Bicyclic il-17a / f inhibitor, and preparation method therefor and use thereof

Abstract

The present application relates to the technical field of chemical drugs, provides a bicyclic IL-17A / F inhibitor compound, and a preparation method therefor and a use thereof, and specifically relates to a compound represented by general formula (I), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a use thereof as an IL-17A / F inhibitor for treating diseases such as psoriasis and arthritis.

Description

Bicyclic IL-17A / F Inhibitors, Their Preparation Methods and Applications Technical Field

[0001] This invention belongs to the field of chemical drug technology and relates to a class of bicyclic IL-17A / F small molecule inhibitors, specifically to an interleukin-17A / F inhibitor and its preparation method and application. Background Technology

[0002] The IL-17 family comprises six cytokines (IL-17A to IL-17F). Interleukin-17A (IL-17A) is a known pro-inflammatory cytokine involved in the induction of IL-6, IL-8, G-CSF, TNF-α, IL-1P, PGE2, and IFN-γ, as well as numerous chemokines and other effectors. IL-17A can form homodimers or heterodimers with its family member IL-17F and can bind to IL-17 receptors IL-17RA and IL-17RC to mediate signal transduction. IL-17A is a major pathological cytokine expressed by Th17 cells, participating in the pathology of inflammation and autoimmune diseases, and also involved in the activity of CD8+ T cells, Y6 cells, NK cells, NKT cells, macrophages, and dendritic cells. IL-17A is a recognized pro-inflammatory cytokine that plays a crucial role in chronic inflammation and is a major driver of tissue damage. IL-17A induces normal immune and inflammatory responses to pathogens, but it can also contribute to chronic autoimmune diseases, including psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis.

[0003] Although many patents for small molecule IL-17A inhibitors have been published, such as patent publication numbers WO2020182666, WO2023283453, WO2023275301, and WO2023025783, there are currently no effective oral treatments for moderate to severe psoriasis. Therefore, there is a need to develop effective small molecule IL-17A inhibitors to treat inflammatory diseases and other conditions. Summary of the Invention

[0004] In view of the problems existing in the prior art, this application provides a bicyclic IL-17A / F inhibitor, its preparation method and application. As an IL-17A / F inhibitor, this compound can inhibit the production of cytokine IL-17A / F, thereby regulating inflammatory responses and related diseases.

[0005] In a first aspect, this application provides a compound of general formula (I), or a racemic mixture thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0006] In a second aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0007] Thirdly, the present invention also provides the use of a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition, said condition being an IL-17A / F-related disease, specifically selected from psoriasis and arthritis.

[0008] Specifically, the present invention is achieved through the following technical solution:

[0009] In a first aspect, the present invention provides a compound of formula (I) or a racemic mixture thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0010] Among them, m1, m2, and m3 are individually selected from 0, 1, or 2;

[0011] n is 0, 1, 2, 3 or 4;

[0012] X is selected from O, N, and S. When X is selected from O and S, R 7 It does not exist;

[0013] Ring A is selected from R 1 Substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said R 1 Selected from alkyl, alkoxy, halogen, cycloalkyl, haloalkyl, haloalkoxy, halocycloalkyl, -O-cycloalkyl;

[0014] R 2 Selected from substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH(R) 2a (R) 2b The substituent is selected from alkyl, alkoxy, and halogen groups, and the R group is selected from alkyl, alkoxy, and halogen groups. 2a and R 2b Independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups;

[0015] R 3 Selected from hydrogen, halogen, alkyl, and alkoxy groups;

[0016] R 4 Selected from hydrogen, halogen, alkyl, alkoxy, and cycloalkyl;

[0017] Z is selected from

[0018] R Z1 R Z2It is selected alone from alkyl, alkenyl, alkynyl, nitrile, alkylnitrile, halogen, haloalkyl, haloalkenyl, -NT1T2, or substituted or unsubstituted -(CH2). c -N T1T2, or substituted or unsubstituted -(CH2). f -cycloalkyl, -(CH2) k -O-alkyl, -(CH2) t -O-cycloalkyl, -CT3T4-O-alkyl, alkyl heterocycloalkyl, haloheterocycloalkyl, or substituted or unsubstituted aryl, heteroaryl, or substituted or unsubstituted cycloalkyl, heterocycloalkyl, wherein the substitution is selected from alkyl, alkoxy, halogen, cycloalkyl, wherein T1, T2, T3, T4 are individually selected from hydrogen, halogen, nitrile, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, or T3 and T4 together cyclized into substituted or unsubstituted cycloalkyl, heterocycloalkyl, wherein the substitution is selected from alkyl, halogen, alkoxy, haloalkyl, wherein c, f, k, t are selected from 1, 2, 3, 4, 5 or 6;

[0019] R 5 and R 6 Together they cyclize into substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, wherein the substitution is selected from alkyl, alkoxy, halogen, haloalkyl, or cycloalkyl groups, and at least one substitution is performed.

[0020] R 7 Selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, and cycloalkyl;

[0021] Among them, when R 1 The replaced A ring is selected from R 2 Selected from R 5 and R 6 When they cyclize together to form a cyclopropyl group, R Z1 Not for

[0022] As a preferred embodiment of the present invention, when m1 and m2 are 0, m3 is 2, R 5 and R 6 When cyclized together into a cycloalkyl group, the structure is selected from that shown in formula (II). Where p is selected from 0, 1, 2, 3 or 4, n, A ring, R 2 R 3 R 4 R 7 X and Z are as defined above.

[0023] When p is 0, a cyclopropyl group is formed. For example, when p is 0, Selected from

[0024] As a preferred embodiment of the present invention, when m1 and m2 are 0, m3 is 2, and n is 1, R 5 and R 6 Together they cyclize to form cyclopropyl, R 3 Selected from fluorine, R 4 When selected from methyl, it is selected from the structure shown in formula (III).

[0025] Among them, ring A and ring R 2 R 7 Z is as defined above.

[0026] As a preferred embodiment of the present invention, when m1 and m2 are 0, m3 is 2, and n is 1, R 5 and R 6 Together they cyclize into a cyclopropyl group, R 2 Selected from -CH(R) 2a (R) 2b ), and R 2a R 2b Together they cyclize to form cyclopropyl, R 3 Selected from fluorine, R 4 When selected from methyl, it is selected from the structure shown in formula (IV).

[0027] Among them, ring A and ring R 7 Z is as defined above.

[0028] As a preferred embodiment of the present invention, the alkyl group is selected from C. 1-6 alkyl group, the C 1-6 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0029] The alkenyl group is selected from C. 2-6 alkenyl, C 2-6The alkenyl group is selected from vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl 3-Methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl 2-Methyl-3-pentenyl, 3-Methyl-3-pentenyl, 4-Methyl-3-pentenyl, 1-Methyl-4-pentenyl, 2-Methyl-4-pentenyl, 3-Methyl-4-pentenyl, 4-Methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl alkenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;

[0030] The alkoxy group is selected from C. 1-6 Alkoxy, the C 1-6The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy.

[0031] The alkynyl group is selected from C. 2-6 The alkynyl group, the C 2-6 The alkynyl group is selected from ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, and 3-hexynyl.

[0032] The alkyl nitrile is selected from acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valerate, isovaleritrile, and hexanonitrile;

[0033] The aryl group is selected from five-membered or six-membered aryl groups; the heteroaryl group refers to an aryl group in which at least one carbon atom is replaced by a heteroatom.

[0034] The heteroaryl group is selected from 5-membered or 6-membered heteroaryl groups.

[0035] As a preferred embodiment of the present invention, the cycloalkyl group is selected from C 3-12 The cycloalkyl group, preferably, is selected from C10. 3-8 cycloalkyl, C 3-8 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and spirocycloalkyl, wherein the spirocycloalkyl group refers to two rings sharing a carbon atom; the heterocycloalkyl group refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom; and the alkyl heterocycloalkyl group refers to a heterocycloalkyl group in which at least one hydrogen atom is replaced by an alkyl group.

[0036] Spirocycloalkyl groups include, but are not limited to:

[0037] As a preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine; halogenated alkyl means that at least one hydrogen atom on an alkyl group is replaced by a halogen; halogenated heterocyclic alkyl means that at least one hydrogen atom on a heterocyclic alkyl group is replaced by a halogen; halogenated cycloalkyl means that at least one hydrogen atom on a cycloalkyl group is replaced by a halogen; halogenated alkoxy means that at least one hydrogen atom on an alkoxy group is replaced by a halogen; halogenated alkenyl means that at least one hydrogen atom on an alkenyl group is replaced by a halogen.

[0038] As a preferred embodiment of the present invention, the heteroatom is selected from nitrogen, oxygen, and sulfur, and there are one or more heteroatoms.

[0039] Specifically, the heterocyclic alkyl group is selected from...

[0040] In a preferred embodiment of the present invention, m1 and m2 are 0, m3 is 2, n is 0, 1 or 2, and c, f, k, and t are 1;

[0041] When X is O or N, and X is selected from O, R 7 It does not exist;

[0042] The A ring is selected from: The R 1 The replaced A ring is selected from

[0043] R 2 Selected from cyclohexyl, cycloheptyl,

[0044] R 3 Selected from fluorine;

[0045] R 4 Selected from methyl;

[0046] Z is selected from

[0047] R Z1 Selected from ethyl,

[0048] R Z2 Selected from ethyl and cyclopropyl;

[0049] R 5 and R 6 They cyclize together to form cyclopropyl and cyclobutyl groups;

[0050] R 7 It can be hydrogen, methyl, or ethyl.

[0051] As a preferred embodiment of the present invention, the compound, or its racemate, its isomer, or its pharmaceutically acceptable salt, is selected from the compound represented by formula (Ia), or its racemate, its isomer, or its pharmaceutically acceptable salt:

[0052] Where n is 1, R 2 Selected from cyclohexyl, cycloheptyl, m1, m2, m3, Z, ring A, R 3 R 4 X, R 5 R 6 R 7 As defined above.

[0053] As a preferred technical solution of the present invention, in formula (I) Selected from Further selection R 7 As defined above, when X is selected from O, R 7 It does not exist.

[0054] As a preferred embodiment of the present invention, the compound, or its racemate, its isomer, or its pharmaceutically acceptable salt, is selected from the compound represented by formula (IIa), or its racemate, its isomer, or its pharmaceutically acceptable salt:

[0055] Among them, R 2 Selected from cyclohexyl, cycloheptyl, p is selected from 0, 1, 2, 3, or 4, A ring, Z, R 3 R 4 X, R 7 As defined above.

[0056] When p is 0, a cyclopropyl group is formed. For example, when p is 0, Selected from

[0057] As a preferred embodiment of the present invention, the compound, or its racemate, its isomer, or its pharmaceutically acceptable salt, is selected from the compound represented by formula (IIIa), or its racemate, its isomer, or its pharmaceutically acceptable salt:

[0058] Among them, R 2 Selected from cyclohexyl, cycloheptyl, A ring, Z, R 7 As defined above.

[0059] As a preferred embodiment of the present invention, the compound, or its racemate, its isomer, or its pharmaceutically acceptable salt, is selected from the compound represented by formula (IVa), or its racemate, its isomer, or its pharmaceutically acceptable salt:

[0060] A ring, Z, R 7 As defined above.

[0061] As a preferred embodiment of the present invention, the compound, or its racemate, its isomer, or its pharmaceutically usable salt is selected from the structures shown in Table 1.

[0062] As a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to a compound, or its isomer, or its racemate, prepared with a pharmaceutically acceptable acid or base.

[0063] As a preferred embodiment of the present invention, at least one hydrogen atom of the compound, or its isomer, racemate, or pharmaceutically usable salt thereof, is replaced by the isotope deuterium.

[0064] As a preferred embodiment of the present invention, the deuterated compound is selected from the structures shown in Table 2.

[0065] In a second aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the preceding compounds, or a racemic mixture thereof, an isomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

[0066] Thirdly, the present invention also provides the use of the compound, or its racemate, its isomer, its pharmaceutically usable salt, or the above-described pharmaceutical composition, in the preparation of a medicament for treating a disease, wherein the disease is an IL-17A / F-related disease, specifically selected from diseases such as psoriasis and arthritis.

[0067] For clarity, this article defines the general terminology used in the description of compounds.

[0068] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein 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 undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0069] The term "medicinal salt" refers to a salt of the compounds of the present invention, prepared by combining a compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0070] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0071] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0072] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including 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 invention. 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 invention.

[0073] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, transisomers, etc., can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, 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).

[0074] The atoms in the compounds of this invention are isotopes. Isotope derivatization can typically prolong half-life, reduce clearance rate, stabilize metabolism, and enhance in vivo activity. Furthermore, one embodiment is included, wherein at least one atom is replaced by an atom having the same number of atoms (protons) but different mass numbers (protons and neutrons). Examples of isotopes included in the compounds of this invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising... 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F,36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomical examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with quantity and are not radioactive, therefore they can be used safely. When the atoms constituting the compounds of this invention are isotopes, the isotopes can be converted according to common methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0075] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0076] Furthermore, one or more hydrogen atoms in the compound of the present invention are coated with the isotope deuterium ( 2 The compounds of this invention, after being substituted with H), have the effects of prolonged half-life, reduced clearance rate, metabolic stabilization, and increased in vivo activity.

[0077] The preparation methods of the isotope derivatives typically include phase-transfer catalysis. For example, a preferred deuteration method employs a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Using a phase-transfer catalyst to exchange the methylene protons of a diphenylmethane compound results in the introduction of higher levels of deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with Lewis acids such as aluminum trichloride using sodium deuterated borate.

[0078] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0079] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0080] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0081] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0082] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0083] Indicates a connection key.

[0084] The compounds of the present invention 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 the present invention. Attached Figure Description

[0085] Figure 1 is a schematic diagram of the single crystal structure of compound 12B of the present invention.

[0086] Figure 2 is a graph showing the change in ear thickness corresponding to compound N of the present invention.

[0087] Figure 3 shows the efficacy curve of compound N in arthritis rats. Detailed Implementation

[0088] The present application will be described in further detail below with reference to the embodiments, but the implementation of the present application is not limited thereto.

[0089] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (R shifts) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-III NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d₆) and deuterated chloroform (CDCl₃) as the solvents and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).

[0090] High-performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD system. The CombiFlash rapid preparation system used a CombiFlash Rf+LUMEN (TELEDYNE ISCO) instrument. Thin-layer chromatography (TLC) used Yantai Yinlong HSGF254 or GF254 silica gel plates. The silica gel plates used for TLC had a diameter of 0.17 mm to 0.23 mm, while the plates used for TLC separation and purification had a diameter of 0.4 mm to 0.5 mm. Silica gel column chromatography generally used Rushan Shangbang 100-200 mesh silica gel as the carrier.

[0091] Synthetic route of this invention:

[0092] Synthesis Route 1:

[0093] Synthesis Route 2:

[0094] Synthesis Route 3:

[0095] Among them, R 2 As defined above, the X and A rings can be synthesized by referring to patent document CN202080079537.5 for detailed steps.

[0096] Intermediate 1

[0097] The synthetic route for intermediate 1 is as follows:

[0098] Step A: (2R,3S)-2-((tert-Butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)benzyl butyrate

[0099] At room temperature, ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyric acid (10 g, 29.2 mmol) was dissolved in DMF (5 mL), and benzyl bromide (5.5 g, 32.12 mmol) and sodium bicarbonate (4.9 g, 58.4 mmol) were added, and the mixture was stirred overnight at room temperature.

[0100] Post-treatment: Add saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to give a yellow oily liquid (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyrate (12.6 g, yield 99%). LC-MS: [M+H] + =433.

[0101] Step B: (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)butyrate benzyl ester

[0102] At room temperature, (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyrate benzyl ester (12.6 g, 29.2 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (33 g, 292 mmol) was added. The mixture was stirred at room temperature for 1 hour.

[0103] Post-treatment: Concentrate the residue, adjust the pH to alkaline with saturated sodium bicarbonate solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and give a yellow oily liquid (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)butyrate (9.6 g, yield 97%). LC-MS: [M+H] + =333.

[0104] Step C: (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-fluoro-4-nitrophenyl)benzyl butyrate

[0105] At room temperature, (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)butyrate benzyl ester (8.6 g, 25.9 mmol) was dissolved in 1,4-dioxane (100 mL) and water (25 mL), and Fmoc-Cl (10.04 g, 38.8 mmol) and sodium bicarbonate (17.4 g, 207 mmol) were added, and the mixture was stirred overnight at room temperature.

[0106] Post-treatment: Dilute with aqueous solution (150 mL), extract with ethyl acetate (200 mL × 3), combine organic phases, wash with saturated brine (100 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and purify by silica gel column chromatography to obtain ((2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyrate (14.3 g, yield 99%). LC-MS: [M+H]+ =555.

[0107] Step D: (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-amino-3-fluorophenyl)benzyl butyrate

[0108] At room temperature, (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyrate benzyl ester (12.3 g, 22.2 mmol) was dissolved in ethanol (100 mL) and water (25 mL), iron powder (6.19 g, 110.9 mmol) and ammonium chloride (5.93 g, 110.9 mmol) were added, and the mixture was heated to 80°C and reacted for 1 hour.

[0109] Post-treatment: The mixture was filtered through diatomaceous earth, concentrated, and the residue was added to a saturated aqueous sodium bicarbonate solution (100 mL). Extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a yellow oily liquid: (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-amino-3-fluorophenyl)butyrate benzyl ester (11.6 g, 97% yield). LC-MS: [M+H] + =525.

[0110] Step E: (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-2-(tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropamido)-3-fluorophenyl)benzyl butyrate

[0111] At room temperature, (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-amino-3-fluorophenyl)butyrate benzyl ester (5 g, 9.53 mmol) was dissolved in pyridine (30 mL), and (2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dicyclopropylpropionic acid (3.85 g, 14.29 mmol) and EDCI (5.48 g, 28.59 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0112] Post-treatment: Concentrate the residue, add saturated sodium bicarbonate aqueous solution (100 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate to dryness, to give (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-2-(tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropamido)-3-fluorophenyl)benzyl butyrate (7.4 g, yield 98%). LC-MS: [M+H] + =776.

[0113] Step F: (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(((S)-2-amino-3-dicyclopropylpropamido)-3-fluorophenyl)benzyl butyrate

[0114] At room temperature, (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-2-(tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropamido)-3-fluorophenyl)benzyl butyrate (5 g, 6.44 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (11.1 g, 96.6 mmol) was added. The mixture was stirred at room temperature for 1 hour.

[0115] Post-treatment: Concentrate, adjust pH to alkaline by adding saturated sodium bicarbonate aqueous solution to the residue, extract with ethyl acetate (50 mL × 3), combine organic phases, wash with saturated brine (50 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness to give a yellow oily liquid (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(((S)-2-amino-3-dicyclopropylpropionamido)-3-fluorophenyl)benzyl butyrate (4.3 g, yield 99%). LC-MS: [M+H] + =676.

[0116] Step G: (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)benzyl butyrate

[0117] At room temperature, (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(((S)-2-amino-3-dicyclopropylpropamido)-3-fluorophenyl)benzyl butyrate (4.3 g, 6.36 mmol) was dissolved in pyridine (40 mL), 1-ethyl-1H-pyrazole-5-carboxylic acid (1.34 g, 9.54 mmol) and EDCI (2.5 g, 13.11 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0118] Post-treatment: Add saturated sodium bicarbonate aqueous solution (100 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate to dryness, and purify by silica gel column chromatography to obtain (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)benzyl butyrate (5 g, yield 99%). LC-MS: [M+H] + =798.

[0119] Step H: (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)butyric acid

[0120] At room temperature, benzyl butyrate (5 g, 6.27 mmol) was dissolved in ethyl acetate (50 mL), and palladium on carbon (0.67 g, 6.27 mmol) was added. The mixture was stirred overnight at 50°C.

[0121] Post-treatment: Diatomaceous earth filtration, concentration, yielding ((2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)butyric acid (1.8 g, yield 41%). LC-MS: [M+H] + =708.

[0122] Step I: (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazol-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate

[0123] At room temperature, (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)butyric acid (910 mg, 1.29 mmol) was dissolved in N,N-dimethylformamide (6 mL), and (S)-1,2-dimethylpiperazine (173 mg, 1.55 mmol), N,N-diisopropylethylamine (1.28 mL, 7.74 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1000 mg, 2.58 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0124] Post-treatment: Add saturated sodium bicarbonate aqueous solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and give (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazol-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (1031 mg, yield 99%). LC-MS: [M+H] + =802.

[0125] Step J: N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0126] At room temperature, (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (1035 mg, 1.29 mmol) was dissolved in DMF (5 mL), and tetrahydropiperidine (930 mg, 10.92 mmol) was added. The mixture was stirred at room temperature for 1 hour.

[0127] Post-treatment: Add saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 1), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and purify by silica gel column chromatography to obtain N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (748 mg, yield 72%). LC-MS: [M+H] + =580.

[0128] Examples 2A and 2B

[0129] Synthesized N-((S)-1,1-bicyclopropyl-3-((2-fluoro-4-((2S,3R)-4-((1S,6R)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide and N-((S)-1,1-bicyclopropyl-3-((2-fluoro-4-((2S,3R)-4-((1R,6S)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0130] The specific synthesis route is as follows:

[0131] Step A: At room temperature, intermediate 1N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (250 mg, 0.43 mmol) and triethylamine (130.54 mg, 1.29 mmol) were dissolved in dichloromethane (5 mL), and then propionic anhydride (83.94 mg, 0.65 mmol) was added. The mixture was reacted at room temperature for 1 h.

[0132] After the reaction was complete, dilute with dichloromethane (50 mL). Wash the mixture with saturated brine (3 x 20 mL), dry with anhydrous Na₂SO₄, filter, and rotary evaporate to the residue. Purify the residue by silica gel column chromatography (eluent: dichloromethane / methanol = 94 / 6, V / V) to obtain a racemic mixture. Then, send the mixture to a chiral column (Chiral column: CHIRALPAK IG-3 3 μm x 4.6 mm x 150 mm; mobile phase: n-hexane / ethanol = 80:20; flow rate 1.0 mL / min). Peak 1 (106 mg, RT: 15.117 min) and Peak 2 (110 mg, RT: 19.674 min) were obtained. LC-MS: [M+H] + =636.

[0133] Examples 12A and 12B

[0134] The specific synthesis route is as follows:

[0135] Step A: Synthesis of N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(S)-2-methoxypropamido)-4-((1S,6R)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-ethyl-1H-pyrazole-5- Formamide and N-((S)-1,1-bicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(S)-2-methoxypropamido)-4-((1R,6S)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0136] At room temperature, intermediates 1N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (300 mg, 0.52 mmol), (2S)-2-methoxypropionic acid (81.20 mg, 0.78 mmol), and N,N-diisopropylethylamine (201.61 mg, 1.56 mmol, 100% purity) were dissolved in DMF (5 mL), and HATU (296.58 mg, 0.78 mmol, 100% purity) was added. The mixture was reacted at room temperature for 1 h.

[0137] After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (3 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and rotary evaporated to the residue. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 94 / 6, V / V) to obtain a racemic mixture. This mixture was then sent to a chiral column (chiral column: CHIRALPAK IG-3 3 μm x 4.6 mm x 150 mm; mobile phase: n-hexane / ethanol = 80:20; flow rate 1.0 mL / min). The resulting peaks were 12A: 77 mg (RT: 23.771 min, purity: 99%) and 12B: 80 mg (RT: 35.124 min, purity: 95%). LC-MS: [M+H] + =666.

[0138] Compound 12A: 1HNMR (Chloroform-d, 400 MHz) δ 8.2 - 8.3 (m, 1H), 8.11 (br d, 1H, J = 2.4 Hz), 7.51 (d, 1H, J = 2.0 Hz), 7.1 - 7.2 (m, 3H), 6.62 (d, 1H, J = 2.1 Hz), 5.37 (t, 1H, J = 9.6 Hz), 4.87 (br dd, 1H, J = 4.4, 8.0 Hz), 4.61 (dq, 2H, J = 2.2, 7.1 Hz), 4.0 - 4.1 (m, 1H), 3.81 (q, 1H, J = 6.7 Hz), 3.4 - 3.5 (m, 3H), 3.2 - 3.3 (m, 1H), 2.8 - 2.9 (m, 1H), 2.4 - 2.7 (m, 2H), 2.3 - 2.4 (m, 3H), 2.2 - 2.3 (m, 2H), 2.0 - 2.1 (m, 1H), 1.4 - 1.5 (m, 3H), 1.3 - 1.4 (m, 6H), 0.8 - 1.0 (m, 3H), 0.7 - 0.8 (m, 1H), 0.68 (br dd, 1H, J = 4.6, 8.0 Hz), 0.5 - 0.6 (m, 4H), 0.3 - 0.5 (m, 2H), 0.26 (br t, 2H, J = 5.4 Hz). Or

[0139] Compound 12B: 1 HNMR (Chloroform-d, 400 MHz) δ 8.15 (br t, 1H, J = 8.3 Hz), 8.09 (br s, 1H), 7.49 (d, 1H, J = 2.0 Hz), 7.0 - 7.2 (m, 4H), 6.60 (d, 1H, J = 2.0 Hz), 5.24 (t, 1H, J = 9.9 Hz), 4.86 (br dd, 1H, J = 4.9, 8.0 Hz), 4.5 - 4.7 (m, 2H), 3.7 - 3.9 (m, 2H), 3.42 (s, 3H), 3.36 (br dd, 1H, J = 7.3, 9.6 Hz), 3.10 (dt, 1H, J = 4.3, 7. Thz), 2.7 - 2.8 (m, 1H), 2.5 - 2. [m, 1H), 2.4 - 2.5 (m, 1H), 2.28 (s, 2H), 1.71 (dt, 1H, J = 2.4, 1.[Hz), 1.4 - 1.5 (m, 3H), 1.35 (t, 7H, J = 6.6 Hz), 0.8 - 0.9 (m, 4H), 0.6 - 0.7 (m, 1H), 0.5 - 0.6 (m, 4H), 0.37 (td, 2H, J = 4.5, 10.3 Hz), 0.23 (br s, 2H).

[0140] Compound 12B (compound N) was dissolved in isopropanol (15 mL) and MTBE (150 mL), then heated to 50 °C. After complete dissolution, the mixture was slowly cooled to room temperature and stirred overnight. The mixture was then filtered and washed with MTBE to obtain compound 12B.

[0141] The crystal form testing conditions are as follows:

[0142] (1) Experimental equipment: Transmission electron microscope: Thermo Scientific Glacios, detector: Thermo Scientific Ceta-D, sample rod: Autoloader.

[0143] (2) Experimental conditions: Voltage: 200kV, Temperature: 83K, Vacuum value: 10-7Pa high vacuum.

[0144] (3) Software: Data collection: Thermo Scientific EPU-D, Data processing: XDS, SHELXT, SHELXL.

[0145] (4) Sample preparation

[0146] A small amount of compound 12B was directly transferred to a TEM grid, and excess powder was blown away with a rubber ball. The grid was then rapidly immersed in liquid ethane using a Thermo Scientific Vitrobot cryo-electron microscopy sample preparation system, frozen, and then transferred to liquid nitrogen for storage before being observed under an electron microscope.

[0147] (5) Image collection

[0148] Select multiple particles of suitable size with clear diffraction signals, and use EPU-D software to automatically collect a series of diffraction data generated by particle rotation.

[0149] (6) Data processing

[0150] The diffraction images were indexed and intensity integrated to obtain unit cell parameters and HKL files. Multiple sets of data were then fused to obtain the crystal structure. Figure 1 shows a schematic diagram of the single-crystal structure of compound 12B, and the specific crystal parameters are as follows:

[0151] Examples 12C and 12D

[0152] Step A: Synthesis of N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(R)-2-methoxypropamido)-4-((1S,6R)-5-methyl-2,5-diazapicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-ethyl-1H-pyrazole-5 -Formamide and N-((S)-1,1-bicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(R)-2-methoxypropamido)-4-((1R,6S)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0153] At room temperature, intermediates 1N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (300 mg, 0.52 mmol), (2S)-2-methoxypropionic acid (81.20 mg, 0.78 mmol) and N,N-diisopropylethylamine (201.61 mg, 1.56 mmol) were dissolved in DMF (5 mL, 5 mL), and HATU (296.58 mg, 0.78 mmol, 100% purity) was added. The mixture was reacted at room temperature for 2 h.

[0154] After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and rotary evaporated to the residue. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 94 / 6, V / V) to obtain a racemic mixture. This mixture was then sent to a chiral column (chiral column: CHIRALPAK IG-3 3 μm x 4.6 mm x 150 mm; mobile phase: n-hexane / ethanol = 80:20; flow rate 1.0 mL / min), yielding a peak of 80 mg (Peak 1 RT: 27.082 min, purity: 95%) and a peak of 76 mg (Peak 2 RT: 35.124 min, purity: 98%). LC-MS: [M+H] + =666.

[0155] Examples 14A and 14B

[0156] Synthesize compounds 14A and 14B

[0157] Step A: Synthesis of 4-nitrophenyl ((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate

[0158] Step K: At 0°C, N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (400 mg, 0.69 mmol) was dissolved in dichloromethane (15 mL), pyridine (1091 mg, 13.8 mmol) was added, and 4-nitrophenyl carbon chloride (417 mg, 2.07 mmol) dissolved in dichloromethane was added dropwise. The mixture was stirred at 0°C for 10 minutes, followed by stirring at room temperature for 1 hour.

[0159] Post-treatment: Concentrate, add saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (50 mL × 3), combine organic phases, wash with saturated brine (50 mL), dry organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness to give 4-nitrophenyl ((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (513 mg, yield 87%). LC-MS: [M+H] + =745.

[0160] Step B: N-((2S)-1,1-dicyclopropyl-3-((2S,3R)-3-(3-cyclopropyl-3-methylurea)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0161] At room temperature, ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyric acid (448 mg, 0.6 mmol) was dissolved in DCM (10 mL), DMAP (22 mg, 0.18 mmol) and DIPEA (388 mg, 3 mmol), and stirred at room temperature for 1 hour.

[0162] Post-treatment: Dilute with saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (50 mL × 3), combine organic phases, wash with saturated brine (50 mL), dry organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and send to reverse column chromatography for purification to obtain two products: N-((2S)-1,1-dicyclopropyl-3-((2S,3R)-3-(3-cyclopropyl-3-methylurea)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide, with peak 1 (RT: 46.903 min, 93.5 mg, yield 29%) and peak 2 (RT: 48.802 min, 104 mg, yield 31%).

[0163] Examples 18A and 18B

[0164] The specific synthetic routes for compounds 18A and 18B are as follows:

[0165] Step A: (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazol-5-carbamoyl)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate

[0166] At room temperature, (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)butyric acid (610 mg, 0.86 mmol) was dissolved in DMF (10 mL), and 2-methyl-2,5-diazabicyclo[4.1.0]heptane (289 mg, 1.29 mmol), DIPEA (1.14 mL, 6.88 mmol), and HATU (654 mg, 1.72 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0167] Post-treatment: Concentrate, add the residue to a saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (40 mL × 3), combine the organic phases, wash the organic phase with saturated brine (50 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate to dryness, to give a yellow oily liquid (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazol-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (690 mg, yield 98%). LC-MS: [M+H] + =802.

[0168] Step B: N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0169] At room temperature, (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (690 mg, 0.86 mmol) was dissolved in DMF (5 mL), and piperidine (0.67 mL, 7.28 mmol) was added. The mixture was stirred at room temperature for 1 hour.

[0170] Post-treatment: The residue was diluted with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 1). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give a yellow oily liquid N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (490 mg, yield 98%). LC-MS: [M+H] + =580.

[0171] Step C: 4-Nitrophenyl ((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate

[0172] At room temperature, N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (400 mg, 0.69 mmol) was dissolved in dichloromethane (15 mL), cooled to 0°C, and pyridine (1.11 mL, 13.8 mmol) and 4-nitrophenyl chloroformate (417 mg, 2.07 mmol) were added. The mixture was then brought back to room temperature and stirred for 2 hours.

[0173] Post-treatment: Add saturated sodium bicarbonate aqueous solution (30 mL), extract with dichloromethane (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 1), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and purify by silica gel column chromatography to obtain 4-nitrophenyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (111 mg, yield 22%). LC-MS: [M+H] + =745.

[0174] Step D: N-((2S)-1-(4-((2S,3R)-3-(3-cyclobutyl-3-methylurea)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0175] At room temperature, 4-nitrophenyl ((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (100 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), and N-methylcyclobutane (17 mg, 0.2 mmol), N,N-diisopropylethylamine (0.11 mL, 0.65 mmol) and 4-dimethylaminopyridine (5 mg, 0.039 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0176] Post-treatment: Add saturated sodium bicarbonate aqueous solution (30 mL), extract with dichloromethane (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and send to a reverse-phase C18 preparative column to prepare N-((2S)-1-(4-((2S,3R)-3-(3-cyclobutyl-3-methylurea)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobutyl-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide, which was then chirally resolved to give peak1 (26 mg, yield 28%) and peak2 (39 mg, yield 42%). LC-MS: [M+H] + =691.

[0177] Examples 19A and 19B

[0178] The specific synthetic routes for compounds 19A and 19B are as follows:

[0179] Step A: Synthesis of tert-butyl(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)-carbamate

[0180] (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyric acid (150 mg, 0.44 mmol) and N,N-dimethylformamide (3 mL) were added to a reaction flask, followed by 2-methyl-2,5-diazabicyclo[4.1.0]heptane (60 mg, 0.53 mmol), DIPEA (347 mg, 2.64 mmol), and HATU (251 mg, 0.66 mmol). The mixture was reacted at room temperature for 30 min.

[0181] Post-treatment: Add 30 mL of saturated sodium bicarbonate solution, extract four times with 5 mL of ethyl acetate, wash the organic phase with saturated brine (20 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to give a yellow solid product, tert-butyl(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)-carbamate (191 mg, 0.44 mmol), calculated according to theoretical yield. LC-MS: [M+H] + =437.2

[0182] Step B: Synthesis of (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)butyl-1-one

[0183] 191 mg (0.44 mmol) of tert-butyl(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)-carbamate and 2 mL of dichloromethane were added to a reaction flask, followed by 1 mL (3.46 mmol) of trifluoroacetic acid. The reaction was carried out at room temperature for 0.5 h.

[0184] Post-treatment: The system was evaporated to dryness to obtain a yellow oil (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)butyl-1-one (147 mg, 0.44 mmol), calculated according to theoretical yield. LC-MS: [M+H] + =337.4

[0185] Step C: Synthesis of N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-butanone-2-yl)propionamide

[0186] (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)butyl-1-one (147 mg, 0.44 mmol) and dichloromethane (2 mL) were added to a reaction flask, followed by triethylamine (445 mg, 4.4 mmol) and propionic anhydride (86 mg, 0.66 mmol). The mixture was reacted at room temperature for 30 min.

[0187] Post-treatment: Add 10 mL of saturated sodium bicarbonate solution, extract four times with 5 mL of ethyl acetate, wash the organic phase with saturated brine (20 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to give a yellow solid product N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-butanone-2-yl)propionamide (171 mg, 0.44 mmol), calculated according to theoretical yield. LC-MS: [M+H] + =394.4

[0188] Step D: Synthesis of N-((2R,3S)-3-(4-amino-3-fluorophenyl-)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-butanone-2-yl)propionamide

[0189] N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-butanone-2-yl)propionamide (171 mg, 0.44 mmol), ethanol (8 mL) and water (4 mL) were added to a reaction flask, along with iron powder (123 mg, 2.2 mmol) and ammonium chloride (118 mg, 2.2 mmol). The reaction was carried out at 80 °C for 1 h.

[0190] Post-treatment: Iron powder was removed by filtration with diatomaceous earth. The sample was washed with dichloromethane (20 mL) and methanol (20 mL). The collected filtrate was concentrated, dissolved in 10 mL of dichloromethane, and extracted four times with 20 mL of saturated sodium bicarbonate solution and 10 mL of dichloromethane. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give N-((2R,3S)-3-(4-amino-3-fluorophenyl-)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-butanone-2-yl)propionamide (159 mg, 0.44 mmol), calculated according to theoretical yield. LC-MS: [M+H] + =362.4

[0191] Step E: Synthesis of tert-butyl(2-((2-fluoro-4-((2R,3S)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxo-3-propamidobutyl-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate

[0192] N-((2R,3S)-3-(4-amino-3-fluorophenyl-)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-butanone-2-yl)propionamide (159 mg, 0.44 mmol) and pyridine (2 mL) were added to a reaction flask, followed by 2-((tert-butoxycarbonyl)amino)-2-(4-methylcyclohexyl)acetic acid (155 mg, 0.57 mmol) and EDCI (253 mg, 1.32 mmol). The reaction was carried out at room temperature for 30 min.

[0193] Post-treatment: Concentration was performed by adding 20 mL of saturated sodium bicarbonate solution to the concentrate and extracting four times with 5 mL of dichloromethane. The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to give tert-butyl(2-((2-fluoro-4-((2R,3S)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxo-3-propamidobutyl-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate (271 mg, 0.44 mmol), calculated according to theoretical yield. LC-MS: [M+H] + =616.8

[0194] Step F: Synthesis of N-((2R,3S)-3-(4-(2-amino-2-(4-methylcyclohexyl)acetamido-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-)-1-oxobut-2-yl)propionamide

[0195] 271 mg (0.44 mmol) of tert-butyl (2-((2-fluoro-4-((2R,3S)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxo-3-propamidobutyl-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate (371 mg, 0.44 mmol) and dichloromethane (3 mL) were added to a reaction flask, followed by trifluoroacetic acid (1 mL, 3.46 mmol). The reaction was carried out at room temperature for 0.5 h.

[0196] Post-treatment: The system was evaporated to dryness to obtain a yellow oil N-((2R,3S)-3-(4-(2-amino-2-(4-methylcyclohexyl)acetamido-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-)-1-oxobut-2-yl)propionamide (210 mg, 0.44 mmol), calculated according to theoretical yield. LC-MS: [M+H] + =516.6.

[0197] Step G: Synthesis of 1-ethyl-N-((1S)-2-((2-fluoro-4-((2R,3S)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxo-3-propamidobutyl-2-yl-)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl-2-oxoethyl)-1H-pyrazole-5-carboxamide

[0198] N-((2R,3S)-3-(4-(2-amino-2-(4-methylcyclohexyl)acetamido-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-)-1-oxobut-2-yl)propionamide (210 mg, 0.44 mmol) and N,N-dimethylformamide (3 mL) were added to a reaction flask, followed by 1-ethyl-1H-pyrazole-5-carboxylic acid (80 mg, 0.57 mmol), DIPEA (347 mg, 2.64 mmol), and HATU (251 mg, 0.66 mmol). The reaction was carried out at room temperature for 30 min.

[0199] Post-processing: Add 30 mL of saturated sodium bicarbonate solution, extract four times with 5 mL of ethyl acetate, wash the organic phase with saturated brine (20 mL), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and then send it to a reverse-phase column for purification, yielding two products: peak 1 (RT: 6.914 min, 63 mg, yield 23%) and peak 2 (RT: 6.966 min, 61 mg, yield 22%). LC-MS: [M+H] + =638.8.

[0200] Example 35

[0201] Step A: Synthesis of ((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-(ethyl-d5)-1H-pyrazol-5-carbamate)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl) tert-butyl carbamate

[0202] At room temperature, tert-butyl carbamate (250 mg, 0.45 mmol) was dissolved in pyridine (5 mL), and 1-(ethyl-d5)-1H-pyrazole-5-carboxylic acid (78.3 mg, 0.54 mmol) and EDCI (258 mg, 1.35 mmol) were added. The mixture was stirred at room temperature for 1 hour.

[0203] Post-treatment: Add saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate to dryness, and purify by silica gel column chromatography to obtain ((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-(ethyl-d5)-1H-pyrazol-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)tert-butyl carbamate (300 mg, yield 94%). LC-MS: [M+H] + =685.

[0204] Step B: Synthesis of N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide

[0205] At room temperature, 300 mg (0.44 mmol) of tert-butyl carbamate (2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-(ethyl-d5)-1H-pyrazole-5-carbamate)propamido)-3-fluorophenyl)-1-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL, 26 mmol) was added. The mixture was stirred at room temperature for 1 hour.

[0206] Post-treatment: Concentrate, adjust pH to alkaline by adding saturated sodium bicarbonate aqueous solution to the residue, extract with ethyl acetate (20 mL × 3), combine organic phases, wash with saturated brine (20 mL × 1), dry organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and give a yellow oily liquid N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide (260 mg, yield 96%). LC-MS: [M+H] + =585.

[0207] Step C: N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-((S)-2-methoxypropamido)-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide

[0208] At room temperature, N-((2S)-1-((4-(2S,3R)-3-amino-4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide (260 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (3 mL), and (S)-2-methoxypropionic acid (54 mg, 0.52 mmol), N,N-diisopropylethylamine (277 mg, 2.6 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (246 mg, 0.65 mmol) were added and stirred at room temperature for 1 hour.

[0209] Post-processing: Add saturated sodium bicarbonate aqueous solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 1), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and send to reverse-phase column chromatography for preparative purification. Then, perform chiral resolution to obtain two products: peak 1 (72 mg, 24%) (RT: 6.506 min) and peak 2 (66 mg, 22%) (RT: 7.518 min). LC-MS: [M+H] + =671.

[0210] Example 36

[0211] Step A: Synthesis of (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)-1-(5-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate

[0212] At room temperature, (2R,3S)-2-(((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)butyric acid (300 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 2-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane (60 mg, 0.52 mmol), N,N-diisopropylethylamine (277 mg, 2.6 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (250 mg, 0.65 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0213] Post-treatment: Add saturated sodium bicarbonate aqueous solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 1), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain a yellow oily liquid (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazol-5-carboxamido)propamido)-3-fluorophenyl)-1-(5-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (328 mg, yield 95%). LC-MS: [M+H] + =805.

[0214] Step B: Synthesis of N-((2S)-1-(4-(2S,3R)-3-amino-4-(5-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0215] At room temperature, (9H-fluorene-9-yl)methyl((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)-1-(5-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-1-oxobut-2-yl)carbamate (328 mg, 0.42 mmol) was dissolved in DMF (5 mL), and tetrahydropiperidine (465 mg, 5 mmol) was added. The mixture was stirred at room temperature for 1 hour.

[0216] Post-treatment: Add saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 1), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and purify by silica gel column chromatography to obtain a white solid N-((2S)-1-(4-(2S,3R)-3-amino-4-(5-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (245 mg, yield 99%). LC-MS: [M+H] + =583.

[0217] Step C: Synthesis of N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-((S)-2-methoxypropamido)-4-(5-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxoprop-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide

[0218] At room temperature, N-((2S)-1-(4-(2S,3R)-3-amino-4-(5-(methyl-d3)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (245 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (3 mL), and (S)-2-methoxypropionic acid (54 mg, 0.52 mmol), N,N-diisopropylethylamine (277 mg, 2.6 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (246 mg, 0.65 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

[0219] Post-treatment: Add saturated sodium bicarbonate aqueous solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 1), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and send to reverse-phase column chromatography for preparative purification. Then, perform chiral resolution to obtain two products: peak 1 (60 mg, 21%) (RT: 7.239 min) and peak 2 (55 mg, 19%) (RT: 8.416 min). LC-MS: [M+H] + =669.

[0220] Example 52

[0221] Synthesis of 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-((1R,6S)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxopropyl-2-yl)-1,2,5-oxadiazole-3-carboxamide And 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-((1S,6R)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxopropyl-2-yl)-1,2,5-oxadiazole-3-carboxamide,

[0222] The synthesis route is as follows:

[0223] Step A: 5-((2R, 3S)-3-(4-((S)-3,3-dicyclopropyl-2-(4-cyclopropyl-1,2,5-oxadiazol-3-carboxamido)propamido)-3-fluorophenyl)-2-(2-methoxyacetamido)butyryl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester

[0224] At room temperature, 2R,3S)-3-(4-(((S)-3,3-dicyclopropyl-2-(4-cyclopropyl-1,2,5-oxadiazol-3-carboxamido)propamido)-3-fluorophenyl)-2-(2-methoxyacetamitoyl)butyric acid (400 mg, 0.49 mmol, 70% purity), 2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (126.29 mg, 0.64 mmol) and DIPEA (379.97 mg, 2.94 mmol) were dissolved in DMF (4 mL), and then HATU (279.47 mg, 0.73 mmol) was added. The mixture was reacted at room temperature for 2 hours.

[0225] After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (3 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and rotary evaporated to the residue. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, V / V) to give a brown solid 5-((2R, 3S)-3-(4-((S)-3,3-dicyclopropyl-2-(4-cyclopropyl-1,2,5-oxadiazol-3-carboxamido)propamido)-3-fluorophenyl)-2-(2-methoxyacetamitoyl)butyryl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (400 mg, yield 97.75%, purity 90%). LC-MS: [M+H-56] + =694.

[0226] Step B: Synthesis of N-((2S)-1-((4-((2S,3R)-4-(2,5-diazabicyclo[4.1.0]heptane-2-yl)-3-(2-methoxyacetamide)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide

[0227] At room temperature, 5-((2R,3S)-3-(4-((S)-3,3-dicyclopropyl-2-(4-cyclopropyl-1,2,5-oxadiazol-3-carboxamido)propamido)-3-fluorophenyl)-2-(2-methoxyacetamyl)butyryl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (80 mg, 0.51 mmol) was dissolved in DCM (2 mL), and then TFA (3070 mg, 26.93 mmol) was added. The reaction was carried out at room temperature for 2 hours.

[0228] After the reaction was complete, the residue was concentrated by rotary evaporation. Dichloromethane was added to dissolve the residue, and the solution was placed in an ice bath. The pH of the solution was adjusted to approximately 8-9 with saturated NaHCO3(aq). The mixture was extracted with dichloromethane (3 x 30 mL), the organic phases were combined, washed with saturated brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain a yellow solid product N-((2S)-1-((4-((2S,3R)-4-(2,5-diazabicyclo[4.1.0]heptane-2-yl)-3-(2-methoxyacetamide)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (300 mg, yield 91.07%). LC-MS: [M+H] + =61.

[0229] Step C: Synthesis of 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-((1R,6S)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxopropyl-2-yl)-1,2,5-oxadiazole-3- Formamide and 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-((1S,6R)-5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-yl)-4-oxobut-2-yl)phenyl)amino)-3-oxopropyl-2-yl)-1,2,5-oxadiazole-3-carboxamide

[0230] At room temperature, N-((2S)-1-((4-((2S,3R)-4-(2,5-diazabicyclo[4.1.0]heptane-2-yl)-3-(2-methoxyacetamide)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide (300 mg, 0.46 mmol) and formaldehyde (72.70 mg, 0.92 mmol) were dissolved in methanol (3 mL), stirred at room temperature for half an hour, and then NaCNBH3 (57.81 mg, 0.92 mmol) was added, and the reaction was carried out at room temperature for 1 hour.

[0231] After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (3 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and rotary evaporated to the residue. The residue was purified by C18 reversed-phase column chromatography (ACN / 0.05% NH₃·H₂O, 55% ACN) to obtain a mixed product. The mixed product was chirally resolved (column: CHIRALCEL OD-H 4.6 mm x 250 mm x 5 μm; mobile phase-gradient conditions Hex:EtOH = 95:5), yielding a leading peak (20 mg, yield 15.68%) and a trailing peak (54 mg, yield 41.90%). LC-MS: [M+H] + =666.

[0232] The compound structures of Examples 1-53 of the present invention are shown in Tables 1 and 2. The preparation of Examples 1, 3-11, 13, 15-17, 20-34, 37-51, and 53 can be carried out with reference to the general formula synthetic route, intermediate 1, Examples 2, 12, 14, 18, 19, 35, 36, and 52, as well as the preparation method in patent application number CN202080079537.5, which can also be incorporated herein by reference in their entirety.

[0233] Table 1

[0234] Table 2

[0235] Comparative Example 1

[0236] The structure of Comparative Example 1 was prepared with reference to patent document WO2023164057.

[0237] Comparative Example 2

[0238] The structure of Comparative Example 2 was prepared with reference to patent document WO2021055376.

[0239] Comparative Example 3

[0240] The structure of Comparative Example 3 was prepared with reference to patent document WO2023164057.

[0241] Example 54: HT-29 cell neutralization experiment with human IL-17A

[0242] The activity of the compound against human IL-17A at the cellular level was evaluated using HT-29 cells. The specific experimental steps are as follows:

[0243] 1. Remove the original culture medium from HT-29 cells in the logarithmic growth phase, wash the cells with PBS, add trypsin to digest for 3 min, centrifuge (1000×3 min), discard the supernatant, resuspend in 3 ml, take 100 μl and dilute 10 times for counting, and then count at 2×10⁻⁶. 5 Cells were seeded at 1 / ml in 96-well plates (#3596; Costar) and cultured as adherent cells for 24 hours.

[0244] 2. Discard the original culture medium and add normal culture medium, culture medium containing different concentrations of the compound (initial concentration 1 μM, 4-fold dilution) and 30 ng / ml or 90 ng / ml human IL-17A, and culture medium containing 30 ng / ml or 90 ng / ml human IL-17A and different concentrations of secukinumab (initial concentration 100 nM, 4-fold dilution) to the plate respectively.

[0245] 3. Continue incubation for 48 hours, then collect the supernatant.

[0246] 4: The CXCL1 / GROa in the culture medium was detected using a commercially available ELISA kit (#DGR00B, R&D Systems). (Wells containing only culture medium were used as the bottom values ​​for CXCL1 / GROa).

[0247] The inhibition rate is calculated using the following formula:

[0248] 5. The experimental results were fitted and analyzed using Prism, and the IC50 values ​​of the compounds were calculated. The test results using 30 ng / ml human IL-17A culture medium are shown in Table 3.

[0249] Table 3

[0250] The compounds of this invention exhibit excellent inhibitory activity relative to IL-17A.

[0251] Example 55: HEK-blue cell assay for IL-17AA inhibitory activity

[0252] 1. Main materials and reagents

[0253] 2. Experimental apparatus

[0254] 3. Experimental methods and procedures

[0255] (1) Reconstitution and repackaging of human IL-17AA

[0256] 1.1 Gently tap the vial containing human IL-17A solid powder to ensure all sample is at the bottom of the vial.

[0257] 1.2 Dissolve human IL-17A in 500 μL of 4 mM HCl under sterile conditions. Gently shake the bottle until all the solid in the bottle dissolves into a colorless and transparent liquid.

[0258] 1.3 Aliquot the dissolved liquid into 10 μL tubes and store the aliquots at -80°C to avoid repeated freeze-thaw cycles. The solution concentration is 100 μg / mL; further dilution is required before use.

[0259] (2) Experimental steps

[0260] Day 0

[0261] 2.1 Cell Preparation: Remove the culture medium, add 3 mL of PBS, and gently shake the culture flask to detach the adherent cells. Resuspend the cells in culture medium containing inactivated FBS and adjust the cell density to 2.2 × 10⁻⁶ cells / mL. 5 per mL.

[0262] 2.2 Add 180 μl of a solution with a density of 2.2 × 10⁻⁶. 5 Add cells per mL to a 96-well plate.

[0263] 2.3 Add 10 μL of the compound to a 96-well plate.

[0264] 2.4 Add 10 μL of IL-17A working solution (final concentration 3 ng / mL)

[0265] 2.5 Negative control wells: Cell control wells containing no IL17A

[0266] 2.6 Positive control wells: Cell control wells containing IL17A (final concentration 3 ng / mL)

[0267] 2.7 The culture plates were incubated at 37°C in a carbon dioxide incubator for 18 hours.

[0268] Day 1:

[0269] 2.8 Take a 96-well black transparent plate, add 25 μL of Tropix@Phospha-Light analysis buffer to each well, then add 25 μL of cell supernatant, and incubate at room temperature for 5 min.

[0270] 2.9 Add 25 μL of Tropix@Phospha-Light Reaction Buffer to each well and incubate at room temperature for 20 min.

[0271] 2.10 Use an enzyme-linked immunosorbent assay (ELISA) reader to detect chemiluminescence.

[0272] (3) Data Analysis

[0273] 3.1 Subtract the blank control value from all readings

[0274] 3.2 The inhibition rate is calculated using the following formula.

[0275] Inhibition rate % = 100 × (RFU) Control -RFU compound ) / RFU Control

[0276] The IC was obtained by fitting the logarithm of compound concentration on the x-axis and the inhibition rate on the y-axis using Graphpad Prism. 50 The values ​​are shown in Table 4.

[0277] Table 4

[0278] Among them, the IC50 value of 24A or 24B or 24C or 24D or 24E or 24F or 24G or 24H or 24I or 24J or 24K or 24L or 24M or 24N or 24O or 24P is less than 100nM.

[0279] As shown in Table 4, the compounds of the present invention have good inhibitory activity against IL-17AA. Compared with Comparative Example 3, the preferred compounds of the present invention have better inhibitory activity against IL-17AA.

[0280] Example 56 Pharmacokinetic Experiment

[0281] 1. Experimental Materials

[0282] SD rats: male, 180-250g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0283] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) were all commercially available. Instrument: AB SCIEX QTRAP 5500+.

[0284] 2 Experimental Methods

[0285] The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After intravenous (iv) or gavage (ig) administration to rats, 200 μL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h (an additional 5 min was collected for the iv group) in EDTA-K2 anticoagulant tubes. The tubes were centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. Accurately pipette 10 μL of each of the above standard series solutions, add 90 μL of blank plasma, vortex to mix, and prepare plasma samples with concentrations equivalent to 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Perform dual-sample analysis for each concentration to establish a standard curve. Take 30 μL of plasma (diluted 5-fold after intravenous administration at 5 min, 15 min, and 30 min), add 150 μL of acetonitrile solution of propranolol (50 ng / mL) as internal standard, vortex to mix, add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and analyze the supernatant by LC-MS. The LC-MS detection conditions are as follows:

[0286] Column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0287] Mobile phase: Water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below (Table 5):

[0288] Table 5

[0289] 3 Data Processing

[0290] After LC-MS was used to detect the blood drug concentration, the pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The results are shown in Table 6.

[0291] Table 6

[0292] As shown in Table 6, the compounds of the present invention have excellent in vivo exposure levels.

[0293] Example 57: Pharmacological Experiment

[0294] Experimental Methods: SD rats were randomly divided into 6 groups (n=6 per group): normal control group, model group, control group (50 mg / kg), and compound treatment group (50 mg / kg). IL-23 protein was injected intradermally into the ear skin for 5 consecutive days to induce local psoriatic lesions. During the modeling period, rats were treated with oral administration of IL-23 protein at doses of 15 mg / kg, 25 mg / kg, 50 mg / kg, or 100 mg / kg, twice daily for 5 consecutive days. Ear thickness was measured on Day 2-Day 5 during the modeling period.

[0295] Dosing group

[0296] Experimental results: After induction with IL-23 protein, the ear thickness of the model group increased significantly, indicating successful model establishment. The results also showed that, compared to the model group and Comparative Example 1, administration of the preferred compound N of this invention had a significant protective effect on the rat ear skin, resulting in a significant reduction in rat ear thickness (see Figure 2).

[0297] Example 58: Evaluation of the efficacy of collagen-induced arthritis in rats

[0298] Experimental Methods: Female Lewis rats were used in the experiment. Modeling was initiated after the rats had acclimatized. Bovine type II collagen was mixed with an equal volume of incomplete Freund's adjuvant (IFA), emulsified, and the model was established through two intradermal injections of the collagen-adjuvant mixture. The first immunization was performed using a three-point injection method: at the base of the tail, the back, and the plantar surface of the paws. A second booster immunization was administered 7 days after the first immunization, using the same method. At the time of the second immunization, the paw volume of the left and right forelimbs was measured, and the average value was used as a reference. Three to six days after the second immunization, rats were grouped based on a 10% increase in paw volume relative to the reference value and a clinical observation score of 1 or higher (appearance of red dots or nodules on the ears, nose, tail, and limbs). Animals were randomly assigned to groups of eight: a model group, a low-dose compound N group, and a high-dose compound N group. A normal control group was also included. After grouping, drug administration began. All groups were administered the drug or solvent via gavage twice daily for 10 days. After administration, the hind paw volume of rats in each group was measured twice a week using a toe volume analyzer.

[0299] The results are shown in Figure 3. The results indicate that compound N can improve the paw volume of arthritic rats, showing anti-inflammatory and arthritis symptom-improving effects.

[0300] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A compound represented by the formula (I) or its racemate, or its isomer, or its pharmaceutically acceptable salt, characterized in that, ###0001### (I) comprises: wherein m1, m2, m3 are independently selected from 0, 1 or 2; n is 0, 1, 2, 3 or 4; X is selected from O, N, S, when X is selected from O, S, R 7 absent; A ring is selected from substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said R 1 substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said R 1 is selected from alkyl, alkoxy, halogen, cycloalkyl, haloalkyl, haloalkoxy, halocycloalkyl, -O-cycloalkyl; R 2 selected from substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH(R 2a )(R 2b ), said substituents being selected from alkyl, alkoxy, halogen, said R 2a and R 2b are independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; R 3 selected from hydrogen, halogen, alkyl, alkoxy; R 4 selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl; Z is selected from R Z1 , R Z2 are independently selected from alkyl, alkenyl, alkynyl, nitrile, alkyl nitrile, halogen, haloalkyl, haloalkenyl, -NT1T2, or substituted or unsubstituted -(CH2) c -NT1T2, or substituted or unsubstituted -(CH2) f -cycloalkyl, -(CH2) k -O-alkyl, -(CH2) t -O-cycloalkyl, -CT3T4-O-alkyl, alkyl heterocycloalkyl, halo heterocycloalkyl, or substituted or unsubstituted aryl, heteroaryl, or substituted or unsubstituted cycloalkyl, heterocycloalkyl, the substitution being selected from alkyl, alkoxy, halogen, cycloalkyl, wherein T1, T2, T3, T4are independently selected from hydrogen, halogen, nitrile, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, or T3, T4together cyclize to substituted or unsubstituted cycloalkyl, heterocycloalkyl, the substitution being selected from alkyl, halogen, alkoxy, haloalkyl, wherein c, f, k, t are selected from 1, 2, 3, 4, 5 or 6; R 5 and R 6 together cyclize to substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, the substitution being selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, cycloalkyl, the substitution being at least one; R 7 selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, cycloalkyl; wherein when the A ring is substituted with R 1 the A ring is selected from R 2 selected from R 5 and R 6 together cyclize to cyclopropyl, R Z1 is not 2. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that, when m1, m2 are 0, m3 is 2, R 5 and R 6 together cyclize to a cycloalkyl group, are selected from the group consisting of structures represented by formula (II), wherein p is selected from 0, 1, 2, 3 or 4, n, A ring, R 2 , R 3 , R 4 , R 7 , X, Z are as defined in claim 1.

3. The compound of claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein, said alkyl is selected from the group consisting of C 1-6 said alkyl is selected from the group consisting of C 1-6 said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, t-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, t-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl; said alkenyl is selected from the group consisting of C 2-6 said alkenyl is selected from the group consisting of C 2-6 said alkenyl is selected from the group consisting of ethenyl, 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1 -propenyl, 2-methyl- 1 -propenyl, 1 -methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1 -butenyl, 2-methyl- 1 -butenyl, 3-methyl- 1 -butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1 -methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1, 1 -dimethyl-2-propenyl, 1,2-dimethyl- 1 -propenyl, 1,2-dimethyl-2-propenyl, 1 -ethyl- 1 -propenyl, 1 -ethyl-2-propenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl- 1 -pentenyl, 2-methyl- 1 -pentenyl, 3-methyl- 1 -pentenyl, 4-methyl- 1 -pentenyl, 1 -methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1 -methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1 -methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, 1 -dimethyl-2-butenyl, 1, 1 -dimethyl-3-butenyl, 1,2-dimethyl- 1 -butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl- 1 -butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl- 1 -butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl- 1 -butenyl, 3,3-dimethyl-2-butenyl, 1 -ethyl- 1 -butenyl, 1 -ethyl-2-butenyl, 1 -ethyl-3-butenyl, 2-ethyl- 1 -butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 1,2-trimethyl-2-propenyl, 1 -ethyl- 1 -methyl-2-propenyl, 1 -ethyl-2-methyl- 1 -propenyl and 1 -ethyl-2-methyl-2-propenyl; said alkoxy is selected from the group consisting of C 1-6 alkoxy, said C 1-6 alkoxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1 -ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, 1 -ethylbutoxy; said alkynyl is selected from the group consisting of C 2-6 alkynyl, said C 2-6 alkynyl is selected from the group consisting of ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl; said alkyl nitrile is selected from acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, isovaleronitrile, hexanitrile; said aryl is selected from five or six-membered aryl; said heteroaryl means at least one carbon atom of aryl is replaced by a heteroatom.

4. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein said cycloalkyl is selected from the group consisting of C 3-12 said cycloalkyl is selected from the group consisting of C 3-8 said cycloalkyl is selected from the group consisting of C 3-8 said cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spirocycloalkyl, said spirocycloalkyl means two rings share one carbon atom, said heterocycloalkyl means at least one carbon atom of the cycloalkyl is replaced by a heteroatom, said alkylheterocycloalkyl means at least one hydrogen atom of the heterocycloalkyl is replaced by an alkyl group.

5. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein said halo is selected from fluorine, chlorine, bromine, iodine; said haloalkyl means at least one hydrogen atom of alkyl is replaced by halo, said halo-heterocycloalkyl means at least one hydrogen atom of heterocycloalkyl is replaced by halo, said halo-cycloalkyl means at least one hydrogen atom of cycloalkyl is replaced by halo, said haloalkoxy means at least one hydrogen atom of alkoxy is replaced by halo, said haloalkenyl means at least one hydrogen atom of alkenyl is replaced by halo.

6. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein said heteroatom is one or more selected from nitrogen, oxygen, sulfur.

7. The compound of claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein, m1, m2 are 0, m3 is 2, n is 0 or 1 or 2, c, f, k, t are 1; X is O or N, R 7 absent; the A ring is selected from: said R 1 substituted A ring is selected from R 2 selected from cyclohexyl, cycloheptyl, R 3 selected from fluorine; R 4 selected from methyl; Z is selected from R Z1 selected from ethyl, R Z2 selected from ethyl, cyclopropyl; R 5 and R 6 together cyclize to cyclopropyl, cyclobutyl; R 7 is hydrogen, methyl, ethyl.

8. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein selected from the compounds represented by formula (Ia), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof: wherein n is 1, R 2 selected from cyclohexyl, cycloheptyl, m1, m2, m3, Z, A ring, R 3 , R 4 , X, R 5 , R 6 , R 7 as defined in claim 1.

9. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (I) selected from further selected from R 7 R is absent when X is selected from O. 7 is absent.

10. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein selected from the structures shown in Table 1.

11. The compound according to claim 1, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein said compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is replaced by deuterium.

12. The compound according to claim 11, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein, said compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is replaced by deuterium is selected from the structures shown in Table 2.

13. A pharmaceutical composition, characterized by, a therapeutically effective amount of the compound of any one of claims 1-12, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. Use of a compound according to any one of claims 1 to 12, or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of a disease, characterized in that, said disease is an IL-17A / F related disease, in particular selected from psoriasis, arthritis.

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