Azacyclo-2-oxo compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of chemical drugs, and relates to an azacyclo-2-oxo compound as well as a preparation method and application thereof, in particular to a compound as shown in a general formula (I), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, a small molecule antagonist serving as alpha4beta7 integrin, and a method for treating various specific diseases or symptoms by using the azacyclo-2-oxo compound.

Description

A nitrogen-containing heterocyclic 2-oxo compound, its preparation method and application Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a nitrogen heterocyclic 2-oxo compound and its preparation method and application. Background Technology

[0002] The integrin family consists of dimers formed by two subunits: α (120-185 KD) and β (90-110 KD). Mammalian species contain 18 α subunits and 8 β subunits. Different combinations can form more than 20 different integrins. α4β7 is a member of the integrin family. Integrins are expressed on the surface of most human cells, and their abnormalities cause a group of different human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidneys, macular degeneration, and various autoimmune and chronic inflammatory diseases. Currently identified intestinal inflammatory diseases associated with α4β7 include Crohn's disease and ulcerative colitis.

[0003] Prior art, for example, WO2021076902 and WO2019200202 discloses small molecule antagonists as α4β7 integrin, and methods of using them to treat a variety of specific diseases or conditions.

[0004] Currently, there are no specific small molecule compounds on the market targeting α4β7-mediated inflammation. Natalizumab, a humanized monoclonal antibody targeting the α4 subunit, is used clinically primarily to treat multiple sclerosis and Crohn's disease; however, it has been shown to cause PML (progressive multifocal leukoencephalopathy) as a side effect during clinical use. Therefore, it is necessary to develop a small molecule compound that can inhibit integrin α4β7 protein for the treatment of diseases related to integrin α4β7. Summary of the Invention

[0005] In view of the problems existing in the prior art, this application provides a nitrogen heterocyclic 2-oxo compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, as well as its preparation method and application. It also provides a method for using it as a small molecule antagonist of α4β7 integrin to treat various specific diseases or symptoms.

[0006] In a first aspect, this application provides a compound of general formula (I), or its isomers, racemates, or pharmaceutically acceptable salts thereof:

[0007]

[0008] 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.

[0009] 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 α4β7-related disease, specifically selected from conditions such as enteritis.

[0010] Specifically, the present invention is achieved through the following technical solution:

[0011] A compound of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

[0012]

[0013] Among them, R 1 Independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl;

[0014] R 2 Selected from alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, and -(CH2) compounds. q -Cycloalkyl, where q is 1, 2, 3 or 4;

[0015] R 3 Selected from hydrogen, alkyl, cycloalkyl, and -(CH2). t -R 3a The t is selected from 1, 2, 3, 4, and the R 3a Selected from substituted or unsubstituted The substitution is selected from alkyl and oxo, and at least one substitution is made;

[0016] R 4 Independently selected from hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, or substituted or unsubstituted cycloalkyl, heterocycloalkyl, -(CH2). k T(R 6 (R) 7 ), wherein T is selected from CH, N, k is 0, 1, 2, 3, 4, 5, and the substitution is selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl;

[0017] Among them, R 6 and R 7 Independently selected from hydrogen, alkyl, or R 6 and R 7 Independently selected from hydrogen, alkyl, or R 6 and R7 Cyclization is performed to form substituted or unsubstituted, saturated or unsaturated 4-6 membered heterocyclic alkyl groups, wherein the substitution is selected from alkyl, alkoxy, hydroxyl, and halogen;

[0018] Ring A is selected from one or more R 5 Substituted or unsubstituted, saturated or unsaturated 4-6 membered rings or heterocyclic rings, 8-10 membered bicyclic rings or heterobicyclic rings (e.g., 8-, 9- and 10-membered);

[0019] R 5 The substituted group is independently selected from oxo, hydroxy, cyano, halogen, alkyl, haloalkyl, thioalkyl, alkoxy, alkylsulfonamide, alkylamide, alkyl ketone, alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ring, substituted or unsubstituted heteroaromatic ring, wherein the substituted group is selected from alkyl, alkoxy, hydroxy, halogen, oxo, amino;

[0020] m and n are 0, 1, 2, 3 or 4, and p is 0, 1, 2, 3 or 4.

[0021] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from the structure shown in formula (I), wherein R 1 Independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl;

[0022] R 2 Selected from alkyl, cycloalkyl, haloalkyl, and heterocycloalkyl; R 3 Selected from hydrogen, alkyl, and cycloalkyl groups;

[0023] R 4 Independently selected from hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, -(CH2). 1-5 N(R 6 (R) 7 ); where R 6 and R 7 Independently selected from hydrogen, alkyl, or R 6 and R 7 Cyclization is performed to form substituted or unsubstituted, saturated or unsaturated 4-6 membered heterocyclic alkyl groups, wherein the substitution is selected from alkyl, alkoxy, hydroxyl, and halogen;

[0024] Ring A is selected from one or more R 5 Substituted or unsubstituted, saturated or unsaturated 4-6 membered rings or heterocyclic rings, 8-10 membered bicyclic rings or heterobicyclic rings;

[0025] R 5The substituted group is independently selected from oxo, hydroxy, cyano, halogen, alkyl, haloalkyl, thioalkyl, alkoxy, alkylsulfonamide, alkylamide, alkyl ketone, alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ring, substituted or unsubstituted heteroaromatic ring, wherein the substituted group is selected from alkyl, alkoxy, hydroxy, halogen;

[0026] m and n are 0, 1, 2, 3 or 4, and p is 0, 1, 2, 3 or 4.

[0027] As a preferred embodiment of the present invention, when ring A is selected from a substituted benzene ring, it is selected from the structure shown in formula (II).

[0028]

[0029] Among them, R 5a The substituted compounds are selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, or substituted or unsubstituted cycloalkyl, wherein the substituted compounds are selected from alkyl, amino, halogen, haloalkyl;

[0030] R 5b Selected from alkyl, halogen, haloalkyl, and cycloalkyl groups;

[0031] R 5c Selected from alkyl, halogen, and cycloalkyl groups;

[0032] R 5d Independently selected from hydrogen, halogen, alkyl, cycloalkyl, and haloalkyl;

[0033] R 1a R 1b R 1c It is selected independently from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, and heterocyclic alkyl;

[0034] R 2 Selected from alkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl groups;

[0035] R 3 Independently selected from hydrogen and alkyl groups;

[0036] R 4a Independently selected from substituted or unsubstituted cycloalkyl, heterocycloalkyl, or -(CH2) groups. 1-5 N(R 6 (R) 7 The substitution is selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl, and R. 6 R 7 Together they are cyclized into substituted or unsubstituted cycloalkyl or heterocycloalkyl groups, wherein the substitution is selected from alkyl or halogen;

[0037] The R4b Selected from alkyl, halogen, haloalkyl, cycloalkyl, and heterocyclic alkyl;

[0038] Where R 4a When R is selected from heterocyclic alkyl groups, 5a Selected from haloalkyl groups, or the R group described above. 5b Selected from haloalkyl, cycloalkyl, or the R 5d Selected from halogens, or the R 2 Selected from cycloalkyl, alkyl, and haloalkyl groups;

[0039] When R 4a Selected from The R 4b When R is selected from alkyl halogenates, 5a Selected from halogens or haloalkyl groups;

[0040] When the R 5a When R is selected from cycloalkyl groups, 4a Selected from substituted or unsubstituted -(CH2) 1-5 N(R 6 (R) 7 ).

[0041] 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.

[0042] The alkoxy group is selected from C. 1-6 Alkoxy, the C 1-6 The 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-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; the alkoxyalkyl group is selected from C 1-4 Alkoxy C 1-4 The alkyl group is further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl.

[0043] As a preferred embodiment of the present invention, the cycloalkyl group is selected from C 3-6 cycloalkanes, the C 3-6 The cycloalkane is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the heterocycloalkyl means that at least one carbon atom on the cycloalkyl group is replaced by a heteroatom.

[0044] As a preferred embodiment of the present invention, the aromatic ring is selected from fused rings containing four-membered rings, five-membered rings, fused rings containing five-membered rings, six-membered rings, and fused rings containing six-membered rings; the aromatic heterocycle refers to an aromatic ring in which at least one carbon atom is replaced by a heteroatom.

[0045] The aromatic ring includes a benzene ring and a naphthalene ring;

[0046] The aromatic heterocycles include indazole, quinoline, isoquinoline, quinoxaline, indole, isoindole, cyclophosphine, quinazoline, phthalazine, purine, naphthidine, pteridine, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzoisoxazole, benzoisothiazole, benzoxadiazole, benzothiazole, benzotriazole, benzotriazine, benzoimidazine, pyrazinopyrazole, pyrazinopyrimidine, pyrazinopyridazine ... Oxadiazole, pyridothiadiazole, pyridofuran, pyridopyrrole, pyrazinoxazole, pyrazinthiazole, pyrazinisoxazole, pyrazinisothiaazole, pyrazinoxadiazole, pyrazinthiadiazole, pyrazinfuran, pyrazinpyrrole, pyrimidinoxazole, pyrimidinthiaazole, pyrimidinisothiaazole, pyrimidinoxadiazole, pyrimidinthiadiazole, pyrimidinfuran, pyrimidinpyrrole, pyrazinoxazole, pyrazinthiaazole, pyrazinisothiaazole, pyrazinoxadiazole, pyrazinthiadiazole, pyrazinfuran, pyrazinpyrrole, triazinoxazole, triazinthiaazole, triazinisothiaazole, triazinoxadiazole, triazinthiadiazole, triazinfuran, triazinpyrrole.

[0047] Specifically, for example, the naphthidine is selected from The pyridine-imidazol is selected from... The pyrazinimidazole is selected from The pyrazinazole is selected from The pyrimidopyrazole is selected from The pyrimidinimidazole is selected from... The pyrimidotriazole is selected from The pyridazinimidazole is selected from The pyridazintriazole is selected from The triazinimidazole is selected from The pyridopyridazine is selected from The pyridinepyrazole is selected from The pyridine-pyrimidine is selected from The pyridotriazine is selected from The pyrimidine triazine is selected from

[0048] Specifically, for example, heterocyclic alkyl groups are selected from

[0049] The aromatic heterocycles include, but are not limited to,

[0050] 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 the alkyl group is replaced by a halogen, halogenated alkoxy means that at least one hydrogen atom on the alkoxy group is replaced by a halogen, and heterocyclic alkyl means that at least one carbon atom on the cycloalkyl group is replaced by a heteroatom.

[0051] As a preferred technical solution of the present invention, the heteroatom is selected from nitrogen, oxygen, and sulfur, and there is one or more heteroatoms; the oxo-substituted refers to the replacement of two hydrogen atoms on ring A by oxygen atoms.

[0052] As a preferred embodiment of the present invention, the saturated or unsaturated 4-6 membered ring is selected from: cyclohexyl group and benzene ring;

[0053] The 4-6 member saturated heterocycles are selected from:

[0054] The 8-10 octyl saturated or unsaturated bicyclic compounds are selected from:

[0055] The 8-10 quinone saturated or unsaturated heterobicyclic compounds are selected from:

[0056] As a preferred embodiment of the present invention, the oxygenated A ring is selected from:

[0057] In a preferred embodiment of the present invention, m is 2 or 3, n is 2, and p is 0, 1, 2, 3, or 4.

[0058] The A ring is selected from: benzene ring, cyclohexyl group, etc.

[0059] The R 1 Selected from fluorine, methyl, and trifluoromethyl; the R 2 Selected from

[0060] The R 3 Selected from hydrogen, ethyl, cyclobutyl,

[0061] The R 4 Selected from trifluoromethyl,

[0062] The R 5 Selected from methyl, ethyl, cyclopropyl, fluorine, oxo, hydroxyl, Methoxy, amino

[0063] As a preferred technical solution of the present invention, it is subjected to at least one R 5 The replaced A ring is selected from:

[0064] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from compounds having the following structure (Ia), or their isomers, racemates, or pharmaceutically acceptable salts thereof:

[0065] Among them, ring A and ring R 1 R 2 R 3 R 4 R 5 And m, n, p are defined as above.

[0066] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from compounds having the following structure (IIa), or their isomers, racemates, or pharmaceutically acceptable salts thereof:

[0067] Among them, R 5a R 5b R 5c R 5d R 1aR 1b R 1c R 2 R 3 R 4a R 4b As defined above.

[0068] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from the structure of compounds 1-102, as described in the specific embodiments in the specification.

[0069] As a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, prepared with a pharmaceutically acceptable acid or base.

[0070] As a preferred embodiment of the present invention, one or more hydrogen atoms of the compound, or its isomer, racemate, or pharmaceutically usable salt thereof, are substituted with the isotope deuterium.

[0071] Deuterated structures can be selected from:

[0072] The present invention further provides a pharmaceutical composition characterized in that it comprises a therapeutically effective amount of the compound, or an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0073] The present invention further provides the pharmaceutical use of the compound, or its isomer, racemate, or pharmaceutically usable salt thereof, and the pharmaceutical composition thereof, specifically, its use in the preparation of a medicament for treating diseases, said diseases being α4β7-related diseases, specifically selected from diseases such as enteritis.

[0074] For clarity, this article defines the general terminology used in the description of compounds.

[0075] 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.

[0076] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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).

[0081] 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 molecules of 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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, transdermal penetration enhancers, etc. 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.

[0086] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0087] 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.

[0088] 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.

[0089] "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.

[0090] 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. Detailed Implementation

[0091] 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.

[0092] The synthesis route for general formula A is as follows:

[0093]

[0094] Example 1: Synthesis of Compound 1

[0095]

[0096] Step A: Synthesis of 4-bromo-3,5-dimethylpyridine-1-oxide

[0097] 5 g (40.6 mmol) of 3,5-dimethylpyridine-1-oxide was dissolved in 100 mL of carbon tetrachloride at room temperature, followed by the sequential addition of liquid bromine (13 g, 81.2 mmol) and potassium carbonate (11.22 g, 81.2 mmol). The reaction mixture was reacted at 80 °C for 5 h. The reaction mixture was diluted with 100 mL of water and 100 mL of dichloromethane, and the mixture was extracted with ethyl acetate (100 mL × 3 times). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6 g of crude brown oily 4-bromo-3,5-dimethylpyridine-1-oxide (yield: 100.00%). LCMS: RT = 0.983 min, [M+H] + =186.0

[0098] Step B: Synthesis of 4-bromo-3,5-dimethylpyridine

[0099] 4-Bromo-3,5-dimethylpyridine-1-oxide (3.4 g, 16.82 mmol) was dissolved in dichloromethane (50 mL) at room temperature, followed by the addition of phosphorus tribromide (9.1 g, 33.64 mmol). The reaction mixture was allowed to react at room temperature for 2 hours until complete. The pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (50 mL × 3 times), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 1) to give 930 mg of brown oily 4-bromo-3,5-dimethylpyridine (yield: 27.35%). LCMS: RT = 0.717 min, [M+H] + =186.0.

[0100] Step C: Synthesis of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate

[0101] Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3-(trifluoromethyl)phenyl)propionate (100 mg, 0.211 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.4 mL) at room temperature. Then, 4-bromo-3,5-dimethylpyridine (59 mg, 0.317 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (17 mg, 0.0211 mmol) and potassium phosphate (90 mg, 0.422 mmol) were added sequentially. The reaction mixture was reacted overnight at 110°C under argon protection until complete. The reaction mixture was diluted with water (5 mL) and ethyl acetate (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3 times). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 50 mg of a brown oily substance, ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate (yield: 50.00%). LCMS: RT = 1.090 min, [M+H + =453.1.

[0102] Step E: Synthesis of ethyl (S)-3-amino-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate

[0103] Ethyl (S)-3-amino-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate (463 mg, 1.023 mmol) was dissolved in 9.2 mL of 1,4-dioxane solution under ice bath conditions, followed by the addition of hydrochloric acid / 1,4-dioxane (4.6 mL). The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 500 mg of the target compound (S)-3-amino-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate (yield: 77.76%) as a yellow oily liquid. LCMS: RT = 0.400 min, [M+H] + =349.1.

[0104] Step F: Synthesis of ethyl (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate

[0105] At room temperature, (S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (120 mg, 0.33 mmol) and (S)-3-amino-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate ethyl ester (150 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N,N-diisopropylethylamine (63 mg, 0.495 mmol), N-hydroxy-7-azabenzotriazole (54 mg, 0.39 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg, 0.39 mmol). The reaction mixture was stirred overnight at room temperature until complete. The reaction solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 110 mg of a yellow oily liquid (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate (yield: 45.91%). LCMS: RT = 1.057 min, [M+H] + =727.3.

[0106] Step G: Synthesis of (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-5-(3-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl)propionic acid

[0107] Ethyl (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(5-(3,5-dimethylpyridin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate (90 mg, 0.124 mmol) and lithium hydroxide monohydrate (16 mg, 0.374 mmol) were dissolved in tetrahydrofuran (2 mL) and water (0.4 mL) at room temperature. The reaction mixture was stirred at room temperature. The reaction was allowed to proceed overnight until complete. The insoluble solids were filtered off, and the residual solution was purified by high-performance liquid chromatography (HPLC) (trifluoroacetic acid) to give 11.15 mg of (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-5-(3-methylpyridin-4-yl)-3-(trifluoromethyl ester)phenyl)propionic acid. LCMS: RT = 4.257 min, [M+H] + =699.5; 1 HNMR (400MHz, DMSO): δ9.22(d,J=7.5Hz,1H),8.40(s,2H),7.83(s,1H),7.61–7.56(m,2H) ,6.79(s,1H),5.58–5.47(m,2H),3.82–370(m,4H),3.01–2.93(m,2H),2.76–2.70(m,2H), 2.75–2.70(m,2H),2.61–2.59(t,J=8.0Hz,2H),1.99(s,6H),2.20–2.14(m,1H),1.991(s, 6H),1.70–1.61(m,1H),1.69–1.66(m,1H),1.24–1.18(m,1H),0.79–0.75(t,J=8.0Hz,6H); 19 FNMR(376.5MHz, DMSO-d6): δ-59.678,-59.710,-62.449,-73.452,-123.116,-123.152.

[0108] Example 4: Synthesis of Compound 4

[0109]

[0110] Step A: Synthesis of 1-(5-bromo-2,4-dimethylphenyl)-3-chloropropane-1-one

[0111] Aluminum trichloride (10.09 g, 75.65 mmol) was dissolved in carbon disulfide (50 mL) at room temperature. 3-Chloropropionyl chloride (4.63 g, 36.47 mmol) and 1-bromo-2,4-dimethylbenzene (5 g, 27.02 mmol) were added at 0°C. The reaction mixture was stirred at 50°C for 0.5 h until complete. The reaction mixture was quenched over ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give 7 g of a yellow solid, 1-(5-bromo-2,4-dimethylphenyl)-3-chloropropane-1-one (yield: 94.02%). LCMS: RT = 1.997 min, [M+2+H] + =276.9.

[0112] Step B: Synthesis of 4-bromo-5,7-dimethyl-2,3-dihydro-1H-inden-1-one

[0113] 7 g (25.4 mmol) of 1-(5-bromo-2,4-dimethylphenyl)-3-chloropropane-1-one was dissolved in concentrated sulfuric acid (50 mL). The reaction mixture was stirred at 90 °C for 1 hour until complete. The reaction mixture was quenched on ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual solution was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to give 4.4 g of a yellow solid, 4-bromo-5,7-dimethyl-2,3-dihydro-1H-inden-1-one (yield: 72.44%). LCMS: RT = 1.937 min, [M+2+H] + =241.0.

[0114] Step C: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate

[0115] At room temperature, ethyl (S)-3-((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)propionate (1.2 g, 2.53 mmol) and 4-bromo-5,7-dimethyl-2,3-dihydro-1H-inden-1-one (484.91 mg, 2.0 mg) were mixed. 3 mmol) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (199.2 mg, 0.253 mmol) and potassium phosphate (1.08 g, 5.07 mmol) were added at room temperature. After purging the reaction solution with argon, the mixture was stirred overnight at 100°C until complete. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual solution was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to give 1.1 g of an orange-yellow oily liquid (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate (yield: 85.82%). LCMS: RT = 1.968 min, [M+H + =506.2.

[0116] Step D: Synthesis of ethyl (3S)-3-amino-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate

[0117] Ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate (1.1 g, 2.18 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and a solution of 1,4-dioxane-hydrochloride (1 mL, 4 mol / L) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour until complete. The reaction solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 700 mg of orange-yellow oily liquid (3S)-3-amino-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate (yield: 80.15%). LCMS: RT = 1.077 min, [M+H] + =402.0.

[0118] Step E: Synthesis of ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate

[0119] At room temperature, 200 mg (0.554 mmol) of (S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)yl)-4-methylpentanoic acid and ethyl (3S)-3-amino-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate were added. (267.36 mg, 0.665 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (215.19 mg, 1.66 mmol), N-hydroxy-7-azabenzotriazole (112.49 mg, 0.832 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (159.59 mg, 0.832 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature until complete. The reaction solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 250 mg of an orange-yellow oily liquid: ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate. LCMS: RT = 1.267 min, [M+H] + =744.2.

[0120] Step F: Synthesis of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[0121] Ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate (240 mg, 0.322 mmol) and lithium hydroxide monohydrate (67.7 mg, 1.61 mmol) were dissolved in tetrahydrofuran (1 mL) and water (1 mL) at room temperature. The reaction mixture was stirred overnight at room temperature until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high-performance liquid chromatography (HPLC) (trifluoroacetic acid) to give 71.94 mg of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionic acid. LCMS: RT = 5.521 min, [MH] - =714.9; 1 HNMR (400MHz, DMSO-d6): 1 HNMR(400MHz,DMSO)δ9.76(s,1H),9.44–9.27(m,1H),7.95(s,1H),7.24–7.08(m,2H),6.83(s,1H),5.81–5 .65(m,1H),5.51(dd,J=12.2,6.1Hz,1H),4.21–3.97(m,4H),3.52–3.44(m,2H),3.23(dd,J=13.0,7.2Hz,2H ),3.02–2.65(m,6H),2.60(d,J=25.1Hz,7H),2.43–2.27(m,2H),2.24(s,3H),2.11(d,J=3.5Hz,3H),1.94–1 .74(m,1H),1.55(ddd,J=14.3,9.3,5.4Hz,1H),1.18(dd,J=15.5,5.6Hz,1H),0.79(dt,J=13.0,5.4Hz,6H); 19 F NMR (377MHz, DMSO-d6): δ-62.50,-73.64,-117.86.

[0122] Example 6: Synthesis of Compound 6

[0123]

[0124] The specific synthesis route is as follows:

[0125] Step A: Synthesis of 5-bromo-4,6-dimethyl-2,3-dihydro-1H-indene

[0126] A mixture of 300 mg (1.26 mmol) of 6-bromo-5,7-dimethyl-2,3-dihydro-1H-indene-1-one and 5-bromo-4,6-dimethyl-2,3-dihydro-1H-indene-1-one was dissolved in 12 mL of 1,2-dichloroethane at room temperature. Sodium cyanoborohydride (591 mg, 9.41 mmol) and zinc iodide (601 mg, 1.88 mmol) were added to the reaction mixture, and the mixture was stirred overnight at 100°C under argon protection until complete. The insoluble solid was filtered off, and the solution was evaporated to dryness to give 230 mg of a yellow solid, 5-bromo-4,6-dimethyl-2,3-dihydro-1H-indene.

[0127] Step B: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate

[0128] Ethyl (S)-3-((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)propionate (486 mg, 1.04 mmol) and 5-bromo-4,6-dimethyl-2,3-dihydro-1H-indene (230 mg, 1.04 mmol) were dissolved in a mixed solvent of 1,4-dioxane (6 mL) and water (1.2 mL) at room temperature. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (40 mg, 0.05 mmol) and potassium phosphate (436 mg, 2.05 mmol) were added at room temperature. The reaction mixture was purged with argon and stirred overnight at 100°C until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 275 mg of an orange-yellow oily liquid (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate (yield: 46.93%). LCMS: RT = 1.423 min, [M+H] + =492.6.

[0129] Step C: Synthesis of ethyl (3S)-3-amino-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate

[0130] Ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate (275 mg, 0.56 mmol) was dissolved in 2.8 mL of 1,4-dioxane solution at room temperature, followed by the addition of 0.28 mL of 1,4-dioxane hydrochloride solution (4 mol / L). The reaction mixture was stirred at room temperature for 2 hours until complete. The reaction mixture was purified by rapid chromatography (mobile phase: water and acetonitrile) to give 180 mg of an orange-yellow oily liquid (3S)-3-amino-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate (yield: 83.10%). LCMS:RT = 1.193 min, [M+H] + =388.2.

[0131] Step D: Synthesis of ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate

[0132] At room temperature, (S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)yl)-4-methylpentanoic acid (83 mg, 0.23 mmol) and (3S)-3-amino-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate (81 mg, 0.21 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (41 mg, 0.31 mmol), N-hydroxy-7-azabenzotriazole (34 mg, 0.25 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (48 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 2 hours until complete. The reaction solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 105 mg of an orange-yellow oily liquid: (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate (yield: 68.84%). LCMS: RT = 1.033 min, [M+H] + =730.8.

[0133] Step E: Synthesis of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[0134] Ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionate (105 mg, 0.14 mmol) and lithium hydroxide monohydrate (22 mg, 0.52 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high-performance liquid chromatography (HPLC) (trifluoroacetic acid) to give 40.06 mg of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,6-difluoro-5-methylphenyl)propionic acid (yield: 39.68%). LCMS: RT = 1.388 min, [M+H] + =702.3; 1 H NMR (400MHz, DMSO-d6): 1 HNMR (400MHz, DMSO) δ9.84(s,1H),9.31(d,J=6.0Hz,1H),7.96(s,1H),7.02(s,1H),6.98(t,J=8.4Hz,1H),6.83(s,1H),5.73(dd,J=11.0 ,5.2Hz,1H),5.51(q,J=7.9Hz,1H),4.22–3.97(m,4H),3.28–3.20(m,2H),2.96(dd,J=16.3,8.7Hz,1H),2.88(t,J=7.4Hz,2H),2.81(dt, J=12.1,6.6Hz,3H),2.70(dd,J=13.9,5.9Hz,2H),2.39(dd,J=19.4,10.1Hz,1H),2.34–2.26(m,1H),2.22(s,3H),2.02(td,J=15.0,7.1H z,2H),1.91(s,3H),1.85(s,3H),1.81(dd,J=13.7,4.6Hz,1H),1.52(ddd,J=18.9,9.6,4.9Hz,1H),1.21–1.14(m,1H),0.82–0.75(m,6H); 19F NMR (377MHz, DMSO-d6): δ-62.52,-73.70,-118.06,-118.08,-118.12,-118.14,-119.17,-119.19,-119.22,-119.24.

[0135] Example 9: Synthesis of Compound 9

[0136]

[0137] Step A: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate

[0138] Ethyl propionate (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl) (600 mg, 3.000 mmol) was dissolved in a mixture of 1,4-dioxane (18 mL) and water (3.6 mL) at room temperature. Then, 4-bromo-2,4,6-trimethylpyridine (1.41 g, 2.980 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (105 mg, 0.134 mmol), and potassium phosphate (1.1 g, 5.374 mmol) were added sequentially. The reaction mixture was reacted overnight at 110°C under argon protection until complete. The reaction mixture was diluted with water (5 mL) and ethyl acetate (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3 times). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 754 mg of a brown oily substance, ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate (yield: 61.94%). LCMS: RT = 1.027 min, [M+H] + =467.0.

[0139] Step B: Synthesize ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate.

[0140] Ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate (754 mg, 1.666 mmol) was dissolved in 1,4-dioxane solution (4 mL) under ice bath conditions, followed by the addition of hydrochloric acid / 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 468 mg of the target compound (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate (yield: 80.00%). LCMS: RT = 0.580 min, [M+H] + =363.2.

[0141] Step C: Synthesis of ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate.

[0142] At room temperature, (S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)yl)-4-methylpentanoic acid (250 mg, 0.661 mmol) and (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate ethyl ester (230 mg, 0.661 mmol) were dissolved in N,N-dimethylformamide (4 mL), followed by the addition of N,N-diisopropylethylamine (128 mg, 0.992 mmol), N-hydroxy-7-azabenzotriazole (108 mg, 0.793 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (152 mg, 0.793 mmol). The reaction mixture was stirred overnight at room temperature until complete. The reaction mixture was purified by rapid chromatography (mobile phase: water and acetonitrile) to give 94 mg of a yellow oily liquid: ethyl (3S)-3-((S)-2-(5-(2-)azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate (yield: 20.09%). LCMS: RT = 0.937 min, [M+H] + =705.1.

[0143] Step D: Synthesis of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionic acid.

[0144] Ethyl (3S)-3-((S)-2-(5-(2-)azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionate (200 mg, 0.282 mmol) and lithium hydroxide monohydrate (35 mg, 0.846 mmol) were dissolved in tetrahydrofuran (3 mL) and water (0.6 mL) at room temperature. The reaction mixture was stirred overnight at room temperature until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high-performance liquid chromatography (HPLC) (trifluoroacetic acid) to give 10.68 mg of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(2,4,6-trimethylpyridin-3-yl)phenyl)propionic acid. LCMS: RT = 3.557 min, [M+H] + =677.9.

[0145] Example 23: Synthesis of compound 23

[0146]

[0147] Step A: Synthesis of 2-bromo-4-(2,2-diethoxyethoxy)-1-methylbenzene

[0148] 3-Bromo-4-methylphenol (4 g, 21.386 mmol) was dissolved in N,N-dimethylformamide (40 mL) at room temperature, followed by the addition of potassium carbonate (5.912 g, 42.774 mmol), and then 2-bromo-1,1-diethoxyethane (5.058 g, 25.664 mmol) at 0 °C. The reaction mixture was stirred overnight at 90 °C until complete. The reaction mixture was purified by rapid chromatography (mobile phase: water and acetonitrile) to give 3.212 g of an orange-yellow oily liquid, ethyl-2-bromo-4-(2,2-diethoxyethoxy)-1-methylbenzene. LCMS: RT = 1.701 min.

[0149] Step B: Synthesis of 4-bromo-5-methylbenzofuran

[0150] Ethyl 2-bromo-4-(2,2-diethoxyethoxy)-1-methylbenzene (3 g, 9.894 mmol) was dissolved in toluene (120 mL) at room temperature, and polyphosphoric acid (3.249 g, 29.683 mmol) was added at room temperature. The reaction mixture was stirred at 130 °C for 2 hours until complete. The reaction mixture was purified by silica gel column chromatography (mobile phase: petroleum ether) to give 1.85 g of orange-yellow oily liquid 4-bromo-5-methylbenzofuran. LCMS: RT = 1.273 min.

[0151] Step C: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionate

[0152] At room temperature, 4-bromo-5-methylbenzofuran (1.85 g, 8.765 mmol) and ethyl (S)-3-((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)propionate (3.813 g, 8.054 mmol) were dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (10 mL). At room temperature, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (317 mg, 0.403 mmol) and potassium phosphate (3.422 g, 16.120 mmol) were added. The reaction mixture was purged with argon and stirred overnight at 100°C until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 2.4 g of an orange-yellow oily liquid, (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionate. LCMS: RT = 1.235 min, [M+H] + =478.1.

[0153] Step D: Synthesis of ethyl(3S)-3-amino-3-(2,6-difluoro-3-methyl-4-(5-methylbenzofuran-4-yl)phenyl)propionic acid

[0154] Ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionate (300 mg, 0.593 mmol) was dissolved in 1,4-dioxane (10 mL) at room temperature, followed by the addition of 1 mL of 1,4-dioxane hydrochloride solution (4 mmol / L). The reaction mixture was stirred at room temperature for 1 hour until complete. The reaction mixture was purified by rapid chromatography (mobile phase: water and acetonitrile) to give 200 mg of orange-yellow oily liquid ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-4-(5-methylbenzofuran-4-yl)phenyl)propionate. LCMS: RT = 1.215 min, [M+H] + =374.1.

[0155] Step E: Synthesis of ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionate

[0156] (S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)yl)-4-methylpentanoic acid (155 mg, 0.431 mmol) and ethyl(3S)-3-amino-3-(2,6-difluoro-3-methyl-4-(5-methylbenzofuran-4-yl)phenyl)propionic acid (139 mg, 0.359 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature. N,N-diisopropylethylamine (93 mg, 0.718 mmol), N-hydroxy-7-azabenzotriazole (59 mg, 0.431 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (83 mg, 0.431 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature until complete. The reaction solution was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 88 mg of an orange-yellow oily liquid: (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionate (yield: 33.62%). LCMS: RT = 1.373 min, [M+H] + =716.2.

[0157] Step F: Synthesis of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionic acid

[0158] Ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionate (100 mg, 0.137 mmol) and lithium hydroxide monohydrate (17 mg, 0.411 mmol) were dissolved in tetrahydrofuran (2 mL) and water (0.4 mL) at room temperature. The reaction mixture was stirred overnight at room temperature until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high-performance liquid chromatography (HPLC) (trifluoroacetic acid) to give 8.21 mg of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(5-methylbenzofuran-4-yl)phenyl)propionic acid. LCMS: RT = 5.812 min, [MH] - =688.4.

[0159] Example 27 Synthesis of compound 27

[0160]

[0161] The specific synthesis route is as follows:

[0162] Step A: Synthesis of ethyl (3S)-3-amino-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate

[0163] Ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate (780 mg, 1.543 mmol) was dissolved in 1,4-dioxane (15.4 mL) at room temperature, followed by the addition of a 1,4-dioxane hydrochloride solution (1.54 mL, 4 mol / L, 6.171 mmol). The reaction mixture was stirred at room temperature for 1 hour until complete. The reaction solution was purified by rapid chromatography (mobile phase: water and acetonitrile) to give 560 mg of an orange-yellow oily liquid, ethyl (3S)-3-amino-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate. LCMS: RT = 0.708 min, [M+H] + =402.1.

[0164] Step B: Synthesis of ethyl (3S)-3-amino-3-(2,6-difluoro-3-(1-hydroxy-5,7-dimethyl-2,3-dihydro-1H-inden-4-yl)-5-methylphenyl)propionate

[0165] Ethyl (3S)-3-amino-3-(3-(5,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-4-yl)-2,6-difluoro-5-methylphenyl)propionate (736 mg, 1.833 mmol) was dissolved in methanol (7.5 mL) at room temperature, and sodium borohydride (69 mg, 1.833 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min until complete. The reaction mixture was purified by rapid chromatography (mobile phase: 0.1% trifluoroacetic acid aqueous solution and acetonitrile) to give 590 mg of orange-yellow oily liquid (3S)-3-amino-3-(2,6-difluoro-3-(1-hydroxy-5,7-dimethyl-2,3-dihydro-1H-inden-4-yl)-5-methylphenyl)propionate. LCMS: RT = 0.893 min, [M+H] + =404.3; RT=0.963min, [M+H] + =404.2.

[0166] Step C: Synthesis of ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(1-hydroxy-5,7-dimethyl-2,3-dihydro-1H-inden-4-yl)-5-methylphenyl)propionate

[0167] At room temperature, (S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (210 mg, 0.521 mmol) and (S)-3-amino-3-(5-(5,7-dimethyl-2,3-dihydro-1H-inden-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl)propionate ethyl ester (225 mg, 0.625 mmol) were dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (101 mg, 0.781 mmol), N-hydroxy-7-azabenzotriazole (85 mg, 0.625 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg, 0.625 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature until complete. The reaction mixture was purified by silica gel plate chromatography (mobile phase: ethanol / dichloromethane = 1 / 15) to give 120 mg of a yellow oily liquid: ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(1-hydroxy-5,7-dimethyl-2,3-dihydro-1H-inden-4-yl)-5-methylphenyl)propionate. LCMS: RT = 1.227 min, [M+H] + =746.2.

[0168] Step D: Synthesis of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(1-hydroxy-5,7-dimethyl-2,3-dihydro-1H-inden-4-yl)-5-methylphenyl)propionic acid

[0169] Ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(1-hydroxy-5,7-dimethyl-2,3-dihydro-1H-inden-4-yl)-5-methylphenyl)propionate (120 mg, 0.160 mmol) and lithium hydroxide monohydrate (32 mg, 0.762 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) at room temperature. The reaction mixture was stirred overnight at room temperature until complete. The insoluble solids were filtered off, and the residual solution was purified by high performance liquid chromatography (trifluoroacetic acid) to give 3.67 mg 27A (yield: 3.20%) and 2.33 mg 27B.

[0170] 27A:LCMS:RT=5.137min,[M+H]+ =718.3.

[0171] 27B: LCMS:RT=5.557min,[M+H] + =718.3; 1 H NMR (400MHz, DMSO-d6): δ9.04(t,J=6.4Hz,1H),7.74(s,1H),7.01(q,J=8.0Hz,1H),6.94(s,1H),6.76(s,1H),5.6 5–5.59(m,1H),5.51(dd,J=14.3,7.8Hz,1H),5.13(s,1H),4.96(s,1H),3.21(d,J=7.6Hz,4H),2.84(dd,J=16.0,10 .1Hz,1H),2.67(t,J=10.2Hz,1H),2.57(dd,J=14.7,8.5Hz,2H),2.34(s,3H),2.21(s,3H),1.99(t,J=6.5Hz,7H),1 .86–1.73(m,2H),1.64–1.56(m,1H),1.49–1.41(m,2H),0.83(dd,J=14.7,7.1Hz,5H),0.77(dd,J=6.3,4.5Hz,3H).

[0172] Example 47 Synthesis of compound 47

[0173]

[0174] The specific synthesis route is as follows:

[0175] Step A: Synthesis of 3-bromo-6-fluoro-2,4-dimethylbenzaldehyde

[0176] Dissolve 7 g of 2-bromo-5-fluoro-1,3-xylene in 70 mL of anhydrous dichloromethane, cool to 0 °C, and slowly add titanium tetrachloride (14.3 g, 75.8 mmol, 14.3 mL). After the addition is complete, stir at 0 °C for 1 hour. Then add 4.36 g of α,α-dichloromethyl methyl ether (37.9 mmol, 3.35 mL) and continue stirring at 0 °C for 1 hour.

[0177] At 0°C, water (100 mL) was added dropwise to the reaction solution to quench the reaction, and then the solution was extracted with dichloromethane (50 mL × 3 times). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 6.4 g of crude 3-bromo-6-fluoro-2,4-dimethylbenzaldehyde.

[0178] Step B: Synthesis of (Z)-1-(3-bromo-6-fluoro-2,4-dimethylbenzyl)-2-methylhydrazine

[0179] At room temperature, 3-bromo-6-fluoro-2,4-dimethylbenzaldehyde (3.40 g, 14.7 mmol) was dissolved in N,N-dimethylacetamide (34 mL). The reaction solution was cooled to 0°C, and then potassium carbonate (3.05 g, 22.0 mmol) and methylamine solution (10.0 g, 87.1 mmol) were added. After the addition was complete, the reaction solution was slowly heated to 100°C and stirred for 12 hours.

[0180] The reaction mixture was cooled to room temperature, quenched with ice water (100 mL), and then extracted with ethyl acetate (50 mL × 3 times). The combined organic phases were washed with saturated brine (70 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 9.60 g of crude product (Z)-1-(3-bromo-6-fluoro-2,4-dimethylbenzyl)-2-methylhydrazine. LC-MS: RT = 0.521 min, [M+H] + =260.9.

[0181] Step C: Synthesis of 5-bromo-1,4,6-trimethyl-1H-indazole

[0182] At room temperature, (Z)-1-(3-bromo-6-fluoro-2,4-dimethylbenzyl)-2-methylhydrazine (3.81 g, 258 mmol) was dissolved in N-methylpyrrolidone (38 mL), potassium tert-butoxide (2.47 g, 22.0 mmol) was added, and the mixture was slowly heated to 80 °C and stirred for 2 hours.

[0183] The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was then extracted with ethyl acetate (50 mL × 3 times). The combined organic phases were washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 1.43 g of 5-bromo-1,4,6-trimethyl-1H-indazole. LC-MS: RT = 0.546 min, [M+H] + =239.0.

[0184] Step D: Synthesis of ethyl (3S)-3-((R)-tert-butylsulfonyl)amino)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate

[0185] At room temperature, ethyl (S)-3-((R)-tert-butylsulfonyl)amino)-3-(2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)phenyl)propionate (890 mg, 1.88 mmol) and 5-bromo-1,4,6-trimethyl-1H-indazole (450 mg, 1.88 mmol) were dissolved in toluene (10 mL) and water (2 mL), and then... Potassium phosphate (798 mg, 3.76 mmol) was added, and the reaction mixture was purged with nitrogen three times. Then, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) (159 mg, 0.188 mmol) was added. The temperature was raised to 95°C, and the mixture was stirred under a nitrogen atmosphere for 12 hours until the reaction was substantially complete as monitored by LC-MS.

[0186] The reaction solution was diluted with water (10 mL), then extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography to give 438 mg of ethyl (3S)-3-((R)-tert-butylsulfonyl)amino)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate. LC-MS: RT = 0.568 min, [M+H] + =506.2.

[0187] Step E: Synthesis of ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate

[0188] At room temperature, ethyl (3S)-3-((R)-tert-butylsulfoxide)amino)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate (438 mg, 0.866 mmol) was dissolved in ethanol (4 mL). The reaction solution was cooled to 0°C, and then concentrated hydrochloric acid (12 mol / L, 0.2 mL) was slowly added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred for 2 hours until the reaction was complete as monitored by LC-MS.

[0189] The reaction solution was cooled to 5–10°C, and the pH was adjusted to 7–8 with a 5% sodium hydroxide aqueous solution. The mixture was then extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 350 mg of crude (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate. LC-MS: RT = 0.456 min, [M+H] +=402.1.

[0190] Step F: Synthesis of ethyl (3S)-3-((R)-2-bromo-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate

[0191] At room temperature, (2R)-2-bromo-4-methylpentanoic acid (221 mg, 1.13 mmol) and (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate ethyl ester (350 mg, 0.871 mmol) were dissolved in N,N-dimethylformamide (4 mL), cooled to 0°C, and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (366 mg, 1.31 mmol) and N-methylimidazole (217 mg, 2.62 mmol, 0.208 mL) were added. The mixture was then brought back to room temperature and stirred for 1 hour until the reaction was complete as monitored by LC-MS.

[0192] The reaction solution was diluted with water (10 mL), then extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was preparatively purified (column: Phenomenex luna C18150*40mm*15um; mobile phase: [water(FA)-ACN]; gradient: 60%-90% B over 15 min) to give 300 mg of ethyl (3S)-3-((R)-2-bromo-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate. LC-MS: RT = 0.603 min, [M+H] + =580.2.

[0193] Step G: Synthesis of ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxoylide-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoylamino)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate

[0194] At room temperature, ethyl (3S)-3-((R)-2-bromo-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionate (200 mg, 0.345 mmol) was dissolved in acetonitrile (4 mL), and then 5-(2-(azidobut-1-yl)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-1-one (110 mg, 0.449 mmol) and potassium carbonate (143 mg, 1.04 mmol) were added. The reaction solution was heated to 60°C and stirred for 36 hours.

[0195] The reaction solution was cooled to room temperature, filtered, and the filtrate was purified using preparative methods (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN]; gradient: 30%-50% B over 10 min) to yield 100 mg of ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indol-5-yl)phenyl)propionate. LC-MS: RT = 0.521 min, [M+H] + =744.4.

[0196] Step H: Synthesis of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxoylide-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indazol-5-yl)phenyl)propionic acid

[0197] At room temperature, ethyl (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indol-5-yl)phenyl)propionate (100 mg, 0.134 mmol) was dissolved in methanol (1.0 mL) and water (0.2 mL), cooled to 0°C, and then lithium hydroxide monohydrate (11.2 mg, 0.268 mmol) was added. The mixture was then brought back to room temperature and stirred for 2 hours until the reaction was complete as monitored by LC-MS.

[0198] The reaction solution was filtered to obtain a filtrate, which was adjusted to pH 6-7 with formic acid. Then, it was purified by preparative chromatography (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 23%-43% B over 10 min) to obtain 36.5 mg of (3S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide-3-(2,6-difluoro-3-methyl-5-(1,4,6-trimethyl-1H-indol-5-yl)phenyl)propionic acid. LC-MS: RT = 0.500 min, [M+H] + =716.3; 1 HNMR(400MHz,DMSO-d6)δ9.15-8.96(m,1H),8.07(s,1H),7.76(s,1H),7.40(s,1H),7.04(t,J=8.4Hz,1H ),6.75(s,1H),5.65-5.57(m,1H),5.56-5.47(m,1H),4.02(s,4H),3.22(qd,J=7.2,14.4Hz,6H),2.85(br dd,J=9.2,15.6Hz,1H),2.70(br dd,J=6.4,15.6Hz,1H),2.62-2.54(m,2H),2.47-2.42(m,2H),2.24(s,3H),2.19(d,J=2.4Hz,3H),2.08(s,3H),2.02-1.94(m,2H), 1.88-1.76(m,1H),1.60(ddd,J=5.6,8.8,14.0Hz,1H),1.28-1.17(m,1H),0.81(dd,J=2.4,6.4Hz,3H),0.76(dd,J=4.0,6.4Hz,3H).

[0199] Examples 47A and 47B

[0200]

[0201] The specific synthetic route was prepared according to the synthetic method of Example 47. The same preparation method as in Example 47 was used, including coupling, deprotection, condensation, substitution, and hydrolysis, to obtain a crude product containing a mixture of isomers of the target compound. The crude product was purified to obtain a pure mixture, which was then resolved by chiral SFC (column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 25%, isocrine mode) to obtain 16.6 mg of 47A and 12.6 mg of 47B.

[0202] 47A:LCMS:RT=0.494min,[M+H] + =716.4; 1H NMR (400MHz, DMSO-d6) δ = 9.17 (brd, J = 7.2Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.41 (s, 1H), 7.05 (br t, J = 8.4Hz, 1H), 6.79 (s, 1H), 5.66 (br dd,J=5.6,10.8Hz,1H),5.52(q,J=7.2Hz,1H),4.02(s,3H),3.02-2.70(m,6H),2.63-2.53(m,4H),2.24(s,3H), 2.20(s,3H),2.16-2.10(m,2H),2.08(s,3H),1.89-1.79(m,1H),1.63-1.51(m,1H),1.22-1.12(m,1H),0.79(br dd,J=6.4,18.0Hz,6H);19FNMR(400MHz,DMSO-d6)δ=-62.48(3F),-118.00(1F),-118.88(1F).

[0203] 47B: RT = 0.496 min, [M+H] +=716.4; 1H NMR (400MHz, DMSO-d6) δ = 9.06 (br d, J = 7.2Hz, 1H), 8.07 (s, 1H), 7.76 (s, 1H), 7.40 (s, 1H), 7.04 (br t, J = 8.4Hz, 1H), 6.76 (s, 1H), 5.60 (br dd,J=5.6,10.4Hz,1H),5.52(q,J=7.2Hz,1H),4.02(s,3H),3.23(qd,J=6.8,14.0Hz,4H),2.88(br s,2H),2.70(br dd,J=6.0,15.6Hz,2H),2.60-2.55(m,2H),2.21(brd,J=18.4Hz,6H),2.08(s,3H),1.99(q,J =7.2Hz,2H),1.89-1.74(m,1H),1.65-1.53(m,1H),1.25-1.17(m,1H),0.87-0.70(m,6H); 19F NMR(400MHz, DMSO-d6)δ=-62.46(3F),-118.07(1F),-118.84(1F).

[0204] Example 48

[0205]

[0206] The specific synthesis route is as follows:

[0207] Step A: Synthesis of ethyl 6-bromo-5,7-dimethylpyrazole[1,5-a]pyridine-3-carboxylate

[0208] 3-Bromo-2,4-dimethylpyridine (2 g, 10.7 mmol, 1 equivalent) was dissolved in acetonitrile (30 mL). A solution of oxy-(2,4-dinitrophenyl)hydroxylamine (2.14 g, 10.7 mmol, 1 equivalent) in acetonitrile (10 mL) was added dropwise at 0°C, and the reaction was continued at 40°C for 2 hours. The reaction solution was concentrated, and N,N-dimethylformamide (20 mL), potassium carbonate (2.97 g, 21.5 mmol, 2 equivalent), and ethyl propynate (1.05 g, 10.7 mmol, 1.05 mL, 1 equivalent) were added. The reaction was then carried out at 25°C for 5 hours until the reaction was complete as monitored by LC-MS.

[0209] Cool the reaction solution to 25°C, filter, concentrate under vacuum, and dilute with 70 mL of water. Add ethyl acetate (50 mL x 2). Combine the organic phases and wash with saturated brine (20 mL x 2). Purify the crude product using reverse-phase chromatography (0.1% ammonia-acetonitrile).

[0210] Ethyl 6-bromo-5,7-dimethylpyrazole[1,5-a]pyridine-3-carboxylic acid was obtained (400 mg, 1.35 mmol, 12.5% ​​yield).

[0211] Step B: Synthesis of 6-bromo-5,7-dimethylpyrazole[1,5-a]pyridine

[0212] The compound 6-bromo-5,7-dimethylpyrazole[1,5-a]pyridine-3-carboxylic acid ethyl ester (1.5 g, 5.05 mmol, 1 equivalent) was dissolved in 20 mL (40%) of sulfuric acid aqueous solution at room temperature and reacted at 110 °C for 3 hours. The reaction was monitored by LCMS and was found to be basically complete.

[0213] The reaction solution was cooled to 25°C, filtered, concentrated under vacuum, and diluted with 50 mL of water. Ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography was used for purification (eluent: ethyl acetate / petroleum ether = 1 / 0-3 / 1) to give 6-bromo-5,7-dimethylpyrazole[1,5-a]pyridine (300 mg, 1.33 mmol).

[0214] Step C: Synthesis of ethyl (3S)-3-[[(R)-tert-butylsulfonyl]amino]-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate

[0215] At room temperature, potassium phosphate (933 mg, 4.40 mmol, 3 equivalents) was added to a solution of ethyl (3S)-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-3-[[(R)-tert-butylsulfoxide]amino]propionate (1.11 g, 2.35 mmol, 1.6 equivalents) and 6-bromo-5,7-dimethylpyrazole[1,5-a]pyridine (330 mg, 1.47 mmol, 1 equivalent) in toluene (8 mL) and water (0.5 mL). The reaction mixture was purged with nitrogen three times. Then add (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) (62.05 mg, 73.31 μmol, 0.05 equivalents), raise the temperature to 100 degrees Celsius, and stir for 5 hours under a nitrogen atmosphere until the reaction is substantially complete as monitored by LC-MS.

[0216] The reaction solution was cooled to 25°C, filtered, concentrated under vacuum, and diluted with 10 mL of water. Ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: ethyl acetate / petroleum ether = 2 / 1) to give 500 mg of ethyl(3S)-3-[[(R)-tert-butylsulfonyl]amino]-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate.

[0217] Step D: Synthesis of ethyl (3S)-3-amino-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate

[0218] At room temperature, concentrated hydrochloric acid (180 mg, 183 mmol, 176 μL, 37% purity, 3 equivalents) was added to an ethanol (3 mL) solution of ethyl (3S)-3-[[(R)-tert-butylsulfonyl]amino]-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate (300 mg, 610 μmol, 1 equivalent). The mixture was stirred at 25°C for 2 hours until the reaction was substantially complete as monitored by LC-MS.

[0219] The reaction solution was adjusted to pH 8 with a saturated sodium bicarbonate aqueous solution. Then it was extracted with ethyl acetate (20 mL × 2), the combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain 300 mg of crude ethyl (3S)-3-amino-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate.

[0220] Step E: Synthesis of ethyl(3S)-3-[[(2R)-2-bromo-4-methylpentyl]amino]-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate

[0221] At room temperature, ethyl (3S)-3-amino-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate (300 mg, 774 μmol, 1 equivalent) and (2R)-2-bromo-4-methylpentanoic acid (196 mg, 1.01 mmol, 1.3 equivalent) were dissolved in a solution of N,N-dimethylformamide (5 mL), followed by the addition of N-methylimidazolium (190 mg, 2.32 mmol, 185 μL, 3 equivalent), and then N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (325 mg, 1.16 mmol, 1.5 equivalent) at 0 °C. The reaction was stirred at 0 °C for 2 hours until the reaction was substantially complete as monitored by LC-MS.

[0222] Concentrate the reaction mixture under vacuum. Dilute with 10 mL of water. Add ethyl acetate (10 mL x 2). Combine the organic phases and wash with saturated brine (10 mL x 2). Dry the combined organic phases with anhydrous sodium sulfate.

[0223] The crude product was used directly in the next step. This yielded (300 mg, 483 μmol, 62.4% yield, 91% purity) ethyl(3S)-3-[[(2R)-2-bromo-4-methylpentyl]amino]-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenyl]propionate.

[0224] Step F: Synthesis of ethyl (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide-3-(3-(5,7-dimethylpyridin-6-yl)[1,5-a]pyridin-6-yl)-2,6-difluoro-5-methylphenyl)propionate

[0225] At room temperature, ethyl(3S)-3-[[(2R)-2-bromo-4-methylpentyl]amino]-3-[3-(4,6-dimethylpyrazol[1,5-a]pyridin-5-yl)-2,6-difluoro-5-methylphenylsuan]propionate (140 mg, 248 μmol, 1 equivalent), 5-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-(trifluoromethyl)-1,2-dihydropyridin-2-one (91.6 mg, 372 μmol, 1.5 equivalent), and potassium carbonate (109 mg, 793 μmol, 3.2 equivalent) were added to acetonitrile (8 mL). The reaction mixture was heated to 60 °C and stirred for 8 hours until the reaction was substantially complete as monitored by LC-MS.

[0226] The reaction mixture was cooled to 25°C and concentrated under vacuum. It was diluted with 10 mL of water. Ethyl acetate (10 mL × 2) was added. The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product (180 mg) ethyl(S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide-3-(3-(5,7-dimethylpyridin-6-yl)[1,5-a]pyridin-6-yl)-2,6-difluoro-5-methylphenyl)propane ester.

[0227] Step G: Synthesis of (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(5,7-dimethylpyrazolino[1,5-a]pyridin-6-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[0228] At room temperature, lithium hydroxide (11.0 mg, 263 μmol, 1.2 equivalents) was added at 0°C to a solution of ethyl(S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide-3-(3-(5,7-dimethylpyridin-6-yl)[1,5-a]pyridin-6-yl)-2,6-difluoro-5-methylphenyl)propane ester (160 mg, 219 μmol, 1 equivalent) in methanol (2 mL) and water (0.5 mL). The mixture was stirred at 25°C for 2 hours until the reaction was substantially complete as monitored by LC-MS.

[0229] The reaction solution was concentrated and purified by high-performance liquid chromatography (Phenomenex Luna C18150*40mm*15um, mobile phase: formic acid-water-acetonitrile). The purified mixture was lyophilized to remove solvent and water, yielding (S)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(5,7-dimethylpyrazolino[1,5-a]pyridin-6-yl)-2,6-difluoro-5-methylphenyl)propane acid (35 mg, 49.5 μmol). LC-MS: RT = 0.492 min, [M+H] + =702.3; 1HNMR(400MHz,DMSO-d6)δ9.10(br d,J=6.4Hz,1H),8.05-8.00(m,1H),7.78-7.71(m,1H),7.61-7.51(m,1H),7.25-7.16(m,1H),6.76(s,1H ),6.61-6.55(m,1H),5.66-5.56(m,1H),5.56-5.44(m,1H),3.32-3.15(m,5H),2.94-2.81(m,1H),2.77- 2.65(m,1H),2.62-2.55(m,2H),2.48-2.44(m,2H),2.44-2.38(m,3H),2.28-2.23(m,3H),2.06-1.92(m, 19F NMR(377MHz, DMSO-d6)δ-62.46(s,1F),-118.30(br s,1F).

[0230] Examples 48A and 48B

[0231]

[0232] Examples 48A and 48B were prepared using the same synthetic route as in Example 48, involving coupling, deprotection, condensation, substitution, and hydrolysis steps to obtain a crude product containing a mixture of isomers of the target compound. This crude product was then purified to obtain a pure mixture, which was then subjected to chiral SFC resolution.

[0233] (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 30%, isocrine elution mode) yielded 37.6 mg of 48A and 31.9 mg of 48B.

[0234] 48A:LCMS:RT=0.498min,[M+H] + =702.4; 1HNMR(400MHz,DMSO-d6)δ=9.19(br d,J=6.4Hz,1H),8.02(d,J=2.0Hz,1H),7.76(s,1H),7.54(s,1H),7.14(t,J=8.4Hz,1H),6.73(s,1H),6.57(d,J=2.4Hz,1H),5.66(dd,J=5.6,11.2Hz,1H),5.45(q,J=7.2Hz,1H),3.19-3.06(m,5H),2.75-2.65(m,1H),2.48-2.43(m,3H),2.42(s,3H),2.41-2.37(m,1H),2.23(s,3H),2.00(s,3H),1.94(br t,J=6.8Hz,2H),1.85-1.75(m,1H),1.65-1.55(m,1H),1.23-1.13(m,1H),0.81(d,J=6.4Hz,3H),0.76(d,J=6.4Hz,3H); 19 FNMR(400MHz,DMSO-d6)δ=-62.50(3F),-117.18(1F),-117.48(1F).

[0235] 48B:LCMS:RT=0.499min,[M+H] + =702.4; 1 H NMR(400MHz,DMSO-d6)δ=9.19(brd,J=5.6Hz,1H),8.02(d,J=2.0Hz,1H),7.75(s,1H),7.55(s,1H),7.15(br t,J=8.0Hz,1H),6.74(s,1H),6.58(d,J=2.0Hz,1H),5.64(dd,J=5.2,10.4Hz,1H),5.44(q,J=6.8Hz,1H),3.14(qd,J=7.2,14.4Hz,5H),2.74(br dd,J=8.8,15.6Hz,1H),2.48-2.42(m,3H),2.40(s,3H),2.37(br s,1H),2.24(s,3H),2.01(s,3H),1.95(q,J=6.8Hz,2H),1.86-1.77(m,1H),1.64-1.55(m,1H),1.22-1.13(m,1H),0.80(d,J=6.4Hz,3H),0.75(d,J=6.4Hz,3H); 19F NMR (400MHz, DMSO-d6) δ = -62.49 (3F), -118.18 (1F), -118.59 (1F).

[0236] Example 62: Synthesis of compound 62

[0237]

[0238] The specific synthesis route is as follows:

[0239] Step A: Synthesis of 5-bromo-4,6-dimethyl-2H-indazole

[0240]

[0241] Solution 1: Dissolve 3-bromo-6-fluoro-2,4-dimethylbenzaldehyde (2.5 g, 10.8 mmol) and 85% hydrazine hydrate (12.8 g, 217 mmol, 12.4 mL) in N,N-dimethylacetamide (100 mL).

[0242] Solution 1 is pumped into pump 1 {S1, P1, 4 mL / min} and arrives at reactor 1 {FLR1, PFA, Coils reactor, 3.175 (1 / 8”) mm, 60 mL, 220°C}.

[0243] The reaction solution resides in reactor 1 for 15 minutes, and the back pressure regulator is adjusted to 4 MPa.

[0244] The reaction mixture was cooled to room temperature, quenched with ice water (100 mL), and then extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate) to give 500 mg of a white solid, 5-bromo-4,6-dimethyl-2H-indazole (yield: 20.5%). LCMS: RT = 0.570 min, [M + H + =226.9.

[0245] Step B: Synthesis of 5-bromo-2,4,6-trimethyl-2H-indazole

[0246] At room temperature, 5-bromo-4,6-dimethyl-2H-indazole (800 mg, 3.55 mmol) was dissolved in ethyl acetate (30 mL), and trimethyloxonium tetrafluoroborate (600 mg, 4.27 mmol) was added. The reaction was allowed to proceed for 1 hour until the reaction was complete as monitored by LCMS.

[0247] The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate) to give 600 mg of 5-bromo-2,4,6-trimethyl-2H-indazole. LCMS: RT = 0.583 min, [M+H] + =239.0.

[0248] The same preparation method as in Example 47 was subsequently used, involving coupling, deprotection, condensation, substitution, and hydrolysis to obtain a crude mixture containing the target product. The crude product was then chirally separated by SFC (column: DAICL CHIRALPAK IE (250mm*30mm, 10um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 45%, isocallicelution mode) to obtain crude 62A and crude 62B. These were further purified to obtain 41 mg of 62A and 35 mg of 62B, respectively.

[0249] 62A: LCMS:RT=1.041min,[M+H] + =716.5; 1 H NMR (400MHz, DMSO-d6) δ8.87-9.14(m,1H),8.36(s,1H),7.75(s,1H),7.33(s,1H),7.05(t,J=8.4Hz,1H),6.76( s,1H),5.37-5.82(m,2H),4.12-4.17(m,3H),3.19-3.24(m,4H),2.78-2.91(m,1H),2.71-2.75(m,1H),2.56(br s,3H),2.41-2.44(m,1H),2.24(s,3H),2.14(s,3H),2.02(br s,5H),1.75-1.87(m,1H),1.54(s,1H),1.17-1.32(m,1H),0.79-0.84(m,3H),0.73-0.79(m,3H); 19 F NMR(377MHz,DMSO-d6)δ-62.44(3F),-117.92(1F),-119.08(1F).

[0250] 62B: LCMS:RT=1.031min,[M+H] + =716.5; 1H NMR(400MHz,DMSO-d6)δ9.07(br d,J=7.2Hz,1H),8.38(s,1H),7.77(s,1H),7.33(s,1H),6.99-7.13(m,1H),6.76(s,1H),5.41-5.70 (m,2H),4.15(s,3H),3.21-3.27(m,4H),2.93(s,1H),2.72-2.77(m,1H),2.59-2.63(m,2H),2.47(br s,2H),2.24(s,3H),2.14(s,3H),1.95-2.03(m,5H),1.78-1.89(m,1H),1.53- 1.67(m,1H),1.14-1.33(m,1H),0.82(d,J=6.8Hz,3H),0.76(d,J=6.4Hz,3H); 19 FNMR(377MHz, DMSO-d6)δ-62.45(3F),-117.97(1F),-119.07(1F).

[0251] Example 63: Synthesis of compounds 63A and 63B

[0252]

[0253] The specific synthesis route is as follows:

[0254] Step A: Synthesis of 3-bromo-6-methoxy-2,4-dimethylpyridine

[0255] 3-Bromo-6-chloro-2,4-dimethylpyridine (1 g, 4.54 mmol) and sodium methoxide methanol solution (5.4 M, 2.52 mL) were dissolved in methanol (10 mL) at room temperature and under nitrogen protection. The mixture was then stirred at 100°C under nitrogen atmosphere for 2 hours until the reaction was substantially complete as monitored by LCMS.

[0256] The reaction mixture was cooled to room temperature, diluted with ice water (80 mL), and extracted with ethyl acetate (50 mL x 3 times). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 850 mg of a yellow oily 3-bromo-6-methoxy-2,4-dimethylpyridine. LCMS: RT = 0.617 min, [M + H] + =216.0.

[0257] Step B: Synthesis of ethyl (3S)-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate

[0258] 3-Bromo-6-methoxy-2,4-dimethylpyridine (500 mg, 2.31 mmol) and ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)propionate (1.64 g, 3.47 mmol) were dissolved in tetrahydrofuran (5 mL) and water. Add 4.6 mL of potassium phosphate (1.47 g, 6.94 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (180 mg, 0.231 mmol), purge with nitrogen three times, then heat to 90°C and stir under nitrogen atmosphere for 1 hour until the reaction is substantially complete as monitored by LCMS.

[0259] The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate) to give yellow oil (3S)-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}ethyl propionate (1.10 g, 1.92 mmol, yield: 46.3%, purity: 84.2%). LCMS: RT = 0.779 min, [M+H] + =483.2.

[0260] Step C: Synthesis of ethyl (3S)-3-amino-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionate

[0261] At room temperature, ethyl (3S)-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (1.10 g, 1.92 mmol) was dissolved in ethanol (10 mL), and then 12 mol / L concentrated hydrochloric acid (0.57 mL) was slowly added dropwise. The reaction was allowed to proceed for half an hour until the reaction was substantially complete as monitored by LCMS.

[0262] The reaction solution was adjusted to pH 7–8 with ice-cold saturated sodium bicarbonate solution, then extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 760 mg of yellow oil (3S)-3-amino-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionate. LCMS: RT = 1.260 min, [M+H] + =379.3.

[0263] Step D: Synthesis of ethyl (3S)-3-[(2R)-2-bromo-4-methylpentamido]-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionate

[0264] Ethyl (3S)-3-amino-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionate (730 mg, 1.51 mmol) and (2R)-2-bromo-4-methylpentanoic acid (382 mg, 1.96 mmol) were dissolved in N,N-dimethylformamide (5 mL), cooled to 0°C, and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (634 mg, 2.26 mmol) and N-methylimidazole (371 mg, 4.52 mmol, 360 μL) were added in portions. The mixture was then allowed to return to room temperature and reacted for 0.5 h until the reaction was substantially complete as monitored by LCMS.

[0265] The reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (75 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate) to give 650 mg of yellow oil (3S)-3-[(2R)-2-bromo-4-methylpentanamido]-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionate (650 mg, 0.875 mmol. LCMS: RT = 1.552 min, [M+H)). + =557.3.

[0266] Step E: Synthesis of ethyl (3S)-3-[(2S)-2-{5-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentamido]-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionate

[0267] Ethyl (3S)-3-[(2R)-2-bromo-4-methylpentamido]-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionate (600 mg, 0.807 mmol) and 5-[2-(azacyclobutan-1-yl)ethyl]-4-(trifluoromethyl)-1,2-dihydropyridin-2-one (396 mg, 1.21 mmol, hydrobromide) were dissolved in acetonitrile (10 mL), and then potassium carbonate (1.12 g, 8.08 mmol) was added. The reaction solution was heated to 60°C and reacted for 5 hours until the reaction was substantially complete as monitored by LCMS.

[0268] The reaction was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (80 mL). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative chromatography (column: Phenomenex luna C18150*40mm*15um, mobile phase: [H2O (0.225% formic acid)-acetonitrile], gradient: 28%-58% B, duration: 15.0 min) to give 300 mg of ethyl (3S)-3-[[(2S)-2-[5-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1-pyridyl]-4-methylpentamido]-3-[3-[4,6-dimethyl-1-(trideuterylmethyl)indazole-5-yl]-2,6-difluoro-5-methylphenyl]propionate. LCMS:RT=0.508min,[M+H] + =721.4.

[0269] Step F: Synthesis of (3S)-3-[(2S)-2-{5-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentamido]-3-[2,6-difluoro-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-5-methylphenyl]propionic acid

[0270] Ethyl (3S)-3-[[(2S)-2-[5-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1-pyridyl]-4-methylpentamido]-3-[3-[4,6-dimethyl-1-(trideutermethyl)indazole-5-yl]-2,6-difluoro-5-methylphenyl]propionate (250 mg, 308 μmol) was dissolved in methanol (2 mL) and water (0.4 mL), then cooled to 0°C, and lithium hydroxide monohydrate (25.8 mg, 616 μmol) was added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 hour until the reaction was substantially complete as monitored by LCMS.

[0271] The reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was then separated by chiral SFC (column: DAICL CHIRALPAKIG (250mm*30mm, 10µm), mobile phase: [CO2-EtOH (0.1% NH3H2O)], B%: 60%, isobaric elution mode) to obtain 60 mg Peak1 and 60 mg Peak2. 60 mg Peak1 was preparatively purified (column: Waters xbridge 150*25mm 10µm; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 36%-56% B for over 10.0 min) to obtain 30.26 mg 63A; 60 mg 63B was preparatively purified (column: Waters xbridge 150*25mm 10µm; mobile phase: [H2O (10mM NH4HCO3)-ACN], ... [NH4HCO3)-ACN]; gradient: 36%-56% B over 10.0 min) yielded 30.44 mg 63B.

[0272] 63A:LCMS:RT=0.439min,[M+H] + =693.4;SFC:RT=0.794min; 1 HNMR(400MHz,DMSO-d6)δ9.04(br d,J=7.20Hz,1H)7.74(s,1H)7.11-7.06(m,1H)6.76(s,1H)6.64(s,1H)5.61-5.5 7(m,1H)5.52-5.47(m,1H)3.84(s,3H)3.26-3.19(m,6H)2.88-2.81(m,1H)2.74-2 .66(m,1H)2.60-2.56(m,2H)2.22(s,3H)2.12-2.07(m,3H)2.01-1.92(m,5H)1.8 5-1.76(m,1H)1.62-1.55(m,1H)1.27-1.17(m,1H)0.78(dd,J=16.8,6.40Hz,6H); 19 FNMR(376MHz, DMSO-d6)δ-62.44(3F),-118.01(1F),-118.15(1F).

[0273] 63B:LCMS:RT=0.438min,[M+H] + =693.4;SFC:RT=1.934min; 1HNMR(400MHz,DMSO-d6)δ9.06(br d,J=6.80Hz,1H)7.75(s,1H)7.09(t,J=8.40Hz,1H)6.76(s,1H)6.64(s,1H)5 .62-5.58(m,1H)5.55-5.44(m,1H)3.85(s,3H)3.28-3.18(m,6H)2.88-2.82(m ,1H)2.73-2.67(m,1H)2.62-2.55(m,2H)2.23(s,3H)2.10(s,3H)2.01-1.93(m ,5H)1.85-1.78(m,1H)1.64-1.57(m,1H)1.27-1.16(m,1H)0.84-0.75(m,6H); 19 F NMR(376MHz, DMSO-d6)δ-62.45(3F),-118.02(1F),-118.14(1F).

[0274] Example 75: Synthesis of Compound 75

[0275]

[0276] The specific synthesis route is as follows:

[0277] Step A: Synthesis of 5-bromo-2-(difluoromethyl)-4,6-dimethyl-2H-indole

[0278]

[0279] 5-Bromo-4,6-dimethyl-2H-indole (1 g, 4.44 mmol) was dissolved in anhydrous acetonitrile (10 mL), potassium fluoride (516 mg, 8.89 mmol) and 1-[[bromo(difluoro)methyl]-ethoxyphospho]oxyethane (1.19 g, 4.44 mmol) were added, the mixture was purged with nitrogen three times, and stirred at room temperature under a nitrogen atmosphere for 12 hours until the reaction was substantially complete as monitored by LCMS.

[0280] The reaction mixture was diluted with water (50 mL), then extracted three times with ethyl acetate (40 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 950 mg of 5-bromo-2-(difluoromethyl)-4,6-dimethyl-2H-indole. LCMS: RT = 0.607 min, [M+H] + =275.1.

[0281] The same steps as in Example 47 were then followed to obtain two isomers of the target compound.

[0282] 75A:LCMS:RT=0.487min,[M+H] + =752.4; 1 HNMR(400MHz,DMSO-d6)δppm 9.09(brd,J=6.80Hz,1H)8.98(s,1H)8.10(t,J=59.2Hz,1H)7.76(s,1H)7.46(s,1H)7.07(t,J=7.60Hz,1H)6.75(s,1H )5.57-5.65(m,1H)5.46-5.55(m,1H)3.17-3.23(m,7H)2.79-2.89(m,2H)2.24(s,3H)2.18(s,3H)2.03(s,3H)1.97(br t,J=6.80Hz,2H)1.77-1.87(m,1H)1.55-1.67(m,1H)1.17-1.28(m,2H)0.82(d,J=6.80Hz,3H)0.76(d,J=6.40Hz,3H); 75B: LCMS: RT=0.477min, [M+H] + =752.4; 1 HNMR(400MHz,DMSO-d6)δppm 9.10(br d,J=7.60Hz,1H)8.95(s,1H)8.11(s,1H)7.75(s,1H)7.46(s,1H)7.06(br t,J=7.60Hz,1H)6.75(s,1H)5.57-5.67(m,1H)5.44-5.55(m,1H)3.15-3.22(m,6H)2.78(br d,J=8.80Hz,2H)2.24(s,3H)2.19(s,3H)2.02(s,3H)1.93-1.99(m,2H)1.81(br d,J=4.40Hz,1H)1.60(s,1H)1.18-1.29(m,2H)0.81(d,J=6.40Hz,3H)0.76(d,J=6.40Hz,3H).

[0283] Example 76: Synthesis of Compound 76

[0284]

[0285] The specific synthesis route is as follows:

[0286]

[0287] Step A: Synthesis of ethyl 5-bromo-4,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0288] 4-Bromo-3,5-dimethylpyridine (4.00 g, 21.5 mmol) was dissolved in acetonitrile (25 mL). A solution of O-(2,4-dinitrophenyl)hydroxylamine (4.71 g, 23.6 mmol) in acetonitrile (25 mL) was slowly added dropwise at 0°C, and the reaction was continued at 40°C for 8 hours. N,N-dimethylformamide (50 mL), potassium carbonate (5.94 g, 43.0 mmol), and ethyl propynate (2.43 g, 24.7 mmol, 2.43 mL) were added to the reaction mixture, and the reaction was continued at 25°C for 5 hours until the reaction was complete as monitored by LC-MS.

[0289] The reaction mixture was cooled to 25°C, filtered, concentrated under vacuum, and diluted with water (200 mL). The mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 2), and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1) to give a pale yellow solid, ethyl 5-bromo-4,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate. LCMS: RT = 0.667 min, [M + H] + =297.0.

[0290] Step B: Synthesis of 5-bromo-4,6-dimethylpyrazolo[1,5-a]pyridine

[0291] Ethyl 5-bromo-4,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (922 mg, 3.10 mmol) was dissolved in 10 mL (40%) of an aqueous sulfuric acid solution at room temperature. The reaction solution was reacted at 110 °C for 3 hours until the reaction was substantially complete as monitored by LCMS.

[0292] Cool the mixture to room temperature. After cooling, dilute the reaction mixture with water, neutralize it first with a 1 mol / L sodium hydroxide aqueous solution, and then neutralize it with a saturated sodium bicarbonate solution to pH 8. Dilute the mixture with water (100 mL) and extract with ethyl acetate (150 mL x 2). Wash with saturated brine (150 mL x 2), then dry the combined organic layers with anhydrous sodium sulfate, filter and concentrate under reduced pressure to give the brown product 5-bromo-4,6-dimethylpyrazolo[1,5-a]pyridine (610 mg, 2.53 mmol).

[0293] The same steps as in Example 47 were then followed to obtain two isomers of the target compound.

[0294] 76A:LCMS:RT=0.527min,[M+H] + =702.4;1 1H NMR (400 MHz, DMSO-d6) δ 9.10 (broad d, J = 6.40 Hz, 1H) 8.56 (s, 1H) 7.96 (d, J = 2.40 Hz, 1H) 7.76 (s, 1H) 7.15 (t, J = 8.40 Hz, 1H) 6.76 (s, 1H) 6.65 (d, J = 2.00 Hz, 1H) 5.63 - 5.59 (m, 1H) 5.56 - 5.47 (m, 1H) 3.29 - 3.15 (m, 5H) 2.88 - 2.82 (m, 1H) 2.77 - 2.66 (m, 1H) 2.61 - 2.55 (m, 2H) 2.47 (broad s, 1H) 2.25 (s, 3H) 2.15 (s, 3H) 2.03 - 1.93 (m, 5H) 1.87 - 1.76 (m, 1H) 1.65 - 1.57 (m, 1H) 1.30 - 1.17 (m, 1H) 0.85 - 0.75 (m, 6H); 19 19F NMR (376 MHz, DMSO-d6) δ = -62.45 (3F), -117.61 (1F), -118.13 (1F);

[0295] 76B: LCMS: RT = 0.528 min, [M + H] + = 702.4; 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (broad d, J = 7.20 Hz, 1H) 8.55 (s, 1H) 7.95 (d, J = 2.00 Hz, 1H) 7.75 (s, 1H) 7.14 (t, J = 8.40 Hz, 1H) 6.76 (s, 1H) 6.65 (d, J = 2.00 Hz, 1H) 5.61 - 5.58 (m, 1H) 5.56 - 5.45 (m, 1H) 3.29 - 3.16 (m, 5H) 2.89 - 2.83 (m, 1H) 2.76 - 2.65 (m, 1H) 2.63 - 2.54 (m, 2H) 2.47 - 2.44 (m, 1H) 2.24 (s, 3H) 2.13 (s, 3H) 2.03 - 1.92 (m, 5H) 1.86 - 1.74 (m, 1H) 1.64 - 1.57 (m, 1H) 1.25 - 1.18 (m, 1H) 0.84 - 0.73 (m, 6H); 19 19F NMR (376 MHz, DMSO-d6) δ = -62.45 (3F), -117.59 (1F), -118.20 (1F). [[ID=​​​​​​

[0298] The specific synthesis route is as follows:

[0299] Step A: Synthesis of 5-bromo-1-(difluoromethyl)-4,6-dimethyl-1H-indole

[0300]

[0301] 5-Bromo-4,6-dimethyl-2H-indole (50.0 mg, 222 μmol) was dissolved in N,N-dimethylformamide (2 mL), potassium hydroxide (24.9 mg, 444 μmol) was added, and then ethyl 2-bromo-2,2-difluoroacetate (49.6 mg, 244 μmol) was added to the reaction mixture. The mixture was stirred at 25°C for 12 hours until the reaction was substantially complete as monitored by LCMS. A total of 20 batches of parallel reactions were performed.

[0302] The reaction mixture was quenched at 0°C with saturated ammonium chloride aqueous solution (10 mL) at room temperature, and then extracted three times with ethyl acetate (10 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product, 5-bromo-1-(difluoromethyl)-4,6-dimethyl-1H-indole (1.22 g), was obtained as a yellow oil and was combined with the scale-up batch for purification.

[0303] The same steps as in Example 47 were then followed to obtain two isomers of the target compound.

[0304] 80A: LCMS:RT=0.566min,[M+H] + =752.5; 1 HNMR(400MHz,CHLOROFORM-d)δppm8.09(s,1H)7.45-7.62(m,2H)7.11-7.18(m,2H)7.00(s,1H)6.85-6.92(m,1H)6.06(br d,J=1.20Hz,1H)5.64(dd,J=8.40,7.20Hz,1H)3.00-3.15(m,2H)2.84-2.94(m,1H)2.62-2.72(m,2H)2.44-2.56(m,3H)2.3 0(s,6H)2.18(s,3H)2.00-2.11(m,4H)1.72-1.80(m,2H)1.38-1.47(m,1H)1.24-1.31(m,1H)0.90(dd,J=8.80,7.20Hz,6H);

[0305] 80B:LCMS:RT=0.561min,[M+H] + =752.5;1 HNMR(400MHz,CHLOROFORM-d)δppm8.08(s,1H)7.49(d,J=24.00Hz,2H)7.13-7.18(m,2H)7.00(s,1H)6.89(t,J=8.40Hz,1H)6.06(br s,1H)5.60-5.68(m,1H)2.98-3.13(m,2H)2.84-2.93(m,1H)2.66(br t,J=12.80Hz,2H)2.44-2.53(m,3H)2.30(s,7H)2.18(s,3H)2.00-2.09( m,4H)1.72-1.81(m,2H)1.39-1.46(m,1H)0.90(dd,J=8.40,6.80Hz,6H).

[0306] Example 88: Synthesis of Compound 88

[0307]

[0308] Step A: Synthesis of 2-bromo-5-(difluoromethyl)-1,3-dimethylbenzene

[0309]

[0310] 4-Bromo-3,5-dimethylbenzaldehyde (500 mg, 2.35 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Diethylaminosulfur trifluoride (DAST) (1.9 g, 11.75 mmol) was slowly added dropwise at -30°C. After the addition was complete, the mixture was allowed to return to room temperature for 2 hours. TLC monitoring showed that the starting material was almost completely reacted. The reaction solution was quenched with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic phase was washed twice with saturated brine (10 mL), dried, and concentrated to give 416 mg of a pale yellow oily liquid, 2-bromo-5-(difluoromethyl)-1,3-dimethylbenzene. 1 H NMR (400MHz, DMSO-d6) δ7.40 (s, 2H), 6.98 (t, J = 55.8Hz, 1H), 2.43 (s, 6H).

[0311] Subsequently, using the general synthetic route described above, compounds 89A and 89B were obtained through steps such as coupling, deprotection, condensation, substitution, and hydrolysis.

[0312] 88A:LC-MS:RT=1.85min,[M+H] + =740.07; 1H NMR (400MHz, Methanol-d4) δ8.03 (s, 1H), 7.30 (s, 2H), 7.00 (t, J = 8.1Hz, 1H), 6.89 (s, 1H),6.72(t,J=56.4Hz,1H),5.83–5.67(m,2H),3.90–3.65(m,2H),3.60–3.45(m,3H),3 .23–2.86(m,3H),2.59–2.43(m,1H),2.29(s,3H),2.25–2.14(m,1H),2.07(s,6H),1.8 6–1.77(m,2H),1.40(d,J=6.4Hz,6H),1.36–1.22(m,1H),0.89(dd,J=16.1,6.6Hz,6H);

[0313] 88B:LC-MS:RT=1.86min,[M+H] + =740.04.

[0314] Example 98: Synthesis of compound 98

[0315]

[0316] The specific synthesis route is as follows:

[0317] Step A: Synthesis of ethyl (3S)-3-{[(R)-tert-butylsulfinyl]amino}-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-bisphenyl]-3-yl}propionate

[0318] Ethyl (3.03 g, 6.40 mmol) of (3S)-3-[2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl]-3-{[(R)-tert-butylsulfinyl]amino}propionate and 2-bromo-5-fluoro-1,3-dimethylbenzene (400 mg, 1.75 mmol) were dissolved in toluene (10 mL) and water (2 mL). Add potassium phosphate (2.09 g, 9.85 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) (208 mg, 0.24 mmol), purge with nitrogen three times, then heat to 100°C and stir under nitrogen atmosphere for 1 hour until the reaction is substantially complete as monitored by LCMS.

[0319] The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography (eluent: acetonitrile / water, 0.1% formic acid) to give 600 mg of a yellow oil (3S)-3-{[(R)-tert-butylsulfinyl]amino}-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionate (yield: 25.9%). LCMS: RT = 0.678 min, [M+H] + =470.2

[0320] Step B: Synthesis of ethyl (3S)-3-amino-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionate

[0321] Ethyl (3S)-3-{[(R)-tert-butylsulfinyl]amino}-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-bisphenyl]-3-yl}propionate (600 mg, 1.28 mmol) was dissolved in ethanol (6 mL), and then concentrated hydrochloric acid (12 mol / L, 0.42 mL) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 2 hours until the reaction was substantially complete as monitored by LCMS.

[0322] The reaction solution was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, then extracted with dichloromethane (20 mL * 3). The combined organic phases were washed with saturated brine (5 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 700 mg of yellow oil (3S)-3-amino-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionate. LCMS: RT = 0.568 min, [M + H] + =366.2.

[0323] Step C: Synthesis of ethyl (3S)-3-[(2R)-2-bromo-4-methylpentamido]-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionate

[0324] (2R)-2-bromo-4-methylpentanoic acid (384 mg, 1.97 mmol) and (3S)-3-amino-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-bisphenyl]-3-yl}propionate ethyl ester (600 mg, 1.64 mmol) were dissolved in acetonitrile (6 mL), cooled to 0°C, and N,N,N,N-tetramethylchloromethanemidazone hexafluorophosphate (691 mg, 2.46 mmol) and N-methylimidazole (404 mg, 4.93 mmol) were added in portions. The mixture was then allowed to return to room temperature and reacted for 1 hour until the reaction was substantially complete as monitored by LCMS.

[0325] The reaction solution was diluted with water (20 mL), then extracted with dichloromethane (10 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative purification (column: Phenomenex luna C18150 * 40 mm * 15 μm; mobile phase: [H2O (0.225% FA) - ACN]; gradient: 70% - 100% B over 15.0 min) to give 600 mg of yellow oil (3S)-3-[(2R)-2-bromo-4-methylpentamido]-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionate (yield: 67.3%). LCMS: RT = 0.715 min, [M+H]+ = 544.1.

[0326] Step D: Synthesis of ethyl (3S)-3-[(2S)-4-methyl-2-{2-oxoylide-5-[1-(propane-2-yl)azacyclobutane-3-yl]-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}pentamido]-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionate

[0327] Ethyl (3S)-3-[(2R)-2-bromo-4-methylpentamido]-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-bisphenyl]-3-yl}propionate (200 mg, 0.36 mmol) and 5-[1-(propan-2-yl)azacyclobutan-3-yl]-4-(trifluoromethyl)-1,2-dihydropyridin-2-one hydrobromide (188 mg, 0.56 mmol) were dissolved in acetonitrile (5 mL), and then potassium carbonate (254 mg, 1.84 mmol) was added. The reaction mixture was heated to 60°C and stirred for 12 hours until the reaction was substantially complete.

[0328] The reaction was cooled to room temperature, the reaction solution was filtered, washed with acetonitrile, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative purification (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 25%-55% B over 15.0 min) to give 70 mg of yellow solid (3S)-3-[(2S)-4-methyl-2-{2-oxonyl-5-[1-(propane-2-yl)azacyclobutane-3-yl]-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}pentamido]-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionate (yield: 26.3%). LC-MS: RT=0.624min, [M+H]+=722.3.

[0329] Step E: Synthesis of (3S)-3-[(2S)-4-methyl-2-{2-oxoylide-5-[1-(propane-2-yl)azacyclobutane-3-yl]-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}pentamido]-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-diphenyl]-3-yl}propionic acid

[0330] At room temperature, ethyl (3S)-3-[(2S)-4-methyl-2-{2-oxoylide-5-[1-(propane-2-yl)azacyclobutane-3-yl]-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}pentamido]-3-{2,4,4'-trifluoro-2',5,6'-trimethyl-[1,1'-bisphenyl]-3-yl}propionate (45.0 mg, 0.06 mmol) was dissolved in methanol (0.5 mL) and water (0.1 mL), and then lithium hydroxide monohydrate (5.23 mg, 0.12 mmol) was added. The mixture was stirred for 2 hours until the reaction was substantially complete as monitored by LC-MS.

[0331] The reaction solution was adjusted to pH 8-9 with formic acid, and the solvent was removed by concentration under reduced pressure. The crude product was then purified (column: Waters xbridge 150*25mm10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 44%-64% B over 10.0 min) to give compound 89 (yield: 92.6%). LCMS: RT = 0.583 min, [M+H] + =694.3; 1HNMR (400MHz, DMSO-d6) δ = 9.06 (br d, J = 6.24Hz, 1H) 7.68 (s, 1H) 7.12-6.98 (m, 3H) 6.85 (s, 1H) 5.72-5.59 (m, 1H) 5.51 (br t,J=7.57Hz,1H)3.83-3.72(m,2H)3.64-3.49(m,1H)3.47-3.41(m,1H)2.85-2.74(m,1H)2.71-2.65(m,2H)2.23(s,3H)1.98(d,J=5.52Hz ,6H)1.84-1.72(m,1H)1.69-1.52(m,1H)1.26-1.26(m,1H)1.33-1.18(m,1H)0.96(dd,J=8.63,6.38Hz,6H)0.80(dd,J=6.56,3.80Hz,6H).

[0332] The synthetic routes for the compounds in Table 1 are the same as those in the above embodiments.

[0333] Table 1

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343] Comparative Example 1

[0344] (S)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propionic acid

[0345]

[0346] The synthetic route of the compound in Comparative Example 1 can be found in patent WO2021076902.

[0347] Example 103: In vitro evaluation of the inhibitory activity of human MAdCAM / α4β7 integrin binding.

[0348] TBS buffer containing 1% BSA, 1mM CaCl2, 1mM MgCl2, and 1mM MnCl2 was used as the wash buffer and drug / antibody dilution buffer. 100 μL of recombinant human MAdCAM-1Fc chimeric compound (purchased from R&D, 6056-MC-050) was added to the coating solution of a 96-well microplate and incubated overnight at 4°C. The plate was then washed three times with washing buffer, drained, and blocked with blocking buffer (purchased from R&D, DY008) and incubated at 37°C for 1 h. After washing three times with washing buffer and draining, 50 μL of α4β7 integrin protein (purchased from R&D, 5397-A3-050) and 50 μL of different concentrations of 2X compounds were added, and the plates were incubated at room temperature for 2 h. After incubation, the plate was washed three times with washing buffer, drained, and then incubated at room temperature for 1 hour with 100 μL of biotinylated anti-β7 antibody (purchased from R&D, BAF4669) to bind α4β7 protein. The plate was then washed three times with washing buffer, drained, and then incubated at room temperature in the dark with 100 μL of Streptavidin-HRP-labeled anti-β7 antibody for 20 minutes. After washing three times with washing buffer and draining, 100 μL of TMB was added for color development, and the plate was incubated at room temperature in the dark for 20 minutes. Finally, 50 μL of stop solution was added, and the absorbance (OD450) was read at 450 nm using a microplate reader.

[0349] Calculate the inhibitory rate of the compound at different concentrations: Inhibition rate (%) = [1 - (OD450)] Control -OD450 cpd ) / OD450 Control -OD450 blank )]*100, where OD450 blank OD450 values ​​for pores without compounds and integrins. cpd The OD450 value of the pore of the compound to be tested. controlThe OD450 value is the value of the compound-free pore. A nonlinear regression curve is fitted with the logarithm of the compound concentration on the x-axis and the inhibition rate on the y-axis to calculate the IC50. 50 The value (Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)) is shown in Table 2.

[0350] Table 2 Inhibitory activity of the compounds of the present invention against MAdCAM / α4β7 integrin binding.

[0351]

[0352]

[0353] As shown in Table 2, compared with Comparative Example 2, the compound of the present invention has better inhibitory activity against the binding of MAdCAM / α4β7 integrin.

[0354] Example 104: Evaluation Experiment of the In Vitro Human VCAM-1 / α4β1 Integral Binding Inhibitory Activity of the Present Invention

[0355] The α4β1 integrin selective screening assay used TBS buffer containing 1% BSA, 1 mM CaCl2, 1 mM MgCl2, and 0.5 mM MnCl2 as wash buffer and drug / antibody dilution buffer. 100 μL of coating buffer containing recombinant human VCAM-1Fc chimera was added to a 96-well microplate and incubated overnight at 4°C. The plate was then washed three times with washing buffer, blocked with blocking buffer, and incubated at 37°C for 1 h. After washing and drying, 50 μL of α4β1 integrin protein and 50 μL of different concentrations of 2X compounds were added, and the plate was incubated at room temperature for 2 h. After incubation, the plate was washed and dried, and 100 μL of biotinylated secondary antibody β1 was used to bind α4β1 protein and incubated at room temperature for 1 h. After washing and drying, 100 μL of Streptavidin-HRP-labeled secondary antibody was used and incubated at room temperature in the dark for 20 min. After washing and drying the plate, add 100 μL of chromogenic solution and incubate at room temperature in the dark for 20 min. Then add 50 μL of stop solution and read the absorbance at 450 nm using a microplate reader. Calculate the inhibitory rate (%) for different concentrations of the compound: Inhibition rate (%) = [1 - (FI)] Control -FI cpd ) / FI Control -FI blank )]*100, where FI blank FI values ​​for compound-free and Jurkat E6.1 cells, FI cpd FI is the pore FI value of the compound to be tested. controlThe FI value is for compounds without pores.

[0356] Calculate the inhibitory rate of the compound at different concentrations: Inhibition rate (%) = [1 - (OD450)] Control -OD450 cpd ) / OD450 Control -OD450 blank )]*100, where OD450 blank OD450 values ​​for pores without compounds and integrins. cpd The OD450 value of the pore of the compound to be tested. control The OD450 value is the value of the compound-free pore. A nonlinear regression curve is fitted with the logarithm of the compound concentration on the x-axis and the inhibition rate on the y-axis to calculate the IC50. 50 Value (Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))).

[0357] The compounds of this invention exhibit excellent selectivity for binding to VCAM-1 / α4β1 integrative proteins, as detailed in Table 3.

[0358] Table 3

[0359]

[0360] Example 105 In vitro human whole blood α4β7 receptor occupancy experiment

[0361] (1) Reagents

[0362]

[0363]

[0364] (2) Instruments

[0365]

[0366] (3) Experimental methods:

[0367] 3.1 Buffer preparation: HBSS solution containing 20 mM HEPES and 0.1% BSA.

[0368] 3.2 Compound preparation: Each compound was prepared as a 10 mM stock solution. During the experiment, a series of concentration gradients with 5 concentration points were prepared, with each concentration point corresponding to a whole blood sample.

[0369] 3.3 Experimental Procedure: Venous blood from healthy volunteers was collected in blood collection tubes containing heparin sodium. Manganese chloride (4mM final concentration) was added, and the tubes were incubated at room temperature for 30 min. Whole blood samples were added to flow cytometry tubes at a rate of 100 μL / sample. 11 μL of the diluted compound was added to the sample corresponding to each compound's number, with a solvent control group included. The mixture was thoroughly mixed and incubated at room temperature for 15 min. 2.2 μL of Biotinylated Human MAdCAM-1 Protein was added to the corresponding sample to achieve a final concentration of 2 μg / mL. The mixture was thoroughly mixed and incubated at 4°C in the dark for 60 min. 1.5 μL of Biotin Monoclonal Antibody was added to the corresponding sample. The mixture was gently shaken and incubated at 4°C in the dark for 60 min. Equal amounts of CD4 Monoclonal Antibody and CD45 RAMonoclonal Antibody were then added. Antibody and Anti-Integrinβ7 Antibody were thoroughly mixed to prepare antibody mix for later use. According to the tube numbering table, 5 μL of antibody mix was added to the corresponding flow cytometry tubes, gently shaken to mix, and incubated at 4°C in the dark for 30 min. 10× erythrocyte lysis buffer was diluted to 1× with ddH2O for later use. For the stained samples, 2 mL of 1× erythrocyte lysis buffer (approximately 20 times the volume of whole blood) was added to each tube and incubated at room temperature for 5 min. The cells were then centrifuged at room temperature for 8 min at 2000 rpm. Cells were washed with HBSS assay buffer and centrifuged at room temperature for 8 min at 2000 rpm. The supernatant was discarded, and the cells were resuspended in 400 μL of HBSS buffer for flow cytometry analysis.

[0370] 3.4 Calculation:

[0371]

[0372] Note: Positive rate X = Percentage of Biotinylated MAdCAM-1 positive cells when the concentration of the test substance is X; Positive rate 0 = Percentage of Biotinylated MAdCAM-1 positive cells when the concentration of the test substance is 0; Positive rate b = Percentage of Biotinylated MAdCAM-1 positive cells in the FMO group.

[0373] Using the logarithm of compound concentration as the x-axis and receptor occupancy as the y-axis, a nonlinear regression curve was fitted to calculate the IC50. 50 Value (Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))).

[0374] Table 4

[0375] Example number IC 50 (nM) Example number IC 50 (nM) Example number IC 50 (nM) Example number IC 50 (nM)17F47F47AF48F48BF61F62AF62BF63AF63BF65F67AF67BF68BF70BF71F73F74F75AF76AF76BF77BF79AF79BF80AF81AF82F83BF surface

[0376] Where F≤10nM.

[0377] As shown in Table 4, compared with Comparative Example 1, the compound of the present invention exhibits better binding activity to human whole blood α4β7 integrin receptor and shows a better whole blood receptor occupancy (RO) inhibition rate.

[0378] Example 106 In vitro human whole blood α4β1 receptor occupancy experiment

[0379] (1) Reagents

[0380]

[0381]

[0382] (2) Instruments

[0383]

[0384] (3) Experimental methods

[0385] 3.1 Buffer preparation: HBSS solution containing 20 mM HEPES and 0.1% BSA.

[0386] 3.2 Compound preparation: Each compound was prepared as a 10 mM stock solution. During the experiment, a series of concentration gradients with 5 concentration points were prepared, with each concentration point corresponding to a whole blood sample.

[0387] 3.3 Experimental Procedure: Venous blood from healthy volunteers was collected in blood collection tubes containing heparin sodium. Manganese chloride (4mM final concentration) was added, and the tubes were incubated at room temperature for 30 min. Whole blood samples were added to flow cytometry tubes at a rate of 100 μL / sample. 11 μL of the diluted compound was added to the sample corresponding to each compound's number, with a solvent control group included. The mixture was thoroughly mixed and incubated at room temperature for 15 min. 1.1 μL of Biotinylated Human Vcam-1 Protein was added to the corresponding sample to achieve a final concentration of 2 μg / mL. The mixture was thoroughly mixed and incubated at 4°C in the dark for 60 min. 1.5 μL of Biotin Monoclonal Antibody was added to the corresponding sample. The mixture was gently shaken and incubated at 4°C in the dark for 60 min. Equal amounts of CD4 Monoclonal Antibody, CD45 Ramonoclonal Antibody, and anti-human were then collected. Prepare an antibody mix by thoroughly mixing CD49dAntibody. Add 5 μL of antibody mix to the corresponding numbered flow cytometry tubes according to the tube numbering table, gently shake to mix, and incubate at 4°C in the dark for 30 min. Dilute 10× erythrocyte lysis buffer to 1× with ddH2O. After staining, add 2 mL of 1× erythrocyte lysis buffer (approximately 20 times the volume of whole blood) to each tube and incubate at room temperature for 5 min. Centrifuge at room temperature for 8 min at 2000 rpm. Wash cells with HBSS assay buffer and centrifuge at room temperature for 8 min at 2000 rpm. Discard the supernatant, resuspend cells in 400 μL of HBSS buffer, and perform flow cytometry analysis.

[0388] 3.4 Calculation:

[0389]

[0390] Note: Positive rate X = percentage of Biotinylated VCAM-1 positive cells when the concentration of the test substance is X; Positive rate 0 = percentage of Biotinylated VCAM-1 positive cells when the concentration of the test substance is 0; Positive rate b = percentage of Biotinylated VCAM-1 positive cells in the FMO group.

[0391] Using the logarithm of compound concentration as the x-axis and receptor occupancy as the y-axis, a nonlinear regression curve was fitted to calculate the IC50. 50 The value is calculated as (Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)). The results are shown in Table 5.

[0392] Table 5

[0393]

[0394] Where H≥200.

[0395] As shown in Table 5, compared with Comparative Example 1, some compounds of the present invention exhibit excellent selectivity for binding to the α4β1 / α4β7 integrin receptor.

[0396] Example 107 Pharmacokinetic Experiment

[0397] 1. Experimental Materials

[0398] SD rats: male, 180-250g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0399] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0400] Instruments: Thermo Fisher LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[0401] 2 Experimental Methods

[0402] The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After intravenous or gavage administration to rats, 200 μL of venous blood was collected in EDTA-K2 anticoagulant tubes at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h (an additional 5 min for the IV group). The blood was 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. 20 μL of each of the above standard solutions was accurately pipetted and added to 180 μL of blank plasma. The mixture was vortexed to prepare plasma samples equivalent to concentrations of 10, 30, 100, 300, 1000, 3000, 10000, and 30000 ng / mL. Two samples were analyzed for each concentration to establish a standard curve. Collect 30 μL of plasma (diluted 10-fold at 5 min, 15 min, 30 min, and 1 h after intravenous administration), add diclofenac acetonitrile solution (internal standard, 50 ng / mL) to precipitate proteins, then add 100 μL of water, vortex to mix, centrifuge at 4000 rpm for 5 min, and collect the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:

[0403] Chromatographic column: Thermo Fisher Scientific Hypersil Gold C-18 UPLC column, 100*2.1mm, 1.7μm.

[0404] Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 0.5 mL / min, gradient elution as shown in Table 6:

[0405] Table 6

[0406] Time (min) A (%) B (%) 0 90% 10% 0.60 90% 10% 1.00 10% 90% 2.50 10% 90% 2.51 90% 10% 3.30 90% 10% surface

[0407] 3 Data Processing

[0408] After detecting the blood drug concentration by LC-MS, the pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The results showed that the rat pharmacokinetic profile of the compound of this invention was metabolized more slowly in vivo and had a higher oral exposure, as detailed in Table 7.

[0409] Table 7

[0410]

[0411] 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 of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Among them, R 1 Independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl; R 2 Selected from alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, and -(CH2) compounds. q -Cycloalkyl, q is 1, 2, 3 or 4; R 3 Selected from hydrogen, alkyl, cycloalkyl, and -(CH2). t -R 3a The t is selected from 1, 2, 3, 4, and the R 3a Selected from substituted or unsubstituted The substitution is selected from alkyl and oxo, and at least one substitution is made; R 4 Independently selected from hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, or substituted or unsubstituted cycloalkyl, heterocycloalkyl, -(CH2). k T(R 6 (R) 7 ), wherein T is selected from CH, N, k is 0, 1, 2, 3, 4, 5, and the substitution is selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl; wherein R 6 and R 7 Independently selected from hydrogen, alkyl, or R 6 and R 7 Cyclization is performed to form a substituted or unsubstituted, saturated or unsaturated 4-6 membered heterocyclic alkyl group, wherein the substitution is selected from alkyl, alkoxy, hydroxyl, or halogen; ring A is selected from one or more R... 5 Substituted or unsubstituted, saturated or unsaturated 4-6 membered rings or heterocyclic rings, 8-10 membered bicyclic rings or heterobicyclic rings; R 5 Independently selected from oxo, hydroxy, cyano, halogen, alkyl, haloalkyl, thioalkyl, alkoxy, alkylsulfonamide, alkylamide, alkyl ketone, alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ring, substituted or unsubstituted heteroaromatic ring, wherein the substitution is selected from alkyl, alkoxy, hydroxy, halogen, oxo, amino; m, n are 0, 1, 2, 3 or 4, and p is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, Selected from the structure shown in equation (I), where R 1 Independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl; R 2 Selected from alkyl, cycloalkyl, haloalkyl, and heterocycloalkyl; R 3 Selected from hydrogen, alkyl, and cycloalkyl; R 4 Independently selected from hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, -(CH2). 1-5 N(R 6 (R) 7 ); where R 6 and R 7 Independently selected from hydrogen, alkyl, or R 6 and R 7 Cyclization is performed to form a substituted or unsubstituted, saturated or unsaturated 4-6 membered heterocyclic alkyl group, wherein the substitution is selected from alkyl, alkoxy, hydroxyl, or halogen; ring A is selected from one or more R... 5 Substituted or unsubstituted, saturated or unsaturated 4-6 membered rings or heterocyclic rings, 8-10 membered bicyclic rings or heterobicyclic rings; R 5 Independently selected from oxo, hydroxy, cyano, halogen, alkyl, haloalkyl, thioalkyl, alkoxy, alkylsulfonamide, alkylamide, alkyl ketone, alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aromatic ring, substituted or unsubstituted heteroaromatic ring, wherein the substitution is selected from alkyl, alkoxy, hydroxy, halogen; m, n are 0, 1, 2, 3 or 4, and p is 0, 1, 2, 3 or 4.

3. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, When ring A is selected from a substituted benzene ring, it is selected from the structure shown in formula (II). Among them, R 5a Selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, or substituted or unsubstituted cycloalkyl, wherein the substitution is selected from alkyl, amino, halogen, haloalkyl; R 5b Selected from alkyl, halogen, haloalkyl, and cycloalkyl; R 5c Selected from alkyl, halogen, and cycloalkyl groups; R 5d Independently selected from hydrogen, halogen, alkyl, cycloalkyl, and haloalkyl; R 1a R 1b R 1c Selected independently from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl; R 2 Selected from alkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl; R 3 Independently selected from hydrogen and alkyl groups; R 4a Independently selected from substituted or unsubstituted cycloalkyl, heterocycloalkyl, or -(CH2) groups. 1-5 N(R 6 (R) 7 The substitution is selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl, and R. 6 R 7 Together they cyclize into substituted or unsubstituted cycloalkyl or heterocycloalkyl groups, wherein the substitution is selected from alkyl groups or halogens; the R 4b Selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl; wherein, when R 4a When R is selected from heterocyclic alkyl groups, 5a Selected from haloalkyl groups, or the R group described above. 5b Selected from haloalkyl, cycloalkyl, or the R 5d Selected from halogens, or the R 2 Selected from cycloalkyl, alkyl, and haloalkyl; when R 4a Selected from The R 4b When R is selected from alkyl halogenates, 5a Selected from halogens or haloalkyl groups; when the R 5a When R is selected from cycloalkyl groups, 4a Selected from substituted or unsubstituted -(CH2) 1-5 N(R 6 (R) 7 ).

4. The compound according to any one of claims 1-3, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, 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; the alkoxy group is selected from C 1-6 Alkoxy, the C 1-6 The 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-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; the alkoxyalkyl group is selected from C 1-4 Alkoxy C 1-4 The alkyl group is further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl; the cycloalkyl group is selected from C10. 3-6 cycloalkanes, the C 3-6 The cycloalkane is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the heterocyclic alkyl refers to a cycloalkyl group in which at least one carbon atom is substituted by a heteroatom; the aromatic ring is selected from fused rings containing four-membered rings, five-membered rings, fused rings containing five-membered rings, six-membered rings, and fused rings containing six-membered rings; the heteroaromatic ring refers to an aromatic ring in which at least one carbon atom is substituted by a heteroatom; the halogen is selected from fluorine, chlorine, bromine, and iodine; the haloalkyl refers to an alkyl group in which at least one hydrogen atom is substituted by a halogen; the halocycloalkyl refers to an alkyl group in which at least one hydrogen atom is substituted by a halogen; the haloheteroalkyl refers to a heterocyclic alkyl group in which at least one hydrogen atom is substituted by a halogen; the heteroatom is selected from nitrogen, oxygen, and sulfur, and the heteroatom is one or more; the oxoalkanization refers to the substitution of two hydrogen atoms on ring A by an oxygen atom.

5. The compound according to any one of claims 1-3, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The saturated or unsaturated 4-6 membered ring is selected from: cyclohexyl, benzene ring; the saturated or unsaturated 4-6 membered heterocycle is selected from: The saturated or unsaturated 8-10 quinary bicyclic compounds are selected from: The saturated or unsaturated 8-10 member heterobicyclic compounds are selected from: The oxygenated ring A is selected from:

6. The compound according to any one of claims 1-3, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The m is 2 or 3, the n is 2, and the p is 0, 1, 2, 3, or 4; the A ring is selected from: benzene ring, cyclohexyl ring, ... The R 1 Selected from fluorine, methyl, and trifluoromethyl; the R 2 Selected from The R 3 Selected from hydrogen, ethyl, cyclobutyl, The R 4 Selected from trifluoromethyl, The R 5 Selected from methyl, ethyl, cyclopropyl, fluorine, oxo, hydroxyl, Methoxy, amino 7. The compound according to any one of claims 1-3, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from compounds having the following structure (Ia), or isomers thereof, racemates thereof, or pharmaceutically acceptable salts thereof: Among them, ring A and ring R 1 R 2 R 3 R 4 R 5 And m, n, p are as defined above.

8. The compound according to any one of claims 1-3, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from:

9. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective amount of any one of claims 1-8, or an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

10. The pharmaceutical use of the compound of any one of claims 1-8, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically usable salt thereof, or the pharmaceutical composition of claim 9, specifically, in the preparation of a medicament for treating a disease, said disease being an α4β7-related disease, specifically selected from conditions such as enteritis.

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