Amide compound and use thereof

Abstract

The present application provides an amide compound and a use thereof. The amide compound is selected from a compound represented by formula (I), a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof, an atropisomer thereof, or a pharmaceutically acceptable salt thereof. In the present application, a series of novel amide compounds is developed. These amide compounds have excellent anti-HIV activity, no significant cytotoxicity, relatively strong affinity for HIV-1 capsid protein, and good specificity, are suitable for intravenous administration, oral administration, subcutaneous administration, and intramuscular injection administration, and show relatively long half-life and relatively high exposure in vivo. In addition, the amide compounds have no significant inhibitory effect on various CYP enzymes, exhibit high plasma protein binding, and have excellent safety and good metabolic stability in vivo, no potential off-target effect, high safety, and the potential to be developed into clinical long-acting drugs.

Description

An amide compound and its uses Technical Field

[0001] This application belongs to the field of chemical and pharmaceutical technology and relates to an amide compound and its uses. Background Technology

[0002] AIDS, also known as Acquired Immunodeficiency Syndrome, is a systemic disease caused by infection with the Human Immunodeficiency Virus (HIV) and has long been one of the world's major public health problems. Over the past forty years, significant breakthroughs have been made in AIDS drug development, from early antiretroviral therapy (ART) to highly active antiretroviral therapy (HAART), with continuously improving treatment outcomes. Today, as long as medication is taken consistently and as prescribed, HIV infection can be controlled as a chronic disease, no longer a terminal illness.

[0003] According to the current HIV / AIDS treatment guidelines recommended by various national organizations, patients need to take medication at regular times and in the prescribed dosage every day. On the one hand, daily medication adherence places significant demands and challenges on patients, especially those struggling with busy work schedules, life changes, or high levels of psychological stress. On the other hand, drug safety significantly impacts patients' willingness to take medication; common adverse reactions such as headaches and dizziness can lead patients to discontinue or stop taking their medication. If patient adherence is poor, with frequent missed doses, incorrect doses, or interrupted doses, the risk of developing drug resistance increases, in addition to the difficulty in ensuring treatment efficacy.

[0004] The development of long-acting anti-HIV drugs has become one of the main directions of current drug development, and is expected to improve patient medication adherence. In 2018, the NMPA approved the marketing of the long-acting HIV fusion enzyme drug Abovite, for once-weekly intravenous administration; in 2020, the EMA approved Cabotegravir, the world's first long-acting HIV-1 integrase inhibitor developed by ViiV Healthcare, for monthly or bi-monthly intramuscular injection; in 2022 and July 2025, the FDA successively approved Lenacapavir, developed by Gilead Sciences, as a novel mechanism HIV capsid protein inhibitor for HIV-1 treatment after multidrug resistance and as a pre-exposure prophylaxis (PrEP) drug, administered subcutaneously, with the dosing frequency further reduced to once every six months.

[0005] The availability of long-acting HIV-1 drugs has greatly enriched the personalized options for HIV patients and high-risk exposure groups. However, due to the highly variable mutational nature of HIV genes, long-acting drugs can still develop resistance after prolonged use, leading to decreased efficacy. According to the latest report from the International Association for Antiviral Therapy in the United States (IAS-USA) Resistance Group in 2025, several new resistance sites have been found in the recently marketed Lenacapavir (Top Antivir Med, 2025, 33(2) 457-473). Therefore, there is an urgent need to develop drugs with higher activity, fewer toxic side effects, and a better metabolic half-life (T0). 1 / 2 Novel capsid protein inhibitors that detect both drug exposure and AUC are more beneficial for the treatment of HIV patients. Summary of the Invention

[0006] This application provides an amide compound and its use therein, specifically 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.

[0007] In a first aspect, this application provides an amide compound selected from compounds of formula (I), their tautomers, their meso compounds, their racemates, their enantiomers, their diastereomers, their transisomers, or their pharmaceutically acceptable salts.

[0008] In formula (I), each R1 is independently selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl and 3-10 membered cycloalkyl may be divided by 1-3 R1 groups. a replace;

[0009] Each R2 is independently selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be selected by 1-3 R2 groups. a replace;

[0010] R3 is selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be surrounded by 1-3 R3 groups. a replace;

[0011] R4 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be surrounded by 1-3 R4 groups. a replace;

[0012] R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, or 3-10 membered cycloalkyl; the alkyl or 3-10 membered cycloalkyl may optionally be surrounded by 1-3 R... a replace;

[0013] R7 and R8 are each independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be distinguished by 1-3 R groups. a replace;

[0014] R8' is selected from C1-C6 alkyl or deuterated C1-C6 alkyl;

[0015] R9 is selected from hydrogen, C1-C6 alkyl, or 3-10 membered cycloalkyl; the alkyl or 3-10 membered cycloalkyl may be surrounded by 1-3 Rs. a replace;

[0016] R 10 Selected from hydrogen, deuterium, C1-C6 alkyl, and deuterated C1-C6 alkyl;

[0017] R 11 R 12 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, and deuterated C1-C6 alkyl;

[0018] R 13 R 14 R 15 R 16 R 17 R 18 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl;

[0019] Each R a Each alkyl group is independently selected from hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, or 3-10 membered cycloalkyl; the alkyl group or 3-10 membered cycloalkyl group may optionally be surrounded by 1-3 R groups. c replace;

[0020] 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;

[0021] Each n is independently selected from 0, 1, 2 or 3;

[0022] Each k is independently selected from 0, 1, 2, 3, 4 or 5;

[0023] Furthermore, the compound shown in formula (I) satisfies any one or at least a combination of two of the following conditions:

[0024] (1) Structure yes

[0025] (2) R3 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens;

[0026] (3) R7 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens;

[0027] (4) R8 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens;

[0028] (5)R 10 Selected from deuterium or deuterated C1-C6 alkyl groups;

[0029] (6)R 11 R 12 Each is independently selected from deuterium, halogen, or deuterated C1-C6 alkyl groups;

[0030] (7)R 13 R 14 Each is independently selected from deuterium or deuterated C1-C6 alkyl groups;

[0031] (8) R2 is fluorine.

[0032] 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.

[0033] This application develops a series of novel amide compounds that exhibit excellent anti-HIV activity without significant cytotoxicity. These compounds have a strong affinity for HIV-1 capsid proteins and good specificity. They are suitable for intravenous, oral, subcutaneous, and intramuscular administration, and possess a long half-life and high exposure levels in vivo. Furthermore, these amide compounds do not show significant inhibitory effects on various CYP enzymes, exhibit high plasma protein binding, excellent safety and good metabolic stability in vivo, and no potential off-target effects. They demonstrate high safety and have the potential to be developed into long-acting clinical drugs.

[0034] In some embodiments, the compound represented by formula (I) satisfies any one or a combination of at least two of the following conditions:

[0035] (1) Structure yes

[0036] (2) R3 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens;

[0037] (3) R7 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens;

[0038] (4) R8 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens;

[0039] (5)R 10 Selected from deuterium or deuterated C1-C6 alkyl groups;

[0040] (6)R 11 R 12 Each is independently selected from deuterium, halogen, or deuterated C1-C6 alkyl groups.

[0041] In some implementations, in condition (2), R3 is selected from -CD2CF3 or -CD2CD3.

[0042] In some implementations, in condition (3), R7 is selected from deuterated methyl or deuterated ethyl.

[0043] In some implementations, in condition (4), R8 is selected from deuterated methyl or deuterated ethyl.

[0044] In some implementations, in condition (5), R 10 It is deuterium.

[0045] In some implementations, in condition (6), R 11 R 12 All are deuterium.

[0046] In some implementations, each R1 in formula (I) is independently selected from hydrogen or fluorine.

[0047] In some implementations, each R2 in formula (I) is independently selected from hydrogen, chlorine, or fluorine.

[0048] In some implementations, R3 in formula (I) is selected from -CH2CF3 and -CH2CHF2.

[0049] In some implementations, R4 in formula (I) is selected from -CF3 or -CHF2.

[0050] In some implementations, R5 in formula (I) is hydrogen and R6 is hydrogen.

[0051] In some implementations, R7 in formula (I) is selected from hydrogen, methyl, or ethyl.

[0052] In some implementations, R8 in formula (I) is selected from hydrogen, methyl, or ethyl.

[0053] In some implementations, R9 in formula (I) is selected from methyl or cyclopropyl.

[0054] In some implementations, R in equation (I) 10 It is hydrogen.

[0055] In some implementations, R in equation (I) 11 It is hydrogen.

[0056] In some implementations, R in equation (I) 12 It is hydrogen.

[0057] In some implementations, R in equation (I) 13 For hydrogen, R 14 It is hydrogen.

[0058] In some implementations, R in equation (I) 15 For hydrogen, R 16 For hydrogen, R 17 For hydrogen, R 18 It is hydrogen.

[0059] In some embodiments, the compound represented by formula (I) is selected from any of the following structures:

[0060] In some embodiments, the compound represented by formula (I) is selected from any of the following structures:

[0061] In some embodiments, the compound represented by formula (I) is selected from any of the following structures:

[0062] 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.

[0063] 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.

[0064] 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 viral infectious diseases.

[0065] In some implementations, the viral infection is HIV infection.

[0066] In some embodiments, the medicament further comprises 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.

[0067] Fifthly, this application provides a method for inhibiting HIV capsid proteins, the method comprising administering to a desired patient an effective dose of the amide compound of the first aspect or the pharmaceutical composition of the second aspect.

[0068] In a sixth aspect, this application provides a method for preventing and / or treating viral infectious diseases, the method comprising administering to a desired patient a preventive and / or therapeutically effective dose of the amide compound of the first aspect or the pharmaceutical composition of the second aspect.

[0069] In some implementations, the viral infection is HIV infection.

[0070] 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.

[0071] Terms and related explanations used in this application:

[0072] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0073] 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.

[0074] 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 a Etc. 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.

[0075] The term “therapeutic effective amount” means the following amounts of the compound of this application, which (i) treat a specific disease, symptom or disorder; (ii) reduce, alleviate or eliminate one or more symptoms of a specific disease, symptom or disorder; or (iii) prevent or delay the onset of one or more symptoms of the specific disease, symptom or disorder described in this application.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 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.

[0080] 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.

[0081] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0082] 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.

[0083] 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.

[0084] The term "hydroxyl group" refers to the -OH group.

[0085] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0086] The term "cyano" refers to -CN.

[0087] The term "nitro" refers to -NO2.

[0088] 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:

[0089] (i) Suppress the disease or disease state, that is, curb its development;

[0090] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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).

[0095] 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. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0096] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0097] As pharmaceutically acceptable salts, examples include metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids. Pharmaceutical compositions.

[0098] For administration purposes, in some embodiments, the compounds described herein are administered as raw material chemicals or formulated into pharmaceutical compositions. The pharmaceutical compositions disclosed herein comprise compounds of formula (I) with suitable pharmaceutically acceptable excipients. The compounds of formula (I) are present in the composition in an amount effective in treating a particular disease or condition.

[0099] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, and aerosols. The pharmaceutical compositions of this application are formulated to allow the active ingredients contained therein to be bioavailable when the composition is administered to a patient. The composition administered to a subject or patient is in the form of one or more dose units, wherein, for example, a tablet may be a single dose unit.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] For example, when the pharmaceutical composition is to be administered by injection, it may be formulated into a suitable unit dosage form of sterile solution, suspension or lyophilized product.

[0104] The compounds of this application or their pharmaceutically acceptable salts are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the specific compound used; the metabolic stability and duration of action of the compound; the patient's age, weight, general health status, sex, and diet; the route and timing of administration; the rate of excretion; the combination of drugs; the severity of the specific disorder or condition; and the treatment the subject is currently undergoing.

[0105] Combination therapy

[0106] In some embodiments, a method is provided for treating or preventing HIV infection in a mammal (e.g., a human) that is infected or at risk of infection, comprising administering to the mammal a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more other therapeutic agents.

[0107] In some embodiments, a pharmaceutical composition is provided comprising the compounds disclosed herein, pharmaceutically acceptable salts thereof, in combination with one or more additional therapeutic agents, and with suitable pharmaceutically acceptable excipients.

[0108] In some embodiments, a pharmaceutical preparation is provided, comprising a combination of the compounds disclosed herein or their pharmaceutically acceptable salts with one or more other therapeutic agents.

[0109] In some embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from compounds that inhibit HIV protease, HIV non-nucleoside / non-nucleotide 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, capsid protein inhibitors, pharmacokinetic enhancers, and other drugs for the treatment of HIV, and combinations thereof.

[0110] In some embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with two, three, four, or more additional therapeutic agents. In some embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In further embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, or they may be selected from different classes of therapeutic agents.

[0111] In some embodiments, one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a dosage form of a unit for simultaneous or sequential administration to a patient. In some embodiments, a pharmaceutical composition is provided comprising one or more of the compounds disclosed herein in combination with one or more other active therapeutic agents. In some embodiments, the compounds disclosed herein are combined with one or more other active therapeutic agents in a solid dosage form. The combination therapy may be administered in a simultaneous or sequential manner. When administered sequentially, the combination may be administered with two or more doses.

[0112] In some embodiments, one or more of the compounds disclosed herein are co-administered with one or more other active therapeutic agents. Co-administration of the compounds disclosed herein with one or more other active therapeutic agents generally means the simultaneous or sequential administration of the compounds disclosed herein and one or more other active therapeutic agents such that therapeutically effective amounts of the disclosed compounds and one or more other active therapeutic agents are present in the patient's body.

[0113] The compound described in the dosing regimen, such as the compound shown in any formula (I), can be administered to an individual according to an effective dosing regimen for a desired period of time or duration, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual's life.

[0114] The dosage or frequency of administration of any compound represented by formula (I) may be adjusted during the treatment, for example, based on the judgment of the administering physician. The compound may be administered to an individual (e.g., a human) in an effective amount. In one aspect, the compound is administered once daily. In another aspect, the compound is administered twice daily. In yet another aspect, the compound is administered three times daily.

[0115] 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. In order 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 process based on existing embodiments.

[0116] Compared with the prior art, this application has the following advantages:

[0117] This application develops a series of novel amide compounds that exhibit excellent anti-HIV activity without significant cytotoxicity. These compounds have a strong affinity for HIV-1 capsid proteins and good specificity. They are suitable for intravenous, oral, subcutaneous, and intramuscular administration, and possess a long half-life and high exposure levels in vivo. Furthermore, these amide compounds do not show significant inhibitory effects on various CYP enzymes, exhibit high plasma protein binding, excellent safety and good metabolic stability in vivo, and no potential off-target effects. They demonstrate high safety and have the potential to be developed into long-acting clinical drugs. Attached Figure Description

[0118] Figure 1 is a blood drug concentration-time curve of the PO administration test in Examples 12, 40 and GS6207 mice.

[0119] Figure 2 is a blood drug concentration-time curve for IV dosing experiments in mice of Examples 12, 40, and GS6207.

[0120] Figure 3 is a pharmacokinetic curve of IM administration in Beagle dogs in Experiment 7. Detailed Implementation

[0121] 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.

[0122] 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.

[0123] Examples 1 and 2 N-((S)-1-(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)-2-(3,5-difluorophenyl)ethyl-1-d)-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(1)&N Synthesis of -((R)-1-(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)-2-(3,5-difluorophenyl)ethyl-1-d)-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 (2)

[0124] Intermediates 1.7, 1.9, and 1.11 were prepared according to the preparation method described in WO2019161280A1.

[0125] Step 1: Compound 1.1 (100.00 g, 580.961 mmol), DMF (1000 mL), and dimethylhydroxylamine hydrochloride (67.70 g, 697.722 mmol) were added to a 3 L single-necked flask. The mixture was cooled in an ice bath, and DIPEA (225.30 g, 1.743 mol) was added dropwise. HATU (265.10 g, 697.211 mmol) was added slowly, and the mixture was allowed to rise naturally to room temperature for 15 hours. The reaction mixture was cooled to 0 °C, and water (3000 mL), MTBE (500 mL), and EA (500 mL) were added. The mixture was separated, and the organic phase was washed with water (1000 mL × 3), washed with saturated sodium chloride (1500 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. Column chromatography was performed, and the concentration was increased. Compound 1.2 (111.07 g, yield 88.841%) was obtained.

[0126] Step 2: Add lithium magnesium chloride (2,2,6,6-tetramethylpiperidine) (76.75 g, 316.625 mmol, 317 mL) to a 1 L four-necked flask. Under nitrogen protection, cool to approximately -25 to -20 °C. Slowly add 2,5-dibromopyridine (50.00 g, 211.067 mmol) dissolved in THF (210 mL). Incubate at -18 to -25 °C for approximately 1 hour. Add compound 1.2 (90.95 g, 422.638 mmol) dissolved in THF (90 mL) and maintain the reaction temperature for 2 hours. Add 100 mL of ice water to the system in an ice bath. After the addition is complete, extract with 1 L of isopropyl acetate and wash with 500 mL of saturated brine and 500 mL of saturated ammonium chloride. Dry the organic phase with anhydrous magnesium sulfate and concentrate to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–2%). The crude product was then slurried with ethanol, filtered, and dried to obtain compound 1.3 (23.85 g, yield 28.899%).

[0127] Step 3: Compound 1.3 (10.00 g, 25.575 mmol) was dissolved in deuterated methanol (150 mL) and added to a 50 mL single-necked flask. The mixture was cooled to 0 °C on an ice bath, and sodium borodeide (3.23 g, 77.162 mmol) was added. The reaction was carried out at 20 °C for 2.5 hours. The mixture was then extracted with water (8 mL) and DCM (8 mL) on an ice bath, washed with saturated sodium chloride, and dried over anhydrous magnesium sulfate. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–5%–15%). Compound 1.4 (8.61 g, yield 85.440%) was obtained.

[0128] Step 4: Compound 1.4 (8.61 g, 21.851 mmol) dissolved in THF (5 mL) was added to a 50 mL single-necked flask. DMAP (276 mg, 2.259 mmol) was added, and TEA (3.32 g, 32.810 mmol) and MsCl (3.01 g, 26.277 mmol) were added under nitrogen protection and in an ice bath. The reaction was carried out at 20 °C for 1.5 hr. Water (20 mL) and EA (20 mL) were added to the system, and the mixture was extracted, dried, and evaporated to dryness. Compound 1.5 (10.31 g, yield 99.938%) was obtained.

[0129] Step 5: At room temperature, compound 1.5 (5.00 g, 10.591 mmol) was dissolved in NH3·H2O (30 mL) and MeOH (10 mL) in a 50 mL thermos. The system was heated to 90 °C and reacted for 18 hours. The system was cooled to room temperature, transferred to a single-necked flask, and the methanol was evaporated. The residue was extracted with DCM (20 mL × 3). The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–15%) to give compound 1.6 (0.95 g, yield 22.823%).

[0130] Step Six: At room temperature, compound 1.6 (0.95 g, 2.417 mmol) and compound 1.7 (0.75 g, 2.658 mmol) were added to DMF (8.00 mL) in a 100 mL single-necked flask. HATU (1.11 g, 2.919 mmol) and DIPEA (0.95 g, 7.351 mmol) were added to the above reaction solution. The mixture was purged with nitrogen and reacted at 25 °C for 18 hours. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with water (30 mL × 2) and saturated sodium chloride aqueous solution (30 mL), respectively. The mixture was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–20%). Compound 1.8 (1.58 g, yield 99.467%) was obtained.

[0131] Step 7: At room temperature, compound 1.8 (1.50 g, 2.282 mmol) and compound 1.9 (367 mg, 2.510 mmol) were added to a 250 mL single-necked flask and dissolved in DMF (15 mL). TEA (693 mg, 6.849 mmol), tetratetraphenylphosphine palladium (132 mg, 114.229 μmol, 0.1 eq), and cuprous iodide (43 mg, 225.781 μmol) were added. The mixture was purged with nitrogen and reacted at 35 °C for 15 h. The system was then poured into three volumes of ice water containing DMF, and extracted with DCM (20 mL × 3). The organic phase was washed with saturated sodium chloride (30 mL), dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–20%). Compound 1.10 (1.20 g, yield 72.770%) was obtained.

[0132] Step 8: At room temperature, compound 1.10 (1.2 g, 1.661 mmol) and compound 1.11 (936 mg, 2.492 mmol) were added to a 100 mL single-necked flask, dissolved in water (4 mL) and butyl acetate (16 mL). Potassium bicarbonate (499 mg, 4.984 mmol) and dichlorobis(tricyclohexyl)palladium (123 mg, 166.626 μmol) were then added. The mixture was purged with nitrogen and reacted at 90 °C for 12 hours. The system was directly concentrated to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 5:1–3:1). Compound 1.12 (700 mg, yield 47.291%) was obtained.

[0133] Step 9: At room temperature, compound 1.12 (700 mg, 785.461 μmol) was added to a 50 mL single-necked flask, dissolved in DCM (10 mL), and TEA (477 mg, 4.714 mmol) was added. Methanesulfonic anhydride (270 mg, 2.357 mmol) was added under ice bath conditions, and the mixture was then heated to 25 °C and reacted for 1 hour. An appropriate amount of ice water was added to the system, and extraction was performed. A small amount of DCM was added for dilution, and the organic phase was directly evaporated to dryness. Compound 1.13 (800 mg, yield 97.244%) was obtained.

[0134] Step 10: At room temperature, compound 1.13 (822 mg, 784.817 μmol) was added to a 50 mL single-necked flask, dissolved in 10 mL of ethanol, and 1.96 mL of 2N sodium hydroxide was added. The reaction was carried out at 25 °C. Acetic acid was added to adjust the pH to weakly acidic, and then DCM was added for dilution. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate, concentrated, and evaporated to dryness. The crude product was prepared by silica gel column chromatography (PE:EA = 3:1 to 2:1) to obtain an oily substance, which was slurried with n-heptane:methyl tert-methyl ether (5:1), filtered, and lyophilized to obtain compound 1.14 (200 mg, yield 26.291%).

[0135] Step 11: Compound 1.14 was prepared by chirality (separation conditions: (S,S)Whelk O1, 250×30mm ID, 10μm, A for CO2 and B for Isopropanol (0.1% NH3.H2O)), and its corresponding components were collected and concentrated under reduced pressure to obtain compound 1 (187 mg) and compound 2 (87 mg).

[0136] Compound 1:

[0137] 1 H NMR (400MHz, DMSO-d6) δ10.00(br s,1H),9.23(s,1H),7.85–7.71(m,2H),7.35–7.28(m,1H),7.03(br t,J=9.2Hz,1H),6.86(dd,J=7.6,2.0Hz,1H),6.55–6.45(m,2H),6.58–6.41(m,1H),4.87–4.73(m,2H),4.37–4.35(m,1H),4.06–3.99(m,1 H),3.27(s,3H),3.17(s,3H),3.03–2.91(m,2H),2.64–2.55(m,2H),1.75(s,6H),1.42–1.39(m,1H),0.96–0.95(m,1H).LCMS[M+1]+=969.2

[0138] Compound 2:

[0139] 1 H NMR (400MHz, DMSO-d6) δ10.00(br s,1H),9.23(s,1H),7.85–7.71(m,2H),7.35–7.28(m,1H),7.03(br t,J=9.2Hz,1H),6.86(dd,J=7.6,2.0Hz,1H),6.55–6.45(m,2H),6.58–6.41(m,1H),5.00–4.64(m,1H),4.55–4.31(m,1H),4.06–3.90(m,1 H),3.27(s,3H),3.17(s,3H),3.03–2.91(m,2H),2.64–2.55(m,2H),1.75(s,6H),1.46–1.35(m,1H),1.01–0.92(m,1H).LCMS[M+1]+=969.2

[0140] Example 3 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl-1,1-d2)-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 (3)

[0141] Intermediate 3.1 was synthesized using the same steps as in patent WO2019161280A1.

[0142] Synthesis of intermediate 3.2:

[0143] Synthesis of compound 3.2.2: Lithium aluminum deuteride (1.89 g, 45 mmol) was added to a 250 mL three-necked flask, and anhydrous THF (50 mL) was slowly added. The temperature was lowered to 0–5 °C, and methyl 2,2,2-trifluoroacetate (5.00 g, 39 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 2 hours. Water (2 mL), 15% sodium hydroxide solution (2 mL), and water (6 mL) were added sequentially to quench the reaction. The mixture was diluted with THF (200 mL), filtered under nitrogen pressure, dried over anhydrous sodium sulfate, and then p-toluenesulfonyl chloride (14.87 g, 78 mmol) and triethylamine (7.89 g, 78 mmol) were added. The reaction was carried out for 12 hours, concentrated, and purified by column chromatography (n-heptane / ethyl acetate = 150 / 1) to obtain compound 3.2.2 (5.34 g, yield 53.4%).

[0144] Synthesis of compound 3.2.3: Compound 3.2.2 (3.14 g, 12 mmol), 7-bromo-4-chloro-1H-indazole-3-amine (2.74 g, 11 mmol), K3PO4 (3.61 g, 17 mmol) and N,N-dimethylformamide (27 mL) were added to a 100 mL three-necked flask and reacted at 70–80 °C for 15 h. Ethyl acetate (100 mL) was added, followed by washing with water (100 mL × 3), then washing with saturated brine (100 mL), concentrating, column purification (dichloromethane), then adding ethyl acetate (20 mL) and 1 g activated carbon, stirring at 40 °C for 0.5 h, filtering, concentrating, adding anhydrous ethanol (2 mL) and n-heptane (10 mL), stirring at room temperature for 0.5 h, filtering, and drying to obtain compound 3.2.3 (1.8 g, yield 49.8%).

[0145] Synthesis of compound 3.2: Compound 3.2.3 (1.00 g, 3 mmol), bis(pinacol)diboron (2.3 g, 9 mmol), potassium acetate (0.89 g, 3 eq), and bis(triphenylphosphine)palladium dichloride (0.1 g, 0.12 mmol) were added to a 100 mL three-necked flask, followed by the addition of N,N-dimethylformamide (5 mL) and 1,4-dioxane (5 mL). Under nitrogen protection, the mixture was heated to 110 °C and reacted for 12 h. Ethyl acetate (100 mL) was added, followed by washing with water (100 mL × 3), then washing with saturated brine (100 mL), drying over anhydrous sodium sulfate, concentrating, column purification (dichloromethane), slurrying with n-heptane at room temperature for 0.5 h, filtering, and drying to obtain compound 3.2 (0.68 g, yield 59.6%).

[0146] Synthesis of compound 3:

[0147] Step 1: At room temperature, compound 3.1 (500 mg, 693.017 μmol) and compound 3.2 (420 mg, 1.112 mmol) were added to a 100 mL single-necked flask, dissolved in water (1 mL), butyl acetate (5 mL), followed by potassium bicarbonate (208 mg, 2.078 mmol) and dichlorobis(tricyclohexyl)palladium (77 mg, 104.311 μmol). The mixture was purged with nitrogen and reacted at 90 °C for 15 hours. The system was directly concentrated to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 5:1 to 3:1). Compound 3.3 (270 mg, yield 43.667%) was obtained.

[0148] Step 2: At room temperature, compound 3.3 (270 mg, 302.622 μmol) was added to a 50 mL single-necked flask, dissolved in DCM (5 mL), followed by TEA (184 mg, 1.818 mmol). Methanesulfonic anhydride (104 mg, 907.900 μmol) was added under ice bath conditions. The reaction was carried out at 0 °C for 30 min. An appropriate amount of ice water was added to the system for extraction. The mixture was diluted with a small amount of DCM, and the organic phase was directly evaporated to dryness. Compound 3.4 (300 mg, yield 94.559%) was obtained.

[0149] Step 3: Under ice bath conditions, compound 3.4 (300 mg, 286.155 μmol) was added to a 50 mL single-necked flask, dissolved in ethanol (5 mL), and 2N sodium hydroxide (0.70 mL) was added to bring the temperature to 0 °C and react for 1 hour. An appropriate amount of ice water was added to the system for extraction, followed by dilution with a small amount of DCM. The organic phase was directly evaporated to dryness to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 3:1–2:1), and the resulting oil was slurried with n-heptane and tertiary methyl ether (5:1), filtered, and evaporated to dryness. This yielded title compound 3 (70 mg, yield 25.211%).

[0150] 1H NMR (400MHz, DMSO) δ10.00(s,1H),9.23(d,J=8.0Hz,1H),7.85–7.71(m,2H),7.32(d,J=8 .0Hz,1H),7.02(s,1H),6.85(d,J=7.6Hz,1H),6.47(d,J=8.0Hz,2H),4.97-4.87(m,1H),4 .75-4.66(m,1H),4.62–4.55(m,1H),3.26(s,3H),3.16(s,3H),3.03–2.87(m,2H),2.68-2 .57(m,2H),1.74(s,6H),1.44-1.37(m,1H),1.03-0.97(m,1H).LCMS(ES)m / z970.1[M+H]+

[0151] Example 4 Synthesis of N-((S)-1-(3-(4-chloro-1-(ethyl-d5)-3-(methylsulfonamido)-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]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (4)

[0152] Intermediate 4.1 was prepared according to the preparation method of WO2019161280A1.

[0153] Step 1: Compound 4.1 (1.37 g, 5.59 mmol, 1.0 eq.), cesium carbonate (2.19 g, 6.71 mmol, 1.2 eq.), DMF (15 mL), and deuterated iodoethane (0.90 g, 5.60 mmol, 1.0 eq.) were added to a reaction flask and stirred at 60 °C. TLC showed that the starting material reacted completely. The reaction was quenched with water (10 mL), extracted with MTBE (20 mL × 3), and the organic phases were combined. The organic phases were washed with water (10 V), dried over anhydrous sodium sulfate, and subjected to sand column chromatography to give compound 4.2 (1.09 g), with a yield of 70%.

[0154] Step 2: Compound 4.2 (1.00 g, 3.58 mmol, 1.0 eq.), potassium acetate (0.53 g, 5.37 mmol, 1.5 eq.), 1,4-dioxane (5 mL), DMF (5 mL), (Bpin)2 (1.36 g, 5.37 mmol, 1.5 eq.), and Pd(PPh3)2Cl2 (20 mg) were added sequentially to the reaction flask. The reaction was carried out overnight at 110 °C. TLC showed that the starting material reacted completely. The reaction was quenched with water (5 mL), extracted with MTBE (10 mL × 3), and the organic phases were combined. The organic phases were washed with water (3V), dried over anhydrous sodium sulfate, prepared as sinter, and subjected to column chromatography to obtain compound 4.3 (0.85 g), with a yield of 73%.

[0155] Step 3: Compound 3.1 (1.00 g, 1.386 mmol) and compound 4.3 (591.392 mg, 1.811 mmol) were added to a 50 mL single-necked flask, dissolved in butyl acetate (2 mL) and water (0.4 mL). Potassium bicarbonate (580 mg, 4.197 mmol) and dichlorobis(tricyclohexyl)palladium (30 mg, 40.999 μmol) were then added. The mixture was purged with nitrogen and reacted at 80 °C for 15 hours. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure. The mixture was purified by column chromatography (n-heptane:ethyl acetate = 1:1). Compound 4.4 (675 mg, yield 57.890%) was obtained.

[0156] Step 4: Compound 4.4 (473 mg, 562.258 μmol) was dissolved in DCM (5 mL) and added to a 50 mL single-necked flask. Then, methanesulfonic anhydride (191 mg, 1.675 mmol) and TEA (340 mg, 3.360 mmol) were added. The reaction mixture was reacted at 25 °C for 22 hours. The reaction was monitored by LCMS until complete. Water (30 mL) and DCM (30 mL × 3) were added for extraction. 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 4.5 (400 mg, yield 71.325%).

[0157] Step 5: Compound 4.5 (400 mg, 401.030 μmol) was added to a 100 mL single-necked flask, dissolved in 0.8 mL of water and 4 mL of ethanol (0.8 g sodium hydroxide dissolved in 10 mL of water). The reaction was carried out at 25 °C for 1 hour. The reaction was monitored by TLC until it ended. Acetic acid was added to adjust the pH to weakly acidic, and then DCM was added for dilution. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate, concentrated, and evaporated to dryness. The mixture was purified by column chromatography (n-heptane:ethyl acetate = 2:1). The title compound 4 (350 mg, yield 94.932%) was obtained.

[0158] 1H NMR(400MHz,DMSO-d6 9.83(d,J=2.2Hz,1H,9.13-8.98(m,1H),7.94-7.73(m,1H),7.72-7.70(m,1H),7.24-7.11(m,1H),7.02-6.91(m,2H),6.89-6.45(m,2H) ,4.87-4.73(m,3H),3.17(s,3H),3.16-3.08(m,5H),2.57-2.55(m,2H),1.74(s,6H),1.42-1.39(m,1H),0.91(s,1H).LCMS[M]=919.10.

[0159] Example 5 Synthesis of N-(1-(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)-2-(3,5-difluorophenyl)ethyl-2,2-d2)-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 (5)

[0160] Step 1: Lithium aluminum hydride deuterated (2.62 g, 62.30 mmol, 1.1 eq.) was added to the reaction flask. THF (80 mL) was added in an ice-water bath. Compound 5.1 (10.00 g, 56.64 mmol, 1.0 eq.) in THF (20 mL) was added dropwise while maintaining the temperature below 20°C in the ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours. TLC showed that the starting material reacted completely. The reaction was quenched dropwise with 15% sodium hydroxide aqueous solution in an ice-water bath. Diatomaceous earth was used as a filter aid. The organic phase was dried over anhydrous magnesium sulfate and filtered. The solution was concentrated to obtain compound 5.2 (8.11 g), with a yield of 98%.

[0161] Step 2: Under nitrogen protection, compound 5.2 (8.00 g, 54.75 mmol, 1.0 eq.) and DCM (80 mL) were added to the reaction flask. The mixture was cooled to 0°C in an ethanol bath, and phosphorus tribromide (14.82 g, 54.75 mmol, 1.0 eq.) was slowly added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and reacted overnight. TLC showed that the starting material had reacted completely. A 10% sodium carbonate aqueous solution was added to the mixture in an ice-water bath until the pH of the system was approximately 8. The mixture was separated, and the organic phase was concentrated under reduced pressure at low temperature. The solution was purified by column chromatography, and the eluent was concentrated under reduced pressure at 35°C to obtain compound 5.3 (10.53 g, 50.37 mmol), with a yield of 92%.

[0162] Step 3: Compound 5.4 (9.75 g, 36.80 mmol, 1.0 eq.), diphenylmethylamine (1.88 g, 10.24 mmol, 1.05 eq.), and toluene (60 mL) were added to the reaction flask and reacted at 60 °C for 1 h. TLC showed that the starting material reacted completely. A toluene solution of compound 5.5 (36.80 mmol) was obtained, calculated as a 100% yield.

[0163] Step 4: To a toluene solution of compound 5.5 (36.80 mmol, 1.0 eq.), TBAB (3.56 g, 11.04 mmol, 0.3 eq.), compound 5.3 (10.00 g, 47.84 mmol, 1.3 eq.), and potassium hydroxide (10.32 g, 184 mmol, 5.0 eq.) were added sequentially. The reaction was continued at 60 °C for 2–4 h, and TLC showed that the starting material had completely reacted. The reaction was quenched with water (30 mL), washed with water (30 mL), and the organic phase was retained to obtain a solution of compound 5.6 (36.80 mmol). The yield was calculated as 100%.

[0164] Step 5: Add 25% sulfuric acid aqueous solution (18.41 g, 184 mmol, 5 eq.) to the solution of compound 5.6 (36.80 mmol, 1.0 eq.), react at 60 °C for 1–2 h, cool, extract with n-heptane (50 mL × 5), adjust the aqueous phase to alkaline with KOH aqueous solution (20.64 g, 368 mmol, 50%, 10 eq.), extract with EA, concentrate the organic phase under reduced pressure, and then perform column chromatography to obtain compound 5.7 (2.911 g), yield 20%.

[0165] Step 6: Compound 5.7 (1.323 g, 3.36 mmol, 1.0 eq.), compound 1.7 (1.0 g, 3.55 mmol, 1.057 eq.), HATU (1.50 g, 3.96 mmol, 1.18 eq.), DIPEA (1.3 g, 10.08 mmol, 3.0 eq.), and DMF (14 mL, 10V) were added to the reaction flask. The reaction was carried out at room temperature (25°C) for 4 h under nitrogen protection, and the reaction was stopped by TLC. The reaction was quenched with water in an ice bath (3V), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was prepared by column chromatography to give compound 5.8 (1.42 g, 2.17 mmol), with a yield of 64.5%.

[0166] Step 7: Compound 5.8 (1.42 g, 2.17 mmol, 1.0 eq.) and compound 1.9 (475 mg, 3.25 mmol, 1.5 eq.) dissolved in DMF (14 mL, 10 V) were added to the reaction flask. TEA (0.87 g, 8.68 mmol, 4.0 eq.), palladium dichloride bis(triphenylphosphine) (0.0456 g, 0.0651 mmol, 0.03 eq.), and cuprous iodide (0.0123 g, 0.0651 mmol, 0.03 eq.) were added. The mixture was purged with nitrogen and reacted overnight at room temperature. The reaction was monitored by TLC until completion. The mixture was quenched with water in an ice bath (3 V), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was prepared into slurry and subjected to column chromatography to obtain compound 5.9 (1.28 g, 1.77 mmol), yield 81.8%.

[0167] Step 8: Compound 5.9 (1.28 g, 1.77 mmol, 1.0 eq.) and compound 1.11 (0.86 g, 2.30 mmol, 1.3 eq.) were added to the reaction flask and dissolved in butyl acetate (13 mL, 10V). Potassium bicarbonate (0.53 g, 5.31 mmol, 3.0 eq.) and palladium dichloride (0.0372 g, 0.0531 mmol, 0.03 eq.) were then added. The mixture was purged with nitrogen and reacted overnight at 90°C. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure and subjected to sand column chromatography to obtain compound 5.10 (0.715 g, 0.80 mmol), with a yield of 45.3%.

[0168] Step 9: Compound 5.10 (300 mg, 336.246 μmol) was dissolved in DCM (2 mL) in a 50 mL single-necked flask, followed by the addition of methanesulfonic anhydride (114 mg, 1000.000 μmol) and TEA (201 mg, 1.986 mmol). The reaction mixture was incubated at 25 °C for 2 hours. The reaction was monitored by LCMS until complete. The mixture was extracted with water (30 mL) and DCM (30 mL × 3), washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5.11 (300 mg, yield 85.103%).

[0169] Step 10: Compound 5.11 (300 mg, 286.155 μmol) was added to a 100 mL single-necked flask, dissolved in 0.8 mL of water and 4 mL of ethanol (0.8 g sodium hydroxide dissolved in 10 mL of water). The reaction was carried out at 25 °C for 1 hour. The reaction was monitored by LCMS until completion. Acetic acid was added to adjust the pH to weakly acidic, followed by dilution with DCM. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate. The solution was concentrated and evaporated to dryness. The solution was purified by column chromatography (n-heptane:ethyl acetate = 2:1). The title compound 5 (192 mg, yield 69.151%) was obtained.

[0170] 1 H NMR(400MHz, DMSO–d6)10.06(d,J=2.2Hz,1H),9.26–9.23(m,1H),7.80–7.75(m,2H),7.33(d,J= 2.0Hz,1H),7.32–7.30(m,1H),6.86(d,J=2.0,Hz,1H),6.51–6.49(m,2H),4.90–4.77(m,1H),4.7 3–4.69(m,1H),4.60–4.59(m,1H),4.58–4.57(m,1H),3.90–4.01(m,1H),3.33–3.23(m,3H),3.17 (s,3H),2.54–2.52(m,2H),1.74(s,6H),1.43–1.39(m,1H),1.24–1.18(m,1H).LCMS[M]=969.90.

[0171] Examples 6 and 7 N-((S)-1-(3-(4-chloro-3-(N-(methanesulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl-2,2-d2)-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 (6) & N Synthesis of -((R)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-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-2,2-d2)-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)

[0172] Compound 5 was subjected to SFC ((S,S)Whelk O1, 250×30mm ID, 10μm, A for CO2 and B for Isopropanol) to give compound 6 (31 mg) and compound 7 (45 mg).

[0173] Compound 6: 1H NMR(400MHz,DMSO-d6)δ10.00(br s,1H),9.25–8.91(m,1H),7.81–7.74(m,2H),7.26(m,1H),7.05–7.02(m,1H) ,6.84–6.82(m,1H),6.50–6.48(m,2H),4.93–4.73(m,2H),4.61–4.59(m,1H) ,4.37(s,1H),4.01–3.91(m,1H),3.32–3.31(s,3H),3.26(s,3H),2.52–2.51 (m,2H),1.74(s,6H),1.41–1.39(m,1H),0.90–0.85(m,1H).LCMS[M]=969.90.

[0174] Compound 7: 1 H NMR(400MHz,DMSO-d6)δ9.24–8.91(m,1H),7.81–7.74(m,2H),7.27(s,1H ),7.05–7.03(m,1H),7.02–6.82(m,1H),6.48–6.46(m,2H),4.93–4.57(m ,4H),3.99–3.91(m,1H),3.32–3.30(m,4H),3.26(s,3H),2.54–2.51(m,2 H),1.74(s,6H),1.41–1.39(m,1H),0.97–0.96(m,1H).LCMS[M]=969.90.

[0175] Example 8 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(methyl-d3)-3-(methylsulfonyl)but-1-yn-1-yl-4,4,4-4-d3)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]cyclopentane[1,2-c]pyrazol-1-yl)acetamide (8)

[0176] Intermediate 8.6 was prepared according to the preparation method disclosed in WO2024006982 A1.

[0177] Step 1: Compound 8.1 (5.00 g, 30.085 mmol) was dissolved in DMF (50 ml). Deuterated iodomethane (9.39 g, 66.156 mmol) was added at 0 °C. The reaction mixture was brought to room temperature and stirred overnight. The reaction was confirmed by TLC. The mixture was then extracted with EA. The organic phases were combined, dried, evaporated to dryness, prepared as sinter, and subjected to column chromatography (PE:EA = 3:1) to obtain compound 8.2 (2.00 g, yield 33.192%).

[0178] Step 2: Compound 8.2 (2.00 g, 9.986 mmol) was dissolved in THF (30 mL). LAH (227 mg, 5.981 mmol) was added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 12 hours. The reaction was detected by TLC upon completion. The reaction was quenched, and the mixture was extracted with EA. The organic phases were combined, dried, evaporated to dryness, prepared as sinter, and subjected to column chromatography (PE:EA = 1:1) to obtain compound 8.3 (700 mg, yield 44.297%).

[0179] Step 3: Compound 8.3 (700 mg, 4.423 mmol) was dissolved in DCM (15 mL), and Dess-Martin (1.99 g, 4.693 mmol) was added in portions at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was detected by TLC upon completion. The system was directly filtered, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate, 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 the target compound 8.4 (400 mg, yield 57.880%).

[0180] Step 4: Compound 8.4 (400 mg, 2.560 mmol) was added to a 100 mL single-necked flask and dissolved in MeOH (100 mL). K₂CO₃ (708 mg, 5.123 mmol) was then added. Under nitrogen protection, the temperature was lowered to 0 °C, and dimethyl (1-diazo-2-oxopropyl)phosphonate (492 mg, 2.561 mmol) was added. After the addition was complete, the system was gradually heated to 25 °C and reacted for 15 hours. The reaction was monitored by TLC until completion. Water was added to the system, followed by extraction with n-pentane:diethyl ether (1:1). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to dryness at low temperature. Compound 8.5 (150 mg, 38.482%) was prepared by the forward reaction using n-pentane:diethyl ether (1:1).

[0181] Step 5: Compound 8.6 (464 mg, 707.115 μmol) and compound 8.5 (140 mg, 919.575 μmol) were added to a 250 mL single-necked flask and dissolved in DMF (10 mL). TEA (214 mg, 2.115 mmol), tetraphenylphosphine palladium (41 mg, 356.522 μmol), and cuprous iodide (9 mg, 47.256 μmol) were added. The reaction was carried out at 25 °C under nitrogen for 15 hours. After the reaction was complete, 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 (PE:THF = 10%–15%–20%–25%) to obtain compound 8.7 (220 mg, yield 42.750%).

[0182] Step Six: Compound 8.7 (220 mg, 302.397 μmol) was added to a 50 mL single-necked flask and dissolved in butyl acetate (5 mL) and water (1 mL). Potassium bicarbonate (90 mg, 898.921 μmol) was then added, followed by compound 1.11 (170 mg, 452.632 μmol) and dichlorobis(tricyclohexyl)palladium (44 mg, 59.606 μmol). The mixture was purged with nitrogen and reacted at room temperature for 15 hours. The reaction was monitored by LCMS until completion. The system was directly purified into sand and subjected to column chromatography (PE:EA = 10:1–3:1) to obtain compound 8.8 (170 mg, yield 62.727%).

[0183] Step 7: Compound 8.8 (170 mg, 189.684 μmol) was added to a 50 mL single-necked flask and dissolved in DCM (2 mL). Methanesulfonic anhydride (64 mg, 561.404 μmol) and TEA (114 mg, 1.127 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), washing with saturated sodium chloride, drying over anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain compound 8.9 (160 mg, yield 80.150%).

[0184] Step 8: Compound 8.9 (170 mg, 161.534 μmol) was added to a 100 mL single-necked flask, dissolved in 0.4 mL of water and 2 mL of ethanol (0.8 g sodium hydroxide dissolved in 10 mL of water). The reaction was carried out at 25 °C for 1 hour. The reaction was monitored by LC-MS until completion. Acetic acid was added to adjust the pH to weakly acidic, followed by dilution with DCM. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate. The solution was concentrated and evaporated to dryness. Column chromatography (n-heptane:ethyl acetate = 2:1) was used for purification, followed by evaporation to dryness, yielding compound 8 (36 mg, yield 22.874%).

[0185] 1H NMR(400MHz,DMSO-d6)δ10.14–9.98(m,1H),9.30–8.91(m,1H),7.85–7.74(m,2H),7.38– 7.30(m,1H),7.23–7.02(m,1H),6.95(s,1H),6.58–6.43(m,2H),4.97–4.88(m,1H),4.75– 4.68(m,1H),4.65–4.46(m,2H),4.01–3.91(m,1H),3.28–3.22(m,4H),3.17(s,2H),3.07– 2.92(m,2H),2.64–2.56(m,2H),1.44–1.37(m,1H),0.90–0.78(m,1H).LCMS=974.10[M+1] + .

[0186] Examples 9-10

[0187] Example 11 Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(3-(4-fluoro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)ethyl)acetamide (11)

[0188] Step 1: Compound 11.1 (10 g, 45.8 mmol), hydrazine hydrate (0.44 g, 137.4 mmol), and isopropanol (100 mL) were mixed and heated to reflux. After reacting for 4 h, the reaction was confirmed to be complete by TLC. The mixture was then slowly cooled to room temperature for 2 h to crystallize. After filtration, the mixture was washed sequentially with isopropanol (10 mL) and water (20 mL) and dried to obtain 6.63 g of compound 11.2, with a yield of 62.8%.

[0189] Step 2: Compound 11.2 (6.5 g, 28.3 mmol), CF3CH2OTf (9.8 g, 42.5 mmol), K3PO4 (9.0 g, 42.5 mmol), and DMF (20 mL) were mixed and stirred at 20–30 °C for 16–18 h. The reaction was confirmed to be complete by TLC. Water (26 mL) was added, the mixture was heated to 40 °C and stirred for 1 h, then cooled to room temperature and stirred for 1 h. The mixture was filtered, washed with water (20 mL), and the filter cake was mixed with anhydrous ethanol (33 mL). The mixture was stirred at room temperature for 1 h, filtered, and dried to obtain 4.4 g of compound 11.3, with a yield of 50.0%.

[0190] Step 3: Compound 11.3 (4 g, 12.8 mmol), (Bpin)2 (4.88 g, 19.2 mmol), K3PO4 (8.15 g, 38.4 mmol), DMF (20 mL) and 1,4-dioxane (20 mL) were added. The mixture was purged with nitrogen and, under protection, PdCl2PPh2 (0.4 g, 0.5 mmol) was added. The mixture was heated to 110 °C and reacted for 12 h. TLC confirmed the complete reaction. EA (100 mL) was added, followed by washing with water (100 mL × 3), then with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and stirred in n-heptane at room temperature for 0.5 h. After filtration and column purification (DCM), 2.0 g of compound 11.4 was obtained, with a yield of 43.4%.

[0191] Step 4: Compound 3.1 (591.392 mg, 1.811 mmol) was added to a 50 mL single-necked flask, dissolved in butyl acetate (2 mL) and water (0.4 mL). Potassium bicarbonate (580 mg, 4.197 mmol), dichlorobis(tricyclohexyl)palladium (30 mg, 40.999 μmol), and compound 11.4 (975.757 mg, 2.717 mmol) were then added. The mixture was purged with nitrogen and reacted at 80 °C for 15 hours. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure. The mixture was purified by column chromatography using n-heptane:ethyl acetate as eluent (1:1). Compound 11.5 (675 mg, yield 57.890%) was obtained.

[0192] Step 5: Compound 11.5 (473 mg, 562.258 μmol) was dissolved in DCM (5 mL) and added to a 50 mL single-necked flask. Then, methanesulfonic anhydride (191 mg, 1.675 mmol) and TEA (340 mg, 3.360 mmol) were added. The reaction mixture was reacted at 25 °C for 22 hours. The reaction was monitored by LCMS until complete. Water (30 mL) and DCM (30 mL × 3) were added for extraction. 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 11.6 (400 mg, yield 71.325%).

[0193] Step Six: Compound 11.6 (400 mg, 401.030 μmol) was added to a 100 mL single-necked flask, dissolved in 0.8 mL of water and 4 mL of ethanol (0.8 g sodium hydroxide dissolved in 10 mL of water). The reaction was carried out at 25 °C for 1 hour. The reaction was monitored by TLC until it ended. Acetic acid was added to adjust the pH to weakly acidic, and then DCM was added for dilution. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate, concentrated, and evaporated to dryness. The mixture was purified by column chromatography (n-heptane:ethyl acetate = 2:1). The title compound 11 (350 mg, 94.932%) was obtained.

[0194] 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.23(br d,J=8.3Hz,1H),7.84–7.72(m,2H),7.10–6.98(m,2H),6.91-6.90(m,1H),6.56–6 .41(m,2H),4.92(d,J=16.4Hz,1H),4.70(s,1H),4.65–4.59(m,1H),4.54–4.40(m ,1H),4.01–3.85(m,1H),3.27(s,3H),3.10(s,3H),3.06–2.90(m,2H),2.65–2.54 (m,2H),1.74(d,J=1.22Hz,6H),1.46–1.36(m,1H),1.02–0.92(m,1H).LCMS[M+1] + =952.10.

[0195] Example 12 Synthesis of N-((S)-1-(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)-2-(2,3,5-trifluorophenyl)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 (12)

[0196] Step 1: At room temperature, compound 30.16 (1.90 g, 2.818 mmol, 1.00 eq.) and compound 1.9 (453 mg, 3.098 mmol, 1.099 eq.) dissolved in DMF (20 mL) were added to a 250 mL single-necked flask. TEA (855 mg, 8.450 mmol, 2.998 eq.), tetraphenylphosphine palladium (164 mg, 141.921 μmol, 0.05 eq.), and cuprous iodide (57 mg, 299.291 μmol, 0.11 eq.) were added. The mixture was purged with nitrogen three times and reacted at 35 °C for 15 hours. The reaction was monitored by TLC until completion. The system was poured into three volumes of ice water containing DMF, and EA (20 mL × 3) was added for extraction. The organic phase was washed with saturated sodium chloride (30 mL), dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry. PE:EA = 0%–30% column chromatography yielded compound 12.1 (2.00 g, 2.705 mmol, 95.968%) as a white solid.

[0197] Step 2: At room temperature, compound 12.1 (200 mg, 270.463 μmol, 1 eq.) and compound 1.11 (172 mg, 457.957 μmol, 1.693 eq.) were added to a 100 mL single-necked flask, dissolved in water (4 mL), butyl acetate (20 mL), potassium bicarbonate (81 mg, 809.029 μmol, 2.991 eq.) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (19 mg, 25.739 μmol, 0.095 eq.). After purging with nitrogen 5-6 times, the reaction was carried out at 90 °C for 15 hours. The reaction was monitored by LCMS until it ended. The system was directly concentrated to prepare sand, and PE:EA = 5:1 to 3:1 column chromatography was used to obtain compound 12.2 (200 mg, 220.220 μmol, 81.424%) as a yellow solid.

[0198] Step 3: Compound 12.2 (200 mg, 220.220 μmol, 1 eq.) dissolved in DCM (2 mL) was added to a 50 mL single-necked flask. Then, methanesulfonic anhydride (98 mg, 859.649 μmol, 3.904 eq.) and TEA (147 mg, 1.453 mmol, 6.597 eq.) were added. The reaction mixture was incubated at 25 °C for 2 hours. The reaction was monitored by LCMS until complete. The mixture was extracted with water (30 mL) and DCM (30 mL × 3), washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A yellow solid 12.3 (200 mg, 187.906 μmol, 85.326%, 1 eq.) was obtained.

[0199] Step 4: Add compound 12.3 (200 mg, 187.906 μmol, 1 eq.), sodium hydroxide (30 mg, 750.056 μmol, 3.992 eq.) dissolved in water (0.8 mL), and ethanol (4 mL) (0.8 g sodium hydroxide dissolved in 10 mL water) to a 100 mL single-necked flask. React at 25 °C for 1 hour. Monitor the reaction end using LC-MS. 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 using n-heptane:ethyl acetate = 2:1 as eluent to obtain a white solid 12 (50 mg, 50.696 μmol, 26.979%, 1 eq.).

[0200] 1H NMR (400MHz, DMSO-d6) δ = 10.03 (br s, 1H), 9.16 (br d, J = 8.6Hz, 1H), 7.88-7.70 (m, 2H), 7.40-7.22 (m, 2H), 6.86 (br d,J=7.8Hz,1H),6.79-6.67(m,1H),4.93(d,J=16.4Hz,1H),4.84-4.75(m,1H),4.69(d,J=16.4Hz,1H),4.62-4.45(m,1H),4.08-3.90(m,1H), 3.27(s,3H),3.19-3.09(m,4H),3.00-2.90(m,1H),2.64-2.54(m,2H), 1.75(d,J=1.0Hz,6H),1.46-1.37(m,1H),1.02-0.94(m,1H).LCMS[M+1] + =986.10.

[0201] Example 13 Synthesis of N-(1-(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)-2-(3,5-difluorophenyl)-2,2-difluoroethyl)-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 (13)

[0202] Step 1: Compound 1.3 (8 g, 20.46 mmol, 1.0 eq.) and α-phenylethylamine (2.97 g, 24.552 mmol, 1.2 eq.) were added to a reaction flask and dissolved in toluene (80 mL, 10V). Trifluoroacetic acid (2.79 g, 24.552 mmol, 1.2 eq.) was added while stirring. The reaction mixture was refluxed, and water was separated using a water separator. The mixture was kept at this temperature overnight. MS analysis showed no starting material. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with methyl ether (5V), washed with saturated sodium bicarbonate solution (3V × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 13.1 (10.53 g, calculated at 100% yield). This compound was used directly as the starting material for the next step without further purification.

[0203] Step 2: Compound 13.1 (10.53 g, 21.316 mmol, 1.0 eq.) and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane di(tetrafluoroborate) (15.10 g, 42.632 mmol, 2.0 eq.) were added to the reaction flask and dissolved in anhydrous acetonitrile (100 ml, 10 V). The reaction was refluxed for 3.5 h. MS analysis showed no starting material. The reaction solution was cooled to room temperature, and 1 ml of concentrated hydrochloric acid was added. After stirring for 10 min, the solution was concentrated under reduced pressure. Extraction was performed with methyl ether (20 V), followed by washing with saturated sodium bicarbonate aqueous solution (5 V × 2). The pH was adjusted to approximately 8. The organic phase was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solution was slurried in methanol (30 ml) to obtain compound 13.2 (6.2 g), with a yield of 68%.

[0204] Step 3: Compound 13.2 (4.0 g, 9.36 mmol, 1.0 eq.), tert-butylsulfonamide (2.31 g, 18.72 mmol, 2.0 eq.), and tetraisopropyl titanate (4.07 g, 14.04 mmol, 1.5 eq.) were added to the reaction flask and dissolved in THF (40 mL, 10 V). The reaction was carried out at 60 °C. After MS analysis showed no reaction starter, the reaction solution was concentrated under reduced pressure, quenched with water (5 V), extracted with EA (10 V), washed with saturated brine (3 V), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. No purification was required (based on 100% yield).

[0205] Step 4: Add sodium borohydride (0.78 g, 20.46 mmol, 2.0 eq.) and methanol (40 ml, 10V) to the reaction flask from the previous step. React at room temperature for 3 h. After MS detection shows no starting material, add 6M HCl aqueous solution (6.3 ml, 4.0 eq.) to deprotect the group. React for 2 h. After MS detection shows the reaction is complete, perform post-processing. Concentrate the reaction solution under reduced pressure, extract with EA, adjust the pH to approximately 10 with 10% sodium hydroxide, wash with saturated brine (2V), collect the organic phase, concentrate under reduced pressure, prepare sintered sand, and purify by column chromatography to obtain compound 13.3 (1.6 g), yield 39.8%.

[0206] Step 5: Compound 13.3 (1.0 g, 2.34 mmol, 1.0 eq.), compound 1.7 (0.697 g, 2.47 mmol, 1.057 eq.), HATU (1.05 g, 2.76 mmol, 1.18 eq.), DIPEA (7.02 g, 0.91 mmol, 3.0 eq.), and DMF (10 mL, 10V) were added to the reaction flask. The reaction was carried out at room temperature (25°C) for 4 h under nitrogen protection, and the reaction was stopped by TLC. The reaction was quenched with water in an ice bath (3V), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was prepared by column chromatography to obtain compound 13.4 (0.99 g), with a yield of 61.2%.

[0207] Step Six: Compound 13.4 (0.99 g, 1.43 mmol, 1.0 eq.) and compound 1.9 (0.31 g, 2.14 mmol, 1.5 eq.) dissolved in DMF (10 mL, 10 V) were added to the reaction flask. TEA (0.58 g, 5.72 mmol, 4.0 eq.), palladium dichloride bis(triphenylphosphine) (0.0301 g, 0.0429 mmol, 0.03 eq.), and cuprous iodide (0.0081 g, 0.0429 mmol, 0.03 eq.) were added. The mixture was purged with nitrogen and reacted overnight at room temperature. The reaction was monitored by TLC until completion. The mixture was quenched with water in an ice bath (3 V), extracted with EA, dried over anhydrous magnesium sulfate, filtered, and the filtrate was prepared into sand and subjected to column chromatography to obtain compound 13.5 (0.56 g), yield 52.2%.

[0208] The synthesis of compounds 13.5-13 was carried out according to the synthetic method of compound 1, yielding compound 13 (44 mg, yield 22.6%).

[0209] 1 H NMR (400MHz, DMSO-d6) δ10.17–9.98(m,1H),9.55–9.34(m,1H),7.99–7.84(m,2H),7.30(br d,J=8.1Hz,2H),7.01–6.94(m,1H),6.78–6.71(m,2H),5.55–5.23(m,1H),5.15–4.83(m,2H),3.86(td,J=16.3,8.2Hz,2H),3.27–3.24 (m,3H),3.23–3.19(m,1H),3.15–3.10(m,2H),2.68–2.56(m,2H),1.78–1.70(m,6H),1.48–1.38(m,1H),1.05–0.90(m,1H)LCMS(ES)m / z 1004.10[M+1] + .

[0210] Examples 14-17

[0211] Example 18 Synthesis of N-(1-(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)-2-(perfluorophenyl)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 (18)

[0212] According to WO2019161280A1, compound 18a was prepared by replacing 3,5-difluorobenzyl bromide with perfluorobenzyl bromide. Compound 18a was then processed using the same steps as compound 12 to obtain title compound 18 (17 mg, yield 8.30%).

[0213] 1 H NMR(400MHz,DMSO-d6)δ10.25–9.90(m,1H),9.11–8.90(m,1H),8.05–7.80(m,2H),7.45 –7.25(m,1H),7.11–6.98(m,1H),5.07–4.94(m,1H),4.86(s,2H),4.63–4.51(m,1H),4. 22–4.06(m,1H),3.29–3.25(m,4H),3.23–3.03(m,3H),2.64–2.57(m,2H),1.77–1.73(m ,6H),1.45–1.37(m,1H),1.28–1.23(m,1H),1.03–0.71(m,1H).LCMS(ES)m / z1022[M+1] + .

[0214] Example 19 Synthesis of N-(1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-enyl)pyridin-2-yl)-2-(2,4,6-trifluorophenyl)ethyl-1-d)-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 (19)

[0215] Step 1: Compound 19.1 (10 g, 52.59 mmol, 1.0 eq.), DMF (100 mL, 10 V), DIPEA (20.4 g, 157.79 mmol, 3.0 eq.), and dimethylhydroxylamine hydrochloride (6.15 g, 63.11 mmol, 1.2 eq.) were added to the reaction flask under nitrogen protection. HATU (24 g, 63.11 mmol, 1.2 eq.) was added in portions under an ice-water bath, and the mixture was then transferred to room temperature for 3 h. A 10% sodium chloride aqueous solution (5 V) was added to the mixture in an ice-water bath, and the mixture was extracted with MTBE (5 V × 5). The organic phases were combined and washed successively with 0.5 M HCl (3 V × 2), 7% NaHCO3 (3 V), and 10% sodium chloride (3 V). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 19.2 (12.3 g, 49.31 mmol), with a yield of 93.7%.

[0216] Step 2: Under nitrogen protection at -30℃, add 56.9 mL of tetramethylpiperidinyl magnesium chloride lithium chloride complex (1 M / L in THF, 1.5 eq.) to the reaction flask. Then, add 19.3 g (8.98 g, 37.93 mmol, 1.0 eq.) of 2,5-dibromopyridine in 45 mL (5V) THF solution at -25 to -20℃. After reacting for 1 to 2 hours, add 19.2 g (12.3 g, 49.31 mmol, 1.3 eq.) of THF in 45 mL (5V) solution at -25 to -20℃. Incubate the reaction for 2 hours. The system was quenched with 10% ammonium chloride aqueous solution (5V), separated, and the aqueous phase was extracted again with EA (3V×2). The organic phases were combined, dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and slurried with anhydrous methanol (2-4V) at 10-20℃ for 1h. After filtration, the mother liquor was subjected to wet column chromatography again (EA / PE = 0%-1%-2%-3%). The eluent was concentrated and combined to give compound 19.4 (9.94g), with a yield of 49.3%.

[0217] Step 3: Compound 19.4 (5.0 g, 12.22 mmol, 1.0 eq.) and methanol (40 mL, 8V) were added to the reaction flask. Sodium deuterated borohydride (0.76 g, 18.33 mmol, 1.5 eq.) was slowly added in an ice-water bath. The mixture was transferred to room temperature and reacted for 3 h. The reaction was quenched by adding 1 M HCl (3V) to the system (the system pH was about 1). The mixture was stirred for 5 min, and then 10% sodium hydroxide was added to adjust the pH to about 8 or higher. The reaction solution was concentrated, the aqueous phase was extracted with EA (3V×3), and the organic phase was dried with anhydrous magnesium sulfate and filtered. After concentration under reduced pressure, compound 19.5 (4.91 g) was obtained, with a yield of 97.5%.

[0218] Step 4: Compound 19.5 (4.91 g, 11.91 mmol, 1.0 eq.), THF (40 mL, 8V), triphenylphosphine (3.74 g, 14.29 mmol, 1.2 eq.), and phthalimide (2.11 g, 14.29 mmol, 1.2 eq.) were added to the reaction flask under nitrogen purging protection. DEAD (2.49 g, 14.29 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. The reaction was quenched with water (3V), and the aqueous phase was extracted with EA (3V×2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to sand column chromatography to obtain compound 19.6 (3.76 g), with a yield of 58.3%.

[0219] Step 5: Compound 19.6 (3.76 g, 6.94 mmol, 1.0 eq.), anhydrous ethanol (32 mL, 8V), dichloromethane (16 mL, 4V), and hydrazine hydrate (80%, 1.73 g, 27.76 mmol, 4.0 eq.) were added to the reaction flask, and the reaction was carried out at 60 °C for 4 h. After cooling to room temperature, the mixture was filtered, and the filtrate was prepared by column chromatography to obtain compound 19.7 (2.34 g), with a yield of 81.98%.

[0220] Step 6: Compound 19.7 (1.37 g, 3.33 mmol, 1.0 eq.), compound 1.14 (1 g, 3.51 mmol, 1.057 eq.), HATU (1.5 g, 3.93 mmol, 1.18 eq.), DIPEA (1.3 g, 9.99 mmol, 3.0 eq.), and DMF (14 mL, 10 V) were added to the reaction flask. The reaction was carried out at room temperature (25 °C) for 4 h under nitrogen protection. The reaction was quenched with water in an ice bath (3 V). The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the filtrate was prepared by column chromatography to obtain compound 19.8 (1.43 g), with a yield of 63.7%.

[0221] Step 7: Compound 19.8 (1.43 g, 2.12 mmol, 1.0 eq.) and compound 1.9 (0.46 g, 3.18 mmol, 1.5 eq.) were added to the reaction flask and dissolved in DMF (14 mL, 10 V). TEA (0.86 g, 8.48 mmol, 4.0 eq.) was added, followed by palladium dichloride bis(triphenylphosphine) (0.0446 g, 0.0636 mmol, 0.03 eq.) and cuprous iodide (0.0121 g, 0.0636 mmol, 0.03 eq.). The mixture was purged with nitrogen and reacted overnight at room temperature. The reaction was quenched with water in an ice bath (3 V). The mixture was extracted with EA, dried over anhydrous magnesium sulfate, filtered, and the filtrate was prepared by column chromatography to obtain compound 19.9 (1.27 g), with a yield of 81.1%.

[0222] Step 8: Compound 19.9 (1.27 g, 1.72 mmol, 1.0 eq.) and compound 1.11 (0.84 g, 2.24 mmol, 1.3 eq.) dissolved in butyl acetate (13 mL, 10 V) were added to the reaction flask. Potassium bicarbonate (0.52 g, 5.16 mmol, 3.0 eq.) and palladium dichloride (0.0362 g, 0.0516 mmol, 0.03 eq.) were then added. The mixture was purged with nitrogen and reacted overnight at 90 °C. The reaction solution was concentrated under reduced pressure, prepared as sinter, and subjected to column chromatography to obtain compound 19.10 (0.737 g), with a yield of 47.1%.

[0223] Step 9: Compound 19.10 (500.000 mg, 549.942 μmol) was added to a 50 mL single-necked flask and dissolved in DCM (5 mL). Methanesulfonic anhydride (188 mg, 1.649 mmol) and TEA (333 mg, 3.291 mmol) were added at 0 °C. The reaction mixture was reacted at 25 °C for 2 hours. Extraction was performed with water (30 mL) and DCM (30 mL × 3), followed by washing with saturated sodium chloride, drying over anhydrous magnesium sulfate, filtration, and concentration of the filtrate under reduced pressure. Compound 19.11 (300 mg, yield 51.204%) was obtained.

[0224] Step 10: Add 19.11 (300 mg, 281.593 μmol) to a 100 mL single-necked flask, dissolved in water (0.4 mL) and ethanol (2 mL). React at 25 °C for 1 hour. Monitor the reaction for completion using 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, and obtain compound 19 (70 mg, yield 25.179%).

[0225] 1H NMR (400MHz, DMSO-d6) δ10.03–10.01(m,1H),9.01–8.81(m,1H),7.81–7.74(m,2H),7.27–7.26(m,1H),7.12 –7.01(m,2H),6.99–6.52(m,1H),4.99–4.78(m,2H),4.72–4.68(m,1H),4.04–4.02(m,1H),3.37(m,4H),3.31 -3.26(m,2H),3.17-3.16(m,1H),2.51(S,2H),1.74–1.73(m,6H),1.26–1.25( m,1H),1.19–1.18(m,4H),1.16–0.88(m,1H),0.86–0.84(m,2H).LCMS(ES)m / z 987.10[M+1] + .

[0226] Example 20 Synthesis of N-(1-(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)-2-(2,4,5-trifluorophenyl)ethyl-1-d)-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 (20)

[0227] Step 1: Compound 20.1 (10 g, 52.59 mmol, 1.0 eq.), DMF (100 mL, 10V), DIPEA (20.4 g, 157.79 mmol, 3.0 eq.), and dimethylhydroxylamine hydrochloride (6.15 g, 63.12 mmol, 1.2 eq.) were added to the reaction flask under nitrogen protection. HATU (24 g, 63.118 mmol, 1.2 eq.) was added in portions under an ice-water bath. The mixture was then transferred to room temperature and reacted for 3 h. TLC showed that the starting material had completely reacted. A 10% sodium chloride aqueous solution (5V) was added to the reaction flask under an ice-water bath, and the mixture was extracted with MTBE (5V×5). The organic phases were combined and then washed successively with 0.5 M HCl (3V×2), 7% NaHCO3 (3V), and 10% sodium chloride (3V). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 20.2 (11.56 g), with a yield of 94.25%.

[0228] Step 2: Under nitrogen protection at -30℃, add 57.8 ml of tetramethylpiperidinyl magnesium chloride lithium chloride complex (1 M / L in THF, 1.5 eq.) to the reaction flask. Add 45 ml of THF (5V) solution of 19.3 g (9.14 g, 38.58 mmol, 1.0 eq.) of 2,5-dibromopyridine at -25 to -20℃. After reacting for 1 to 2 hours, add 45 mL of THF (5V) solution of 20.2 g (11.56 g, 49.57 mmol, 1.3 eq.) of compound 20.2 at -25 to -20℃. Incubate the reaction for 2 hours. TLC showed that the starting materials reacted completely. The system was quenched by adding 10% ammonium chloride aqueous solution (5V), separated, and the aqueous phase was extracted again by EA (3V×2). The organic phases were combined, dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, slurried with anhydrous methanol (2-4V), filtered, and 5.0 g of compound 20.3 was obtained, with a yield of 24.67%.

[0229] Step 3: Compound 20.3 (5.0 g, 12.22 mmol 1.0 eq.) and methanol (40 mL, 8V) were added to the reaction flask. Sodium deuterated borohydride (0.75 g, 18.33 mmol, 1.5 eq.) was slowly added in an ice-water bath. The mixture was transferred to room temperature and reacted for 3 h. TLC showed that the starting material reacted completely. The reaction was quenched by adding 1M HCl (3V) to the system (the system pH was approximately 1), and the mixture was stirred for 5 min. Then, 10% sodium hydroxide was added to adjust the pH to approximately 8 or higher. The reaction solution was concentrated to remove most of the methanol. The remaining aqueous phase was extracted with EA (3V × 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 20.4 (4.9 g), with a yield of 98.2%.

[0230] Step 4: Compound 20.4 (4.9 g, 12.01 mmol, 1.0 eq.), THF (40 mL, 8 V), triphenylphosphine (3.77 g, 14.41 mmol, 1.2 eq.), and phthalimide (2.12 g, 14.41 mmol, 1.2 eq.) were added to the reaction flask under nitrogen purging protection. DEAD (2.51 g, 14.41 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 reaction was complete. Water (3 V) was added to quench the reaction. The aqueous phase was then extracted with EA (3 V × 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, and the mixture was prepared as a granulation solution. Column chromatography was performed to obtain compound 20.5 (4.73 g), with a yield of 72.8%.

[0231] Step 5: Compound 20.5 (4.73 g, 8.75 mmol, 1.0 eq.), anhydrous ethanol (40 mL, 8V), dichloromethane (20 mL, 4V), and hydrazine hydrate (80%, 2.18 g, 35.0 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 20.6 (2.23 g), with a yield of 61.9%.

[0232] Step 6: Compound 20.6 (1.00 g, 2.433 mmol, 1 eq.) was dissolved in DMF (6 mL) in a reaction flask. Compound 1.7 (718 mg, 2.678 mmol), HATU (1.11 g, 2.919 mmol), and DIEA (943 mg, 7.297 mmol) were added. Nitrogen gas was purged, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction solution was added dropwise to 20 mL of ice water and extracted with ethyl acetate (30 × 2 mL). The organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 20.7 (1.10 g, yield 66.965%).

[0233] Step 7: Compound 20.7 (1.10 g, 1.629 mmol) was added to a 50 mL single-necked flask and dissolved in DMF (6 mL). 3-Methyl-3-methylsulfonyl-but-1-yne (308 mg, 2.107 mmol), TEA (493 mg, 4.872 mmol), tetrakis(triphenylphosphine)palladium (95 mg, 82.211 μmol), and cuprous iodide (38 mg, 199.527 μmol) were added, purging with nitrogen. The mixture was then heated to 35 °C and stirred for 16 hours. After the reaction was complete as monitored by TLC, 30 mL of ice water was added to the reaction solution. The mixture was then extracted with ethyl acetate (20 × 2 mL), dried, concentrated, and purified by column chromatography to obtain compound 20.8 (710 mg, yield 58.85%).

[0234] Step 8: Compound 20.8 (710 mg, 958.838 μmol) was added to a 50 mL single-necked flask and dissolved in butyl acetate (5 mL) and water (1 mL). Potassium bicarbonate (287 mg, 2.867 mmol) was then added, followed by compound 1.11 (540 mg, 1.438 mmol) and dichlorobis(tricyclohexyl)palladium (141 mg, 191.010 μmol). The mixture was purged with nitrogen and reacted at room temperature for 15 hours. The reaction was monitored by LCMS until completion. The system was directly purified into sand and subjected to column chromatography (PE:EA = 10:1–3:1) to obtain compound 20.9 (800 mg, 91.768%).

[0235] Step 9: Compound 20.9 (800 mg, 879.907 μmol) was dissolved in DCM (10 mL) in a 50 mL single-necked flask. Methanesulfonic anhydride (300 mg, 2.632 mmol) and TEA (532 mg, 5.257 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 20.10 (870 mg, yield 92.807%).

[0236] Step 10: Compound 20.10 (870 mg, 816.619 μmol, 92.807%) was added to a 100 mL single-necked flask, dissolved in 0.4 mL of water and 2 mL of ethanol (0.8 g sodium hydroxide dissolved in 10 mL of water). The reaction was carried out at 25 °C for 1 hour. The reaction was monitored by LCMS until completion. Acetic acid was added to adjust the pH to weakly acidic, followed by dilution with DCM. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate. The solution was concentrated and evaporated to dryness. The solution was purified by column chromatography (heptane:ethyl acetate = 2:1) and evaporated to dryness. The title compound 20 (200 mg, yield 26.977%) was obtained.

[0237] 1 H NMR(400MHz,DMSO-d6)δ10.10–9.95(m,1H),9.19–8.80(m,1H),7.96–7.74(m,2H) ,7.41–7.13(m,3H),7.00–6.89(m,1H),4.95–4.64(m,2H),4.58–4.32(m,1H),4.1 0–3.90(m,1H),3.30–3.14(m,6H),3.11–3.02(m,1H),2.91–2.80(m,1H),2.63–2. 52(m,2H),1.79–1.69(m,6H),1.48–1.35(m,1H),1.02–0.90(m,1H).LCMS(ES)m / z 987.10[M+1] + .

[0238] Example 21 Synthesis of N-(1-(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)-2-(3,4,5-trifluorophenyl)ethyl-1-d)-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 (21)

[0239] Step 1: Compound 21.1 (10 g, 52.59 mmol, 1.0 eq.), DMF (100 mL, 10 V), DIPEA (20.4 g, 157.79 mmol, 3 eq.), and dimethylhydroxylamine hydrochloride (6.15 g, 63.12 mmol, 1.2 eq.) were added to a reaction flask under nitrogen protection. HATU (24 g, 63.118 mmol, 1.2 eq.) was added in portions under an ice-water bath. The mixture was then transferred to room temperature and reacted for 3 h. TLC showed that the starting material had completely reacted. A 10% sodium chloride aqueous solution (5 V) was added to the reaction flask under an ice-water bath, and the mixture was extracted with MTBE (5 V × 5). The organic phases were combined and then washed successively with 0.5 M HCl (3 V × 2), 7% NaHCO3 (3 V), and 10% sodium chloride (3 V). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 21.2 (11.09 g), with a yield of 90.4%.

[0240] Step 2: Under nitrogen protection at -30℃, add 56.04 mL of tetramethylpiperidinyl magnesium chloride lithium chloride complex (1 M / L in THF, 1.5 eq.) to the reaction flask, then add 19.3 g (8.85 g, 37.36 mmol, 1.0 eq.) of 2,5-dibromopyridine in THF (44 mL, 5V) at -25 to -20℃. After reacting for 1 to 2 hours, add 11.09 g (11.09 g, 47.56 mmol, 1.3 eq.) of compound 21.2 in THF (44 mL, 5V) at -25 to -20℃ and maintain the temperature for 2 hours. TLC shows that the starting materials have reacted completely. The system was quenched by adding 10% ammonium chloride aqueous solution (5V), separated, and the aqueous phase was extracted again by EA (3V×2). The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and slurried with anhydrous methanol (2-4V) at 10-20℃. After filtration, compound 21.3 (8.8g) was obtained, with a yield of 45.2%.

[0241] Step 3: Compound 21.3 (5 g, 12.22 mmol, 1.0 eq.) and methanol (40 mL, 8V) were added to the reaction flask. Sodium deuterated borohydride (0.76 g, 18.36 mmol, 1.5 eq.) was slowly added in an ice-water bath. The mixture was transferred to room temperature and reacted for 3 h. TLC showed that the starting material reacted completely. The reaction was quenched by adding 1M HCl (3V) to the system (the system pH was approximately 1), and the mixture was stirred for 5 min. Then, 10% sodium hydroxide was added to adjust the pH to approximately 8 or higher. The reaction solution was concentrated, and the remaining aqueous phase was extracted with DCM (3V × 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 21.4 (4.89 g), with a yield of 97.2%.

[0242] Step 4: Compound 21.4 (4 g, 9.70 mmol, 1 eq.), THF (32 mL, 8V), triphenylphosphine (3.05 g, 11.64 mmol, 1.2 eq.), and phthalimide (1.71 g, 11.64 mmol, 1.2 eq.) were added to the reaction flask under nitrogen purging protection. DEAD (2.03 g, 11.64 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 (3V), and the aqueous phase was extracted with EA (3V×2). The organic phases were combined, concentrated under reduced pressure, and then slurried with ethanol / water. The mixture was filtered to obtain compound 21.5 (3.9 g, 7.27 mmol), with a yield of 75.1%.

[0243] Step 5: Compound 21.5 (3.9 g, 7.27 mmol, 1.0 eq.), anhydrous ethanol (32 mL, 8V), dichloromethane (16 mL, 4V), and hydrazine hydrate (80%, 4.0 eq.) were added to the reaction flask. The mixture was reacted at room temperature for 4 h, and TLC showed that the starting material reacted completely. The mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized from methanol / water to give compound 21.6 (1.58 g), with a yield of 52.8%.

[0244] Step Six: At room temperature, compound 1.7 (1.00 g, 2.433 mmol) and compound 21.6 (756 mg, 2.679 mmol) were added to DMF (10 mL) in a 100 mL single-necked flask. HATU (1.20 g, 3.156 mmol) and DIPEA (944 mg, 7.304 mmol) were added to the above reaction solution. The mixture was purged with nitrogen and reacted at 25 °C for 18 hours. The mixture was poured into water (40 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with water (30 mL × 2) and saturated sodium chloride aqueous solution (30 mL), respectively. The mixture was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry to obtain crude compound 21.7. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–15%). Compound 21.7 (1.30 g, yield 79.140%) was obtained.

[0245] Step 7: At room temperature, compound 21.7 (1.30 g, 1.925 mmol) and compound 1.9 (310 mg, 2.120 mmol) were added to a 250 mL single-necked flask and dissolved in DMF (15 mL). TEA (585 mg, 5.781 mmol), tetraphenylphosphine palladium (111 mg, 96.056 μmol), and cuprous iodide (50 mg, 262.536 μmol) were added. The mixture was purged with nitrogen and reacted at 35 °C for 15 h. The reaction was monitored by LCMS until completion. The system was poured into three volumes of ice water containing DMF, and EA (40 mL × 3) was added for extraction. The organic phase was washed with saturated sodium chloride (30 mL), dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry. Column chromatography (PE:EA = 0%–30%) yielded compound 21.8 (1.00 g, yield 70.140%).

[0246] Step 8: At room temperature, compound 21.8 (1.00 g, 1.350 mmol) and compound 1.11 (862 mg, 2.295 mmol) were added to a 100 mL single-necked flask, dissolved in water (2 mL) and butyl acetate (10 mL). Potassium bicarbonate (406 mg, 4.055 mmol) and dichlorobis(tricyclohexyl)palladium (101 mg, 136.823 μmol) were then added. The mixture was purged with nitrogen and reacted at 90 °C for 15 h. The reaction was monitored by LCMS until completion. The system was directly concentrated to produce sand. Column chromatography (PE:EA = 5:1–3:1) yielded compound 21.9 (1.00 g, yield 81.444%).

[0247] Step 9: Compound 21.9 (500 mg, 549.942 μmol) dissolved in DCM (5 mL) was added to a 50 mL single-necked flask, followed by TEA (328 mg, 3.241 mmol) and methanesulfonic anhydride (186 mg, 1.632 mmol). The reaction mixture was incubated at 25 °C for 2 hours. The reaction was monitored by LCMS until complete. The mixture was extracted with water (30 mL) and DCM (30 mL × 3), washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 21.10 (580 mg, yield 98.995%).

[0248] Step 10: Compound 21.10 (500 mg, 469.321 μmol) was added to a 100 mL single-necked flask, dissolved in 0.8 mL of water and 4 mL of ethanol (0.8 g sodium hydroxide dissolved in 10 mL of water). The reaction was carried out at 25 °C for 1 hour. The reaction was monitored by LCMS until completion. Acetic acid was added to adjust the pH to weakly acidic, followed by dilution with DCM. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate. The solution was concentrated and evaporated to dryness. The solution was purified by column chromatography (n-heptane:ethyl acetate = 2:1). Compound 21 (172 mg, 37.121%) was obtained.

[0249] 1 H NMR (400MHz, CD3SOCD3, 0K) δ (ppm) = 10.03 (s, 1H), 9.19 (s, 1H), 7.86-7.82 (m, 1H), 7.80-7.7 5(m,1H),7.38(dd,J=2.8,7.7Hz,1H),7.09(dd,J=3.7,7.6Hz,1H),6.77-6.68(m,2H),4.90- 4.71(m,2H),4.59-4.33(m,1H),4.06-3.95(m,1H),3.27(s,3H),3.18(s,3H),3.02-2.90(m, 2H), 2.50 (m, 1H), 2.00-1.99 (m, 1H), 1.74 (d, J = 1.0Hz, 6H), 1.44-1.37 (m, 1H), 0.90 (m, 1H). LCMS[M+1]+=987.0

[0250] Example 22 Synthesis of N-(1-(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)-2-(2,3,5-trifluorophenyl)ethyl-1-d)-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 (22)

[0251] Step 1: Compound 22.1 (6 g, 31.56 mmol, 1.0 eq.), DMF (60 mL, 10 V), DIPEA (12.3 g, 94.68 mmol, 3 eq.), and dimethylhydroxylamine hydrochloride (3.7 g, 37.87 mmol, 1.2 eq.) were added to the reaction flask under nitrogen protection. HATU (14.4 g, 37.87 mmol, 1.2 eq.) was added in portions under an ice-water bath. The mixture was then transferred to room temperature and reacted for 3 h. TLC showed that the starting material had completely reacted. A 10% sodium chloride aqueous solution (5 V) was added to the reaction flask under an ice-water bath, and the mixture was extracted with MTBE (5 V × 5). The organic phases were combined and then washed successively with 0.5 M HCl (3 V × 2), 7% NaHCO3 (3 V), and 10% sodium chloride (3 V). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 22.2 (7.07 g), with a yield of 96.03%.

[0252] Step 2: Under nitrogen protection at -30℃, add tetramethylpiperidinyl magnesium chloride lithium chloride complex (35.13 mL, 1 M / L in THF, 1.5 eq.) to the reaction flask, then add 2,5-dibromopyridine 19.3 (5.55 g, 23.42 mmol, 1.0 eq.) in THF (28 mL, 5V) at -25 to -20℃. After reacting for 1 to 2 hours, add compound 22.2 (7.07 g, 30.45 mmol, 1.3 eq.) in THF (28 mL, 5V) at -25 to -20℃, and maintain the temperature for 2 hours. TLC shows that the starting materials have reacted completely. The system was quenched by adding 10% ammonium chloride aqueous solution (5V), separated, and the aqueous phase was extracted again by EA (3V×2). The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and subjected to wet column chromatography to obtain compound 22.3 (5.55g), with a yield of 38.62%.

[0253] Step 3: Compound 22.3 (5 g, 12.22 mmol, 1.0 eq.) and methanol (40 mL, 8V) were added to the reaction flask. Sodium deuterated borohydride (0.76 g, 18.36 mmol, 1.5 eq.) was slowly added in an ice-water bath. The mixture was transferred to room temperature and reacted for 3 h. TLC showed that the starting material reacted completely. The reaction was quenched by adding 1M HCl (3V) to the system (the system pH was approximately 1), and the mixture was stirred for 5 min. Then, 10% sodium hydroxide was added to adjust the pH to approximately 8 or higher. The mixture was concentrated, and the remaining aqueous phase was extracted with DCM (3V × 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 22.4 (4.76 g, 11.55 mmol), with a yield of 94.5%.

[0254] Step 4: Compound 22.4 (4 g, 9.70 mmol, 1 eq.), THF (32 mL, 8 V), triphenylphosphine (3.05 g, 11.64 mmol, 1.2 eq.), and phthalimide (1.71 g, 11.64 mmol, 1.2 eq.) were added to the reaction flask under nitrogen purging protection. DEAD (2.03 g, 11.64 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 (3 V), and the aqueous phase was extracted with EA (3 V × 2). The organic phases were combined, concentrated under reduced pressure, and then slurried with ethanol / water. The mixture was filtered to obtain compound 22.5 (3.7 g), with a yield of 70.5%.

[0255] Step 5: Compound 22.5 (3.7 g, 6.84 mmol, 1.0 eq), anhydrous ethanol (32 mL, 8 V), dichloromethane (16 mL, 4 V), and hydrazine hydrate (80%, 4.0 eq.) were added to the reaction flask and reacted at room temperature for 4 h. TLC showed that the starting material reacted completely. The mixture was filtered, and the filtrate was concentrated under reduced pressure and recrystallized from methanol / water to give compound 22.6 (0.63 g), with a yield of 22.3%.

[0256] Step Six: At room temperature, compound 22.6 (500 mg, 1.216 mmol) and compound 1.7 (378 mg, 1.340 mmol) were added to DMF (8.00 mL) in a 100 mL single-necked flask. HATU (603 mg, 1.586 mmol) and DIPEA (472 mg, 3.652 mmol) were added to the above reaction solution. The mixture was purged with nitrogen three times and reacted at 25 °C for 6 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with water (30 mL × 2) and saturated sodium chloride aqueous solution (30 mL), respectively. The mixture was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–15%). Compound 22.7 (400 mg, yield 48.702%) was obtained.

[0257] Step 7: At room temperature, compound 22.7 (400 mg, 592.431 μmol, 1.00 eq.) and compound 1.9 (96 mg, 656.603 μmol) were added to a 250 mL single-necked flask and dissolved in DMF (15 mL). TEA (180 mg, 1.779 mmol), tetraphenylphosphine palladium (34 mg, 29.423 μmol), and cuprous iodide (12 mg, 63.009 μmol) were added. The mixture was purged with nitrogen and reacted at 35 °C for 15 h. The system was then poured into three volumes of ice water containing DMF, and EA (20 mL × 3) was added for extraction. The organic phase was washed with saturated sodium chloride (30 mL), dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry. The crude product was obtained. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–30%). Compound 22.8 (250 mg, yield 56.989%) was obtained.

[0258] Step 8: At room temperature, compound 22.8 (250 mg, 337.619 μmol) and compound 1.11 (204 mg, 543.159 μmol) were added to a 100 mL single-necked flask, dissolved in water (1 mL), butyl acetate (5 mL), and then potassium bicarbonate (102 mg, 1.019 mmol) and dichlorobis(tricyclohexyl)palladium (38 mg, 51.478 μmol). The mixture was purged with nitrogen and reacted at 90 °C for 15 hours. The system was directly concentrated to prepare slag, and the crude product was prepared by silica gel column chromatography (PE:EA = 5:1 to 3:1). Compound 22.9 (200 mg, yield 65.155%) was obtained.

[0259] Step 9: At room temperature, compound 22.9 (200 mg, 219.977 μmol) was added to a 50 mL single-necked flask, dissolved in DCM (5 mL), and TEA (134 mg, 1.324 mmol) was added. Methanesulfonic anhydride (76 mg, 663.466 μmol) was added under ice bath conditions. The reaction was carried out at 0 °C for 30 min. An appropriate amount of ice water was added to the system, and a small amount of DCM (10 mL) was added for dilution. The organic phase was directly evaporated to dryness. Compound 22.10 (200 mg, yield 85.340%) was obtained.

[0260] Step 10: At room temperature, compound 22.10 (200 mg, 187.729 μmol) was added to a 50 mL single-necked flask and dissolved in ethanol (3 mL) under ice bath conditions. 0.5 mL of 2N sodium hydroxide was added. The reaction was carried out at 0 °C for 30 min. Acetic acid was added to adjust the pH to weakly acidic, followed by dilution with DCM (10 mL). The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate. The solution was concentrated and evaporated to dryness to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 3:1–2:1), slurried with n-heptane and tertiary methyl ether (5:1), filtered, and lyophilized. The title compound 22 (50 mg, yield 26.977%) was obtained.

[0261] 1H NMR(400MHz,DMSO)δ10.02(s,1H),9.14(s,1H),7.84–7.70(m,2H),7.37–7.24(m,2H), 6.86(dt,J=9.5,4.8Hz,1H),6.74(s,1H),4.95–4.82(m,1H),4.74–4.65(m,1H),4.55–4 .40(m,1H),4.03–3.95(m,1H),3.26(s,3H),3.16(s,3H),3.14–3.11(m,1H),2.97–2.9 1(m,1H),2.61–2.55(m,2H),1.74(s,6H),1.43–1.36(m,1H),0.96(s,1H).LCMS(ES)m / z 987.0[M+H] + .

[0262] Example 23 Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(4-fluoro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)ethyl-1-d)acetamide (23)

[0263] Compound 23.1 was obtained by the same steps as compound 22.8.

[0264] Step 1: At room temperature, compound 23.1 (500 mg, 692.052 μmol) and compound 11.4 (423 mg, 1.178 mmol) were added to a 100 mL single-necked flask, dissolved in water (1 mL), butyl acetate (5 mL), potassium bicarbonate (208 mg, 2.078 mmol), and dichlorobis(tricyclohexyl)palladium (52 ​​mg, 70.444 μmol). The mixture was purged with nitrogen and reacted at 90 °C for 15 hours. The system was then directly concentrated to produce sand. The crude product was prepared by silica gel column chromatography (PE:EA = 5:1 to 3:1) to obtain compound 23.2 (400 mg, yield 66.076%).

[0265] Step 2: At room temperature, compound 23.2 (400 mg, 457.278 μmol) was added to a 50 mL single-necked flask, dissolved in DCM (5 mL), and TEA (278 mg, 2.747 mmol) was added. Methanesulfonic anhydride (157 mg, 1.371 mmol) was added under ice bath conditions. The reaction was carried out at 0 °C for 30 min. An appropriate amount of ice water was added to the system for extraction. A small amount of DCM was added for dilution, and the organic phase was directly evaporated to dryness to obtain compound 23.3 (470 mg, yield 99.699%).

[0266] Step 3: At room temperature, compound 23.3 (470 mg, 455.902 μmol) was added to a 50 mL single-necked flask and dissolved in ethanol (5 mL). 2N sodium hydroxide (1.15 mL) was added under ice bath conditions. The reaction was carried out at 0 °C for 30 min. Acetic acid was added to adjust the pH to weakly acidic, followed by dilution with DCM. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate. The solution was concentrated to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 3:1–2:1), slurried with n-heptane and tertiary methyl ether (5:1), filtered, and lyophilized. The title compound 23 (150 mg, 34.531%) was obtained.

[0267] 1 H NMR(400MHz,DMSO)δ10.28(s,1H),9.23(s,1H),7.85–7.68(m,2H),7.08–7.00(m,2H) ,6.96–6.84(m,1H),6.58–6.36(m,2H),4.98–4.79(m,1H),4.77–4.64(m,1H),4.50–4 .32(m,1H),4.00–3.90(m,1H),3.26(s,3H),3.13(s,3H),3.03–2.92(m,2H),2.60(dd d,J=13.9,7.3,4.5Hz,2H),1.74(s,6H),1.43–1.35(m,1H),0.95(s,1H).LCMS(ES)m / z 953.1[M+H]+

[0268] Example 24 Synthesis of N-(1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl-1,1-d2)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,4,5-trifluorophenyl)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 (24)

[0269] The title compound 24 (155 mg, yield 54.809%) was obtained by following the same procedure as compound 3.

[0270] 1 H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.19(d,J=8.1Hz,1H),7.87–7.82(m,1H),7.79–7.7 3(m,1H),7.38(dd,J=7.6,2.7Hz,1H),7.09(dd,J=7.7,3.8Hz,1H),6.78–6.68(m,2H),4.92 –4.69(m,2H),4.67–4.56(m,1H),3.26(s,3H),3.19–3.13(m,3H),3.03–2.90(m,2H),2.63– 2.53(m,2H),1.76–1.72(m,6H),1.45–1.36(m,1H),1.00–0.93(m,1H).LCMS[M+1]=988.10.

[0271] Example 25 Synthesis of N-(1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(methyl-d3)-3-(methylsulfonyl)but-1-yn-1-yl-4,4,4-d3)pyridin-2-yl)-2-(3,4,5-trifluorophenyl)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 (25)

[0272] The same procedure as compound 8 was followed to obtain title compound 25 (100 mg, yield 35.957%).

[0273] 1H NMR(400MHz,DMSO-d6)δ10.02(br s,1H),9.19(br d,J=8.1Hz,1H),7.96–7.69(m,2H),7.38(dd,J=7.5,2.3Hz,1H),7.09(dd,J=7.7,3.8Hz,1H),6.85–6.57(m,2H),4.97–4.67(m,2H),4.65– 4.57(m,1H),4.55–4.34(m,1H),4.05(s,1H),3.26(s,3H),3.17(s,3H),3.04–2.89(m,2H),2.64–2.54(m,2H),1.46–1.36(m,1H),0.96(br s,1H).LCMS[M+1]=992.10.

[0274] Example 26 Synthesis of N-(1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(methyl-d3)-3-(methylsulfonyl)but-1-yn-1-yl-4,4,4-d3)pyridin-2-yl)-2-(2,3,5-trifluorophenyl)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 (26)

[0275] Title compound 26 (83.0 mg, 12% yield) was obtained using the same procedure as compound 8.

[0276] 1 H NMR (400MHz, DMSO-d6) δ10.15–9.99(m,1H),9.23–9.09(m,1H),7.88–7.75(m,2H),7.68 –7.53(m,2H),7.41–7.22(m,1H),6.90–6.69(m,1H),4.95–4.66(m,3H),4.58–4.32(m,1H ),4.10–3.91(m,1H),3.29–3.24(m,2H),3.21–3.09(m,4H),3.01–2.92(m,1H),2.63–2. 53(m,2H),1.45–1.37(m,1H),1.28–1.22(m,1H),1.02–0.94(m,1H).LCMS[M+1]=992.10.

[0277] Example 27 Synthesis of N-(1-(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)-2-(3,4,5-trifluorophenyl)ethyl-2,2-d2)-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 (27)

[0278] The same procedure as compound 5 was followed to obtain title compound 27 (200 mg, yield 59.945%).

[0279] 1 H NMR (400MHz, DMSO-d6) δ10.09–9.96(m,1H),9.28–9.09(m,1H),7.88–7.74(m,1H),7.67–7.49(m,1H),7.41–7.32(m,1H),7.11–7.04(m,1H) ),6.80–6.65(m,1H),4.95–4.70(m,2H),4.64–4.57(m,1H),4.10–3.96(m,1H),3.32(s,3H),3.27–3.25(m,3H),3.16–3.14(m,2H),2.55(br d,J=3.7Hz,2H),1.77–1.73(m,6H),1.44–1.36(m,1H),1.00–0.94(m,1H).LCMS[M+1]=988.1.

[0280] Example 28 Synthesis of N-(1-(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)-2-(2,3,5-trifluorophenyl)ethyl-2,2-d2)-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 (28)

[0281] Step 1: Compound 28-1 (15.0 g, 85.2 mmol, 1 eq.) and CDI (27.6 g, 170.4 mmol, 2 eq.) were added to a reaction flask, along with 75 mL of THF. The mixture was stirred at room temperature for 2 h until no gas was generated. Then, 20 mL of methanol was added, and the mixture was stirred for 0.5 h after the addition was complete. TLC showed that the starting material had reacted completely. The reaction solution was concentrated to dryness, and 100 mL of EA was added. The mixture was washed successively with 100 mL of 1N hydrochloric acid solution, 100 mL of saturated NaHCO3 solution, and 100 mL of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 28-2 (15.4 g, 55.50 mmol, yield 95%).

[0282] Step 2: Add lithium aluminum hydride deuterated (3.74 g, 61 mmol, 1.1 eq.) to the reaction flask. Add THF (100 mL) to an ice-water bath. While maintaining the temperature below 20°C in the ice-water bath, add a THF solution of compound 28-2 (15.4 g, 55.5 mmol, 1.0 eq.) in 20 mL. After the addition is complete, react at room temperature for 3 hours. TLC plate dot matrix shows that the starting material has reacted completely. Quench the reaction by adding 15% sodium hydroxide aqueous solution (3 times the mass of the reducing agent; a paste-like substance will form during the process, making stirring difficult; add THF until stirring is good). Filter with diatomaceous earth as an aid. Dry the resulting organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain colorless oil 28-3 (9.0 g, 57.2 mmol, yield 100%).

[0283] Step 3: Under nitrogen protection, add 28-3 (4.54 g, 23.92 mmol, 1.0 eq.) and DCM (50 mL) to the reaction flask, cool to 0 °C, and slowly add phosphorus tribromide (6.47 g, 23.92 mmol, 1.0 eq.). After the addition is complete, allow the mixture to naturally warm to room temperature and react for 2 hours. TLC plate analysis shows that the starting material has reacted completely. Add 10% sodium carbonate aqueous solution to an ice-water bath until the pH of the system is about 8. Separate the mixture, dry with anhydrous sodium sulfate, filter, and concentrate the eluent under reduced pressure at 35 °C to obtain a colorless oily substance 28-4 (5.43 g, 23.92 mmol, yield 100%).

[0284] Step 4: Compound 30.7 (4.87 g, 18.4 mmol, 1.0 eq.), compound 30.8 (3.54 g, 19.32 mmol, 1.05 eq.), and toluene (30 mL) were added to the reaction flask and reacted at 60 °C for 1 h. TLC showed that the starting material reacted completely, yielding a toluene solution of compound 30.9 (7.80 g, 18.4 mmol, yield 100%).

[0285] Step 5: To a toluene solution of compound 30.9 (7.80 g, 18.4 mmol, 1.0 eq.), TBAB (1.8 g, 5.52 mmol, 0.3 eq.), compound 28-4 (5.43 g, 23.92 mmol, 1.3 eq.), and potassium hydroxide (5.16 g, 92 mmol, 5.0 eq.) were added sequentially. The reaction was continued at 60 °C for 2-4 h. TLC showed that the starting material had reacted completely. Water (15 mL) was added to quench the reaction, and the mixture was washed with water (15 mL). The organic phase was retained to obtain a solution of compound 28-5 (10.06 g, 18.4 mmol, yield 100%).

[0286] Step 5: Add 25% sulfuric acid aqueous solution (9.2g, 92mmol, 5eq.) to the solution of 28-5 (10.06g, 18.4mmol, 1.0eq.), react at 60℃ for 1-2h, cool down, extract with n-heptane (50mL × 5 times), adjust the pH of the aqueous phase to >7 with 15% sodium hydroxide aqueous solution, extract and separate the liquid phase with EA, concentrate the organic phase under reduced pressure, and then perform column chromatography. After slurrying with methanol, solid 28-6 (2.26g, 5.48mmol, yield: 29.8%) is obtained.

[0287] Step Six: At room temperature, compound 28.6 (900 mg, 2.184 mmol, 1 eq.) and compound 1.7 (679 mg, 2.406 mmol, 1.102 eq.) were added to DMF (10 mL) in a 100 mL single-necked flask. HATU (1.08 g, 2.840 mmol, 1.300 eq.) and DIPEA (848 mg, 6.561 mmol, 3.004 eq.) were added to the above reaction solution. The mixture was purged with nitrogen three times and reacted at 25 °C for 6 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with water (30 mL x 2) and saturated sodium chloride aqueous solution (30 mL), respectively. The mixture was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–15%) to obtain compound 28-7 (700 mg, 1.035 mmol, 47.394%) as an off-white solid.

[0288] Step 7: At room temperature, add compound 28-7 (700 mg, 1.035 mmol, 1.00 eq.) and compound 1.9 (168 mg, 1.149 mmol, 1.110 eq.) dissolved in DMF (10 mL) to a 250 mL single-necked flask. Add TEA (315 mg, 3.112 mmol, 3.007 eq.), compound 1.9 (60 mg, 51.912 μmol, 0.05 eq.), and cuprous iodide (21 mg, 110.243 μmol, 0.1 eq.). Purge with nitrogen three times and react at 35 °C for 15 hours. After the reaction is complete, pour the system into three volumes of ice water (DMF), extract with EA (20 mL × 3), wash the organic phase with saturated sodium chloride (30 mL), dry with anhydrous magnesium sulfate, filter, and distill under reduced pressure until dry. Perform column chromatography with PE:EA = 0%–30%. Compound 28-8 (700 mg, 944.051 μmol, 91.213%, 1 eq.) was given as a white solid.

[0289] Step 8: At room temperature, add compound 28-8 (700 mg, 944.051 μmol, 1.0 eq.) and compound 1.11 (570 mg, 1.518 mmol, 1.608 eq.) dissolved in water (1 mL), butyl acetate (5 mL), then add potassium bicarbonate (285 mg, 2.847 mmol, 3.015 eq.) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (107 mg, 144.951 μmol, 0.1 eq.). After purging with nitrogen 5-6 times, react at 90 °C for 15 hours. Once the reaction is complete, perform column chromatography (PE:EA = 5:1 to 3:1) to obtain 28-9 (500 mg, 549.334 μmol, 58.189%, 1 eq.) as a yellow solid.

[0290] Step 9: At room temperature, compound 28-9 (500 mg, 549.334 μmol, 1 eq.) was added to a 50 mL single-necked flask, dissolved in DCM (5 mL), and TEA (335 mg, 3.311 mmol, 6.027 eq.) was added. Mesylate anhydride (190 mg, 1.659 mmol, 3.019 eq.) (approximately 1 drop of 20 mg) was added under ice bath conditions. The reaction was carried out at 0 °C for 30 min. Upon completion of the reaction, an appropriate amount of ice water was added to the system for extraction. A small amount of DCM was added for dilution, and the organic phase was directly evaporated to dryness. This was directly introduced into the next step to obtain compound 28-10 (500 mg, 468.879 μmol, 85.354%, 1 eq.) as a yellow solid.

[0291] Step 9: At room temperature, compound 28-10 (500 mg, 468.879 μmol, 1 eq.) was added to a 50 mL single-necked flask and dissolved in ethanol (5 mL). 2N sodium hydroxide (0.5 mL) was added under ice bath conditions. The reaction was carried out at 0 °C for 30 min. After TLC monitoring, the pH was adjusted to weakly acidic by adding acetic acid, followed by dilution with DCM, extraction, separation, drying the organic phase with saturated anhydrous magnesium sulfate, concentration, rotary evaporation, and mixing. The mixture was then subjected to column chromatography with a PE:EA ratio of 3:1 to 2:1 and lyophilized. Compound 28 (200 mg, 202.371 μmol, yield 43.161%) was obtained as a white solid.

[0292] 1 H NMR (400MHz, DMSO) δ10.02 (s, 1H), 9.14 (dd, J = 8.4, 2.8Hz, 1H), 7.87–7.72 (m, 2H), 7. 36–7.25(m,2H),6.86(dd,J=7.8,2.4Hz,1H),6.74(d,J=3.2Hz,1H),4.94–4.83(m,1H) ,4.79–4.66(m,2H),4.56–4.37(m,1H),4.04–3.95(m,1H),3.26(s,3H),3.17(d,J=2.0 Hz,3H),2.63–2.55(m,2H),1.74(s,6H),1.45–1.36(m,1H),0.96(s,1H).LCMS(ES)m / z 988.43[M+H] + .

[0293] Example 29 Synthesis of N-(1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl-1,1-d2)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(2,3,5-trifluorophenyl)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 (29)

[0294] The same procedure as compound 3 was followed to obtain title compound 29 (50 mg, yield 26.975%).

[0295] 1H NMR(400MHz,DMSO)δ10.02(s,1H),9.30–8.90(m,1H),7.83–7.75(m,2H),7.34–7.2 7(m,2H),6.89–6.84(m,1H),6.78–6.71(m,1H),4.95–4.83(m,1H),4.82–4.76(m,1 H),4.75–4.66(m,1H),3.27(s,3H),3.17(s,3H),3.14–3.11(m,1H),2.99–2.94(m, 1H),2.62–2.56(m,2H),1.75(s,6H),1.43–1.39(m,1H),0.97(s,1H).LCMS(ES)m / z 988.1[M+H]+

[0296] Example 30 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl-1,1-d2)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(2,3,5-trifluorophenyl)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 (30)

[0297] Step 1: Add THF (800 mL), compound 30.1 (100.00 g, 567.891 mmol, 1 eq.) and CDI (184.17, 1.136 mol, 2 eq.) to a four-necked flask, heat to 40 °C, and react for 4 h. The reaction is confirmed to be complete by TLC. Add methanol (400 mL) and react until no gas is produced (about 40 min). Concentrate the reaction solution under reduced pressure, evaporate until no solvent is present, add EA (1.0 L), transfer to a reaction vessel, wash with water (1.0 L), acid (1.0 L 1N hydrochloric acid solution), alkali (10 L saturated sodium bicarbonate solution), and saturated brine (1.0 L). Collect the organic layer, dry with anhydrous sodium sulfate, filter, and concentrate the organic layer under reduced pressure to obtain oil 30.2 (108.00 g, yield 100%).

[0298] Step 2: Add anhydrous THF (700 mL) to a four-necked flask, cool to 0°C, purge with nitrogen, and add lithium aluminum hydride (23.71 g, 0.624 mmol, 1.1 eq.) in batches, controlling the temperature at around 0°C. Then, dissolve compound 30.2 (108.00 g, 567.891 mmol, 1 eq.) in anhydrous THF (300 mL) and add slowly dropwise, controlling the temperature below 20°C. React for 3 hours, and check for complete reaction by TLC. Cool to -20°C, quench with water (23 mL), controlling the temperature not to exceed 10°C, and continue quenching with 15% sodium hydroxide solution (45 mL). Adjust the pH to around 9-10, and add 200 mL of THF. The reaction solution was filtered through diatomaceous earth and washed twice with THF (100 L × 2). The filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain an oily substance of 30.3 g (61.00 g, 376.288 mmol, yield 66%).

[0299] Step 3: Add compound 30.3 (61.00 g, 376.288 mmol, 1 eq.) and DCM (550 mL) to a four-necked flask. Under nitrogen protection, cool to 0 °C. Dissolve phosphorus tribromide (50.90 g, 177.792 mmol, 0.5 eq.) in DCM (50 mL) and add slowly dropwise. After the addition is complete, raise the temperature to room temperature (about 15 °C) and react for 3 hours. The reaction is complete when detected by TLC. Control the temperature at around 0 °C and quench with water (500 mL). Stir, allow to stand, separate the liquids, collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the filtrate, and concentrate under reduced pressure to obtain an oily substance 30.40 (849 g, 376.288 mmol, yield 100%).

[0300] Step 4: Add compound 30.5 (400.00 g, 1.594 mol, 1 eq.) and THF (2.8 L) to a four-necked flask, cool to 0 °C, and stir. Add tert-butyl nitrite (213.7 g, 2.072 mol, 1.3 eq.) and potassium tert-butoxide (268.30 g, 2.391 mol, 1.5 eq., dissolved in 1.2 L THF) dropwise. React for 6 h, and the reaction is confirmed by TLC. Adjust the pH to 7 with saturated ammonium chloride solution. Concentrate the reaction solution under reduced pressure to remove THF, filter, and collect the wet product compound 30.6 (537.4 g, 1.594 mol, yield 100%). All of this product is added to the next step.

[0301] Step 5: Compound 30.6 (537.40 g, 1.594 mol, 1 eq.) was added to a four-necked flask, followed by 4.0 L of 2-oxoacetic acid (10 V. 40-50%). The mixture was heated to 80 °C and reacted for 6.5 h. The reaction was confirmed by TLC. The mixture was then cooled, filtered, and the filter cake was washed with a large amount of water. The wet product was collected, dried, and crude product 30.7 (264.20 g) was obtained. The dried crude product 30.7 was added to a reaction vessel, and 500 mL of ethanol was added. The mixture was heated to reflux until the solution was clear. After stirring for 1 h, the mixture was cooled to allow crystallization. The crystals were filtered, and the filter cake was collected and dried to obtain compound 30.7 (214.55 g, 809.928 mmol, two-step yield 51%).

[0302] Step Six: Add toluene (700 mL), compound 30.7 (76.67 g, 289.770 mmol, 1 eq.), and compound 30.8 (53.04 g, 289.770 mmol, 1 eq.) to a four-necked flask. Heat to 60 °C and react for 1.5 h. The reaction is complete as determined by TLC, yielding a toluene solution of compound 30.9 (124.642 g, 289.770 mmol). The yield is assumed to be 100%, and the compound can be used directly in the next step without further processing.

[0303] Step 7: Cool the toluene solution of compound 30.9 to 20°C. Add TBAB (320.72 g, 0.3 eq.), 30.4 (82.90 g, 370.701 mmol, 1.3 eq.), toluene (100 mL), and 50 wt% potassium hydroxide solution (containing 81.20 g, 1.449 mol, 5 eq. of potassium hydroxide) sequentially to the reaction solution. Heat to 60°C and react for 3 h. The reaction is complete as detected by TLC. Cool down and add 250 mL of water. After separation, add another 250 mL of water, stir, and let stand. Separate again to obtain a toluene solution of compound 30.10 (166.40 g, 289.77 mmol). Based on a 100% yield, it can be used directly in the next reaction without further processing.

[0304] Step 8: Add 25 wt% sulfuric acid aqueous solution (containing 141.97 g, 1.4489 mol, 5 eq. of sulfuric acid) to the toluene solution of compound 30.10. Heat the reaction solution to 60 °C and react for 2.5 h. The reaction is complete as detected by TLC. Allow the solution to stand and separate the liquids. Collect the aqueous phase. Add 15 wt% sodium hydroxide aqueous solution (containing 115.77 g of sodium hydroxide) to the aqueous phase to adjust the pH to >7. Add EA (700 mL), stir, allow the solution to stand and separate the liquids. Collect the organic phase, dry it with anhydrous sodium sulfate, filter and collect the organic phase to obtain an EA solution of compound 30.11 (118.81 g, 289.770 mmol). Calculate the yield based on 100%.

[0305] Step 9: Add dioxane hydrochloride solution (4N, 72.3ml, 1eq.) to the EA solution of compound 30.11, stir, and hydrochloride precipitates out of the reaction solution. Add EA (840mL), stir for 4h, filter and collect the hydrochloride, rinse the filter cake with EA, and dry to obtain compound 30.12 (86.40g, 193.509mmol).

[0306] Step 10: Compound 30.12 (86.40 g, 193.509 mmol, 1 eq.) and EA (850 mL) were added to a reaction vessel, and sodium bicarbonate aqueous solution (containing 243.15 g, 193.509 mmol, 1 eq.) was added. The mixture was stirred and separated, and the organic phase was collected and concentrated under reduced pressure. The concentrated organic phase was collected, and anhydrous ethanol (100 mL) was added. The temperature was raised to 75 °C. After the reaction solution was cleared, N-acetyl-D-leucine (50.13 g, 193.509 mmol, 1 eq.) was added. Then, the mixture was cooled gradually to crystallize (cooled to 20 °C). The mixture was stirred for 3 h, centrifuged, and the filter cake was collected to obtain compound 30.13 (20.80 g, 35.66 mmol, yield: 35.7%).

[0307] Step 11: Compound 30.13 (80 g, 137.165 mmol, 1 eq.) and TEA (27.7 g, 274.330 mmol, 2 eq.) were added to a reaction flask. After freeing the compound, Boc anhydride (38.8 g, 177.778 mmol, 1.3 eq.) was added. The mixture was stirred at 25 °C and reacted for 1.5 h. The reaction was confirmed by TLC. 200 ml of water was added, and the mixture was stirred and separated. The mixture was then washed with 200 ml of saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a white solid powder. 10 V of n-heptane and 0.5 V of EA were added, and the mixture was stirred at 50 °C for 1 h. The mixture was cooled to crystallize. The filter cake was collected to obtain a white solid 30.14 (64.0 g, 125.453 mmol, yield: 91.5%).

[0308] Step 12: Add compound 30.14 (10.00 g, 19.602 mmol, 1 eq..) to a 250 mL single-necked flask, followed by DCM (50 mL) and dioxane hydrochloride (80 mL). React at 20 °C for 1 h. The system was then concentrated and evaporated to dryness to obtain crude compound 30.15 (8.04 g, 19.602 mmol, yield 100%).

[0309] Step 12: At room temperature, compounds 30.15 (3.00 g, 7.317 mmol, 1 eq.) and 1.7 (2.48 g, 8.789 mmol, 1.201 eq.) were added to DMF (30 mL) in a 100 mL single-necked flask. HATU (3.62 g, 9.521 mmol, 1.301 eq.) and DIPEA (2.84 g, 21.974 mmol, 3.003 eq.) were added to the above reaction solution. The mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. TLC monitoring showed that the starting material disappeared. The mixture was poured into water (20 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with water (30 mL × 2) and saturated sodium chloride aqueous solution (30 mL), respectively. The mixture was dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–15%) to give compound 30.16 (1.90 g, 2.818 mmol, 38.519%, 1 eq.) as an off-white solid.

[0310] Step 13: At room temperature, add compound 30.16 (1.90 g, 2.818 mmol, 1.00 eq.) and 1.9 (453 mg, 3.098 mmol, 1.099 eq.) dissolved in DMF (20 mL) to a 250 mL single-necked flask. Add TEA (855 mg, 8.450 mmol, 2.998 eq.), tetratetraphenylphosphine palladium (164 mg, 141.921 μmol, 0.05 eq.), and cuprous iodide (57 mg, 299.291 μmol, 1.062e-1 eq.). Purge with nitrogen three times and react at 35 °C for 15 hours. After the reaction is complete as monitored by TLC, pour the system into three volumes of ice water equal to the volume of DMF. Extract with EA (20 mL × 3). Wash the organic phase with saturated sodium chloride (30 mL), dry with anhydrous magnesium sulfate, filter, and distill under reduced pressure until dry. PE:EA = 0%–30% column chromatography yielded compound 30.17 (2.00 g, 2.705 mmol, 95.968%) as a white solid.

[0311] Step Fourteen: At room temperature, add compound 30.17 (2.00 g, 2.705 mmol, 1 eq.) and 3.2 (3.41 g, 5.689 mmol, 2.103 eq.) dissolved in water (4 mL), butyl acetate (20 mL), and then add potassium bicarbonate (816 mg, 8.150 mmol, 3.013 eq.) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (200 mg, 270.937 μmol, 0.1 eq.). After purging with nitrogen 5-6 times, react at 90 °C for 15 hours. The reaction was monitored by TLC until completion. The system was directly concentrated to prepare sand, and then subjected to PE:EA = 5:1 to 3:1 column chromatography. Compound 30.18 (750 mg, 824.001 μmol, yield 30.462%) was obtained as a yellow solid.

[0312] Step 15: At room temperature, add compound 30.18 (750 mg, 824.001 μmol, 1 eq.) to a 50 mL single-necked flask, dissolve in DCM (10 mL), add TEA (503 mg, 4.971 mmol, 6.0 eq.), and add methanesulfonic anhydride (285 mg, 2.488 mmol, 3 eq.) (approximately 1 drop of 20 mg) under ice bath conditions. React at 0 °C for 30 min. TLC monitoring indicates the reaction is complete, yielding compound 30.19 (800 mg, 750.206 μmol, 91.04%) as a yellow solid. Proceed directly to the next step.

[0313] Step 16: Add compound 30.19 (800 mg, 750.206 μmol, 1 eq.) to a 50 mL single-necked flask, dissolve in Me-THF (10 mL), add sodium hydroxide (92 mg, 2.300 mmol, 3.07 eq.) (1 M aqueous solution, 0.4 g sodium hydroxide added to 10 mL water) under ice bath, and react at 20 °C for 15 h. After TLC monitoring, 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, evaporate to dryness, and mix. Perform column chromatography with PE:EA = 3:1 to 2:1, homogenize with n-heptane and tertiary methyl ether (5:1) (6 mL), filter, and lyophilize. 30 (700 mg, 708.298 μmol, 94.414%) is a yellow solid.

[0314] 1H NMR (400MHz, DMSO) δ10.02 (s, 1H), 9.16 (d, J = 8.5Hz, 1H), 7.84–7.70 (m, 2H), 7.41–7.1 9(m,2H),6.97–6.77(m,1H),6.77–6.63(m,1H),4.96–4.89(m,1H),4.82–4.75(m,1H), 4.72–4.64(m,1H),3.26(s,3H),3.17(s,3H),3.13(s,1H),2.99–2.92(m,1H),2.61–2. 56(m,2H),1.74(s,6H),1.44–1.35(m,1H),1.00–0.93(m,1H).LCMS(m / z)=988.1[M+H] + .

[0315] Example 31 Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(methyl-d3)-3-(methylsulfonyl)but-1-yn-1-yl-4,4,4-4-d3)pyridin-2-yl)-2-(2,3,5-trifluorophenyl)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 (31)

[0316] Step 1: At room temperature, compound 30.16 (1.40 g, 2.077 mmol, 1.00 eq.) and compound 8.5 (347 mg, 2.279 mmol, 1.098 eq.) dissolved in DMF (15 mL) were added to a 250 mL single-necked flask. TEA (630 mg, 6.226 mmol, 2.998 eq.), tetrakis(triphenylphosphine)palladium (119 mg, 102.979 μmol, 4.959e-2 eq.), and cuprous iodide (54 mg, 283.539 μmol, 1.365e-1 eq.) were added. The mixture was purged with nitrogen three times and reacted at 35 °C for 15 hours. The reaction was monitored by LCMS until it ended. The system was poured into three volumes of DMF in ice water, and EA (50 mL x 3) was added for extraction. The organic phase was washed with saturated sodium chloride (50 mL), dried with anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry. PE:EA = 0%–30% column chromatography was used to obtain compound 31.1 (1.30 g, 1.744 mmol, 83.972%, 1 eq.) as a yellow solid.

[0317] Step 2: At room temperature, add compound 31.1 (1.30 g, 1.744 mmol, 1 eq.) and 1.11 (1.10 g, 2.929 mmol, 1.680 eq.) to a 100 mL single-necked flask, dissolved in water (4 mL), butyl acetate (20 mL), then add potassium bicarbonate (522 mg, 5.214 mmol, 2.990 eq.) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (122 mg, 165.271 μmol, 9.478 e-2 eq.). After purging with nitrogen 5-6 times, react at 90 °C for 15 hours. The reaction was monitored by LCMS until completion. The system was directly concentrated to prepare sand. PE:EA = 5:1 to 3:1 column chromatography yielded compound 30.2 (1.30 g, 1.422 mmol, 81.546%, 1 eq.) as a yellow solid.

[0318] Step 3: Compound 30.2 (1.30 g, 1.422 mmol, 1 eq.) was dissolved in DCM (15 mL) in a 50 mL single-necked flask. Then, methanesulfonic anhydride (632 mg, 5.544 mmol, 3.899 eq.) and TEA (949 mg, 9.378 mmol, 6.595 eq.) were added. The reaction mixture was incubated at 25 °C for 2 hours. LC-MS was used to monitor the reaction until complete. The mixture was extracted with water (40 mL) and DCM (40 mL × 3), washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A yellow solid 30.3 (1.50 g, 1.401 mmol, 98.549%) was obtained and directly added to the next step.

[0319] Step 4: Compound 30.3 (500 mg, 467.116 μmol, 1 eq.) was added to a 100 mL single-necked flask, along with sodium hydroxide (77 mg, 1.925 mmol, 4.121 eq.) dissolved in water (1 mL) and ethanol (5 mL) (0.8 g sodium hydroxide dissolved in 10 mL of water). The reaction was carried out at 25 °C for 15 hours, and the reaction was monitored by LC-MS until completion. Acetic acid was added to adjust the pH to weakly acidic, followed by dilution with DCM. The mixture was extracted, separated, and the organic phase was dried over anhydrous magnesium sulfate, concentrated, and evaporated to dryness. The mixture was purified by column chromatography using n-heptane:ethyl acetate = 2:1 as the eluent. A white solid 31 (170 mg, 171.318 μmol, 36.676%, 1 eq.) was obtained.

[0320] 1H NMR(400MHz,DMSO-d6)δ=10.03(br s,1H),9.17(d,J=8.8Hz,1H),7.85-7.80(m,1H),7.79-7.76(m,1H),7.41-7.26(m,2H),6.87 (d,J=7.6Hz,1H),6.78-6.71(m,1H),4.93(d,J=16.4Hz,1H),4.85-4.74(m,1H),4.73-4.64(m ,1H),4.62-4.48(m,1H),4.06-3.92(m,1H),3.27(s,3H),3.17(s,3H),3.15-3.08(m,1H),2.9 5-2.91(m,1H),2.61-2.54(m,2H),1.46-1.37(m,1H),1.01-0.94(m,1H).LCMS[M+1]=992.10.

[0321] Example 32 Synthesis of N-(1-(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)-2-(2,3,5-trifluorophenyl)ethyl-1-d)-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 (32)

[0322] Step 1: Add 32.1 (21g, 110.46mmol, 1.0eq.), DMF (210ml, 10V), DIPEA (43.05g, 331.38mmol, 3eq.), and dimethylhydroxylamine hydrochloride (12.95g, 132.54mmol, 1.2eq.) to the reaction flask. Under nitrogen protection, add HATU (50.4g, 132.55mmol, 1.2eq.) in portions under an ice-water bath. Then transfer to room temperature and react for 3 hours. TLC plate spotting shows that the starting material has reacted completely. Add 10% sodium chloride aqueous solution (5V) to the ice-water bath and extract with MTBE (5V × 5 times). Combine the organic phases, and then extract sequentially with 0.5M HCl (3V × 2 times) and 7% HCl. Washed with NaHCO3 (3V) and 10% sodium chloride (3V), the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 32.2g (24.75g, 106.09mmol, yield 96.03%) of yellow oil.

[0323] Step 2: Under nitrogen protection at -30℃, add tetramethylpiperidinyl magnesium chloride lithium chloride complex (122.96 ml, 1.5 eq., 1 M / L in) to the reaction flask. THF was added to compound 32.2 (24.75 g, 30.45 mmol, 1.3 eq.) in THF (98 ml, 5V) at -25 to -20 °C. After the reaction was complete for 1-2 h, compound 32.2 (24.75 g, 30.45 mmol, 1.3 eq.) in THF (98 ml, 5V) was added to the mixture. The reaction was maintained at this temperature for 2 h. TLC showed that the starting material had completely reacted. The mixture was quenched with 10% ammonium chloride aqueous solution (5V), separated, and the aqueous phase was extracted with EA (3V × 2 times). The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and subjected to wet column chromatography (EA / PE = 0%-1%-2%-3%) to give a white solid compound 32.3 (19.425 g, 47.50 mmol, yield: 38.62%).

[0324] Step 3: Compound 32.3 (17.5 g, 42.77 mmol, 1.0 eq.) and methanol (140 ml, 8V) were added to the reaction flask. Sodium deuterated borohydride (2.66 g, 64.26 mmol, 1.5 eq.) was slowly added in an ice-water bath. The mixture was transferred to room temperature and reacted for 3 h. TLC showed that the starting material had reacted completely. 1 M HCl (3V) was added to the system to quench the reaction (the system pH was about 1). The mixture was stirred for 5 min, and then 10% sodium hydroxide was added to adjust the pH to about 8 or higher. The reaction solution was concentrated to remove most of the methanol. The remaining aqueous phase was extracted with DCM (3V×3). The organic phase was dried with anhydrous magnesium sulfate and filtered. After concentration under reduced pressure, a colorless oily compound 32.4 (16.66 g, 40.43 mmol, yield: 94.5%) was obtained.

[0325] Step 4: Compound 32.4 (14 g, 33.95 mmol, 1 eq.), THF (112 ml, 8 V), triphenylphosphine (10.68 g, 40.74 mmol, 1.2 eq.), and phthalimide (5.99 g, 40.74 mmol, 1.2 eq.) were added to the reaction flask under nitrogen purging protection. DEAD (7.11 g, 40.74 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. Water (3 V) was added to quench the reaction, and the aqueous phase was extracted with EA (3 V × 2 times). The organic phases were combined, concentrated under reduced pressure, and then slurried with ethanol / water (the solid was precipitated by adding water after dissolving in ethanol). The mixture was filtered to obtain a white solid compound 32.5 (12.95 g, 23.94 mmol, yield: 70.5%).

[0326] Step 5: Add compound 32.5 (12.95 g, 23.94 mmol, 1.0 eq.), anhydrous ethanol (112 ml, 8V), dichloromethane (56 ml, 4V), and hydrazine hydrate (80% concentration, 4.0 eq.) to the reaction flask. React at room temperature for 4 h. TLC showed that the starting material reacted completely. Filter, concentrate the filtrate under reduced pressure, and recrystallize from methanol / water (heat to 60 °C, add methanol to dissolve completely, add water dropwise until turbid, cool to crystallize), and precipitate a white solid 32.6 (2.21 g, 5.36 mmol., yield: 22.3%).

[0327] Step 6: Add compound 32.6 (2 g, 1 eq.) and isopropanol (12 mL) to the reaction flask, heat to 75 °C, and after the reaction solution is cleared, add N-acetyl-D-leucine (0.85 g, 1 eq.), then gradually cool down to crystallize (cool to 20 °C), stir for 3 h, filter and collect the filter cake, repeat the recrystallization step twice, collect the filter cake after the second separation, and obtain compound 32.7 (0.47 g, 0.8 mmol, yield: 16.3%).

[0328] Step 7: Compound 32.7 (10 g, 17.116 mmol, 1 eq.) and TEA (3.46 g, 34.232 mmol, 2 eq.) were added to a reaction flask. After freeing the compound, Boc anhydride (38.8 g, 177.778 mmol, 1.3 eq.) was added. The mixture was stirred at 25 °C and reacted for 1.5 h. The reaction was confirmed by TLC. 200 ml of water was added, and the mixture was stirred and separated. The mixture was then washed with 200 ml of saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a white solid powder. 10 V of n-heptane and 0.5 V of EA were added, and the mixture was stirred at 50 °C for 1 h. The mixture was cooled to crystallize. The filter cake was collected to obtain a white solid 32.8 (7.87 g, 15.404 mmol, yield: 90%).

[0329] Step 8: Add compound 32.8 (7.87 g, 15.404 mmol, 1 eq..) to a 250 mL single-necked flask, followed by DCM (50 mL) and dioxane hydrochloride (80 mL). React at 20 °C for 1 h. The system was then concentrated and evaporated to dryness to obtain crude compound 32.9 (4.74 g, 115.404 mmol, yield 100%).

[0330] Step 9: At room temperature, compound 32.9 (1.76 g, 4.282 mmol, 1 eq.) and compound 1.7 (1.32 g, 4.678 mmol, 1.093 eq.) were added to DMF (10 mL) in a 100 mL single-necked flask. HATU (2.10 g, 5.523 mmol, 1.290 eq.) and DIPEA (1.65 g, 12.767 mmol, 2.982 eq.) were added to the above reaction solution. The mixture was purged with nitrogen three times and reacted at 25 °C for 18 hours. TLC monitoring showed that the starting material disappeared. The mixture was poured into water (60 mL) and extracted with ethyl acetate (60 mL × 3). The organic phases were combined and washed with water (40 mL × 2) and saturated sodium chloride aqueous solution (40 mL), respectively. The mixture was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure until dry to obtain the crude product. The crude product was prepared by silica gel column chromatography (PE:EA = 0%–15%). Compound 32.10 (2.00 g, 2.962 mmol, 69.179%) was obtained as a white solid.

[0331] Step 10: Compound 32.10 (2.00 g, 2.962 mmol, 1 eq.) was dissolved in DMF (6 mL), and compound 1.9 (556 mg, 3.803 mmol, 1.284 eq.), TEA (895 mg, 8.845 mmol, 2.986 eq.), tetraphenylphosphine palladium (169 mg, 146.248 μmol, 0.05 eq.), and cuprous iodide (66 mg, 346.548 μmol, 0.117 eq.) were added. The mixture was purged with nitrogen three times, then heated to 35 °C and stirred for 16 hours. 30 mL of ice water was added to the reaction mixture, followed by extraction with ethyl acetate (20 × 2 mL), drying, concentration, and column chromatography. The pale yellow product 32.11 (1.70 g, 2.296 mmol, 77.505%, 1 eq.) was obtained.

[0332] Step 11: Compound 32.11 (1.60 g, 2.161 mmol, 1 eq.) was dissolved in water (2 mL) in a 50 mL single-necked flask, followed by potassium bicarbonate (648 mg, 6.472 mmol, 2.995 eq.) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (238 mg, 322.415 μmol, 0.15 eq.). The reaction solution was reacted at 90 °C for 15 h. The reaction was monitored by TLC until complete. Water (30 mL) and DCM (30 mL × 3) were added for extraction, followed by washing with saturated sodium chloride, drying with anhydrous magnesium sulfate, filtration, concentration of the filtrate under reduced pressure, and column chromatography to obtain a yellow solid 32.12 (1.30 g, 1.430 mmol, 66.173%, 1 eq.).

[0333] Step 12: Compound 32.12 (300 mg, 329.965 μmol, 1 eq.) was dissolved in DCM (5 mL) in a 50 mL single-necked flask. Then, methanesulfonic anhydride (112 mg, 982.456 μmol, 2.977 eq.) and TEA (100 mg, 988.250 μmol, 2.995 eq.) were added. The reaction mixture was incubated at 25 °C for 1 hour. The reaction was monitored by TLC until complete. The mixture was extracted with water (30 mL) and DCM (30 mL × 3), washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A yellow solid, compound 32.13 (330 mg, 309.752 μmol, 93.874%), was obtained.

[0334] Step 13: Add 32.13 (1.30 g, 1.220 mmol, 1 eq.) to a 100 mL single-necked flask, dissolved in 1 mL of water and 5 mL of ethanol (0.8 g sodium hydroxide dissolved in 10 mL of water). React at 25 °C for 1 hour. Monitor the reaction for completion by TLC. Adjust the pH to weakly acidic by adding acetic acid, then dilute with DCM, extract, separate, dry the organic phase to anhydrous magnesium sulfate, concentrate, and evaporate to dryness. Purify by column chromatography using n-heptane:ethyl acetate = 2:1 as eluent to give a white solid compound 32 (1.10 g, 1.114 mmol, 91.308%).

[0335] 1 H NMR (400MHz, DMSO-d6) δ = 10.03 (m, 1H), 9.16 (m, 1H), 7.88-7.76 (m, 2H), 7.33-7.3 1(m,2H),6.86(m,1H),6.3(m,1H),4.98-4.53(m,2H),4.32-4.09(m,1H),4.05-3.7 4(m,1H),3.29-3.23(m,3H),3.16-3.07(m,4H),3.02-2.90(m,1H),2.65-2.53(m, 2H),1.79-1.68(m,6H),1.46-1.36(m,1H),1.04-0.91(m,1H).LCMS[M+1]=987.23.

[0336] Examples 33 and 34 N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl-1,1-d2)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,4,5-trifluorophenyl)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 (33) and N Synthesis of -((R)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl-1,1-d2)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,4,5-trifluorophenyl)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 (34)

[0337] Compound 33 and (40 mg, yield 25.8%) were obtained by chiral resolution of compound 24. The chiral resolution method is as follows:

[0338] Instrument: Waters 150 preparative SFC (SFC-26) column: ChiralPak AD, 250×30mm inner diameter, 10μm

[0339] Mobile phase: A: CO2, B: Isopropanol

[0340] Gradient: B 20%

[0341] Flow rate: 120 mL / min

[0342] Back pressure: 100 bar

[0343] Column temperature: 38℃

[0344] Wavelength: 220nm

[0345] Cycle time: Approximately 4.5 minutes

[0346] Sample preparation: The compound was dissolved in approximately methanol / DCM (20 mL).

[0347] Compound 33:

[0348] 11H NMR (400 MHz, DMSO-d6) δ 10.02 (broad d, J = 2.2 Hz, 1H), 9.19 (d, J = 8.3 Hz, 1H), 7.86–7.82 (m, 1H), 7.78–7.75 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.77–6.71 (m, 2H), 4.79 (q, J = 16.3 Hz, 2H), 4.65–4.58 (m, 1H), 3.26 (s, 3H), 3.17 (s, 3H), 3.04–2.91 (m, 2H), 2.62–2.53 (m, 2H), 1.74 (d, J = 1.2 Hz, 6H), 1.44–1.37 (m, 1H), 0.98 - 0.96 (m, 1H). LCMS [M+1] + = 988.10.

[0349] Compound 34:

[0350] 1 1H NMR (400 MHz, DMSO-d6) δ 10.02 (broad d, J = 2.2 Hz, 1H), 9.19 (d, J = 8.3 Hz, 1H), 7.86–7.82 (m, 1H), 7.78–7.75 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.77–6.71 (m, 2H), 4.79 - 4.58 (m, 3H), 3.26 (s, 3H), 3.17 (s, 3H), 3.04–2.91 (m, 2H), 2.62–2.53 (m, 2H), 1.74 (d, J = 1.2 Hz, 6H), 1.44–1.37 (m, 1H), 0.98 - 0.96 (m, 1H). LCMS [M+1] + = 988.10.

[0351] Examples 35 and 36 N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(methyl-d3)-3-(methylsulfonyl)but-1-yn-1-yl-4,4,4-4-d3)pyridin-2-yl)-2-(3,4,5-trifluorophenyl)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 (35) and Synthesis of N-((R)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(methyl-d3)-3-(methylsulfonyl)but-1-yn-1-yl-4,4,4-4-d3)pyridin-2-yl)-2-(3,4,5-trifluorophenyl)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 (36)

[0352] Compound 25 was chirally isolated to obtain compound 35 (40 mg) and compound 36 (40 mg).

[0353] The chiral separation method is as follows: Instrument: Waters 150 preparative SFC (SFC-26)

[0354] Column: ChiralPak AD, 250×30mm inner diameter, 10μm

[0355] Mobile phase: A: CO2, B: Isopropanol

[0356] Gradient: B 20%

[0357] Flow rate: 120 mL / min

[0358] Back pressure: 100 bar

[0359] Column temperature: 38℃

[0360] Wavelength: 220nm

[0361] Cycle time: Approximately 4.5 minutes

[0362] Sample preparation: The compound was dissolved in approximately 20 mL of methanol / DCM.

[0363] Compound 35:

[0364] 11H NMR (400 MHz, DMSO-d6) δ 10.08–9.96 (m, 1H), 9.19 (d, J = 8.1 Hz, 1H), 7.87–7.81 (m, 1H), 7.79–7.74 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.77–6.72 (m, 2H), 4.79 - 4.55 (m, 3H), 4.50–4.33 (m, 1H), 4.10–3.95 (m, 1H), 3.26 (s, 3H), 3.17 (s, 3H), 3.03–2.91 (m, 2H), 2.63–2.54 (m, 2H), 1.44–1.37 (m, 1H), 1.00–0.92 (m, 1H). LCMS (ES) m / z 992.10 [M+1] + .

[0365] Compound 36:

[0366] 1 1H NMR (400 MHz, DMSO-d6) δ 10.08–9.96 (m, 1H), 9.19 (d, J = 8.1 Hz, 1H), 7.87–7.81 (m, 1H), 7.79–7.74 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.77–6.72 (m, 2H), 4.79 (q, J = 16.4 Hz, 2H), 4.66–4.55 (m, 1H), 4.50–4.33 (m, 1H), 4.10–3.95 (m, 1H), 3.26 (s, 3H), 3.17 (s, 3H), 3.03–2.91 (m, 2H), 2.63–2.54 (m, 2H), 1.44–1.37 (m, 1H), 1.00–0.92 (m, 1H). LCMS (ES) m / z 992.10 [M+1] + .

[0367] Examples 37 and 38 N-((S)-1-(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)-2-(3,4,5-trifluorophenyl)ethyl-2,2-d2)-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 (37)&N Synthesis of -((R)-1-(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)-2-(3,4,5-trifluorophenyl)ethyl-2,2-d2)-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 (38)

[0368] Compound 27 was prepared by SFC ((S,S)Whelk O1, 250×30mm ID, 10μm, A for CO2 and B for Isopropanol). Its corresponding components were collected and concentrated under reduced pressure to obtain compound 37 (32mg) and compound 38 (47mg).

[0369] Compound 37:

[0370] 1 H NMR(400MHz,DMSO-d6)δ10.02(m,1H),9.19–9.09(m,1H),7.84–7.75(m,2 H),7.38–7.36(m,1H),7.08–7.06(m,1H),6.76–6.72(m,2H),4.85–4.73(m ,3H),4.60–4.02(m,2H),3.33(m,3H),3.26–3.17(m,3H),2.58–2.53(m,2 H),1.74(m,6H),1.42–1.39(m,1H),1.02–0.94(m,1H).LCMS[M+1]=988.1.

[0371] Compound 38:

[0372] 1H NMR(400MHz,DMSO-d6)δ10.02(m,1H),9.19–9.05(m,1H),7.82(m,2H),7.38–7.36(m,1H),7.08–7.06(m,1H),6.76–6.72(m,2H),4.91–4.5 4(m,4H),4.02(m,1H),3.28(m,3H),3.17(m,3H),2.53–2.52(m,2H),1.74(m,6H),1.42–1.39(m,1H),0.96–0.94(m,1H)LCMS[M+1]=988.1.

[0373] Examples 39 and 40N-((R)-1-(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)-2-(2,3,5-trifluorophenyl)ethyl-2,2-d2)-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(3 9) Synthesis of N-((S)-1-(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)-2-(2,3,5-trifluorophenyl)ethyl-2,2-d2)-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 (40)

[0374] Compound 28 was isolated by chiral preparation to obtain compound 39 (38 mg) and compound 40 (30 mg).

[0375] The chiral decomposition method is as follows:

[0376] Instrument: Waters 150 preparative SFC (SFC-26)

[0377] Column: ChiralPak AD, 250×30mm inner diameter, 10μm

[0378] Mobile phase: A: CO2, B: Isopropanol

[0379] Gradient: B 20%

[0380] Flow rate: 120 mL / min

[0381] Back pressure: 100 bar

[0382] Column temperature: 38℃

[0383] Wavelength: 220nm

[0384] Cycle time: Approximately 4.5 minutes

[0385] Sample preparation: The compound was dissolved in approximately 20 mL of methanol / DCM.

[0386] Compound 39:

[0387] 1 H NMR (400MHz, DMSO) δ10.02 (s, 1H), 9.14 (d, J = 8.5Hz, 1H), 7.84–7.72 (m, 2H), 7.3 4–7.23(m,2H),6.86(d,J=7.7Hz,1H),6.74(s,1H),4.89–4.81(m,1H),4.79–4.7 1(m,2H),4.45–4.37(m,1H),4.06–3.95(m,1H),3.26(s,3H),3.17(s,3H),2.62– 2.54(m,2H),1.74(s,6H),1.43–1.38(m,1H),0.96(s,1H).MS(m / z)=988.1[M+1] + .

[0388] Compound 40:

[0389] 1 H NMR(400MHz, DMSO-d6)δ=10.03(m,1H),9.17–9.15(m,1H),7.83-7.77(m,2H),7.35-7 .28(m,2H),6.85-6.75(m,1H),6.74-6.73(m,1H),4.95-4.91(m,1H),4.79-4.66(m,2H ),4.53-4.51(m,1H),4.01–3.99(m,1H),3.29-3.24(m,3H),2.81-2.75(m,3H),2.64-2 .54(m,2H),1.78-1.70(m,6H),1.46-1.36(m,1H),1.03-0.92(m,1H)LCMS=988.1[M+1] + .

[0390] Unless otherwise specified, all reagents used in the following experimental examples are standard commercially available products.

[0391] Experimental Example 1: Anti-HIV-1 Bioactivity

[0392] Test materials

[0393] Test compounds: The compounds in this application, Lenacapavir (development code GS-6207) was prepared according to method WO2019161280A1 as a positive control (HPLC purity 99.78%); Raltegravir (RAL) is an approved anti-HIV drug and was purchased from the market as a positive control.

[0394] Virus: HIV-PsV; Cells: HEK293T cells;

[0395] 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), and reporter gene assay kits were purchased from PerkinElmer (catalog number 6066769).

[0396] Composition of cell culture medium: DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin antibiotics.

[0397] Test Plan

[0398] This test examined the inhibitory activity of the test compounds against HIV-1. GS-6207 and RAL were used as positive controls. The specific procedure was as follows: 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. 50The curve fitting method is log(inhibition) vs. response -- variable slope. The calculation formula is as follows:

[0399] Antiviral activity (%) EC 50 = (Test well reading - Virus control average) / (Cell control average - Virus control average) × 100

[0400] The results are shown in Table 1.

[0401] Table 1. Antiviral (HIV-PsV) activity of the compounds in HEK293T cells.

[0402] Conclusion: The compounds provided in this application all exhibit good antiviral activity against HIV-1. The EC50 values ​​of some of the compounds in the examples (such as compounds 1, 3, 6, 12, 30-32, and 40) are also shown. 50 The values ​​were superior to GS-6207. Furthermore, none of the compounds in the examples showed significant cytotoxicity to the cells used in the experiments, and the half-maximal concentration (CC) was within acceptable limits. 50 The values ​​were all greater than the highest test concentration in each experiment, indicating a high antiviral selectivity index (CC). 50 / EC 50 ).

[0403] Experimental Example 2: Affinity of HIV-1 Capsid Protein

[0404] Test compounds: The test compounds were prepared in the aforementioned examples; the reference drug GS-6207 was prepared according to the method of WO2019161280A1.

[0405] Reagents: Tris-HCl was purchased from Merck, β-mercaptoethanol was purchased from Merck, loading buffer was purchased from Biorad, CM5 chip was purchased from Cytiva, and CA protein was prepared in-house.

[0406] The CA protein is HIV-1CA A14C / E45C / W184A / M185A as described in the literature (Disulfide bond stabilization of the hexameric capsomer of human immunodeficiency virus. Pornillos et al. J Mol Biol. 2010 September 3; 401(5):985–995.).

[0407] Instrument: Biacore TM 1K+SPR molecular interaction system (Cytiva, model Biacore)TM 1K+)

[0408] Experimental Protocol: SPR technology was used to accurately determine the binding affinity and kinetic parameters of the test compound to HIV-1 capsid protein (CA). His antibody was immobilized on a CM5 chip using a standard amine coupling method, and CA protein was captured to a specified level via a His tag to create an activity detection channel. The test compound was serially diluted (500, 250, 125, 62, 31, 16, 8 nM) with running buffer (20 mM Tris-HCl, pH 8.0, 150 mM NaCl, 0.02% Tween, 1% DMSO) to ensure consistent DMSO concentration in all samples. The compound solutions of different concentrations were sequentially passed through the chip surface immobilized with CA protein, and the SPR instrument monitored the changes in the response signal (RU) during binding and dissociation in real time.

[0409] The sensing curve was fitted using a 1:1 kinetic model, and key parameters were calculated: binding rate constant (ka), dissociation rate constant (kd), and equilibrium dissociation constant (KD). The calculation formula is KD = kd / ka. The KD value directly reflects the strength of the binding affinity.

[0410] Experimental results: The affinity KD value of Example 40 was 101 nM, and the affinity KD value of Example 12 was 73.4 nM.

[0411] Conclusion: The compound provided in this application has a strong affinity for HIV-1 capsid protein and exhibits good specificity.

[0412] Experimental Example 3: Mouse Pharmacokinetic Study

[0413] This study investigated the pharmacokinetic behavior of the compound in mice by measuring the plasma concentrations of the compound and the positive control GS-6207 at different time points after administration by gavage (PO) and intravenous bolus (IV) to evaluate its pharmacokinetic characteristics.

[0414] Test animals: SPF-grade ICR male mice, 10 weeks old, weighing about 32g; 6 animals were tested for each compound.

[0415] Experimental formulation:

[0416] PO / IV: 10% DMAC+10% Solutol HS15+80% Saline.

[0417] 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.

[0418] Sampling methods: For mice administered via PO: 20 μL of blood was collected from the saphenous vein of the hind limb before administration and at 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 120 and 168 hours after administration; For mice administered via IV: 20 μL of blood was collected from the saphenous vein of the hind limb before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 120 and 168 hours after administration.

[0419] All blood samples were placed in EDTA-K2 anticoagulant blood collection tubes, and plasma samples were obtained by centrifugation (4℃, 3500rpm, 10min) for testing.

[0420] Detection: 10 μL of mouse plasma was collected at each time point, and 100 μL of methanol containing internal standard (100 ng / mL) was added. The mixture was vortexed for 1 min and centrifuged (4℃, 12000 rpm, 5 min). 1 μL of the supernatant from the plasma sample was analyzed by LC-MS / MS to determine the content of the analyte in the mouse plasma. Pharmacokinetic analysis was performed on the plasma concentration-time data. The pharmacokinetic parameters of the PO and IV dosing tests are shown in Tables 2-1 and 2-2.

[0421] The blood drug concentration-time curves of PO and IV administration tests of Examples 12, 40 and GS6207 in mice are shown in Figures 1 and 2. Under the same pharmacokinetic experiment, at the same time after administration, the blood drug concentrations of Examples 12 and 40 were significantly higher than those of GS6207.

[0422] Table 2-1 Pharmacokinetic parameters of mice after IV dosing

[0423] Table 2-2 Pharmacokinetic parameters of mice after PO administration

[0424] Conclusion: At the same dose, the in vivo exposure (AUC) of the compound in this application after intravenous administration to mice was [data missing]. 0-168h It is significantly superior to GS6207; it has a lower in vivo clearance rate (Cl). The in vivo exposure in mice after oral administration is several times that of GS6207, and the half-life (T) is significantly higher. 1 / 2 All of these compounds have a Th > 10h, indicating their potential for development into long-acting drugs; the Th of some of the compounds in the examples... 1 / 2 The value was higher than that of the positive control GS-6207.

[0425] Experimental Example 4: Pharmacokinetic Study in Beagle Dogs

[0426] This study investigated the pharmacokinetic behavior of the compound in dogs and evaluated its pharmacokinetic characteristics by measuring the plasma concentrations of the compound and the positive control GS-6207 at different time points after intravenous (IV) administration in Beagle dogs.

[0427] Test animals: Beagle dogs, 6-12 months old, weighing about 10 kg; 3 male animals were tested for each compound.

[0428] Experimental formulation: 5% ETOH + 20% PG + 45% PEG300 + 30% 10mM PB Buffer.

[0429] Administration method: Intravenous drip (IV), the dosage is 2 mg / kg, and food and water are not restricted before administration.

[0430] Sampling method: 50 μL of blood was collected from the jugular vein before administration and at 0.017, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 120 and 168 hours 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.

[0431] 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 at 4℃ (12000 rpm, 5 min), take 1 μL of supernatant from the plasma sample for LC-MS / MS analysis to determine the content of the analyte in the animal plasma, and perform pharmacokinetic analysis on the plasma concentration-time data. The pharmacokinetic parameters are shown in Table 3.

[0432] Table 3 Pharmacokinetic parameters of IV administration in Beagle dogs

[0433] Conclusion: The compound provided in this application, when administered intravenously, showed higher exposure levels (AUC0-t) in dogs than the positive control GS-6207, exhibiting lower in vivo clearance and a shorter half-life (T0) in dogs. 1 / 2 It has a relatively long duration and has the potential to be developed into a long-acting drug.

[0434] Experimental Example 5: Pharmacokinetic Study of Subcutaneous Administration in Rats

[0435] This experiment investigated the pharmacokinetic behavior of the compound in SD rats and evaluated its pharmacokinetic characteristics by measuring the plasma concentrations of the compound and the positive control GS-6207 at different time points after subcutaneous injection (SC) in SD rats.

[0436] Experimental animals: SD rats, 6-8 weeks old, weighing about 200g; 3 male animals were used for each compound test.

[0437] Experimental formulation: PEG / Water solution: 68.2% PEG 300 / 31.8% Water for Injection.

[0438] Administration: The dosage is 10 mg / kg. Food and water are not restricted before administration.

[0439] Sampling method: 50 μL of blood was collected from the jugular vein before administration and at 1 h, 4 h, 8 h, 24 h, 32 h, 48 h, 56 h, 72 h, 80 h, 96 h, D5, D7, D14, D19, D24, D35, D42, D49, and D56 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.

[0440] 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 4.

[0441] Table 4 Pharmacokinetic parameters of rat SC administration

[0442] Conclusion: Subcutaneous injection administration experiments in rats showed that the compound provided in this application has a long half-life and a high exposure level, indicating its potential to be developed into a long-acting clinical drug.

[0443] Experimental Example 6: Pharmacokinetic Study of Subcutaneous Administration in Beagle Dogs

[0444] This experiment investigated the pharmacokinetic behavior of the compound in dogs and evaluated its pharmacokinetic characteristics by measuring the plasma drug concentration at different time points after subcutaneous injection (SC) of the compound and the positive control GS-6207 in Beagle dogs.

[0445] Test animals: Beagle dogs, 6-12 months old, weighing about 10 kg; 3 male animals were tested for each compound.

[0446] Experimental formulation: 77:10:13 w / w / w [PEG200:Ethanol:Water].

[0447] Administration method: subcutaneous injection (SC), the dosage is 12 mg / kg, and food and water are not restricted before administration.

[0448] Sampling method: 50 μL of blood was collected from the jugular vein before administration and at 1 h, 4 h, 8 h, 24 h, 32 h, 48 h, 56 h, 72 h, 80 h, 96 h, D5, D7, D14, D19, D24, D35, D42, and D49 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.

[0449] 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 5.

[0450] Table 5. Pharmacokinetic parameters of SC administration in Beagle dogs (ng / mL)

[0451] Conclusion: Subcutaneous injection administration studies in beagle dogs demonstrate that the compound provided in this application has a long half-life and high exposure levels, indicating its potential for development into a long-acting clinical drug.

[0452] Experimental Example 7: Pharmacokinetic Study of Intramuscular Injection in Beagle Dogs

[0453] This experiment aimed to study the pharmacokinetic characteristics of the compound in Beagle dogs by measuring the plasma concentration of the compound at different time points after intramuscular injection (IM) in Beagle dogs.

[0454] Test animals: Beagle dogs, 6-12 months old, weighing about 8 kg; 3 male animals were tested for each compound.

[0455] Experimental formulation: PEG200 / ethanol / Water solution: 77% / 10% / 13%.

[0456] Administration: The dosage is 12 mg / kg or 150 mg / kg. Food and water are not restricted before administration.

[0457] Sampling method: 50 μL of blood was collected from the jugular vein before administration and at 1 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, D5, D7, D14, D21, D28, D35, D45, D55, D65, D75, D85, D95, D105, D110, and D135 after administration. All blood samples were placed in EDTA-K2 anticoagulant blood collection tubes, and the blood samples were centrifuged (4℃, 3500 rpm, 10 min) to obtain plasma samples for testing.

[0458] Detection: 10 μL of plasma was collected at each time point after drug administration, and 100 μL of methanol containing an internal standard (100 ng / mL) was added. The mixture was vortexed for 1 min and centrifuged (4℃, 12000 rpm, 5 min). 1 μL of the supernatant from the plasma sample was analyzed by LC-MS / MS to determine the content of the analyte compound in animal plasma after administration of different drug concentrations. Pharmacokinetic analysis was performed on the plasma concentration-time data. The pharmacokinetic parameters of Example 40 are shown in Table 6 and Figure 3.

[0459] Table 6. Pharmacokinetic parameters of IM administration in Beagle dogs (ng / mL)

[0460] Conclusion: Intramuscular injection administration studies in Beagle dogs showed that the systemic exposure of the compound provided in this application increased significantly with increasing dose in Beagle dogs, with a half-life (T0) of [missing value]. 1 / 2 The effect also increases with increasing dosage, giving it a clear advantage in being developed into a long-acting drug.

[0461] Experimental Example 8: Repeated-dose toxicity study in rats

[0462] Experimental Objective: In the toxicology experiment, SD rats were used as test animals. The compound of this application was subcutaneously injected once every 2 weeks for 6 consecutive weeks (4 times in total). After a 6-week recovery period, the nature, extent, dose-effect and time-effect relationship and reversibility of the toxic reactions that the compound of this application may cause were observed. The target organs or tissues of toxicity were identified. At the same time, its toxicokinetics were studied to understand the relationship between exposure dose and toxicological results, so as to provide reference information for clinical research.

[0463] Experimental animals: SPF-grade SD rats, 6-9 weeks old, males 200-370g and females 160-260g; 38 animals were tested for each compound, half male and half female.

[0464] Test formulation: Solvent for subcutaneous injection (SC): 77% PEG200 + 10% ethanol + 13% sterile aqueous solution for injection.

[0465] Administration method: The rats were administered subcutaneous injections at doses of 10, 30, and 100 mg / kg, once every 2 weeks for 6 consecutive weeks (4 times in total), that is, once on days 1, 15, 29, and 43 of the experiment, followed by a 6-week recovery period after drug withdrawal.

[0466] Observation and examination: Daily clinical observation of animals was conducted, and daily weight and food intake were recorded. Ophthalmological examinations were performed before the end of the administration period and the end of the recovery period. Samples were collected at the end of the administration period and the end of the recovery period for hematological, blood biochemistry, and urine tests. Gross dissection and histopathological examination of the animals were also performed. Bone marrow smears were prepared on the day of animal dissection. Blood samples were collected before the first and last administration and after administration for toxicokinetics.

[0467] Results: All rats in all groups tolerated the drugs administered in Examples 12 and 40 after four consecutive administrations, with no signs of near-death or death. Except for abnormal local irritation observed at the injection site during gross anatomy, no toxic changes related to the test substance were observed in body weight, food intake, urinalysis, hematology and coagulation, blood biochemistry, gross anatomy, or organ weight in any group of rats. Combined with clinical observation, body weight and food intake, hematology, blood biochemistry, urinalysis, bone marrow smears, and pathological tissue examination, no abnormalities were found, and no toxic target organs or tissues were identified.

[0468] Experimental Example 9: Repeated-dose toxicity study in Beagle dogs

[0469] Purpose of the experiment: In the toxicology study, Beagle dogs were used as test animals. The compound of this application was subcutaneously injected once every 2 weeks for 6 consecutive weeks (4 times in total), followed by a 6-week recovery period after drug withdrawal. The study aimed to observe the nature, extent, dose-effect and time-effect relationship and reversibility of the toxic reactions that the compound may cause, to identify the target organs or tissues of toxicity, and to study its toxicokinetics to understand the relationship between exposure dose and toxicological results, so as to provide reference information for clinical research.

[0470] Test animals: ordinary grade Beagle dogs, 6-7 months old, weighing 6-10 kg; 10 animals were tested for each compound, half male and half female.

[0471] Test formulation: Solvent for subcutaneous injection (SC): 77% PEG200 + 10% ethanol + 13% sterile aqueous solution for injection.

[0472] Administration: The subcutaneous injection doses for dogs were 10, 30, and 100 mg / kg, administered once every 2 weeks for 6 consecutive weeks (4 times in total), i.e., once on days 1, 15, 29, and 43 of the experiment, followed by a 6-week recovery period after drug withdrawal.

[0473] Observation and examination: Daily clinical observation of animals was conducted, and daily weight and food intake were recorded. Ophthalmological examinations were performed before the end of the administration period and the end of the recovery period. Samples were collected at the end of the administration period and the end of the recovery period for hematological, blood biochemistry, and urine tests. Gross dissection and histopathological examination of the animals were also performed. Bone marrow smears were prepared on the day of animal dissection. Blood samples were collected before the first and last administration and after administration for toxicokinetics.

[0474] Results: After four consecutive administrations in Examples 12 and 40, all dogs in the groups tolerated the medication well, and no near-death or death was observed. Except for local irritation observed at the injection site during gross anatomy, no toxic changes related to the test compound were found in body weight, food intake, urinalysis, hematology and coagulation, blood biochemistry, gross anatomy, or organ weight in any group of dogs. Combined with clinical observation, body weight and food intake, hematology, blood biochemistry, urinalysis, bone marrow smears, and pathological tissue examination, no abnormal results were found, and no toxic target organs or tissues were identified.

[0475] Conclusion: The compounds provided in this application have excellent safety in a variety of animals.

[0476] Experimental Example 10: Hepatic Microsomal Metabolic Stability

[0477] This study used liver microsomes from five species (CD-1 mice, SD rats, Beagle dogs, and human livers purchased from BioIVT, and cynomolgus monkeys purchased from RILD) to evaluate the in vitro metabolic stability of the compounds in this application.

[0478] Liver microsomes were mixed with an equal volume of promethazine working solution by pipetting and incubating in an ice-water bath for 15 minutes, and then dispensed into 96-well plates. Pre-cooled acetonitrile solution containing tolbutamide was added to the 0-minute wells of the experimental group, negative control group, and positive group. The drug administration solution (NADPH:UDPGA, 1:1), testosterone drug administration solution (NADPH), 7-hydroxycoumarin drug administration solution (UDPGA), and the compound solution of this application (1 μM) were added to the corresponding sample wells, and the plates were incubated at 37°C while being shaken at room temperature. Finally, pre-cooled internal standard solution (200 ng / mL tolbutamide) was added to each group at the corresponding time point after the reaction to terminate the reaction. After shaking and incubating at room temperature, the entire sample was extracted under positive pressure and analyzed by LC-MS / MS.

[0479] Experimental results: After incubation for 120 minutes in CD-1 mice, SD rats, Beagle dogs, cynomolgus monkeys, and human liver microsomes, the remaining percentage contents of Example 12 were 136.77%, 113.76%, 113.00%, 93.62%, and 108.08%, respectively, and were relatively stable after incubation in liver microsomes in vitro for 120 minutes.

[0480] Conclusion: The compounds provided in this application have good metabolic stability.

[0481] Experimental Example 11: CYP Inhibition Test

[0482] The purpose of this study was to investigate the in vitro inhibitory effects of the compound of this application on multiple isoenzymes of human liver microsomal cytochrome P450 (CYP), namely CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A, and to determine the IC50. 50 The value was used to assess its potential inhibitory effect.

[0483] Different concentrations (range 0.05-50 μM) of the test compound, human liver microsomes (purchased from Corning), and specific substrates of seven CYP enzymes—phenacetin (purchased from Dr.), bupropion hydrochloride (BP, purchased from TCI), amodiaquine (ADQ, purchased from TCI), diclofenac sodium (DCF, purchased from Sigma), S-metphenytoin (MPT, purchased from TRC), dextromethorphan hydrobromide (DM, purchased from the National Institutes for Food and Drug Control), and testosterone (TS, purchased from Aladdin)—were mixed and incubated at 37°C for 10 min. Then, 15 μL of NADPH working solution was added to initiate the reaction, followed by the addition of ice-cold acetonitrile solution containing the internal standard to terminate the reaction. After mixing, the mixture was filtered using a positive pressure extraction instrument, and the amount of each CYP enzyme-specific metabolite generated was analyzed by LC-MS / MS. The inhibition rate was calculated based on the decrease in metabolite generation, and a dose-response curve was fitted to determine the IC50 value.

[0484] Results: Example 12 showed that seven CYP enzymes were IC 50 Values ​​greater than 50 μM did not show significant inhibitory effects. At the highest concentration (50 μM), the remaining enzyme activities were 99.2%, 105.7%, 84.9%, 77.1%, 104.6%, 84.0%, and 81.9%, respectively.

[0485] Conclusion: The compounds provided in this application exhibit good liver microsomal stability against all seven CYP enzymes, suggesting that they possess good metabolic stability in the liver.

[0486] Experimental Example 12: Plasma Protein Binding Assay

[0487] The plasma protein binding rates of the compounds described in this application in rat, beagle dog, and human plasma were determined using an equilibrium dialysis method. First, the plasma was treated and the dialysis membrane was pretreated. Then, the test compounds were added to the plasma (concentrations of 50, 50, and 5000 ng / mL), and placed on one side of the dialysis apparatus (donor side). The other side (recipient side) contained a buffer solution (an aqueous solution containing 100 mM sodium phosphate and 150 mM sodium chloride, pH 7.4 ± 0.1). The apparatus was incubated at 37°C for 4 hours to allow free drug to pass through the membrane and reach equilibrium. After incubation, 50 μL of each well was aspirated, and 450 μL of a 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 corresponding species-specific blank plasma was added. The mixtures were homogenized, filtered under positive pressure, and the results were analyzed by LC-MS / MS to calculate the binding percentage.

[0488] Results: At all concentrations, the protein binding rates of Examples 12 and 40 to human, SD rat, and Beagle dog plasma were all >95%.

[0489] Conclusion: The compounds provided in this application exhibit high plasma protein binding, and no species differences or concentration dependence were observed.

[0490] Experimental Example 13: hERG Test

[0491] This experiment used a manual patch-clamp system with hERG(Kv11.1)-HEK293 cells as the experimental system. A positive control group (0.1 μM Cisapride) and the compound group of this application (concentrations of 0.3 μM, 1 μM, 3 μM, and 10 μM, respectively) were set up. The effect of each drug-treated formulation on hERG current in hERG-HEK293 cells was detected using the manual patch-clamp system. The inhibition rate of the compound of this application on hERG current at each concentration was calculated, and the IC50 was fitted by the concentration-mean inhibition rate.

[0492] Results: Examples 12 and 40 showed an average inhibition rate of less than 50% of hERG current at the highest concentration of 10 μM, and an IC50 of greater than 10 μM for the inhibition of hERG current.

[0493] Conclusion: No potential risk to cardiac safety was found in the compounds provided in this application.

[0494] Experimental Example 14: In vitro safety screening

[0495] The potential activation and inhibition effects of the compounds in this application on 95 targets (14 ion channels, 45 G protein-coupled receptors, 3 transporters, 16 kinases, 14 enzymes, and 3 nuclear receptors) were evaluated using a high-throughput real-time fluorescence detection and analysis system. 10 μL of reaction buffer and 60 nmL of the compound in this application were added to cell culture plates containing the corresponding cell line (CHO cell line / HEK293 cells). 10 μL of 2× dye was added to each well of the cell culture plate, which was then shaken and incubated sequentially at 37°C for 2 hours and 25°C for 15 minutes. A reference agonist or inhibitor was added to the cell culture plate, and the readings were taken using the high-throughput real-time fluorescence detection and analysis system. Finally, the IC50 of the reference compound was calculated using XLfit software based on the percentage inhibition and concentration of the compound.

[0496] Results: When the percentage activation or inhibition rate of the test compound at any target site is greater than 50% at a test concentration of 10 μM, the test compound is considered to have potential off-target activity for that target site. In this experiment, Examples 12 and 40 showed no significant off-target activity on any of the 95 targets selected in this screening.

[0497] Conclusion: No potential off-target effects were observed in the compounds provided in this application.

[0498] Experimental Example 15: In vivo prophylactic efficacy test in humanized mice

[0499] 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.

[0500] 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.

[0501] Conclusion: The compound provided in this application has a significant effect on preventing HIV infection in animals.

[0502] Experimental Example 16: In vivo therapeutic efficacy trial in humanized mice

[0503] 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".

[0504] Conclusion: The compound provided in this application has a significant therapeutic effect on HIV infection in animals.

[0505] 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.

[0506] The preferred 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.

[0507] 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 selected from the compound of formula (I), its tautomers, its meso compound, its racemic compound, its enantiomers, its diastereomers, its transisomers, or a pharmaceutically acceptable salt thereof. in, Each R1 is independently selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be selected by 1-3 R1 groups. a replace; Each R2 is independently selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be selected by 1-3 R2 groups. a replace; R3 is selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be surrounded by 1-3 R3 groups. a replace; R4 is selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, halogen, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be surrounded by 1-3 R4 groups. a replace; R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, or 3-10 membered cycloalkyl; the alkyl or 3-10 membered cycloalkyl may optionally be surrounded by 1-3 R... a replace; R7 and R8 are each independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, or 3-10 membered cycloalkyl; the aforementioned alkyl groups and 3-10 membered cycloalkyl groups may be distinguished by 1-3 R groups. a replace; R8' is selected from C1-C6 alkyl or deuterated C1-C6 alkyl; R9 is selected from hydrogen, C1-C6 alkyl, or 3-10 membered cycloalkyl; the alkyl or 3-10 membered cycloalkyl may be surrounded by 1-3 Rs. a replace; R 10 Selected from hydrogen, deuterium, C1-C6 alkyl, and deuterated C1-C6 alkyl; R 11 R 12 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, and deuterated C1-C6 alkyl; R 13 R 14 R 15 R 16 R 17 R 18 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, or deuterated C1-C6 alkyl; Each R a Each alkyl group is independently selected from hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, or 3-10 membered cycloalkyl; the alkyl group or 3-10 membered cycloalkyl group may optionally be surrounded by 1-3 R groups. c replace; 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; Each n is independently selected from 0, 1, 2 or 3; Each k is independently selected from 0, 1, 2, 3, 4 or 5; Furthermore, the compound shown in formula (I) satisfies any one or at least a combination of two of the following conditions: (1) Structure yes (2) R3 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens; (3) R7 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens; (4) R8 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens; (5)R 10 Selected from deuterium or deuterated C1-C6 alkyl groups; (6)R 11 R 12 Each is independently selected from deuterium, halogen, or deuterated C1-C6 alkyl groups; (7)R 13 R 14 Each is independently selected from deuterium or deuterated C1-C6 alkyl groups; (8) R2 is fluorine.

2. The amide compound according to claim 1, wherein, The compound shown in formula (I) satisfies any one or at least a combination of two of the following conditions: (1) Structure yes (2) R3 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens; (3) R7 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens; (4) R8 is selected from deuterated C1-C6 alkyl groups, wherein the alkyl group may optionally be substituted with 1-3 halogens; (5)R 10 Selected from deuterium or deuterated C1-C6 alkyl groups; (6)R 11 R 12 Each is independently selected from deuterium, halogen, or deuterated C1-C6 alkyl groups; Preferably, in condition (2), R3 is selected from -CD2CF3 or -CD2CD3; Preferably, in condition (3), R7 is selected from deuterated methyl or deuterated ethyl; Preferably, in condition (4), R8 is selected from deuterated methyl or deuterated ethyl; Preferably, in condition (5), R 10 It is deuterium; Preferably, in condition (6), R 11 R 12 All are deuterium.

3. The amide compound according to claim 1, wherein, In equation (I), each R1 is independently selected from hydrogen or fluorine; Preferably, each R2 in formula (I) is independently selected from hydrogen, chlorine or fluorine.

4. The amide compound according to claim 1, wherein, In formula (I), R3 is selected from -CH2CF3 and -CH2CHF2; Preferably, R4 in formula (I) is selected from -CF3 or -CHF2; Preferably, in formula (I), R5 is hydrogen and R6 is hydrogen.

5. The amide compound according to claim 1, wherein, In formula (I), R7 is selected from hydrogen, methyl, and ethyl; Preferably, in formula (I), R8 is selected from hydrogen, methyl, or ethyl; Preferably, R9 in formula (I) is selected from methyl or cyclopropyl.

6. The amide compound according to claim 1, wherein, In formula (I) R 10 It is hydrogen; Preferably, R in formula (I) 11 It is hydrogen; Preferably, R in formula (I) 12 It is hydrogen; Preferably, R in formula (I) 13 For hydrogen, R 14 It is hydrogen; Preferably, R in formula (I) 15 For hydrogen, R 16 For hydrogen, R 17 For hydrogen, R 18 It is hydrogen.

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

8. The amide compound according to claim 7, wherein, The compound shown in formula (I) is selected from any of the following structures:

9. The amide compound according to claim 8, wherein, The compound shown in formula (I) is selected from any of the following structures:

10. A pharmaceutical composition comprising the amide compound of any one of claims 1-9, and a pharmaceutically acceptable carrier and / or excipient.

11. Use of the amide compound of any one of claims 1-9 or the pharmaceutical composition of claim 10 in the preparation of HIV capsid protein inhibitors.

12. Use of the amide compound of any one of claims 1-9 or the pharmaceutical composition of claim 10 in the preparation of a medicament for the prevention and / or treatment of viral infectious diseases.

13. The use according to claim 12, wherein, The viral infection mentioned is HIV infection; Preferably, 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.

14. A method of inhibiting HIV capsid proteins, comprising administering to a desired patient an inhibitory dose of any of the amide compounds of claims 1-9 or the pharmaceutical composition of claim 10.

15. A method of preventing and / or treating a viral infectious disease, comprising administering to a desired patient a preventive and / or therapeutically effective dose of the amide compound of any one of claims 1-9 or the pharmaceutical composition of claim 10; Preferably, the viral infection is HIV infection.

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