound 16.4 was obtained (8.00 g, yield 93.33%). MS (m / z) = 321.38 [M+H] + .

[0247] Step 4: Following the synthetic method for compound 5.9, crude compound 16.5 was obtained (8.00 g, 100% yield). MS (m / z) = 221.27 [M+H] + .

[0248] Step 5: Compound 16.5 (3.47 g, 15.682 mmol, 1 eq.) was added to a 250 mL single-necked flask and dissolved in acetonitrile (80 mL). Potassium carbonate (4.77 g, 34.514 mmol, 2.20 eq.) and PBMCL (2.58 g, 16.474 mmol, 1.05 eq.) were then added. The reaction was carried out at 80 °C for 15 h under nitrogen protection. After cooling to room temperature, water (50 mL) and EA (50 mL) were added for extraction. The organic phase was dried over anhydrous magnesium sulfate and prepared as a precipitate. Column chromatography (PE:EA = 10:1–3:1) yielded compound 16.6 (4.95 g, 92.45% yield). MS (m / z) = 341.42 [M+H] + .

[0249] Step Six: Following the synthetic method for compound 3.5, compound 16.7 (1.56 g, yield 37.71%) was obtained. MS (m / z) = 285.35 [M+H] + .

[0250] Step 7: Following the synthetic method for compound 9.6, compound 16.8 was obtained (1.20 g, yield 77.46%). MS (m / z) = 283.34 [M+H] + .

[0251] Step 8: Following the synthetic method for compound 3.7, compound 16.9 was obtained (1.06 g, yield 89.60%). MS (m / z) = 279.35 [M+H] + .

[0252] Step 9: Following the synthetic method for compound 5.8, title compound 16.10 was obtained (1.47 g, yield 57.87%). MS (m / z) = 854.63 [M+H] + .

[0253] Step 10: Following the synthetic method for compound 9.11, compound 16.11 was obtained (229 mg, yield 32.99%). MS (m / z) = 1023.33 [M+H] + .

[0254] Step 11: Following the synthetic method for compound 9.12, crude compound 16.12 was obtained (263 mg, 100% yield). MS (m / z) = 1179.51 [M+H] + .

[0255] Step 12: Following the synthetic method for compound 9, crude compound 16.13 was obtained (245 mg, 100% yield). MS (m / z) = 1101.42 [M+H] + .

[0256] Step 13: Compound 16.13 (245 mg, 222.439 μmol, 1 eq.) was added to a 50 mL single-necked flask and dissolved in 2 mL DCM. Under nitrogen protection, trifluoroacetic acid (2 mL) was added to the system in an ice bath, and the reaction was carried out at 20 °C for 8 hours. After the trifluoroacetic acid was evaporated to dryness, DCM was added to dissolve and prepare a slurry. Column chromatography (PE:EA = 10:1–2:1), followed by stirring with n-heptane, filtration, and drying, yielded the title compound 16 (58 mg, yield 26.57%). 1 H NMR(400MHz,DMSO)δ9.99(s,1H),9.26-9.28(m,1H),7.80-7.82(m,1H),7.72-7.74(m,1H),7.4 8(m,1H),7.30-7.33(m,1H),7.03(m,1H),6.82-6.88(m,1H),6.46-6.48(m,2H),4.90-4.96(m,1 H),4.68-4.72(m,1H),4.68-4.72(m,1H),3.97(m,1H),3.24-3.32(m,3H),3.16(m,3H),2.99(m ,2H),2.68(m,1H),2.59-2.60(m,3H),1.71(m,3H),1.41(m,1H),0.96(m,1H), MS(m / z)=979[MH] - .

[0257] Example 17 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-2,5,5-trimethyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (17)

[0258] Steps 1-3: Following the synthetic methods for compounds 3.3 to 3.5, compound 17.5 was obtained (21.40 g, yield 82.49%). MS (m / z) = 164.22 [M+H] + .

[0259] Step 4: Imidazole (12.00 g, 176.271 mmol, 1.5 eq.) was added to a stirred solution of compound 17.5 (19.30 g, 117.524 mmol, 1 eq.) in 200 mL of DCE. The mixture was then cooled to 0 °C, and tert-butyldimethylchlorosilane (11.62 g, 141.100 mmol, 1.201 eq.) was added. The mixture was stirred at 20 °C for approximately 15 h. The resulting mixture was washed with brine (200 mL × 2), dried over MgSO4, and concentrated under reduced pressure. Column chromatography was performed to give compound 17.6 (31.95 g, 97.64% yield). MS (m / z) = 278.48 [M + H] + .

[0260] Step 5: Under nitrogen protection, compound 17.6 (10.00 g, 35.909 mmol, 1 eq.) was dissolved in tetrahydrofuran (200 mL), followed by the addition of tetramethylethylenediamine (8.35 g, 71.856 mmol, 10.774 mL, 2.001 eq.). The mixture was then cooled to -78 °C, and n-butyllithium (2.65 g, 41.367 mmol, 17 mL, 1.152 eq.) was slowly added dropwise. The solution was stirred for another 0.5 h, and iodomethane (5.61 g, 39.524 mmol, 2.461 mL, 1.101 eq.) was added. The solution was then heated to -50 °C for approximately 1.5 h. TLC showed no residue of the starting material. The resulting mixture was cooled to -78°C, and tetramethylethylenediamine (8.35 g, 71.856 mmol, 10.774 mL, 2.001 eq.) was added, followed by the slow dropwise addition of n-butyllithium (2.30 g, 35.904 mmol, 17 mL, 1.0 eq.). The solution was stirred for another 15 min, and methyl iodoform (5.61 g, 39.524 mol, 2.461 mL, 1.101 eq.) was added. The mixture was then stirred at -65°C for approximately 0.5 h. A saturated aqueous solution of NH₄Cl (50 mL), a saturated brine solution (150 mL), and EA (100 mL) were added sequentially to separate the organic phase. The mixture was washed with saturated brine (200 mL × 3) and dried over MgSO₄. Column chromatography yielded compound 17.7 (6.05 g, yield 54.96%). MS (m / z) = 306.53 [M + H]. + .

[0261] Step Six: Add 1N HCl (30 mL, 1 eq.) to a stirred solution of compound 17.7 (6.41 g, 20.911 mmol, 1 eq.) in acetonitrile (90 mL). Stir the reaction mixture at room temperature for approximately 15 h. Concentrate the mixture to dryness, then dissolve it in EA (50 mL) and prepare a precipitate. Column chromatography yielded compound 17.8 (4.00 g, 99.47% yield). MS (m / z) = 192.27 [M+H] + .

[0262] Steps seven and eight: Following the synthetic method for compounds 9.6-9.7, compound 17.10 was obtained (2.32 g, yield 78.14%). MS (m / z) = 190.25 [M+H] + .

[0263] Step Nine: Following the synthetic method for compound 5.8, the compound was prepared chirally (separation conditions: ChiralPak IC, 250 × 50 mm ID, 10 μm; mobile phase: A: CO2, B: methanol, flow rate: 150 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to give compound 17.11 (1.42 g, yield 88.75%). MS (m / z) = 597.51 [M+H] + And 17.12 (1.38 g, yield 86.25%), MS (m / z) = 597.51 [M+H] + .

[0264] Step 10: Following the synthetic method of compounds 15.1-15, title compound 17 (75 mg, yield 21.67%) was obtained. 1H NMR (400MHz, DMSO) δ10.00(s,1H),9.24(d,J=8.2Hz,1H),7.80(d,J=8.1Hz,1H),7.69(d,J=8.0Hz,1H),7.33(d,J=7.7Hz,1H),7.02 (t,J=9.5Hz,1H),6.91(d,J=7.7Hz,1H),6.48(d,J=6.6Hz,2H),4.91(d,J=16.4Hz,1H),4.71(d,J=16.4Hz,1H),4.60(dd,J=14.2,8. 5Hz,1H),4.50(dd,J=16.2,8.4Hz,1H),3.96(dd,J=16.4,8.6Hz,1H),3.17(s,3H),2.98(dt,J=21.8,10.4Hz,2H),2.56(d,J=20.8H z,2H),2.46(d,J=10.6Hz,1H),2.28–2.13(m,3H),1.69(s,3H),1.51–1.43(m,3H),1.41(d,J=6.4Hz,1H),1.37(s,3H),1.25(s,1H). MS(m / z)=1008.30[M+H] + .

[0265] Example 18 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-2,5,5-trimethyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (18)

[0266] Following the synthetic method of compounds 15.1-15, title compound 18 (58 mg, yield 33.72%) was obtained. 1H NMR (400MHz, DMSO) δ10.02(s,1H),9.16(d,J=8.4Hz,1H),7.79(d,J=8.0Hz,1H),7.68(d,J=7.9Hz,1H),7.30(d,J=7.7Hz,1H),7 .04–6.97(m,1H),6.81(d,J=7.7Hz,1H),6.45(d,J=6.3Hz,2H),4.91(d,J=16.4Hz,1H),4.69(d,J=16.4Hz,1H),4.64–4.58(m,1 H),4.50(dd,J=16.3,8.1Hz,1H),3.96(dd,J=16.8,8.4Hz,1H),3.15(s,3H),3.03–2.90(m,2H),2.63–2.53(m,2H),2.46–2.42( m,1H),2.23–2.06(m,3H),1.67(s,3H),1.46(s,3H),1.41(d,J=6.7Hz,1H),1.35(s,3H),0.94(s,1H)., MS(m / z)=1008.52[M+H] - .

[0267] Example 19 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((6-methyl-5,5-dioxy-5-thiaspiro[2,4]heptane-6-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-trifluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (19)

[0268] Step 1: Compound 19.2 (1.00 g, 7.452 mmol, 1.0 eq.) was dissolved in DMF (5 mL), cooled to 0 °C, and a solution of potassium tert-butoxide (1.62 g, 14.437 mmol, 2.0 eq.) in DMF (5 mL) was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, a solution of compound 19.1 (1.69 g, 7.415 mmol, 1.0 eq.) in DMF (5 mL) was added dropwise. The reaction was allowed to proceed at 30 °C for 14 h. Extraction was performed with water (20 mL) and EA (20 mL). The organic phase was washed with water, dried, and prepared as granules. Column chromatography (PE:EA = 20:1) was performed to obtain compound 19.3 (1.00 g, yield 66.9%). MS (m / z) = 201 [M+H] + .

[0269] Step 2: Compound 19.3 (1.00 g, 4.993 mmol, 1.0 eq.) dissolved in acetonitrile (10 mL) and acetic acid (2 mL) was added to a 100 mL single-necked flask. 30% hydrogen peroxide (1.38 g, 12.173 mmol, 2.5 eq.) was slowly added dropwise. The reaction was carried out at 90 °C for 14 h. The reaction was quenched with saturated sodium sulfite, and the mixture was extracted with EA (20 mL). The organic phase was washed twice with saturated sodium bicarbonate, dried, and prepared by column chromatography (EA:PE = 1:10) to give compound 19.4 (0.80 g, yield 68.9%). MS (m / z) = 231 [MH]. + .

[0270] Step 3: Compound 19.5 (600 mg, yield 91.57%) was obtained following the procedure for compound 6.7. MS (m / z) = 189 [MH] + .

[0271] Step 4: Compound 19.6 (400 mg, yield 62.79%) was obtained following the procedure for compound 6.8. MS (m / z) = 187 [MH] + .

[0272] Step 5: Compound 19.7 (300 mg, yield 76.62%) was obtained following the procedure for compound 6.9. MS (m / z) = 183 [MH] + .

[0273] Step 6: Following the procedure for compound 6.10, we obtained title compound 19.8 (500 mg, yield 86.39%). MS (m / z) = 760 [M+H] + .

[0274] Step 7: Compound 19.8 (0.25 g, 0.329 mmol, 1 eq.) was dissolved in dioxane (10 mL) and water (2 mL), and intermediate 1.9 (194 mg, 0.427 mmol, 1.299 eq.), potassium bicarbonate (99 mg, 0.988 mmol, 3.004 eq.), and Pd(dppf)Cl2 (24 mg, 32.915 μmol, 0.1 eq.) were added. The mixture was purged with nitrogen and heated to 70 °C for 12 h. The supernatant was collected, prepared as a slurry, and subjected to column chromatography (PE:EA = 5:1 to 2:1) to obtain the title compound 19 (5.2 mg, yield 1.57%). 1H NMR (400MHz, DMSO) δ10.00(s,1H),9.23-9.26(m,1H),7.71-7.83(m,2H),7.32-7.33(m,1H),6.81-6.91(m,2H),6.48(s,2H),4.58-4. 92(m,4H),3.96(m,1H),3.16(s,3H),3.07(m,2H),2.63–2.53(m,2H),2.26(m,2H),1.76(s,3H),1.24-1.41(s,4H),0.78-0.96(m,4H). MS(m / z)=1006[MH] - .

[0275] Example 20 Synthesis of N-((S)-1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(((R)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (20)

[0276] Step 1: Compound 20.1 (5.00 g, 20.28 mmol, 1.0 eq.) was dissolved in DMF (50 mL) under nitrogen protection. Compound 20.2 (4.67 g, 24.33 mmol, 1.2 eq.) was added, followed by cesium carbonate (9.91 g, 30.42 mmol, 1.5 eq.). The reaction was carried out at 70 °C for 12 h. After the reaction was complete, water (20 mL) and EA (100 mL) were added for extraction. The organic phase was washed twice with water, dried, and prepared by column chromatography (PE:EA = 3:1) to obtain compound 20.3 (4.10 g, yield 65.1%). MS (m / z) = 311 [M+H] + .

[0277] Step 2: Compound 20.3 was dissolved in a mixed solvent of DMF (2 mL) and toluene (6 mL) under nitrogen protection. Then, pinacol diborate (981 mg, 3.863 mmol, 1.2 eq.) and palladium dichloride bis(triphenylphosphine) (32 mg, 45.591 μmol, 1.416 e) were added. -2The mixture was reacted at 110 °C for 12 h. After the reaction was complete, water (10 mL) and EA (50 mL) were added for extraction. The organic phase was washed with water, dried, and prepared by column chromatography (PE:EA = 3:1) to give compound 20.4 (730 mg, yield 63.3%). MS (m / z) = 358 [M+H] + .

[0278] Step 3: Compound 20.4 (700 mg, 1.95 mmol, 1.0 eq.) was dissolved in a mixed solution of THF (10 mL) and TEA (1 mL), and methanesulfonic anhydride (409 mg, 2.34 mmol, 1.2 eq.) was added. The mixture was reacted at 80 °C for 12 h. After the reaction was complete, water (10 mL) and EA (50 mL) were added for extraction. The organic phase was washed with water, dried, and prepared as precipitate. Column chromatography (PE:EA = 3:1) was performed to obtain compound 20.5 (720 mg, yield 71.5%). MS (m / z) = 514 [M+H] + .

[0279] Step 4: Compound 3.10.2 (285 mg, 388.552 μmol, 9.981 e) -1 Compound 20.5 (300 mg, 583.91 μmol, 1.5 eq.) and compound 20.5 (300 mg, 583.91 μmol, 1.5 eq.) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) under nitrogen protection, and then dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine-palladium(II) (45 mg, 57.10 μmol, 1.467 eq.) was added. -1 K2CO3 (161 mg, 1.16 mmol, 3.0 eq.) was added and reacted at 80 °C for 12 h. After the reaction was complete, water (10 mL) and EA (50 mL) were added for extraction. The organic phase was washed with water, dried and sanded to give title compound 20 (15 mg, yield 4.00%). 1 H NMR(400MHz,DMSO)δ9.94(s,1H),9.30–8.87(m,1H),7.99–7.50(m,2H),7.39–6.83(m, 3H),6.52(s,2H),6.10(t,J=54.8Hz,1H),5.18–4.48(m,4H),4.05(m,J=13.1Hz,1H),3 .72(m,J=15.0Hz,1H),3.17(s,3H),3.08–2.92(m,2H),2.54(s,2H),2.46–2.40(m,1H) ,2.26(s,3H),1.69(s,3H),1.45–1.14(m,2H),0.95(s,1H), LC-MS(m / z)=962.15[M+H] + .

[0280] Example 21 Synthesis of N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (21)

[0281] Step 1: In a 100 mL single-necked flask, dissolve compound 3.10.2 (500 mg, 681.669 μmol, 100% purity, 1 eq.) and intermediate 2.8 (512 mg, 1.363 mmol, 2.000 eq.) in 1,4-dioxane (15 mL) and water (3 mL), then add potassium carbonate (283 mg, 2.048 mmol, 3.004 eq.) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine-palladium(II) (97 mg, 136.620 μmol, 2.004 eq.). -1 The mixture was purged with nitrogen and heated to 80 °C for 15 h. Column chromatography (PE:EA = 10:1–2:1) yielded compound 21.1 (163 mg, yield 26.50%). MS (m / z) = 902.20 [M+H]+.

[0282] Step 2: Compound 21.1 (163 mg, 180.669 μmol, 1 eq.) and DMAP (45 mg, 368.348 μmol, 2.039 eq.) were added to a 50 mL single-necked flask and dissolved in pyridine (3 mL). Cyclopropanesulfonyl chloride (188 mg, 1.337 mmol, 7.401 eq.) was added under nitrogen protection in an ice bath, and the reaction was carried out at 80 °C for 48 h. An appropriate amount of ice water (10 mL) was added to the system, and EA (20 mL × 2) was added for extraction. The organic phase was washed with dilute citric acid aqueous solution (20 mL × 4), dried over anhydrous magnesium sulfate, and then directly evaporated to dryness. A PE:acetone ratio of 1.5:1 was used to prepare a thick plate, followed by column chromatography (DCM:MeOH = 1:0–10:1). The plate was concentrated, MTBE was added, and then n-heptane was added for slurry mixing. The mixture was filtered and dried. The title compound 21 was obtained (30 mg, yield 16.57%). 1H NMR (400MHz, DMSO) δ9.98 (s, 1H), 9.25 (d, J = 7.8Hz, 1H), 7.81 (d, J = 8.1Hz, 1H), 7.73 (d, J = 8.0Hz, 1H), 7.30 (d, J = 7.5Hz, 1H), 7.04 (t,J=9.4Hz,1H),6.81(d,J=7.7Hz,1H),6.48(d,J=6.3Hz,2H),4.94(d,J=16.4Hz,2H),4.70(d,J=16.3Hz,1H),4.62(dd,J=14.2,8 .6Hz,1H),4.47(s,2H),3.96(dd,J=16.2,8.1Hz,2H),3.40(ddd,J=12.4,10.4,5.5Hz,3H),3.05–2.92(m,2H),2.78(dd,J=12.7,6 .4Hz,1H),2.60(d,J=4.7Hz,1H),2.31–2.18(m,3H),1.69(s,3H),1.44–1.37(m,1H),0.94(d,J=7.1Hz,3H), MS(m / z)=1004.14[MH] - .

[0283] Example 22 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((2-ethyl-1,1-dioxotetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (22)

[0284] Step 1: Compounds 22.2-22.6 can be synthesized using the same method as compounds 1.2-1.6, yielding compound 22.6 (1.12 g). MS (m / z) = 171 [MH] + .

[0285] Step 2: Compound 22.6 (1.12 g, 6.503 mmol, 1.0 eq.) and intermediate 1.7 (3.36 g, 6.827 mmol, 1.05 eq.) were added to DMF (20 mL) in a 100 mL single-necked flask. Then, triethylamine (1.97 g, 19.469 mmol, 3.0 eq.), bis(triphenylphosphine)palladium(II) dichloride (375 mg, 324.67 μmol, 0.05037 eq.), and CuI (74 mg, 388.55 μmol, 0.05049 eq.) were added, and the reaction was carried out at room temperature for 14 h. The system was poured into three times its volume of ice water, extracted with EA, and the organic phases were combined and washed with brine. The mixture was dried over anhydrous magnesium sulfate, prepared as sinter, and subjected to column chromatography (PE:EA = 1:1) to obtain compound 22.7 (1.55 g, yield 40.85%). MS(m / z) = 584[M+H] + .

[0286] Step 3: Compound 22.7 (1.55 g, 2.656 mmol, 1 eq.) was dissolved in dioxane hydrochloride (20 mL) and DCM (10 mL), and reacted at 20 °C for 15 h. The mixture was then evaporated to dryness, and THF was distilled off and used directly in the next step to obtain compound 22.8 (1.28 g, yield 99.68%). MS (m / z) = 484 [M+H] + .

[0287] Step 4: Compound 22.8 (1.28 g, 2.648 mmol, 1.0 eq.) was added to a single-necked flask along with intermediates 1.12 (784 mg, 2.779 mmol, 1.05 eq.), HATU (1.51 g, 3.971 mmol, 1.5 eq.), and DIPEA (1.02 g, 7.892 mmol, 3.0 eq.). DMF (20 mL) was added, and the mixture was reacted at 25 °C for 14 h under nitrogen protection. Water (50 mL) was added to the mixture, followed by extraction with EA. The organic phases were combined, dried, evaporated to dryness, prepared as slurry, and subjected to column chromatography (PE:EA = 1:1) to obtain compound 22.9 (1.00 g, yield 50.51%). MS (m / z) = 748 [M+H]. + .

[0288] Step 5: Compounds 22.10-22 can be synthesized according to the method of compounds 6.11-6.13 to obtain title compound 22 (73.5 mg, yield 17%). 1H NMR (400MHz, DMSO-d6) δ = 10.00 (s, 1H), 9.20-9.25 (m, 1H), 7.81-7.73 (m, 2H), 7.3 1-7.34(m,1H),6.86-7.05(m,2H),6.47-6.49(m,2H),4.94-4.89(m,1H),4.73-4.6 0(m,4H),4.02-4.04(m,2H),3.32-3.43(m,2H),3.16(s,3H),3.96-3.01(m,2H),2 .22-2.24(m,3H),1.95-2.01(m,3H),1.41(s,1H),1.16-1.23(m,3H),0.97(m,1H). MS(m / z)=1016[M+Na] + .

[0289] Example 23 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((5-methyl-4,4-dioxy-4-thiaspiro[2,4]heptane-5-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (23)

[0290] Step 1: Compounds 23.2-23.4 can be synthesized using the same method as compounds 1.2-1.4, yielding compound 23.4 (19.30 g), MS (m / z) = 163 [MH]. + .

[0291] Step 2: Compound 23.4 (19.30 g, 117.52 mmol, 1.0 eq.), imidazole (12.00 g, 176.27 mmol, 1.5 eq.), and tert-butyldimethylchlorosilane (21.25 g, 141.00 mmol, 1.2 eq.) were added to a 500 mL single-necked flask and dissolved in DCM (200 mL). The reaction was allowed to proceed for 15 h, followed by extraction with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate, prepared as slurry, and subjected to column chromatography (PE:EA = 20:1–5:1) to obtain compound 23.5 (31.95 g, yield 97.62%). MS (m / z) = 277 [MH]. + .

[0292] Step 3: Compound 23.5 (2.00 g, 7.182 mmol, 1.0 eq.) and tetramethylethylenediamine (1.66 g, 14.286 mmol, 2.0 eq.) were added to a 250 mL single-necked flask and dissolved in THF (50 mL). The mixture was cooled to -10 °C and a solution of n-butyllithium in n-heptane (2.5 M, 7.525 mmol, 1.05 eq.) was added. The reaction was allowed to proceed for 1 h. A solution of ethylene oxide in THF (3 M, 7.147 mmol, 1.0 eq.) was added, and the reaction was allowed to proceed at room temperature for 1 h. The reaction was quenched with a saturated ammonium chloride aqueous solution. Extraction was performed with EA. The organic phase was dried over anhydrous magnesium sulfate, prepared as sinter, and subjected to column chromatography (PE:EA = 1:1) to obtain compound 23.6 (1.41 g, yield 60.87%). MS (m / z) = 321 [MH]. + .

[0293] Step 3: Compound 23.6 (1.41 g, 4.372 mmol, 1.0 eq.) and triethylamine (0.663 g, 6.55 mmol, 1.5 eq.) were added to a 100 mL single-necked flask and dissolved in DCM (20 mL). The mixture was cooled to -10 °C, and benzenesulfonyl chloride (849 mg, 4.807 mmol, 1.1 eq.) was added. The mixture was then heated to 25 °C and reacted for 14 h. Water (50 mL) was added for extraction. The organic phase was dried over anhydrous magnesium sulfate, prepared as sinter, and subjected to column chromatography (PE:EA = 5:1) to obtain compound 23.7 (1.70 g, yield 84.04%). MS (m / z) = 463 [M+H] + .

[0294] Step 4: Compound 23.7 (1.70 g, 3.674 mmol, 1.0 eq.) was added to THF (50 mL) in a 100 mL single-necked flask. The mixture was cooled to -30 °C, and under nitrogen protection, a hexane solution of LDA (2 M, 3.855 mmol, 1.05 eq.) was added. The mixture was then heated to 25 °C and reacted for 4 h. Extraction was performed with saturated ammonium chloride solution (50 mL). The organic phase was dried over anhydrous magnesium sulfate, prepared as sinter, and subjected to column chromatography (PE:EA = 5:1) to give compound 23.8 (0.90 g, yield 80.44%). MS (m / z) = 303 [MH]. + .

[0295] Step 5: In a 100 mL single-necked flask, compound 23.8 (0.90 g, 2.955 mmol, 1.0 eq.) was dissolved in 10 mL of THF, and a TBAF THF solution (1 M, 3.00 mmol, 1.05 eq.) was added. The reaction was carried out at 15 °C for 14 h. The solution was evaporated to dryness and purified by column chromatography (PE:EA = 1:1) to give compound 23.9 (0.50 g, yield 88.91%). MS (m / z) = 189 [MH]+ .

[0296] Step 6: Compounds 23.10-23 can be synthesized according to the method of compounds 19.6-19 to obtain title compound 23 (5.6 mg, 5.56 μmol, yield 1.7%). 1 H NMR (400MHz, DMSO) δ10.00(s,1H),9.21-9.26(m,1H),7.70-7.82(m,2H),7.29-7.33(m,1H),6.81-6.91(m,2H),6.47-6.48(m,2H),4. 89-4.96(m,1H),4.50-4.47(m,4H),4.08-4.09(m,2H),3.16(s,3H),3.01(m,2H),2.21-2.23(m,2H),1.74(s,3H),0.98-1.41(m,8H). MS(m / z)=1006[M+H] + .

[0297] Example 24 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((7,7-dioxy-7-thiabicyclo[2.2.1]heptane-1-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (24)

[0298] Step 1: Under nitrogen protection, compound 24.1 (3.50 g, 29.125 mmol, 1 eq.) was dissolved in THF (70 mL). After cooling the system to below -75 °C, n-butyllithium (13.4 mL, 1.15 eq.) was added dropwise. The mixture was stirred below -70 °C for about 2 h. The system was then cooled to -80 °C, and tert-butyl-(2-iodoethoxy)dimethylsilane (9.17 g, 32.038 mmol, 1.1 eq.) dissolved in THF (10 mL) was added dropwise. The reaction mixture was stirred below -65 °C for about 2 h. The reaction mixture was quenched with saturated brine (100 mL), extracted with EA (60 mL), washed with saturated brine (100 mL × 1), dried over anhydrous magnesium sulfate, concentrated, prepared as sinter, and subjected to column chromatography. Compound 24.2 (2.72 g, yield 33.53%) was obtained. MS(m / z) = 278.48[M+H] + .

[0299] Step 2: Dissolve compound 24.2 (2.72 g, 9.767 mmol, 1 eq.) in THF (60 mL) and stir. Add LiHMDS (1.64 g, 9.801 mmol, 10 mL, 1.003 eq.) dropwise at -70 °C. Stir the mixture at -70 °C for about 1.5 h, cool to -80 °C, and then add isopropyl chloroformate (1.20 g, 9.792 mmol, 1.003 eq.) dropwise at -75 °C. After stirring the mixture at -70°C for approximately 1 hour, isopropyl chloroformate (1.20 g, 9.792 mmol, 1.003 eq.) was added again. The mixture was cooled to -80°C, and LiHMDS (1.64 g, 9.801 mmol, 10 mL, 1.003 eq.) was added dropwise again. The mixture was stirred for 1 hour, and LiHMDS (1.64 g, 9.801 mmol, 10 mL, 1.003 eq.) was added dropwise again. The resulting mixture was stirred for approximately 1 hour. Brine (100 mL) was added dropwise at below 0°C, followed by extraction with EA (50 mL). The organic phase was washed with saturated brine (100 mL × 2), concentrated, prepared as sinter, and subjected to column chromatography to give compound 24.3 (2.49 g, yield 69.92%). MS (m / z) = 364.57 [M+H] + .

[0300] Step 3: Compound 24.3 (2.49 g, 6.830 mmol, 1 eq.) was dissolved in THF (25 mL), and tetrabutylammonium fluoride (2.31 g, 10.259 mmol, 11 mL, 1.502 eq.) was added. The system was stirred at room temperature (20 °C) for about 10 h. The mixture was extracted with saturated brine (50 mL) and EA (50 mL), and the organic phase was washed with saturated brine (50 mL × 3). The mixture was dried over MgSO4, concentrated, prepared as sintered sand, and subjected to column chromatography to obtain compound 24.4 (1.29 g, yield 75.45%). MS (m / z) = 250.31 [M+H] + .

[0301] Step 4: Compound 24.4 (1.29 g, 5.154 mmol, 1 eq.) was dissolved in DCM (20 mL). Under nitrogen protection, the system temperature was lowered to 0 °C, and triethylamine (782 mg, 7.728 mmol, 1.1 mL, 1.5 eq.) was added, followed by dropwise addition of benzenesulfonyl chloride (1.00 g, 5.662 mmol, 1.099 eq.). The system was stirred at 20 °C for approximately 15 h. Extraction was performed with ice water (50 mL) and dichloromethane (20 mL). The organic phase was washed with water (50 mL × 2), dried over anhydrous magnesium sulfate, concentrated, and prepared as sinter. Column chromatography yielded compound 24.5 (1.62 g, 80.50% yield). MS (m / z) = 390.47 [M+H] + .

[0302] Step 5: Under nitrogen protection, compound 24.5 (500 mg, 1.281 mmol, 1 eq.) was dissolved in DMF (25 mL). The system temperature was lowered to -20 °C, and NaH (62 mg, 1.550 mmol, 60%, 1.2 eq.) was slowly added. The system was then slowly heated to 20 °C and stirred for approximately 15 h. The system was poured into ice water (150 mL) and extracted with EA (50 mL). The organic phase was washed with saturated brine (80 mL × 3), dried over anhydrous magnesium sulfate, concentrated, prepared as sintered glass, and subjected to column chromatography (PE:EA = 5:1 - PE:EA = 2:1) to obtain compound 24.6 (380 mg, yield 58.06%). MS (m / z) = 232.29 [M+H] + .

[0303] Steps six through fourteen: Following the synthetic method of compounds 9.5-9, we obtained title compound 24 (10 mg, yield 11.85%). 1 H NMR (400MHz, DMSO) δ10.00(s,1H),9.29(d,J=8.3Hz,1H),7.81(d,J=7.9Hz,1H),7.73(d,J=8.0Hz,1H),7.31(d,J=7.4Hz, 1H),7.07–6.99(m,1H),6.84(d,J=7.7Hz,1H),6.48(d,J=6.6Hz,2H),4.94(d,J=16.4Hz,1H),4.70(d,J=16.4Hz,1H),4.63 –4.57(m,1H),4.51–4.45(m,1H),3.95(s,2H),3.51(d,J=4.2Hz,1H),3.16(s,2H),2.99(dd,J=14.0,7.4Hz,2H),2.68(s, 1H),2.35(d,J=8.9Hz,3H),2.18(s,2H),1.98(d,J=6.9Hz,3H),1.41(d,J=6.8Hz,2H),0.97(s,1H), MS(m / z)=993.48[M+H] + .

[0304] Example 25 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((4,4-dimethyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (25)

[0305] Step 1: Compounds 25.3-25.7 can be synthesized using the same method as compounds 19.3-19.7, yielding compound 25.7 (0.58 g). MS (m / z) = 186 [MH] + .

[0306] Step 2: Compounds 25.8-25 can be synthesized using the same method as compounds 22.7-22 to obtain title compound 25 (340 mg, yield 31%). 1 H NMR(400MHz,DMSO)δ9.99(s,1H),9.18-9.25(m,1H),7.80-7.82(m,1H),7.38-7.71(m,1H),7. 30-7.34(m,1H),7.02(m,1H),6.82-6.91(m,1H),6.46-6.48(s,2H),4.88-4.94(m,1H),4.50- 4.73(m,4H),3.96(m,1H),3.32-3.39(m,2H),3.16-3.18(m,3H),2.90-3.00(m,2H),2.51-2.6 0(m,2H),2.43-2.49(m,1H),1.70(s,3H),1.41(s,4H),1.22-1.28(m,4H).MS(m / z)=1008[M+H] + .

[0307] Example 26 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-6-methyl-5,5-dioxy-5-thiospiro[2,4]heptane-6-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-bisfluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (26)

[0308] Step 1: Compound 19.8 was prepared chirally (separation conditions: ChiralCel OX, 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: methanol (0.1% NH3.H2O), flow rate: 2mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to obtain compound 26.1 (1.10g), MS (m / z) = 759.53 [MH]+.

[0309] Step 2: Compounds 26.2-26 can be synthesized according to the method of compounds 22.10-22 to obtain title compound 26 (21.68 mg, yield 31.4%). 1 H NMR(400MHz,DMSO)δ10.00(s,1H),9.23-9.26(m,1H),7.71-7.83(m,2H),7.32-7.33(m,1H),6.81-6.91(m,2H),6.48(s,2H),4.58-4.92(m,4H), 3.96(m,1H),3.16(s,3H),3.07(m,2H),2.63-2.53(m,2H),2.26(m,2H), 1.76(s,3H),1.24-1.41(s,4H),0.78-0.96(m,4H).MS(m / z)=1006[M+H] + .

[0310] Example 27 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-6-methyl-5,5-dioxy-5-thiospiro[2,4]heptane-6-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-bisfluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (27)

[0311] Step 1: Compound 19.8 was prepared chirally (separation conditions: ChiralCel OX, 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: methanol (0.1% NH3.H2O), flow rate: 2mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to obtain compound 27.1 (800mg), MS (m / z) = 759.53 [MH]+.

[0312] Step 2: Compounds 27.2-27 can be synthesized according to the method of compounds 22.10-22 to obtain title compound 27 (386.4 mg, yield 46.12%). 1 H NMR(400MHz,DMSO)δ10.00(s,1H),9.23-9.26(m,1H),7.71-7.83(m,2H),7.32-7.33(m,1H),6.81-6.91(m,2H),6.48(s,2H),4.58-4.92(m,4H), 3.96(m,1H),3.16(s,3H),3.07(m,2H),2.63-2.53(m,2H),2.26(m,2H), 1.76(s,3H),1.24-1.41(s,4H),0.78-0.96(m,4H).MS(m / z)=1006[M+H] + .

[0313] Example 28 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-5-methyl-4,4-dioxy-4-thiospiro[2,4]heptane-5-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (28)

[0314] Step 1: Compound 23.12 was prepared by chirality (separation conditions: ChiralPak IC, 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: methanol, flow rate: 2mL / min), and its corresponding fractions were collected and concentrated under reduced pressure to obtain compound 28.1 (1.1g), MS (m / z) = 759.53 [MH]+.

[0315] Step 2: Compounds 28.2-28 can be synthesized according to the method of compounds 22.10-22 to obtain title compound 28 (29 mg, yield 8.9%). 1H NMR (400MHz, DMSO) δ10.00(s,1H),9.21-9.26(m,1H),7.70-7.82(m,2H),7.29-7.33(m,1H),6.81-6.91(m,2H),6.47-6.48(m,2H),4.89-4.96(m ,1H),4.50-4.47(m,4H),4.08-4.09(m,2H),3.16(s,3H),3.01(m,2H),2 .21-2.23(m,2H),1.74(s,3H),0.98-1.41(m,8H).MS(m / z)=1004.34[MH] - .

[0316] Example 29 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-5-methyl-4,4-dioxy-4-thiospiro[2,4]heptane-5-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (29)

[0317] Step 1: Compound 23.12 was prepared chirally (separation conditions: ChiralPak IC, 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: methanol, flow rate: 2mL / min), and its corresponding fractions were collected and concentrated under reduced pressure to obtain compound 29.1 (1.0g), MS (m / z) = 759.53 [MH]+.

[0318] Step 2: Compounds 29.2-29 can be synthesized according to the method of compounds 22.10-22 to obtain title compound 29 (27 mg, yield 4.98%). 1H NMR (400MHz, DMSO) δ10.00(s,1H),9.21-9.26(m,1H),7.70-7.82(m,2H),7.29-7.33(m,1H),6.81-6.91(m,2H),6.47-6.48(m,2H),4.89-4.96( m,1H),4.50-4.47(m,4H),4.08-4.09(m,2H),3.16(s,3H),3.01(m,2H), 2.21-2.23(m,2H),1.74(s,3H),0.98-1.41(m,8H).MS(m / z)=1006[M+H] - .

[0319] Example 30 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (30)

[0320] Intermediate 30.1 was prepared according to the preparation method of WO2019161280A1.

[0321] Step 1: Compounds 30.2-30 can be synthesized according to the method of compounds 3.10.2-3 to obtain title compound 30 (249.73 mg, yield 10.01%). 1 H NMR (400MHz, DMSO) δ10.00(s,1H),9.19(d,J=8.1Hz,1H),7.77(dd,J=31.4,7.9Hz,2H),7.31(d,J =7.9Hz,1H),7.06–6.77(m,3H),6.47(d,J=6.3Hz,2H),4.88–4.52(m,5H),3.98(dd,J=16.6,8.7Hz ,1H),3.17(s,3H),2.98(dd,J=13.6,7.1Hz,2H),2.73–2.62(m,1H),2.37–2.32(m,1H),2.25(ddd, J=12.4,11.8,6.2Hz,3H),1.69(s,3H),1.44–1.24(m,3H),1.00(s,1H).LC-MS(m / z):962.09[M+H] + .

[0322] Example 31 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (31)

[0323] Intermediate 31.1 was prepared according to the preparation method of WO2019161280A1.

[0324] Step 1: Compounds 31.2-31 can be synthesized according to the method of compounds 3.10.2-3 to obtain title compound 31 (5 mg, yield 1.81%). 1 H NMR (400MHz, DMSO) δ10.01(s,1H),9.20(d,J=8.2Hz,1H),7.76(dd,J=32.1,8.0Hz,2H),7.31( d,J=7.7Hz,1H),7.06-6.82(m,3H),6.50(d,J=6.4Hz,2H),4.86-4.35(m,5H),4.00(dd,J=16. 6,8.3Hz,1H),3.17(s,3H),3.04-2.91(m,2H),2.73-2.62(m,1H),2.37-2.32(m,1H),2.28(dd ,J=13.8,6.3Hz,3H),1.69(s,3H),1.42-1.22(m,3H),0.89(s,1H).LC-MS(m / z):962.09[M+H] + .

[0325] Example 32 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((S)-2-ethyl-1,1-dioxotetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (32)

[0326] Step 1: Compound 22.7 was prepared chirally (separation conditions: WhelkO1-(R,R), 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: methanol (0.1% NH3H2O), flow rate: 2mL / min), and its corresponding fractions were collected and concentrated under reduced pressure to obtain compound 32.1 (1.2g), MS (m / z) = 583.48 [MH]+.

[0327] Step 2: Compounds 32.2-32 can be synthesized using the same method as compounds 22.8-22 to obtain title compound 32 (578.02 mg, yield 44.62%). 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.20-9.22(m,1H),7.81-7.73(m,2H),7.31-7.33(m ,1H),6.86-7.05(m,2H),6.48-6.51(m,2H),4.94-4.90(m,1H),4.69-4.72(m,1H),4.51-4 .62(m,2H),4.02-4.04(m,1H),3.32-3.43(m,2H),3.16(s,3H),2.80-3.02(m,2H),2.22-2 .24(m,3H),1.95-2.01(m,2H),1.41(m,1H),1.20-1.26(m,3H),1.11(s,3H),0.97(m,1H). MS(m / z)=994.30[M+H] + .

[0328] Example 33 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-2-ethyl-1,1-dioxotetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (33)

[0329] Step 1: Compound 22.7 was prepared chirally (separation conditions: WhelkO1-(R,R), 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: methanol (0.1% NH3H2O), flow rate: 2mL / min), and its corresponding fractions were collected and concentrated under reduced pressure to obtain compound 33.1 (1.0g), MS (m / z) = 583.48 [MH]+.

[0330] Step 2: Compounds 33.2-33 can be synthesized using the same method as compounds 22.8-22 to obtain title compound 33 (380.86 mg, yield 50.04%). 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.23-9.25(m,1H),7.82-7.73(m,2H),7.33-7.35(m ,1H),6.92-7.05(m,2H),6.48-6.50(m,2H),4.89-4.93(m,1H),4.69-4.72(m,1H),4.52-4 .58(m,2H),4.02-4.04(m,1H),3.32-3.43(m,2H),3.16(s,3H),2.80-3.02(m,2H),2.22-2 .24(m,3H),1.95-2.01(m,2H),1.41(m,1H),1.20-1.26(m,3H),1.11(s,3H),0.86(m,1H). MS(m / z)=994.20[M+H] + .

[0331] Example 34 Synthesis of N-(((S)-1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-((7,7-dioxo-7-thiabicyclo[2.2.1]heptane-1-yl)ethynyl)pyridin-2-yl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (34)

[0332] Steps 1 to 5: Compounds 34.1-34 can be synthesized according to the method of compounds 10.2.1-10 to obtain title compound 34 (20 mg, yield 15.21%). 1H NMR (400MHz, DMSO) δ9.93–9.83(m,1H),9.27(d,J=8.3Hz,1H),8.97(d,J=8.6Hz,1H),7.86(d,J=8.0Hz,1H),7.72(t,J=8.2Hz,1H) ,7.28(s,1H),7.14(s,1H),7.02(d,J=9.5Hz,1H),6.97–6.86(m,1H),6.52(d,J=6.0Hz,2H),6.01(d,J=54.3Hz,1H),4.86(t,J=12. 4Hz,1H),4.82–4.71(m,1H),4.66(d,J=5.9Hz,2H),4.04(s,1H),3.71(s,1H),3.50(s,1H),3.15(s,2H),3.05–2.89(m,2H),2.67( d,J=1.8Hz,1H),2.40–2.28(m,3H),2.18(s,2H),1.98(d,J=7.1Hz,2H),1.40(d,J=6.6Hz,1H),0.95(s,1H).MS(m / z)=974.40[M+H] + .

[0333] Example 35 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((7,7-dioxo-7-thiadiazolecyclo[2.2.1]heptane-1-yl)ethynyl)pyridin-2-yl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (35)

[0334] Steps 1 to 5: Compounds 35.1-35 can be synthesized according to the method of compounds 10.2.1-10 to obtain title compound 35 (22 mg, yield 12.37%). 1H NMR (400MHz, DMSO) δ10.00(s,1H),9.24(d,J=7.8Hz,1H),7.80(d,J=7.9Hz,1H),7.73(d,J=8.0Hz,1H),7.29(s,1H),7.10–6.99(m,1 H),6.94(d,J=11.2Hz,1H),6.85(d,J=7.2Hz,1H),6.48(d,J=6.3Hz,2H),4.84(d,J=16.4Hz,1H),4.66(d,J=16.3Hz,1H),4.60–4.53 (m,1H),4.51–4.41(m,1H),4.01–3.87(m,2H),3.51(d,J=4.0Hz,1H),3.42(s,1H),3.15(s,2H),3.02–2.90(m,2H),2.68(s,1H),2.3 9–2.30(m,3H),2.18(s,2H),1.95(dd,J=17.3,11.4Hz,2H),1.38(d,J=6.5Hz,1H),1.01(s,1H),0.87(s,1H).MS(m / z)=974.40[M+H] + .

[0335] Example 36 Synthesis of N-((S)-1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(((R)-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (36)

[0336] Steps 1 to 5: Compounds 36.1-36 can be synthesized according to the method of compounds 10.2.1-10 to obtain title compound 36 (71 mg, yield 33.27%). 1H NMR (400MHz, DMSO) δ9.94-9.88(m,1H),9.20-9.14(m,1H),7.85(t,J=6.3Hz,1H),7.73-7.68(m,1H),7.27(t,J=7.3H z,1H),7.02(d,J=9.3Hz,1H),6.88(d,J=7.6Hz,1H),6.54-6.45(m,2H),6.04(d,J=54.0Hz,1H),4.76(t,J=13.2Hz,2H ),4.66-4.60(m,2H),4.02(d,J=17.0Hz,2H),3.72(d,J=11.5Hz,2H),3.52(s,2H),3.17(s,1H),3.04-2.93(m,1H),2. 46-2.42(m,1H),2.28-2.19(m,3H),1.69(s,3H),1.40-1.35(m,1H),1.24(s,1H),0.86(s,1H).MS(m / z)=944.33[M+H] + .

[0337] Example 37 Synthesis of N-(((S)-1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-((7,7-dioxo-7-thiabicyclo[2.2.1]heptane-1-yl)ethynyl)pyridin-2-yl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (37)

[0338] Steps 1 to 5: Compounds 37.1-37 can be synthesized according to the method of compounds 10.2.1-10 to obtain title compound 37 (51 mg, yield 39.12%). 1H NMR(400MHz,DMSO)δ9.90-9.91(s,1H),9.22-9.24(m,1H),7.91(m,1H),7.85(m, 1H),7.27(m,1H),7.04(m,1H),6.90(m,1H),6.50(m,2H),6.10(m,1H),4.80(m,1H ),4.64(m,2H),4.02-4.04(m,1H),3.60(m,1H),3.51(m,1H),3.30(m,3H),3.16(m ,2H),2.46(m,6H),2.35(m,3H),1.99(m,2H),1.37(m,1H).MS(m / z)=956.40[M+H] + .

[0339] Example 38 Synthesis of N-(((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((R)-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (38)

[0340] Steps 1 to 5: Compounds 38.1-38 can be synthesized according to the method of compounds 10.2.1-10 to obtain title compound 38 (149 mg, yield 20.36%). 1H NMR (400MHz, DMSO) δ10.01(s,1H),9.24(d,J=8.3Hz,1H),7.80(d,J=7.9Hz,1H),7.72(d,J=8.0Hz,1H),7.31(d,J=7. 6Hz,1H),7.03(t,J=9.4Hz,1H),6.83(d,J=7.7Hz,1H),6.50(d,J=6.4Hz,2H),4.88(d,J=16.4Hz,1H),4.78-4.70(m,1 H),4.65-4.57(m,1H),4.41(dd,J=16.1,8.3Hz,1H),4.05–3.95(m,1H),3.44-3.35(m,3H),3.17(s,3H),3.06-2.91( m,2H),2.64-2.53(m,2H),2.34-2.17(m,3H),1.69(s,3H),1.41(d,J=7.0Hz,1H),0.96(s,1H).MS(m / z)=980.40[M+H] + .

[0341] Example 39 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((4-hydroxy-2-methyl-1,1-dioxytetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentano[1,2-c]pyrazol-1-yl)acetamide (39)

[0342] Step 1: Add ethyl 2-mercaptopropionate (20.00 g, 149.035 mmol, 1 eq.) and epichlorohydrin (13.78 g, 148.934 mmol, 9.993 e) to a 250 mL single-necked flask. -1 eq.), benzyltrimethylammonium hydroxide (1.55 g, 3.707 mmol, 40% purity, 2.487 e -2 The mixture was reacted at 25°C for 1 hour. Ethyl acetate was added to the system, and the mixture was prepared by column chromatography (EA:PE = 1:5) to give compound 39.2 (25.00 g, yield 73.98%).

[0343] Step 2: Compound 39.2 (47.44 g, 209.245 mmol, 1 eq.) was placed in a 1 L four-necked flask, and DMF (500 mL) was added. The system was cooled to 0 °C under N2 protection, and TBSCl (25.83 g, 313.650 mmol, 1.5 eq.) and imidazole (28.50 g, 418.644 mmol, 2.0 eq.) were added sequentially. The system was stirred at room temperature for approximately 20 h. The system was cooled to 0 °C, and ice water (1000 mL) and MTBE:EA = 1:1 (500 mL) were added. The organic phase was separated, washed with water (500 mL × 3) and brine (500 mL × 2), dried over MgSO4, evaporated to dryness, prepared as sinter, and subjected to column chromatography to obtain compound 39.3 (57.31 g, yield 80.32%).

[0344] Step 3: Compound 39.3 (57.31 g, 168.074 mmol, 1.0 eq.) was added to a four-necked round-bottom flask, and DMF (1200 mL) was added. The system was cooled to -35 °C to -30 °C under N2, and t-BuOK (20.75 g, 184.921 mmol, 1.1 eq.) dissolved in DMF (100 mL) was added dropwise at approximately -30 °C. The system was stirred at -30 °C to -20 °C for approximately 2 h. Ice water (3000 mL) and MTBE:EA = 1:1 (1000 mL) were added to separate the organic phase. The mixture was washed with saturated brine (2000 mL × 3), dried over MgSO4, concentrated, prepared as sinter, and subjected to column chromatography to obtain compound 39.4 (47.74 g, yield 93.27%).

[0345] Step 4: Compound 39.4 (5.00 g, 16.419 mmol, 1 eq.) was dissolved in DCM (50 mL), and m-CPBA (10.119 g, 41.048 mmol, 70%, 2.5 eq.) was slowly added at 0 °C. The system was stirred at 0 °C for about 3 h. A saturated NaHCO3 aqueous solution (100 mL) was added to adjust the pH of the system to 7, and the mixture was filtered. The filter cake was washed with DCM (30 mL), and the DCM phase was separated. The mixture was washed with saturated NaHCO3 aqueous solution (50 mL × 3) and brine (100 mL × 2), dried over MgSO4, and concentrated under reduced pressure. Column chromatography (PE:EA = 3:1 to 1:1) was performed to give compound 39.5 (4.80 g, yield 86.87%).

[0346] Steps 5-12: Compounds 39.6-39 can be synthesized according to the method of compounds 16.7-16.13 to obtain title compound 39 (182 mg, yield 42.08%).

[0347] 1H NMR (400MHz, DMSO) δ10.01(s,1H),9.26(dd,J=10.9,8.3Hz,1H),7.85–7.71(m,2H),7.32(t,J=7.7Hz,1H),7.04(t,J=9.3Hz,1H ),6.86(dd,J=26.7,7.7Hz,1H),6.48(d,J=6.6Hz,2H),5.82(d,J=3.6Hz,1H),4.94(dd,J=16.4,6.6Hz,1H),4.74–4.44(m,5H),3 .98(dd,J=13.9,8.2Hz,1H),3.84(ddd,J=13.7,7.8,3.8Hz,1H),3.26–3.17(m,3H),2.98(ddd,J=29.2,16.6,8.3Hz,2H),2.83–2 .76(m,1H),2.65–2.54(m,2H),2.27–2.19(m,1H),1.78(d,J=1.9Hz,3H),1.45-1.37(m,1H),0.97(s,1H).MS(m / z)=996.78[M+H] + .

[0348] Example 40 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((2S)-4-hydroxy-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetamide (40)

[0349] Step 1: Following the synthetic methods for compounds 3.9 and 3.10, the racemic mixture was prepared chirally (separation conditions: ChiralPak IC, 250 × 50 mm ID, 10 μm; mobile phase: A for CO2 and B for Methanol, flow rate: 150 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to give compound 40.1 (4.40 g, yield 30.95%). MS (m / z) = 699.72 [M+H] + And 40.2 (4.47 g, yield 31.44%) MS (m / z) = 699.72 [M+H] + .

[0350] Step 2: Following the synthetic method of compounds 10.2.1-10, title compound 40 (75 mg, yield 52.95%) was obtained.

[0351] 1 H NMR (400MHz, DMSO) δ10.01(s,1H),9.25(d,J=8.2Hz,1H),7.81(d,J=8.1Hz,1H),7.75(t,J=8.7Hz,1H),7.32(d,J=7.7Hz,1H),7.03(t,J=9.4Hz,1H) ,6.88(d,J=7.6Hz,1H),6.47(d,J=6.4Hz,1H),5.81(d,J=4.4Hz,1H),4.9 2(d,J=16.5Hz,1H),4.71(d,J=16.5Hz,1H),4.62(dd,J=15.7,7.3Hz,2H), 4.50(d,J=8.6Hz,1H), 3.96(dd,J=16.4,8.0Hz,1H), 3.83(dd,J=14.0,7. 8Hz,1H),3.20(d,J=4.7Hz,1H),3.16(s,3H),2.98(dt,J=22.1,10.6Hz,2H ),2.80(dd,J=13.6,6.3Hz,1H),2.56(d,J=24.5Hz,2H),2.26–2.19(m,1H ),1.78(s,3H),1.41(d,J=6.5Hz,1H),0.96(s,2H).MS(m / z)=996.41[M+H] +

[0352] Example 41 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(((2R)-4-hydroxy-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (41)

[0353] Following the synthetic method of compounds 10.2.1-10, title compound 41 (107 mg, yield 43.86%) was obtained.

[0354] 1H NMR (400MHz, DMSO) δ10.00(s,1H),9.23(d,J=8.3Hz,1H),7.81(d,J=7.9Hz,1H),7.73(d,J=8.0Hz,1H),7.31(d,J=7.6Hz,1H),7.03(t,J=9.4Hz ,1H),6.82(d,J=7.6Hz,1H),6.47(d,J=6.6Hz,2H),5.81(d,J=4.4Hz,1H),4.94(d,J=16.4Hz,1H),4.71(d,J=16.4Hz,1H),4.66–4.57(m,2H),4 .52(dd,J=16.1,8.3Hz,1H),3.97(dd,J=16.3,8.4Hz,1H),3.84(dd,J=14.0,7.8Hz,1H),3.24–3.18(m,1H),3.17(d,J=6.4Hz,3H),3.05–2.92( m,2H),2.79(dd,J=13.7,6.2Hz,1H),2.63–2.53(m,2H),2.27–2.20(m,1 H),1.78(s,3H),1.45–1.36(m,1H),0.96(s,1H).MS(m / z)=996.44[M+H] +

[0355] Example 42 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((7-methyl-6,6-dioxo-2-oxa-6-thiospiro[3,4]oct-7-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetamide (42)

[0356] Step 1: Add ethyl 2-mercaptopropionate (5.00 g, 37.259 mmol, 1.00 eq.) to a 1 L single-necked flask and dissolve it in DMF (100 mL). Under nitrogen protection, cool the system to -30 °C and add potassium tert-butoxide (10.46 g, 93.218 mmol, 2.502 eq.) in DMF (50 mL). Stir for 1 hour, then add 3,3-bis(bromomethyl)oxetane (9.09 g, 37.266 mmol, 1.00 eq.) in DMF (50 mL). React at -30 °C for 2 hours. Water (600 mL) was added dropwise to the system at -20 °C, keeping the temperature below 0 °C during the addition. Then, ethyl acetate (200 mL) was added for extraction. The organic phase was washed twice with water, dried, filtered, and subjected to column chromatography (PE:EA = 20:1 to 5:1) to obtain compound 42.3 (4.33 g, yield 53.72%).

[0357] Step 2: Compound 42.3 (7.39 g, 34.166 mmol, 1 eq.) was added to a 250 mL single-necked flask and dissolved in DCM (75 mL). Under nitrogen protection and in an ice bath, m-CPBA (14.77 g, 85.590 mmol, 2.505 eq.) was added, and the reaction was carried out at 20 °C for 14 hours. Under ice bath conditions, saturated sodium bicarbonate solution was added to adjust the pH to weakly alkaline, followed by the addition of saturated sodium sulfite solution. The mixture was extracted with DCM, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and prepared as a granule. Column chromatography (PE:EA = 5:1–2:1) yielded compound 42.4 (7.88 g, 92.88% yield).

[0358] Steps 3-7: Following the synthetic methods of compounds 19.5-19, we obtained title compound 42 (32 mg, yield 12.13%).

[0359] 1H NMR (400MHz, DMSO) δ (ppm) 10.00 (s, 1H), 9.25 (d, J = 8.3Hz, 1H), 9.20 (br d, J = 8.3Hz, 1H), 7.82 (br d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.66-7.54(m,2H),7.35-7.28(m,1H),7.03(br t,J=9.0Hz,1H),6.90(d,J=7.8Hz,1H),6.47(br d,J=8.3Hz,2H),4.96-4.88(m,2H),4.85-4.73(m,2H),4.70-4.65(m,1H),4.69-4.46(m,4 H),4.07-3.86(m,2H),3.16(s,3H),3.14-2.92(m,2H),2.56(m,1H),1.66(s,3H),1.39(br s,1H),0.96(br s,1H).MS(m / z)=1044.48[M+Na] +

[0360] Example 43 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((4,4-difluoro-2-methyl-1,1-tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (43)

[0361] Step 1: Compound 43.1 (47.44 g, 209.245 mmol, 1 eq.) was added to a 1 L four-necked flask, followed by DMF (500 mL). The mixture was cooled to 0 °C under nitrogen protection, and TBSCl (25.83 g, 313.650 mmol, 1.499 eq.) and imidazole (28.50 g, 418.644 mmol, 2.001 eq.) were added sequentially in portions. The mixture was stirred at room temperature for 15 hours. The resulting mixture was cooled to 0 °C, and ice water (1000 mL) and MTBE:EA = 1:1 (500 mL) were added. The organic phase was separated, washed with water (500 mL × 3) and saturated brine (500 mL × 2), dried over anhydrous MgSO4, concentrated, and prepared as sintered precipitate. Column chromatography (PE:EA = 20:1–5:1) was performed to obtain compound 43.2 (57.31 g, yield 80.32%).

[0362] Step 2: Compound 43.2 (57.31 g, 168.074 mmol, 1 eq.) was added to a 1 L four-necked flask, followed by 1200 mL of DMF. The mixture was cooled to -35°C to -30°C under nitrogen protection. At approximately -30°C, t-BuOK (20.75 g, 184.921 mmol, 1.1 eq.) dissolved in 100 mL of DMF was added dropwise for approximately 1.5 hours. The system was stirred at -30°C to -20°C for approximately 2 hours. Ice water (3000 mL) and MTBE:EA = 1:1 (1000 mL) were added for extraction. The mixture was washed with saturated brine (2000 mL × 3), dried over MgSO4, concentrated, and prepared as sintered precipitate. Column chromatography (PE:EA = 20:1 to 5:1) yielded compound 43.3 (47.74 g, 93.27% yield).

[0363] Step 3: Compound 43.3 (36.00 g, 118.219 mmol, 1 eq.) was added to a 1 L single-necked flask and dissolved in THF (180 mL). A 1 M TBAF solution in tetrahydrofuran (44.28 g, 169.357 mmol, 170 mL, 1.433 eq.) was added under ice bath conditions, and the reaction was carried out at 20 °C for 14 h. The THF was evaporated to dryness, and the mixture was extracted with water and ethyl acetate, washed with saturated brine, and the organic phase was dried and evaporated to dryness to obtain a granulation solution. Column chromatography (EA:PE = 1:3) yielded compound 43.4 (20.00 g, yield 88.91%).

[0364] Step 4: Compound 43.4 (20.00 g, 119.06 mmol) was added to a 1 L single-necked flask and dissolved in DCM (200 mL). The mixture was cooled to 0 °C and dess-martin (53.49 g, 126.114 mmol, 1.200 eq.) was added. The mixture was reacted at 25 °C for 14 hours. The mixture was filtered through diatomaceous earth, and the filtrate was directly evaporated to dryness and subjected to column chromatography (EA:EP = 1:20) to obtain compound 43.5 (14.00 g, yield 70.75%).

[0365] Step 5: Under ice bath conditions, compound 43.5 (14.00 g, 74.372 mmol, 1 eq.) was added to a 100 mL single-necked flask and dissolved in DCM (140 mL). Then, BAST (49.37 g, 223.151 mmol, 3.0 eq.) was added dropwise, and the reaction was carried out at 20 °C for 72 h. Under ice bath conditions, an appropriate amount of water was added to the system, and the pH was adjusted to 8 with sodium bicarbonate. The mixture was extracted and separated, the organic phase was dried and prepared as sand, and column chromatography (EA:PE = 1:20) was performed to obtain compound 43.6 (8.79 g, yield 52.21%).

[0366] Steps 6-12: Following the synthetic methods of compounds 39.6-39, compound 43.13 (501 mg, 100% yield, crude product) was obtained.

[0367] Step 13: Compound 43.12 (501 mg, 509.005 μmol, 1 eq.) was added to a 50 mL single-necked flask and dissolved in DCM (5 mL). Under nitrogen protection, m-CPBA (274 mg, 1.270 mmol, 80% purity, 2.496 eq.) was added in an ice bath, and the reaction was carried out at 20 °C for 15 h. The system was then extracted with an appropriate amount of saturated sodium sulfite aqueous solution in an ice bath, and the organic phase was saturated and dried. Column chromatography (PE:EA = 1:0–4:1–2:1) was performed to give the title compound 43 (20 mg, yield 3.86%).

[0368] 1 H NMR(400MHz,DMSO)δ10.00(s,1H),9.24(m,1H),7.83(m,1H),7.73(m,1H) ,7.34(m,1H),6.90(m,1H),6.48(m,2H),4.95(m,1H),4.89(m,1H),4.63(m ,1H),4.50(m,3H),3.97(m,1H),3.35(m,5H),3.07(m,2H),2.51(m,2H),1 .83(m,3H),1.41(m,1H),1.26(m,1H),0.86(m,1H).MS(m / z)=1014.15[MH] -

[0369] Example 44 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indoleazol-7-yl)-6-((1-(methylsulfonyl)cyclopropyl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (44)

[0370] Step 1: Compound 44.1 (12.00 g, 62.424 mmol) was dissolved in methanol (120 ml). LAH (1.53 g, 40.312 mmol) was added in portions at -30 °C, and the reaction mixture was stirred at -30 °C for 8 hours. The reaction was monitored by TLC until complete. Water (2 ml) was added, and after thorough stirring, the reaction mixture was concentrated under reduced pressure. The mixture was purified by column chromatography (n-heptane:ethyl acetate = 80%). Compound 44.2 (8.87 g, yield 94.604%) was obtained.

[0371] Step 2: Compound 44.2 (7.78 g, 51.799 mmol) was dissolved in DCM (10 mL), and Dess-Martin (23.34 g, 55.047 mmol) was added in portions at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC until complete. The system was directly filtered, and the pH was adjusted to weakly alkaline with saturated sodium bicarbonate. The mixture was then extracted with DCM, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The system was concentrated and evaporated to dryness at low temperature (5–10 °C) to obtain compound 44.3 (7.50 g, yield 97.712%).

[0372] Step 3: Compound 44.3 (7.50 g, 50.614 mmol) was added to a 100 mL single-necked flask and dissolved in MeOH (100 mL). K₂CO₃ (15.86 g, 114.756 mmol) was then added. Under nitrogen protection, the temperature was lowered to 0 °C, and dimethyl (1-diazo-2-oxopropyl)phosphonate (11.02 g, 57.363 mmol) was added. The system was gradually heated to 25 °C and reacted for 15 hours. The reaction was monitored by TLC until completion. Water was added directly to the system, followed by extraction with n-pentane:ethyl ether (1:1). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to dryness at low temperature (5-10 °C) for use in the next step. Compound 44.4 (7.50 g, yield 90.676%) was obtained.

[0373] Step 4: Compound 6.2 (1.00 g, 1.524 mmol) was added to a 250 mL single-necked flask. 1-Ethynyl-1-(methylsulfonyl)cyclopropane (329 mg, 2.282 mmol) dissolved in DMF (10 mL) was added, along with TEA (462 mg, 4.566 mmol), tetrakis(triphenylphosphine)palladium (90 mg, 782.609 μmol), and CuI (20 mg, 105.014 μmol). The reaction was carried out at 25 °C for 15 h. After the reaction was completed by TLC, the system was poured into three volumes of ice water containing DMF. EA was added for extraction, the organic phase was washed with water and saturated brine, dried, evaporated to dryness, prepared as sinter, and subjected to column chromatography to obtain compound 44.5 (500 mg, yield 45.602%).

[0374] Step 5: Add compound 44.5 (500 mg, 694.959 μmol) to a 50 mL single-necked flask, dissolve in butyl acetate (5 mL), H2O (1 mL), then add KHCO3 (208.738 mg, 2.085 mmol), followed by compound 2.8 (400 mg, 1.065 mmol) and dichlorobis(tricyclohexyl)palladium (51.300 mg, 69.496 μmol). Purge with nitrogen and heat to 85 °C for 15 hours. After the reaction is complete, monitor the system by TLC and directly prepare sand. Column chromatography (PE:EA = 10:1 to 3:1) yields compound 44.6 (300 mg, yield 48.603%).

[0375] Step 6: Add compound 44.6 (300 mg, 337.771 μmol) to a 50 mL single-necked flask, dissolve in DCM (3 mL), add TEA (204 mg, 2.016 mmol), and add methanesulfonic anhydride (144 mg, 996.195 μmol) under ice bath conditions. Heat to 25 °C and react for 2 hours. Monitor the reaction by TLC until complete. Add an appropriate amount of ice water to the system, extract, dilute with a small amount of DCM, and evaporate the organic phase directly to dryness. This yields compound 44.7 (300 mg, yield 85.045%).

[0376] Step 7: Add compound 44.7 (300 mg, 287.259 μmol) to a 50 mL single-necked flask, dissolve in EtOH (3 mL) and 2N NaOH solution (0.4 mL), and react at 25 °C for 1 hour. The reaction was monitored by TLC until complete. Adjust the pH to weakly acidic by adding acetic acid, then dilute with DCM, extract, separate, dry the organic phase to saturated anhydrous magnesium sulfate, concentrate, and evaporate to dryness. Purify by column chromatography using n-heptane:ethyl acetate = 2:1 as eluent. Compound 44 (66.7 mg, yield 24.030%) was obtained.

[0377] 1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.23(br d,J=8.3Hz,1H),7.88–7.71(m,2H),7.31(d,J=7.6Hz,1H),7.13–6.97(m,1H),6.83(d,J=7.6Hz,1H),6.47(br d,J=6.4Hz,2H),4.92(d,J=16.6Hz,1H),4.80(s,1H),4.76–4.66(m,1H),4.71(br d,J=16.6Hz,1H),4.64–4.44(m,2H),4.05–3.89(m,1H),3.32(br s,3H),3.04–2.92(m,2H),2.65–2.56(m,2H),1.63(br s,5H),1.45–1.37(m,1H),0.97(br d,J=2.4Hz,1H).LCMS(m / z)=966.10[M+H] + .

[0378] Example 45 Synthesis of N-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)(1-(3,5-difluorophenyl)cyclopropyl)methyl)-2-(((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (55)

[0379] Intermediate 45.1 was prepared according to the method disclosed in WO2019035973A1.

[0380] Step 1: Compound 45.1 (2.00 g, 5.11 mmol, 1 eq.), DMSO (20 mL), DCM (20 mL), DBU (2.33 g, 15.33 mmol, 3.0 eq.), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (2.41 g, 6.64 mmol, 1.3 eq.) were added to the reaction flask and reacted overnight at room temperature. The reaction was quenched with 10% ammonium chloride aqueous solution (6 mL), back-extracted with EA (6 mL × 3), and the organic phases were combined. The organic phases were washed with water (6 mL), dried over anhydrous sodium sulfate, and subjected to sand column chromatography to obtain compound 45.2 (1.78 g), with a yield of 84%.

[0381] Step 2: Compound 45.2 (3.00 g, 7.19 mmol, 1 eq.) and methanol (24 mL) were added to the reaction flask. Sodium borohydride (0.41 g, 10.79 mmol, 1.5 eq.) was slowly added in an ice-water bath. The mixture was then transferred to room temperature and reacted for 3 h. TLC showed that the starting material reacted completely. The reaction was quenched by adding 1 M HCl (9 mL) to the system (the system pH was approximately 1), and the mixture was stirred for 5 min. Then, 10% NaOH was added to adjust the pH to approximately 8 or higher. The mixture was concentrated, and the remaining aqueous phase was extracted with EA (10 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 45.3 (2.71 g), with a yield of 90%.

[0382] Step 3: Compound 45.3 (2.50 g, 5.97 mmol, 1.0 eq.), THF (20 mL), triphenylphosphine (1.88 g, 7.16 mmol, 1.2 eq.), and phthalimide (1.05 g, 7.16 mmol, 1.2 eq.) were added to the reaction flask under nitrogen purging protection. DEAD (1.25 g, 7.16 mmol, 1.2 eq.) was added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. TLC showed that the starting material had reacted completely. The reaction was quenched with water (10 mL), and the aqueous phase was extracted with EA (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the mixture was prepared as sintered precipitate. Column chromatography was then performed to obtain compound 45.4 (2.62 g), with a yield of 80%.

[0383] Step 4: Compound 45.4 (2.30 g, 4.20 mmol, 1 eq.), anhydrous ethanol (20 mL), dichloromethane (10 mL), and hydrazine hydrate (80%, 1.05 g, 16.80 mmol, 4.0 eq.) were added to the reaction flask and reacted at 60 °C for 4 h. TLC showed that the starting material reacted completely. After cooling to room temperature, the mixture was filtered, and the filtrate was prepared by column chromatography to give compound 45.5 (1.40 g, 3.36 mmol), with a yield of 80%.

[0384] Step 5: Compound 45.5 was dissolved in DMF (6 mL), and compound 1.12 (424 mg, 1.581 mmol), HATU (655 mg, 1.723 mmol), and DIEA (57 mg, 441.040 μmol) were added. Nitrogen gas was purged, and the mixture was stirred at 25 °C for 16 hours. TLC was used to monitor complete consumption of the starting material. The reaction mixture was added dropwise to ice water (20 mL), and extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, dried, concentrated, and purified by column chromatography. Compound 45.6 (580 mg, yield 59.238%) was obtained.

[0385] Step 6: Compound 45.6 (580 mg, 850.160 μmol) was added to a 50 mL single-necked flask and dissolved in DMF (6 mL). 3-Methyl-3-methylsulfonyl-but-1-yne (137 mg, 937.028 μmol), TEA (258 mg, 2.550 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 43.269 μmol), and CuI (20 mg, 105.014 μmol) were added, purging with nitrogen. The mixture was heated to 35 °C and stirred for 16 hours. After the reaction was complete as monitored by TLC, ice water (30 mL) was added to the reaction solution. The mixture was then extracted with ethyl acetate (2 × 20 mL), dried, concentrated, and purified by column chromatography to obtain compound 45.8 (390 mg, yield 61.368%).

[0386] Step 7: Compound 45.8 (300 mg, 401.327 μmol) was added to a 50 mL single-necked flask and dissolved in butyl acetate (5 mL) and H2O (1 mL). Then, KHCO3 (120 mg, 1.199 mmol), compound 2.8 (226 mg, 601.735 μmol), and dichlorobis(tricyclohexyl)palladium (59 mg, 79.926 μmol) were added. The mixture was purged with nitrogen and reacted at room temperature for 15 hours. The reaction was monitored by LCMS until it ended. Column chromatography (PE:EA = 10:1 to 3:1) was performed to obtain compound 45.9 (270 mg, yield 73.428%).

[0387] Step 8: Compound 45.9 (270 mg, 294.687 μmol) dissolved in DCM (2 mL) was added to a 50 mL single-necked flask. Then, methanesulfonic anhydride (100 mg, 877.193 μmol) and TEA (178 mg, 1.759 mmol) were added at 0 °C. The reaction mixture was reacted at 25 °C for 2 hours. Extraction was performed by adding water (30 mL) and DCM (30 mL × 3). The mixture was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 45.10 (230 mg, yield 72.779%).

[0388] Step 9: Add compound 45.10 (230 mg, 214.471 μmol) to a 100 mL single-necked flask, dissolve in H₂O (0.4 mL), EtOH (2 mL) (0.8 g NaOH dissolved in 10 mL water), and react at 25 °C for 1 hour. Monitor the reaction completion by LCMS. Adjust the pH to weakly acidic by adding acetic acid, then dilute with DCM, extract, separate the layers, dry the organic phase to saturated anhydrous magnesium sulfate, concentrate, and evaporate to dryness. Purify by column chromatography (n-heptane:ethyl acetate = 2:1), evaporate to dryness, to give title compound 45 (23 mg, yield 10.785%).

[0389] 1H NMR (400MHz, DMSO-d6) δ10.15–9.98(m,1H),9.01–8.91(m,1H),7.86–7.74(m,2H),7.45–7.38(m,1H ),7.07–6.94(m,2H),6.51–6.41(m,2H),5.76(s,1H),5.76–5.74(m,1H),5.13–4.84(m,3H),4.65–4. 44(m,1H),3.96–3.79(m,1H),3.26–3.24(m,2H),,3.08(s,2H),2.66–2.54(m,2H),1.74–1.68(m,6H ),1.49–1.38(m,1H),,1.02–0.95(m,1H),0.89–0.82(m,2H),0.71–0.65(m,2H)LCMS(m / z)=994[M+H] + .

[0390] Example 46 Synthesis of N-((S)-1-(3-(4-chloro-3-(1,1-dioxideisothiazo-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (46):

[0391] Intermediate 46.1 was prepared according to the preparation method of WO2019161280 A1.

[0392] Step 1: Compound 46.1 (500 mg, 1.522 mmol) and DCM (10 mL) were added to a 100 mL single-necked flask. TEA (462 mg, 4.566 mmol) was added under nitrogen protection. The mixture was cooled to 0 °C, and then compound 46.2 (674 mg, 3.807 mmol) was added. The reaction was carried out at room temperature for 15 hours. After the reaction was complete, the system was poured into ice water, extracted with DCM, dried over the organic phase, filtered, and the filtrate was evaporated to dryness and subjected to column chromatography. Compound 46.3 (850 mg, yield 91.600%) was obtained.

[0393] Step 2: At 0°C, compound 46.3 (850 mg, 1.394 mmol) and DMAc (10 mL) were added to a 100 mL single-necked flask, followed by potassium tert-butoxide (352 mg, 3.137 mmol). The reaction was carried out at room temperature for 15 hours. After the reaction was complete, the system was poured into ice water, extracted with EA, dried the organic phase, filtered, and the filtrate was evaporated to dryness and subjected to column chromatography. Compound 46.4 (450 mg, yield 74.606%) was obtained.

[0394] Step 3: Add compound 46.4 (1.00 g, 2.311 mmol) and toluene (6 mL), DMF (2 mL) to a 100 mL single-necked flask, then add pinacol diboron ester (0.706 g, 2.78 mmol), potassium acetate (681 mg, 6.93 mmol), and palladium dichloride (23 mg, 0.032 mmol). Under nitrogen protection, heat to 105 °C and react for 12 hours. Monitor the reaction by TLC until completion. Cool the system to room temperature, filter with diatomaceous earth (8.0 g, 0.5 w%), wash the filter cake with EA (10 v), wash with DMF, wash the filtrate with 5% LiCl solution (6 v) and saturated brine (6 v), dry the organic phase with anhydrous magnesium sulfate, and concentrate to dryness. Prepare sand, perform column chromatography (PE:THF = 10:1–5:1), pulverize with cross-linked methyl tert-ether, filter, and dry. Compound 46.5 (560 mg, yield 50.50%) was obtained.

[0395] Step 4: In a 50 mL single-necked flask, compound 2.7 (399 mg, 0.553 mmol) dissolved in butyl acetate (8 mL) and water (1.6 mL) was added, followed by potassium bicarbonate (169 mg, 1.688 mmol), compound 46.5 (450 mg, 0.938 mmol), and bis(tricyclohexylphosphine)palladium dichloride (84 mg, 0.113 mmol). The mixture was heated to 85 °C for 15 hours under nitrogen protection. After the reaction was complete, the mixture was prepared as a precipitate and subjected to column chromatography (PE:EA = 10:1 to 3:1). Compound 46 (300 mg, yield 54.67%) was obtained.

[0396] 1H NMR (400MHz, DMSO) δ9.23-9.25(m,1H),7.82-7.84(m,1H),7.74-7.76(m,1H),7.37-7.39(m,1H) ),7.02-7.05(m,1H),6.94-6.96(m,1H),6.49-6.51(m,1H),4.85-4.90(m,1H),4.70-4.74(m,1H ),4.50(m,2H),4.00(m,1H),3.86-3.87(m,1H),3.35(m,1H),3.26(s,3H),3.03-3.08(m,2H),2. 56(m,2H),1.75(s,6H),1.43–1.39(m,1H),1.11(s,3H),0.97(s,1H).LCMS(ES)m / z=992.20[MH] - .

[0397] Example 47 Synthesis of N-((1S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-((2-(methyl-d3)-1,1-dioxide tetrahydrothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (47)

[0398] Step 1: Compound 47.1 (3.50 g, 13.763 mmol, 1 eq.) was dissolved in DMF (35 mL). NaH (826 mg, 20.652 mmol, 60% purity, 1.501 eq.) was added at -10 °C. After stirring for 1 hr, deuterated iodomethane (3.00 g, 20.696 mmol, 1.504 eq.) was added. The reaction was carried out at 0–25 °C for 2 hr. The system was cooled, and water (20 mL) was added. The mixture was extracted with EA (10 mL × 3). The organic phases were combined, washed with water (20 mL), and then washed with saturated sodium chloride aqueous solution. The organic phase was evaporated to dryness, prepared as sintered sand, and subjected to column chromatography (PE:EA = 5:1) to give compound 47.2 (1.60 g, yield 42.843%). MS (m / z) = 271.347 [M+H]+.

[0399] Step 2: Dissolve compound 47.2 (1.60 g, 5.897 mmol, 1 eq.) in MeOH (20 mL), and add Pd / C (716 mg, 589.522 μmol, 10% purity, 9.998 e)-2 (eq.), hydrogen purging, reaction at 25 °C for 15 hr. Filter palladium on carbon, evaporate the filtrate to dryness, to give compound 47.3 (1.00 g, 5.518 mmol, 93.581%).

[0400] Steps 3 to 5: Compounds 47.4-75 can be synthesized according to the method of compound 1 to obtain title compound 75 (50 mg, yield 46.13%).

[0401] 1 H NMR(400 MHz, DMSO) δ10.03(s,1H),9.35–9.10(m,1H),7.82–7.60(m,2H),7.36–7.21(m,1H),7.07–6.97( m,1H),6.90–6.73(m,1H),6.54–6.38(m,2H),5.04–4.87(m,1H),4.78–4.66(m,1H),4.64–4.56( m,1H),4.53–4.43(m,1H),4.02–3.89(m,1H),3.38–3.35(m,2H),3.14(s,3H),3.02–2.87(m,2H) ,2.63–2.56(m,2H),2.49–2.14(m,4H),1.47–1.34(m,1H),0.96(s,1H).LCMS(m / z)=983.10[M+H] + .

[0402] Unless otherwise specified, all reagents used in the following test examples are standard commercially available products.

[0403] Test Example 1: Anti-HIV-1 viral bioactivity

[0404] Test materials

[0405] Test compounds: Zidovudine (AZT), raltegravir (RAL), and bicitiravir (BIC) are approved anti-HIV drugs and were purchased from the market as positive controls.

[0406] Virus: HIV-1; Cells: MT-4 cells, HEK293T cells.

[0407] Reagents: DMEM medium was purchased from Gibco (catalog number 11995-065), fetal bovine serum (FBS) was purchased from ExCell (catalog number FSP500), penicillin-streptomycin antibiotics were purchased from Hyclone (catalog number SV30010), DMSO was purchased from Sigma (catalog number 472301-1L), and reporter gene assay kits were purchased from Perkin Elmer (catalog number 6066769).

[0408] Composition of cell culture medium: DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin antibiotics.

[0409] Test Plan

[0410] This experiment tested the inhibitory activity of the test compounds against HIV-1, with AZT / RAL / BIC serving as positive controls. The specific procedure was as follows: MT-4 cells / HEK293T cells were seeded into 96-well test plates at a concentration of 55,000 cells per well (counted using a cell counter) and cultured overnight in a 5% CO2, 37°C incubator; DMSO stock solution of the test compound was prepared and diluted to 8 different concentrations (range 0.0012-1000 nM) according to experimental requirements, and then added to the cell culture plates; HIV-1 virus was diluted with cell culture medium to 100 TCID50 / 50 μL, and 50 μL of diluted virus was added to each well; the total volume of cell culture medium was 200 μL per well, and the final concentration of DMSO in the culture medium was 0.5%; the cells were cultured for another 3 days in a 5% CO2, 37°C incubator; after culture, the luciferase activity of each well was measured using a reporter gene assay kit and a multi-mode microplate reader (PerkinElmer, model Envision 2015), and the raw data were used to calculate the anti-HIV-1 activity of the compound. The antiviral activity of the samples was analyzed using nonlinear fitting with GraphPad Prism software to calculate the half-maximal effective concentration (EC50) of the samples. 50 The curve fitting method is log(inhibition) vs. response -- variable slope, and the calculation formula is as follows:

[0411] Antiviral activity (%) EC 50 = (Test well reading - Virus control average) / (Cell control average - Virus control average) × 100

[0412] The results are shown in Tables 1 and 2.

[0413] Table 1. Antiviral effects of the compounds on HIV-1 in MT-4 cells. IIIB )active

[0414] Table 2. Antiviral (HIV-PsV) activity of compounds in HEK293T cells.

[0415] Conclusion: The compounds provided in this application all exhibit good antiviral activity against HIV-1, with antiviral levels significantly superior to those of marketed anti-HIV drugs AZT, RAL, or BIC. Furthermore, all compounds in the examples showed no significant cytotoxicity to cells, with a median cell survival concentration (CC50) of [missing value]. 50 The values ​​were all greater than the highest test concentration in each experiment, indicating a high antiviral selectivity index (CC). 50 / EC 50 ).

[0416] Test Example 2: Bioactivity of anti-HIV-1 capsid protein

[0417] This experiment, based on the principle of homogeneous time-resolved fluorescence, determined the IC50 of the relative inhibition rate of the compound of this application on HIV-1 capsid protein formation. 50 value.

[0418] MAb Anti GST-Eu cryptate was purchased from CISBIO (catalog number 61GSTKLA); MAb Anti 6 HIS-XL 665 was purchased from CISBIO (catalog number 61HISXLF); GST-tagged HIV-I capsid protein was purchased from Universal Gene (catalog number GST-CA); HIS-tagged HIV-I capsid protein was purchased from Universal Gene (catalog number HIS-CA); protein dilution buffer was purchased from Universal Gene (catalog number P102421); Tris-HCl was purchased from Beyotime (catalog number ST788); KF was purchased from 3A (catalog number A07483); ELISA plate was purchased from PerkinElmer (catalog number 6005620); PPI-Europium detection buffer was purchased from CISBIO (catalog number 61DB9RDF).

[0419] HIV-1 capsid proteins tagged with GST and HIS were pre-incubated with their corresponding fluorescent antibodies to form complexes. The pre-complexed protein-antibody mixture, a series of concentration gradients of the test compounds (compounds in this application, concentration range 10-300 μM), and reaction buffer (50 mM Tris-HCl, pH 8.0; 1 M NaCl; 0.8 M KF) were mixed in an ELISA plate and incubated at 37°C for 2 hours, allowing the protein to assemble with or without the test compounds. A benchtop ELISA reader was used. (iD5 Multi-Mode Reader) FRET signal detection: Excitation with 337nm excitation light, fluorescence values ​​at 620nm (donor signal) and 665nm (acceptor signal) were read. The HTRF Ratio for each well was calculated as (665nm signal / 620nm signal) × 1000; using GraphPad Prism software, a curve was fitted to the ratio values ​​with compound concentration to calculate the IC50 for inhibiting capsid protein assembly. 50 The values ​​are shown in Table 3.

[0420] Table 3

[0421] Conclusion: The compound of this application has a strong inhibitory effect on HIV-1 capsid protein and has the ability to inhibit the binding of HIV capsid protein.

[0422] Test Example 3: Rat Pharmacokinetic Test

[0423] This study investigated the pharmacokinetic characteristics of the compound in rats by measuring the plasma concentrations of the compound at different time points after administration via oral gavage (PO) and intravenous infusion (IV bolus).

[0424] Test animals: SPF-grade male SD rats, 6-8 weeks old, weighing about 200g; 3 animals were tested for each compound.

[0425] Experimental formulation:

[0426] Oral administration group (PO) / Intravenous bolus group (IV): 10% DMAC + 10% Solutol HS15 + 80% Saline.

[0427] Administration method: Mice in the PO group were given a dose of 5 mg / kg, and were fasted before administration but allowed free access to water; mice in the IV group were given a dose of 1 mg / kg, and were allowed free access to water before administration.

[0428] Sampling method:

[0429] For rats administered PO: 20 μL of blood was collected from the saphenous vein of the limb before administration and 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 120, and 168 hours after administration; For rats administered IV: 20 μL of blood was collected from the saphenous vein of the limb before administration and 0.017, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 120, and 168 hours after administration.

[0430] All blood samples were placed in EDTA-K2 anticoagulant blood collection tubes, and plasma samples were obtained by centrifugation (4℃, 3500rpm, 10min) for testing.

[0431] Detection: Take 10 μL of rat plasma at each time point, add 100 μL of methanol containing internal standard (100 ng / mL), vortex mix for 1 min, centrifuge (4℃, 12000 rpm, 5 min), take 1 μL of supernatant from the plasma sample for LC-MS / MS analysis, determine the content of the analyte compound in rat plasma, and perform pharmacokinetic analysis on plasma concentration-time data. The pharmacokinetic parameters are shown in Table 4.

[0432] Table 4. Pharmacokinetic results of rat IV administration.

[0433] Conclusion: The compound provided in this application has a long half-life and exposure level in vivo.

[0434] The compound obtained in Example 3 was administered to rats via PO according to the above method, and the pharmacokinetic parameters are shown in Table 5.

[0435] Table 5. Pharmacokinetic results of PO administration in rats

[0436] Conclusion: The compounds provided in this application have good plasma exposure, oral bioavailability and long half-life when administered orally, and have the potential to be developed into long-acting drugs.

[0437] Test Example 4: Pharmacokinetic Study of Subcutaneous Administration in Beagle Dogs

[0438] This study investigated the pharmacokinetic characteristics of the compound in Beagle dogs by measuring the plasma concentration at different time points after subcutaneous (SC) administration.

[0439] Test animals: Beagle dogs, 6-12 months old, weighing about 10 kg; 3 male animals were tested for each compound.

[0440] Experimental formulation: 31.7 w / w% water / 66.7 w / w% PEG300 / 1.6 w / w% poloxamer 188

[0441] Administration method: subcutaneous injection, dosage is 12 mg / kg, administration volume is 0.06 mL / kg, administration concentration is 200 mg / ml, no fasting or drinking is required before administration.

[0442] Sampling method: 50 μL of blood was collected from the jugular vein before administration and at 1 h, 3 h, 8 h, 24 h, 48 h, 72 h, 96 h, D7, D14, D21, D28, D35, and D42 after administration. All blood samples were placed in EDTA-K2 anticoagulant blood collection tubes and centrifuged (4℃, 3500 rpm, 10 min) to obtain plasma samples for testing.

[0443] Detection: Take 10 μL of plasma at each time point, add 100 μL of methanol containing internal standard (100 ng / mL), vortex mix for 1 min, centrifuge (4℃, 12000 rpm, 5 min), take 1 μL of supernatant from the plasma sample for LC-MS / MS analysis, determine the content of the analyte compound in the animal plasma after administration, and perform pharmacokinetic analysis on the plasma concentration-time data. The pharmacokinetic parameters are shown in Table 6.

[0444] Table 6. Pharmacokinetic Results of Canine SC Drug Administration

[0445] Conclusion: The compound provided in this application, when administered subcutaneously, exhibits a long half-life and high blood concentration, demonstrating good long-acting drug properties.

[0446] Test Example 5: Liver Microsomal Metabolic Stability Test

[0447] This experiment uses human liver microsomes as an in vitro model to evaluate the metabolic stability of the compounds in this application.

[0448] At 37°C, the compound of this application at a final concentration of 1 μM was co-incubated with human liver microsomes at a concentration of 0.5 mg / mL (purchased from Corning, catalog number 452117) and coenzyme NADPH for certain times (5, 15, 30, 45, and 60 min). The reaction was terminated by adding cold acetonitrile (4°C, ACN) containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS). The concentration of the compound in the sample was analyzed by LC-MS / MS, and T was calculated using a first-order kinetic equation. 1 / 2 (mic), the results are shown in Table 7.

[0449] Table 7 Parameters of liver microparticle metabolism

[0450] Conclusion: The compounds provided in this application have good metabolic stability in humans and are metabolized at a moderate or slow rate.

[0451] Test Example 6: Cell Permeability Assay

[0452] Experimental materials: Caco-2 cell line was purchased from ATCC, catalog number HTB-37.

[0453] Experimental methods: Caco-2 cells were grown at a concentration of 3.5 × 10⁻⁶. 4 cells / cm 2 The cells were seeded at a density on 96-well Corning insert plates with a pore size of 0.4 μm on polycarbonate (PC) membranes, and the culture medium was replaced every 4-5 days until a confluent cell monolayer was formed in 21-28 days.

[0454] (1) The transport buffer used in this study was Hank's balanced salt buffer (HBSS, pH 7.40±0.05) containing 10.0 mM HEPES. The test compounds were tested for bidirectional (A to B and B to A) administration at a concentration of 10.0 μM, with 2 replicates. The control group: metoprolol, atenolol, and erythromycin were tested for bidirectional (A to B and B to A) administration at 10 μM, with 2 replicates for each. The final concentration of dimethyl sulfoxide (DMSO) in the test system was less than 1%. The cells were cultured for 2 hours in a 37°C, 5% CO2, saturated humidity incubator.

[0455] (2) Collect all sample solutions and mix them with acetonitrile containing internal standard. After centrifugation at 3220×g for 10 min, take the supernatant for testing.

[0456] (3) The concentrations of the test compound and the control compound in the starting solution, donor solution and receiving solution were detected by LC-MS / MS and quantified by the analyte / internal standard peak area ratio.

[0457] (4) After the transport experiment, the integrity of the Caco-2 cell monolayer was determined by fluorescent yellow rejection assay.

[0458] Data processing:

[0459] Apparent permeability coefficient P app The formula for calculating (cm / s) is: P app = (dCr / dt)×Vr / (A×C0),

[0460] dCr / dt is the cumulative concentration of the receiving compound as a function of time; Vr is the volume of the receiving solution (0.0750 mL on the top side and 0.250 mL on the base side); A is the transport surface area, i.e., the area of ​​a 0.143 cm² cell monolayer; and C0 is the initial concentration of the drug-eluting compound.

[0461] The results are shown in Table 8.

[0462] Table 8 Apparent Permeability Coefficient

[0463] The apparent permeability coefficient (P) of AB in Caco-2 cell monolayers was determined. app To determine the permeability of the test compound, P app<0.5×10 -6 cm / s indicates low permeability, 0.5×10 -6 cm / s≤P app <2.5×10 -6 cm / s indicates moderate permeability, P app >2.5×10 -6 cm / s indicates high permeability.

[0464] Conclusion: The compounds provided in this application exhibit low to moderate permeability in Caco-2 cells.

[0465] Test Example 7: Protein Binding Assay

[0466] The plasma protein binding rate of the compound of this application in rat, beagle dog and human plasma was determined by balanced dialysis method.

[0467] First, the plasma was processed and the dialysis membrane was pretreated. Then, the test compound was added to the plasma (concentration of the test compound was 400 μM) and placed on one side of the dialysis apparatus (donor side). The other side (recipient side) was a buffer solution (an aqueous solution containing 100 mM sodium phosphate and 150 mM sodium chloride, pH 7.4 ± 0.1). The mixture was incubated at 37 °C for 4 hours to allow the free drug to pass through the membrane and reach equilibrium. After incubation, 50 μL of each well sample was aspirated and 450 μL of stop solution (containing 200 ng / mL tosylate and 200 ng / mL labetalol in acetonitrile) was added. For the drug-side sample, 50 μL of blank phosphate buffer was added, and for the receiver-side sample, 50 μL of blank plasma of the corresponding species was added. The mixture was mixed, filtered under positive pressure, and the results were detected by LC-MS / MS. The binding percentage (%Bound) was calculated. The results are shown in Table 9.

[0468] Table 9 Plasma protein binding rate

[0469] Conclusion: The compound of this application exhibits extremely high protein binding rates in SD rat, beagle dog, and human plasma.

[0470] Test Example 8: CYP Inhibition Test

[0471] This study aimed to evaluate the in vitro inhibitory activity of the compound presented in this application against five major human CYP enzymes (1A2, 2C9, 2C19, 2D6, 3A4). Different concentrations (0.05–50 μM) of the compound presented in this application, human liver microsomes purchased from Corning (catalog number 452117), a mixture of specific substrates for the five CYP enzymes (phenacetin, diclofenac, S-metphenytoin, dextromethorphan, and midazolam), and the cofactor NADPH were mixed and the reaction was initiated at 37°C. After incubation for 10 min, the reaction was terminated and the samples were processed. The amount of specific metabolites produced by each CYP enzyme was detected using LC-MS / MS. The inhibition rate was calculated based on the decrease in metabolite production, and a dose-response curve was fitted to calculate the IC50. 50 The values ​​are shown in Table 10.

[0472] Table 10

[0473] Conclusion: The compound of this application did not show significant inhibitory effect on CYP enzymes 2D6 / 2C9 / 2C19 / 1A2.

[0474] Experiment Example 9: In vivo prophylactic efficacy test in humanized mice

[0475] Human immune system reconstituted mice (huHSC mice) were selected and administered a single subcutaneous injection of the compound of this application or a blank solvent before HIV-1 infection. The protective effect of the compound of this application at different doses on the humanized mouse HIV-1 infection model was investigated. The huHSC mouse model has CD4 target cells that are infected with HIV-1. + T cells, the virus used in this model is the same as that in humans, HIV-1, and it is widely used in animal models of HIV-1 infection.

[0476] This experiment was designed with three animal groups: a model control group, and low- and high-dose groups of the compound of this application, with 10 mice in each group, for a total of 30 mice. Blood samples were collected from all animals after challenge for virological and immunological marker detection, once a week for a total of 4 weeks. Four weeks after challenge, the mice were dissected, and the spleen, brain, and intestines were collected for virological testing. At the same time, plasma was collected for blood drug concentration detection.

[0477] Conclusion: The compound provided in this application has a significant effect on preventing HIV infection in animals.

[0478] Experimental Example 10: In vivo therapeutic efficacy trial in humanized mice

[0479] The experimental procedure of Experiment Example 15 was adopted, except that "a single subcutaneous injection of the compound of this application or a blank solvent was given to the animal before HIV-1 infection" was replaced with "a single subcutaneous injection of the compound of this application or a blank solvent was given to the animal after HIV-1 infection".

[0480] Conclusion: The compound provided in this application has a significant therapeutic effect on HIV infection in animals.

[0481] The applicant declares that this application illustrates the technical solution of this application through the above embodiments, but this application is not limited to the above embodiments, that is, it does not mean that this application must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this application, equivalent substitutions of the raw materials of this application's products, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this application.

[0482] The optional embodiments of this application have been described in detail above. However, this application is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this application, various simple modifications can be made to the technical solution of this application, and these simple modifications all fall within the protection scope of this application.

[0483] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this application will not describe the various possible combinations separately.

Claims

1. An amide compound, wherein, The amide compound is selected from the group consisting of a compound represented by formula (I), a tautomer thereof, an endo-mer thereof, an exo-mer thereof, an enantiomer thereof, a diastereomer thereof, an atropisomer thereof, or a pharmaceutically acceptable salt thereof; In formula (I), Each R1 is independently selected from hydrogen or halogen; Each R2 is independently selected from hydrogen or halogen; R3is selected from hydrogen, C1-C6alkyl, haloC1-C6alkyl; each of the foregoing alkyl groups is optionally substituted with 1-3 R a substituents; R4is selected from hydrogen, C1-C6alkyl, haloC1-C6alkyl; each of the foregoing alkyl groups is optionally substituted with 1-3 R a substituents; R5or R6are each independently selected from the group consisting of hydrogen, C1-C6alkyl, haloC1-C6alkyl; each of the foregoing alkyl groups is optionally substituted with 1-3 R a substituents; R5 and R6 are independent of each other, or R5 and R6 are connected together and together with the atoms they are connected to form a 3-6 membered cycloalkyl group; R7is selected from hydrogen, C1-C6alkyl, deuterated C1-C6alkyl, haloC1-C6alkyl; each of the foregoing alkyl groups is optionally substituted with 1-3 R a substituents; R8and R8' are each independently selected from the group consisting of hydrogen, C1-C6alkyl, deuterated C1-C6alkyl, halo-substituted C1-C6alkyl, amino-substituted alkyl, amino; each of the foregoing alkyl, amino groups optionally substituted with 1-3 R a substituents; R9is selected from hydrogen, C1-C6alkyl, haloC1-C6alkyl, or 3- to 5-membered cycloalkyl; each of the foregoing alkyl, cycloalkyl groups being optionally substituted with 1-3 R a substituents; Each R a Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, or 3-10 membered cycloalkyl containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, or cycloalkyl group may optionally be surrounded by 1-3 R groups. c replace; Each R c Each group is independently selected from hydrogen, deuterium, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl. R 10 , R 11 , R 12 are each independently selected from hydrogen or Ci-C6alkyl; R 13 , R 14 are each independently selected from hydrogen or C1-C6alkyl; R 15 , R 16 , R 17 , R 18 is selected from hydrogen, Ci-C6alkyl or halogenated Ci-C6alkyl; Where X is NR', R' is selected from hydrogen or C1-C6 alkyl, and R7, R8' and R8 are independent of each other; Or X is O, and the compound shown in formula (I) satisfies any one or at least a combination of two of the following conditions: (1) R8' is selected from hydrogen or C1-C6 alkyl, R7 is connected to R8 and together with the atoms connected to them respectively to form a 3-12 membered cycloalkyl group, wherein the 3-12 membered cycloalkyl group may be replaced by 1-3 Ra; (2) R8' is connected to R8 and together with the atoms to which they are respectively attached form a 3-12 membered heterocyclyl group, which 3-12 membered heterocyclyl group is optionally substituted with 1-3 R a substituents; (3) R8' is simultaneously connected to R7 and R8 and together with the atoms connected to them respectively, to form a 5-10-membered bridged cycloalkyl group, wherein the 5-10-membered bridged cycloalkyl group may optionally be replaced by 1-3 Ra atoms; (4) R9 is attached to -NH- and forms a 5-6 membered heterocyclic group together with the adjacent S atom; (5)R 11 With R 12 They connect and together with the atoms they are attached to, form 3-4 membered cycloalkyl groups; Each n is independently selected from 0, 1, 2 or 3; Each k is independently selected from 0, 1, 2, 3, 4, or 5.

2. The amide compound according to claim 1, wherein, X is O, the compound of formula (I) is of formula (la); wherein ring A is a heterocyclic group having 4 to 8 ring atoms containing 1 to 3 heteroatoms; said heterocyclic group is optionally substituted by 1 to 3 R a substituents; In formula (Ia), R1, R2, R3, R4, R5, R6, R7, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R a , n, k are as defined in claim 1.

3. The amide compound according to claim 2, wherein: selected from Alternatively, R7 is selected from hydrogen, methyl, or ethyl.

4. The amide compound according to claim 1, wherein: selected from 5. The amide compound according to claim 1, wherein, X is O, wherein -NH-S(O)2-R9is and / or, R 11 and R 12 together with the atoms to which they are respectively attached form a cyclopropyl group.

6. The amide compound according to claim 1, wherein, X is NH, where R7, R8', and R8 are independently selected from methyl or ethyl, and R9 is selected from methyl or cyclopropyl.

7. The amide compound according to any one of claims 1-6, wherein, Each R1 is independently selected from either hydrogen or fluorine; Optionally, each R2 is independently selected from hydrogen or chlorine; Alternatively, R3 is selected from -CH2CF3 or -CH2CHF2; Alternatively, R4 can be selected from -CF3 or -CHF2.

8. The amide compound according to any one of claims 1 to 6, wherein, R5 is hydrogen, and R6 is hydrogen; or, the structure is m is selected from 0, 1, or 2.

9. The amide compound according to any one of claims 1 to 6, wherein, R 11 is hydrogen, R 12 is hydrogen; Optionally, R 13 is hydrogen, R 14 is hydrogen; Optionally, R 15 is hydrogen, R 16 is hydrogen, R 17 is hydrogen, R 18 is hydrogen.

10. The amide compound according to claim 1, wherein, The compound of formula (I) is selected from any one of the following structures:

11. The amide compound according to claim 4, wherein, The compound of formula (I) is selected from any one of the following structures:

12. The amide compound according to claim 5, wherein, The structure of the compound of formula (I) is:

13. The amide compound according to claim 6, wherein, The compound of formula (I) is selected from any one of the following structures:

14. A pharmaceutical composition, wherein, The pharmaceutical composition comprises the amide compound of any one of claims 1-13, and a pharmaceutically acceptable carrier and / or excipient.

15. Use of the amide compound of any one of claims 1-13 or the pharmaceutical composition of claim 14 in the preparation of HIV capsid protein inhibitors.

16. Use of the amide compound of any one of claims 1-13 or the pharmaceutical composition of claim 14 in the preparation of a medicament for the prevention and / or treatment of HIV infection.

17. The use according to claim 16, wherein, The drug also contains a therapeutically effective amount of other therapeutic agents, including any one or a combination of at least two of the following: compounds that inhibit HIV protease, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, viral capsid polymerization inhibitors, or non-catalytic site HIV integrase site inhibitors.

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