Integrin alpha4beta7 antagonist compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of chemical drugs, and relates to a compound as shown in a general formula (I), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, as a small molecule antagonist of alpha4beta7 integrin, and a method for treating various specific diseases or symptoms by using the compound. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and particularly relates to an integrin α4β7 antagonist compound, a preparation method thereof, and an application thereof. Background Art

[0002] The integrin family is a dimer formed by two subunit units of α (120 - 185KD) and β (90 - 110KD). There are 18 α subunits and 8 β subunits in mammalian species. More than 20 integrins can be formed according to different combinations. α4β7 is one of the members of the integrin family. Integrins are expressed on the surface of most human cells, and their lesions cause a group of different human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular degeneration, and various autoimmune and chronic inflammatory diseases. Currently, the intestinal inflammatory diseases determined to be related to α4β7 include Crohn's disease, ulcerative colitis, etc.

[0003] The prior art, for example, WO2021076902 and WO2019200202 disclose small molecule antagonists of α4β7 integrin, and methods for treating various specific diseases or conditions using the same.

[0004] Currently, there is no specific small molecule compound targeting the inflammation mediated by α4β7 on the market. Natalizumab used clinically is a humanized monoclonal antibody with the target of the α4 subunit, mainly used for treating multiple sclerosis and Crohn's disease, but side effects such as PML (progressive multifocal leukoencephalopathy) have occurred during clinical use. Therefore, it is necessary to develop a small molecule compound that can inhibit the integrin α4β7 protein for treating diseases related to integrin α4β7. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present application provides an integrin α4β7 antagonist compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, a preparation method thereof, and an application thereof. As a small molecule antagonist of α4β7 integrin, and a method for treating various specific diseases or conditions using the same.

[0006] In the first aspect, the present application provides a compound represented by the general formula (I), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof:

[0007] A compound represented by the general formula (I), or an isomer thereof, or a racemate thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[0008]

[0009] Wherein,

[0010] R 0 is selected from hydrogen, alkyl, halogen;

[0011] R 1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, alkynyl, alkylthio, alkylsulfonamide, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylacyl, substituted or unsubstituted -N(A 1 )(A 2 ), wherein A 1 and A 2 are independently selected from hydrogen, alkyl, or A 1 and A 2 together cyclize to form a substituted or unsubstituted, saturated or unsaturated heterocycloalkyl, substituted or unsubstituted 7-10 membered heterobicyclic, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl; the substitution is selected from alkyl, halogen, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, oxo(=O), hydroxy, halogen;

[0012] R 2 is selected from hydrogen, alkyl, cycloalkyl, halogen, alkenyl, haloalkenyl;

[0013] R 3 is selected from alkyl, cycloalkyl, halogen;

[0014] Each R 4 is independently selected from hydrogen, halogen, alkyl, cyano, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, halocycloalkyl;

[0015] R 5 is selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl;

[0016] R 6 is selected from hydrogen, alkyl,

[0017] R’, R” are independently selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, or R’, R” together cyclize to form a substituted cycloalkyl, heterocycloalkyl, the substitution is selected from alkyl, halogen, haloalkyl;

[0018] Each R 7 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, halocycloalkyl, or a substituted or unsubstituted A ring, -(CH2) 1-5 N(R 8 )(R 9 ), -(CH2) 1-5 C(R 10 )(R11 ), -(CH2) 1-5 C(R 12 )(R 13 )N(R 8 )(R 9 ), -C(R 12 )(R 13 )(CH2) 1-5 N(R 8 )(R 9 ), wherein the substitution is selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oxo(=O), and the substituents are one or more, and multiple adjacent substituents may form cycloalkyl or heterocycloalkyl;

[0019] Wherein, the A ring is selected from substituted or unsubstituted

[0020] Wherein, R 8 , R 9 are independently selected from hydrogen, alkyl, or R 8 and R 9 together cyclize to form a substituted or unsubstituted 4-6 membered heterocycloalkyl, and the substitution is selected from alkyl, alkoxy, hydroxy, halogen, haloalkyl;

[0021] The R 10 , R 11 together cyclize to a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the substitution is selected from alkyl, halogen, haloalkyl;

[0022] The R 12 , R 13 together cyclize to a substituted or unsubstituted cycloalkyl, heterocycloalkyl, and the substitution is selected from alkyl, halogen;

[0023] When R 1 is selected from hydrogen, alkyl, halogen, at least one of the R 7 is independently selected from the A ring, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, substituted -(CH2) 1-5 N(R 8 )(R 9 ), or substituted or unsubstituted -(CH2) 1-5 C(R 10 )(R 11 ), -(CH2) 1-5 C(R 12 )(R 13 )N(R 8 )(R 9 ), -C(R 12 )(R 13)(CH2) 1-5 N(R 8 )(R 9 ),wherein the substitution is selected from alkyl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl;

[0024] m and n are each independently 0, 1, 2, 3 or 4.

[0025] As a preferred embodiment of the present invention, when m and n are both 3, and R 0 is selected from hydrogen, and at least one R 7 is selected from Ring A, and R' and R" are selected from hydrogen, the compounds are selected from the compounds shown in Formula (II) and (IIa):

[0026]

[0027] Wherein, R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, halosubstituted heterocycloalkyl, alkylsulfonamide, alkylamide group, -N(A 1 )(A 2 ), A 1 and A 2 are independently selected from hydrogen, alkyl, or A 1 and A 2 together cyclize to form a saturated or unsaturated, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and the substitution is selected from alkyl, alkoxy, hydroxy, halogen, oxo;

[0028] R 2 , R 3 are independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, halosubstituted heterocycloalkyl;

[0029] R 4a , R 4b , R 4c are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl;

[0030] R 5 is selected from hydrogen, alkyl, cycloalkyl;

[0031] R 6 is selected from hydrogen, alkyl, cycloalkyl;

[0032] R 7a , R 7b are independently selected from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl;

[0033] Ring A is selected from substituted or unsubstituted Among them, the substitution is selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oxo. The substituent(s) can be one or more, and multiple adjacent substituents can form cycloalkyl or heterocycloalkyl.

[0034] As a preferred technical solution of the present invention, when n is 2 and R 0 , R', and R'' are selected from hydrogen, the compound is selected from the compounds shown in formula (III) and (IIIa):

[0035]

[0036] Among them, m is 1, 2, 3, or 4;

[0037] R 1 is selected from hydrogen, alkyl, haloalkyl, alkoxy, substituted or unsubstituted -N(A 1 )(A 2 ), where A 1 and A 2 are independently selected from hydrogen, alkyl, or A 1 and A 2 cyclize together to form a substituted or unsubstituted heterocycloalkyl; the substitution is selected from alkyl, halogen, cycloalkyl, alkoxy, haloalkyl;

[0038] R 2 is selected from alkyl, cycloalkyl, halogen;

[0039] R 3 is selected from alkyl, cycloalkyl, halogen;

[0040] Each R 4 is independently selected from hydrogen, halogen, alkyl, haloalkyl;

[0041] R 5 is selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl;

[0042] R 6 is selected from hydrogen, alkyl;

[0043] R 7a is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl;

[0044] R 7c is independently selected from substituted or unsubstituted The substitution is selected from alkyl, halogen, haloalkyl, alkoxy;

[0045] Among them, X is selected from N or CH, and n is selected from 1, 2, or 3;

[0046] The R a , Rb Cyclize together to form a substituted or unsubstituted heterocycloalkyl group, wherein the substitution is selected from alkyl, halogen, haloalkyl, alkoxy;

[0047] Wherein, when X is selected as N, the R a , R b Cyclize together to Wherein, one of R c , R d is selected from hydrogen, and the other is selected from haloalkyl, alkoxy, or R 1 is selected from alkyl, R c , R d are independently selected from alkyl, halogen, haloalkyl, alkoxy.

[0048] As a preferred technical solution of the present invention, the alkyl is selected from C 1-6 alkyl, and the C 1-6 alkyl 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, 1-ethylbutyl;

[0049] The alkoxy is selected from C 1-6 alkoxy, and the C 1-6 alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentyloxy, 1,2-dimethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, 1-ethylbutoxy; The alkoxyalkyl is selected from C 1-4 alkoxy C 1-4 alkyl, and is further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl;

[0050] The alkenyl is selected from C 2-6 alkenyl, C 2-6The alkenyl group is selected from vinyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;

[0051] The alkoxyalkyl methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyhexyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl;

[0052] The alkynyl group is selected from alkynyl groups of C 2-6 wherein the alkynyl group of C 2-6 is selected from ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl;

[0053] The cycloalkyl group is selected from cycloalkyl groups of C 3-8 wherein the cycloalkyl group of C 3-8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the hetero cycloalkyl group means that at least one carbon atom on the cycloalkyl group is replaced by a heteroatom;

[0054] The alkyl cycloalkyl group means that one or more hydrogen atoms on the cycloalkyl group are replaced by an alkyl group, and the cycloalkyl alkyl group means that one or more hydrogen atoms on the alkyl group are replaced by a cycloalkyl group.

[0055] As a preferred technical solution of the present invention, the aryl group is selected from five-membered rings and six-membered rings; the heteroaryl group means that at least one carbon atom on the aryl group is replaced by a heteroatom, and the heteroatom is selected from nitrogen, oxygen, and sulfur, and the heteroatom is one or more.

[0056] As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine; the haloalkyl group means that at least one hydrogen atom on the alkyl group is replaced by a halogen, the haloalkoxy group means that at least one hydrogen atom on the alkoxy group is replaced by a halogen, and the haloalkenyl group means that at least one hydrogen atom on the alkenyl group is replaced by a halogen.

[0057] As a preferred technical solution of the present invention, the 7- to 10-membered heterobicyclic ring is selected from:

[0058] As a preferred technical solution of the present invention, it is selected from compounds having the following formula (Ia), or their isomers, or their racemates, or their pharmaceutically acceptable salts:

[0059]

[0060] wherein, R 0 , R 1 , R 2 , R3 , R 4 , R 6 , R’, R”, R 7 and m, n are defined as above.

[0061] As a preferred technical solution of the present invention, m is 2, 3 or 4, and n is 1, 2 or 3;

[0062] R 0 is selected from hydrogen, fluorine;

[0063] The R 1 is selected from hydrogen, methyl, ethyl, isopropyl, propyne, chlorine, fluorine, cyclopropyl, methoxy,

[0064] substituted R 1 is selected from:

[0065]

[0066] The R 2 is selected from fluorine, chlorine, methyl, ethyl, haloalkenyl;

[0067] The R 3 is selected from methyl, chlorine, fluorine;

[0068] The R 4 is selected from hydrogen, methyl, fluorine, trifluoromethyl;

[0069] The R 5 is selected from ethyl, propyl,

[0070] The R 6 is selected from hydrogen, methyl, ethyl, isopropyl,

[0071] R’ and R” are hydrogen or cyclized together to form cyclopropyl;

[0072] The R 7 is selected from fluorine, methyl, ethyl, isopropyl, cyclopropyl, methoxy, difluoromethylene, trifluoromethyl,

[0073]

[0074]

[0075] When R 1 is selected from hydrogen, methyl, at least one of the R 7 is independently selected from cyclopropyl, methoxy,

[0076]

[0077] As a preferred technical solution of the present invention, the compound, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt is selected from the structures shown in Table 1.

[0078] As a preferred technical solution of the present invention, the prodrug refers to R 6 selected from the carboxylic acid esters formed by the carboxylic acids corresponding to hydrogen, including but not limited to: alkyl esters, alkylcarbonyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl esters. More preferably, the R 6 is selected from methyl, ethyl, isopropyl,

[0079] As a preferred technical solution of the present invention, the prodrug compound is selected from:

[0080]

[0081] As a preferred technical solution of the present invention, the pharmaceutically acceptable salt refers to the salt prepared from the compound, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt and a pharmaceutically acceptable acid or base.

[0082] As a preferred technical solution of the present invention, one or more hydrogen atoms of the compound, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt are replaced by the isotope deuterium.

[0083] The present invention further provides a pharmaceutical composition, which is characterized by comprising a therapeutically effective amount of the compound, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0084] The present invention further provides the pharmaceutical use of the compound, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt. Specifically, it is used in the preparation of a drug for treating a disease, and the disease is an α4β7-related disease, specifically selected from diseases such as enteritis.

[0085] 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 other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

[0086] For clarity, general terms used in the description of the compound are defined herein.

[0087] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to the corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0088] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention with pharmaceutically acceptable acids or bases.

[0089] In addition to the salt form, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein are readily chemically changed under physiological conditions to convert into the compounds of the present invention. In addition, the prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0090] Certain compounds of the present invention can exist in non-solvated form or solvated form, including hydrate form. Generally, the solvated form is equivalent to the non-solvated form and both are included within the scope of the present invention.

[0091] The prodrugs of the compounds described herein are readily chemically changed under physiological conditions to convert into the compounds. In addition, the prodrugs can be converted to the compounds by chemical or biochemical methods in the in vivo environment.

[0092] Certain prodrug compounds of the present invention can exist in non-solvated form or solvated form, including hydrate form. Generally, the solvated form is equivalent to the non-solvated form and both are included within the scope of the present invention. The compounds or prodrug compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, atropisomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and their mixtures are included within the scope of the present invention.

[0093] For example: isomers of

[0094] Optically active (R)- and (S)-isomers, as well as D and L isomers, atropisomers, etc. can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a certain compound of the present invention is desired, it can be prepared by asymmetric synthesis or the action of a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. 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 diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of carbamates from amines).

[0095] The atoms of the molecules of the compounds of the present invention are isotopes, and by isotope derivatization, effects such as extending the half-life, reducing the clearance rate, metabolic stability, and enhancing in vivo activity can generally be achieved. And, there is included an embodiment in which at least one atom is replaced by an atom having the same number of atoms (proton number) and a different mass number (sum of protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 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 pharmaceutical formulations or local anatomical examinations of compounds in vivo. Stable isotopes neither decay or change in amount nor are radioactive, and thus they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0096] The compounds of the present invention can contain non-natural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, a compound can be labeled with a radioactive isotope, such as deuterium ( 2 H), iodine-125 ( 125I) or C-14( 14 C). All isotopic composition variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0097] Furthermore, one or more hydrogen atoms of the compounds of the present invention are substituted with the isotope deuterium( 2 H). After the compounds of the present invention are deuterated, they have effects such as extended half-life, reduced clearance rate, metabolic stability, and enhanced in vivo activity.

[0098] For example: The deuterated compound

[0099] The preparation methods of the said isotopic derivatives generally include: phase transfer catalysis methods. For example, the preferred deuteration method uses a phase transfer catalyst (e.g., tetraalkylammonium salts, NBu4HSO4). Using a phase transfer catalyst to exchange the methylene protons of diphenylmethane compounds results in a higher deuterium incorporation than reduction with sodium borodeuteride in the presence of an acid (e.g., methanesulfonic acid) using a deuterosilane (e.g., triethylsilyl deuteride) or with a Lewis acid such as aluminum trichloride.

[0100] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is non-toxic and side-effect-free to the host or patient. Representative carriers include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, transdermal enhancers, etc. Their formulations are well-known to those skilled in the art of the cosmetics field or the topical drug field. For other information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the content of which is incorporated herein by reference.

[0101] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0102] Regarding a drug or a pharmacological active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of an active substance in the composition refers to the amount 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 age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art through routine tests.

[0103] 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 condition.

[0104] "Optional" or "optionally" means that the subsequently described event or condition may but does not necessarily occur, and this description includes both the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0105] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Detailed description of the specific embodiments

[0106] The present application will be further described in detail below in conjunction with the examples, but the embodiments of the present application are not limited thereto.

[0107] For the compound structures of Examples 1 - 297, see Table 1. The specific synthetic routes can refer to the patent document CN202080088450.4, as well as the synthetic routes of Examples 8, 58, 60, 181, 192, 204. The difference lies in the substituents of the intermediates, which are determined according to the target compounds.

[0108] Table 1 shows the compound structures

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] Example 8

[0124] Synthesis of (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid

[0125]

[0126] Step A: At room temperature, dissolve ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionate (2 g, 4.225 mmol) and 4-bromo-N,N,3,5-tetramethylaniline (1.157 g, 5.070 mmol) in a mixed solvent of 1,4-dioxane (20 mL) and water (4 mL). At room temperature, add chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (166 mg, 0.211 mmol) and potassium phosphate (2.691 g, 12.675 mmol). Stir the reaction mixture at 100 °C overnight until complete. Filter off the insoluble solids, extract the reaction mixture with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain 1.18 g of a dark brown oily liquid, ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (yield: 56.46%). LCMS: RT = 1.838 min, [M+H] + = 495.2.

[0127] Step B: Synthesis of ethyl (S)-3-amino-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[0128] At room temperature, ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (1.18 g, 2.386 mmol) was dissolved in 1,4-dioxane (11.8 mL), and a hydrogen chloride-1,4-dioxane solution (1.18 mL, 4 mol / L, 4.720 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour until complete. The reaction mixture was purified by flash chromatography (mobile phase: water and acetonitrile) to obtain 680 mg of ethyl (S)-3-amino-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate as an orange-yellow oily liquid (yield: 72.99%). LCMS: RT = 0.617 min, [M+H] + = 391.3.

[0129] Step C: Synthesis of ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate

[0130] At room temperature, (S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (273 mg, 0.758 mmol) and ethyl (S)-3-amino-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (325 mg, 0.833 mmol) were dissolved in dichloromethane (13 mL), and N,N-diisopropylethylamine (147 mg, 1.136 mmol), N-hydroxy-7-azabenzotriazole (124 mg, 0.909 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (174 mg, 0.909 mmol) were added successively. The reaction mixture was stirred at room temperature overnight until complete. The reaction mixture was purified by flash chromatography (mobile phase: 0.1% aqueous trifluoroacetic acid and acetonitrile) to obtain 195 mg of ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate as a yellow oily liquid (yield: 35.10%). LCMS: RT = 1.177 min, [M+H]+ = 733.3.

[0131] Step D: Synthesis of (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid

[0132] At room temperature, ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (195 mg, 0.266 mmol) and lithium hydroxide monohydrate (40 mg, 0.953 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL). The reaction mixture was stirred at room temperature overnight until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high performance liquid chromatography (trifluoroacetic acid) to give 27.35 mg of white solid ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4'-(dimethylamino)-2,4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (yield: 14.59%). LCMS: RT = 6.727 min, [M+H] + = 706.0; 1 1H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.30 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 6.97 (t, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.54 (s, 2H), 5.74 (dd, J = 11.0 Hz, 1H), 5.51 (q, J = 14.6 Hz, 1H), 4.17–3.99 (m, 4H), 3.25 (dt, 2H), 2.98–2.94 (m, 1H), 2.91 (s, 6H), 2.80 (dd, J = 16.0 Hz, 1H), 2.72–2.67 (m, 2H), 2.40 (dd, J = 19.4 Hz, 1H), 2.31–2.25 (m, 1H), 2.21 (s, 3H), 1.92 (s, 6H), 1.87–1.76 (m, 1H), 1.57–1.49 (m, 1H), 1.21–1.14 (m, 1H), 0.79 (t, J = 7.2 Hz, 6H); 1919F NMR (377 MHz, DMSO-d6): δ -62.51, -74.08, -117.62, -117.64, -119.59.

[0133] Example 58

[0134] Synthesis of (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentanamido]propanoic acid

[0135]

[0136] Step A: At room temperature, 4-bromo-3,5-dimethylaniline (10.0 g, 32.2 mmol) was dissolved in toluene (200 mL). Morpholine (4.20 g, 48.2 mmol), cesium carbonate (31.4 g, 96.5 mmol) and bis(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.36 g, 1.61 mmol) were added with stirring. The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction was monitored by LCMS until completion.

[0137] The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (120 mL × 3 times). The combined organic phases were washed with saturated brine (100 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 2.05 g of 4-(4-bromo-3,5-dimethylphenyl)morpholine. LCMS: RT = 0.559 min, [M+H] + = 270.0.

[0138] Step B: Synthesis of 4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine

[0139] At room temperature, 4-(4-bromo-3,5-dimethylphenyl)morpholine (1.50 g, 5.55 mmol) was dissolved in tetrahydrofuran (30.0 mL). The solution was purged with nitrogen three times and cooled to -70 °C. Under a nitrogen atmosphere, n-butyllithium (3.33 mL, 8.33 mmol, 2.5 M in tetrahydrofuran) was slowly added dropwise. The reaction was carried out at -70 °C under a nitrogen atmosphere for 1 hour. 4,4,5,5-Tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (2.07 g, 11.1 mmol) was added dropwise, and the reaction was carried out at 25 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS until completion.

[0140] Water (60.0 mL) was added dropwise to the reaction mixture to quench it completely. The mixture was extracted with ethyl acetate (45.0 mL × 3 times). The organic phases were combined, washed with saturated brine (90.0 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.7 g of 4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine. LCMS: RT = 0.718 min, [M+H] + = 318.2.

[0141] Step C: Synthesis of ethyl (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-{[(R)-2-methylpropan-2-sulfinyl]amino}propionate

[0142] At room temperature, 4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (2.00 g, 6.30 mmol) was dissolved in toluene (20.0 mL) and water (4.00 mL). (3S)-Ethyl 3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-{[(R)-2-methylpropan-2-sulfinyl]amino}propionate (1.30 g, 3.15 mmol), cesium carbonate (6.16 g, 18.9 mmol), and bis(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.668 g, 0.315 mmol) were added. The mixture was purged with nitrogen three times and slowly heated to 95 °C, and stirred for 4 hours. The reaction was monitored by LCMS until completion.

[0143] The reaction solution was cooled to room temperature, diluted with water (50.0 mL), filtered, and the filtrate was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 5) to obtain 1.75 g of ethyl (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate. LCMS: RT = 0.560 min, [M+H] + = 537.3.

[0144] Step D: Synthesis of ethyl (3S)-3-amino-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]propionate

[0145] At room temperature, ethyl (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (1.20 g, 2.24 mmol) was dissolved in ethanol (6 mL), hydrochloric acid (0.560 mL, 6.71 mmol, 12 M aqueous hydrochloric acid) was added, and the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by LCMS until completion.

[0146] The reaction solution was diluted with water (20.0 mL), the pH was adjusted to 7 with saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 780 mg of ethyl (3S)-3-amino-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]propionate. LCMS: RT = 0.441 min, [M+H] + = 433.2.

[0147] Step E: Synthesis of ethyl (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentanamido]propionate

[0148] At room temperature, dissolve ethyl (3S)-3-[(2R)-2-bromo-4-methylpentanamido]-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]propionate (300 mg, 0.492 mmol) in acetonitrile (6.00 mL), add 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1,2-dihydropyridin-2-one (169 mg, 0.640 mmol), potassium carbonate (204 mg, 1.48 mmol), and heat to 50 °C and react for 12 hours. Monitor the reaction by LCMS until completion.

[0149] The reaction solution was diluted with water (25.0 mL), extracted with ethyl acetate (15 mL × 3), the combined organic phases were washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 160 mg of ethyl (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentanamido]propionate. LCMS: RT = 0.521 min, [M+H] + = 793.3.

[0150] Step F: Synthesis of (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentanamido]propionic acid

[0151] At room temperature, dissolve ethyl (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentanamido]propionate (160 mg, 0.202 mmol) in methanol (1.6 mL) and water (0.3 mL), add lithium hydroxide monohydrate (25.4 mg, 0.605 mmol), and stir at room temperature for 1.5 hours. Monitor the reaction by LCMS until completion.

[0152] The reaction solution was filtered, and the crude product was purified by reverse-phase HPLC (C18 150×25 mm, mobile phase: 0.1% formic acid aqueous solution and acetonitrile). After concentration, it was lyophilized to obtain 48 mg of (3S)-3-[2,4-difluoro-2',5,6'-trimethyl-4'-(morpholin-4-yl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl}-4-methylpentanamido]propanoic acid. LCMS: RT = 0.495 min, [M+H] + = 765.4; 1 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 7.20 Hz, 1H), 7.81 (s, 1H), 6.98 (t, J = 8.40 Hz, 1H), 6.73 (d, J = 5.60 Hz, 3H), 5.67 (dd, J = 11.2, 5.13 Hz, 1H), 5.48 (q, J = 7.20 Hz, 1H), 5.24–4.97 (m, 1H), 3.79–3.69 (m, 4H), 3.60–3.50 (m, 2H), 3.14–3.01 (m, 6H), 2.92 (dd, J = 16.0, 8.80 Hz, 1H), 2.84–2.72 (m, 1H), 2.57–2.52 (m, 2H), 2.49–2.42 (m, 2H), 2.21 (s, 3H), 1.92 (s, 6H), 1.88–1.76 (m, 1H), 1.59–1.44 (m, 1H), 1.25–1.11 (m, 1H), 0.77 (dd, J = 14.4, 6.40 Hz, 6H).

[0153] Example 60

[0154] Synthesis of (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propanoic acid

[0155]

[0156] Step A: At room temperature, sodium tert-butoxide (1.92 g, 20 mmol), tris(dibenzylideneacetone)dipalladium (0.46 g, 0.50 mmol) and 2-(2-dicyclohexylphosphinophenyl)-N,N-dimethylaniline (0.39 g, 1 mmol) were successively added to a solution of 2-bromo-5-iodo-1,3-dimethylbenzene (3.11 g, 10 mmol) and N-methylpiperazine (1.01 g, 10.1 mmol) in 1,4-dioxane (20 mL). After replacing with a nitrogen atmosphere, the mixture was stirred in an oil bath at 100 °C for 40 minutes. After the reaction was completed as detected by TLC, it was cooled to room temperature, and water and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (15 mL × 3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain 1-(4-bromo-3,5-dimethylphenyl)-4-methylpiperazine as a colorless oily liquid (1.06 g, yield: 37%). LCMS: RT = 1.72 min, [M+H] + = 283.00.

[0157] Step B: Synthesis of ethyl (S)-3-(((R)-tert-butanesulfinyl)amino)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate

[0158] At room temperature, potassium phosphate (509.45 mg, 2.40 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (62.94 mg, 0.08 mmol) were successively added to a mixed solution of 1-(4-bromo-3,5-dimethylphenyl)-4-methylpiperazine (226.57 mg, 0.8 mmol) and ethyl (3S)-3-(2,6-difluoro-3-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-{[(R)-2-methylpropan-2-ylthio]amino}propionate (378.70 mg, 0.80 mmol) in 1,4-dioxane (20 mL) and water (2 mL). After replacing with a nitrogen atmosphere, the mixture was stirred and reacted in an oil bath at 110 °C for 3 hours. After the reaction was completed as detected by TLC, it was cooled to room temperature, and ethyl acetate and water were added. The aqueous phase was extracted with ethyl acetate (15 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / methanol = 9:1) to obtain ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (516 mg, yield: 99%). LCMS: RT = 1.79 min, [M + H]+ = 550.08.

[0159] Step C: Synthesis of ethyl (S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate

[0160] At room temperature, a solution of hydrogen chloride in dioxane (10 mL, 4 mol / mL) was added to ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (511 mg, 0.88 mmol), and the reaction was stirred at room temperature. After the reaction was completed as detected by TLC, it was concentrated under reduced pressure to obtain the white solid ethyl (S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (390 mg, yield: 98%). LCMS: RT = 1.82 min, [M + H]+ = 461.09.

[0161] Step D: Synthesis of ethyl (S)-3-((R)-2-bromo-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate

[0162] At room temperature, to a solution of ethyl (S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (390 mg, 0.8 mmol) and (2R)-2-bromo-4-methylpentanoic acid (0.21 mg, 1.06 mmol) in acetonitrile (10 mL) were successively added N-methylimidazole (0.11 g, 1.32 mmol) and [chloro(dimethylamino)methylene]-dimethylazanium hexafluorophosphate (0.35 g, 1.23 mmol), and the reaction was stirred at room temperature for 30 minutes. After the reaction was completed as detected by TLC, 15 mL of water was added to the system. The aqueous phase was extracted with a mixed solvent of n-hexane - ethyl acetate (V / V = 10:1) (10 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product ethyl (S)-3-((R)-2-bromo-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (710 mg, yield: 130%). It was directly used in the next reaction without further purification. LCMS: RT = 1.91 min, [M + H]+ = 621.99.

[0163] Step E: Synthesis of ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate

[0164] At room temperature, 5-(2-(azetidin-1-yl)ethyl)-4-(trifluoromethyl)-1,2-dihydropyridin-2-one (70 mg, 0.28 mmol) and potassium carbonate (360 mg, 2.64 mmol) were added to a solution of ethyl (S)-3-((R)-2-bromo-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (710 mg, 0.88 mmol) in acetonitrile (10 mL). After replacing the atmosphere with nitrogen, the mixture was placed in an oil bath at 80 °C and stirred for 16 h. After completion of the reaction detected by LCMS, it was cooled to room temperature, and ethyl acetate and water were added. The aqueous phase was extracted with ethyl acetate (15 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / ethanol = 8:1) to obtain ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (162 mg, yield: 23%). LCMS: RT = 1.78 min, [M+H]+ = 788.00.

[0165] Step F: Synthesis of (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionic acid

[0166] At room temperature, water (2 mL) and lithium hydroxide (88 mg, 2.1 mmol) were added to a mixed solution of ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionate (162 mg, 0.21 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). The reaction was stirred at room temperature for 30 minutes. After the reaction was completed as detected by TLC, the pH of the reaction system was adjusted to 5 - 6 using 2 M hydrochloric acid solution, and the aqueous phase was extracted with ethyl acetate (15 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by preparative chromatography to obtain the white solid (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)propionic acid (23.4 mg, yield: 15%). LCMS: RT = 1.66 min, [M + H] + = 760.03; 1 HNMR(400MHz, DMSO-d6) δ 12.44 (s, 1H), 9.66 (s, 1H), 9.31 (d, J = 7.1 Hz, 1H), 7.98 (s, 1H), 6.99 (t, J = 8.2 Hz, 1H), 6.85 (s, 1H), 6.81 (s, 2H), 5.75 (dd, J = 11.0, 5.2 Hz, 1H), 5.56–5.52 (m, 1H), 4.22–3.78 (m, 7H), 2.97 (dd, J = 16.1, 8.8 Hz, 4H), 2.88–2.79 (m, 4H), 2.70–2.68 (m, 5H), 2.35 (q, J = 1.9 Hz, 2H), 2.24 (s, 3H), 1.95 (s, 6H), 1.88–1.79 (m, 1H), 1.57–1.50 (m, 1H), 1.28–1.16 (m, 2H), 0.81 (t, J = 6.9 Hz, 6H).

[0167] Example 181

[0168] Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propionic acid

[0169]

[0170] Step A: Dissolve 2-methoxy-5-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(trifluoromethyl)pyridine (2.8 g, 10.843 mmol) in methanol (30 mL) at room temperature, and add palladium on carbon (280 mg, 2.631 mmol) at room temperature. After thoroughly displacing hydrogen, the reaction solution was stirred overnight at 50 °C until complete. The reaction solution was purified by flash chromatography (mobile phase: 0.1% aqueous trifluoroacetic acid and acetonitrile) to obtain 2.2 g of 2-methoxy-5-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridine as an orange-yellow liquid (yield: 77.96%). LCMS: RT = 0.898 min, [M+H] + = 261.2.

[0171] Step B: Synthesis of 5-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol

[0172] Dissolve 2-methoxy-5-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridine (2 g, 7.685 mmol) in acetic acid (6.7 mL) at 0 °C, and add 33 wt% hydrobromic acid-acetic acid solution (1.67 mL, 30.738 mmol) at room temperature. The reaction solution was stirred overnight at 50 °C until complete. The reaction solution was dried by a freeze dryer to remove the solvent to obtain 1.777 g of 5-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol as an orange-yellow solid (yield: 93.88%). LCMS: RT = 0.303 min, [M+H] + = 247.0.

[0173] Step C: Synthesis of (2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid

[0174] At room temperature, 5-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol (2.043 g, 8.299 mmol) and (R)-2-bromo-4-methylpentanoic acid (6.475 g, 33.196 mmol) were dissolved in tetrahydrofuran (50 mL). Potassium tert-butoxide (3.725 g, 33.196 mmol) and magnesium tert-butoxide (2.83 g, 16.598 mmol) were added at room temperature. The reaction mixture was stirred at 50 °C overnight until complete. Hydrochloric acid solution (3 mol / L) was added to the reaction mixture to adjust the pH to 6. The reaction mixture was purified by flash chromatography (mobile phase: 0.1% aqueous trifluoroacetic acid and acetonitrile) to obtain 2.053 g of an orange-yellow oily liquid, (2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid (yield: 68.64%). LCMS: RT = 0.553 min, [M+H] + = 361.0.

[0175] Step D: Synthesis of ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-(((2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propionate

[0176] At room temperature, (2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid (250 mg, 0.694 mmol) and ethyl (S)-3-amino-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (209 mg, 0.578 mmol) were dissolved in dichloromethane (10 mL). N,N-Diisopropylethylamine (112 mg, 0.867 mmol), N-hydroxy-7-azabenzotriazole (94 mg, 0.694 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (133 mg, 0.694 mmol) were added successively. The reaction mixture was stirred at room temperature overnight until complete. The reaction mixture was purified by flash chromatography (mobile phase: 0.1% aqueous trifluoroacetic acid and acetonitrile) to obtain 230 mg of an orange-yellow oily liquid, ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-(((2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propionate (yield: 56.57%). LCMS: RT = 1.023 min, [M+H] + = 704.3.

[0177] Step E: Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propanoic acid

[0178] At room temperature, ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propionate (545 mg, 0.774 mmol) and lithium hydroxide monohydrate (78 mg, 1.858 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL). The reaction mixture was stirred at room temperature overnight until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high performance liquid chromatography (trifluoroacetic acid) to obtain 22.33 mg of a white solid, (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propanoic acid stereoisomer Peak1 (yield: 4.27%) and 34.54 mg of a white solid Peak2 (yield: 6.60%).

[0179] Peak1: LCMS: RT = 1.762 min, [M+H] + = 676.0; 1 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.1 Hz, 1H), 7.93 (s, 1H), 7.03–6.85 (m, 3H), 6.71 (s, 1H), 5.62–5.47 (m, 2H), 3.36–3.25 (m, 2H), 3.03–2.87 (m, 2H), 2.75 (t, J = 9.0 Hz, 1H), 2.66–2.53 (m, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 1.91 (s, 3H), 1.89–1.86 (m, 1H), 1.83 (s, 3H), 1.80–1.76 (m, 1H), 1.76–1.64 (m, 1H), 1.37–1.26 (m, 1H), 0.83 (t, J = 5.9 Hz, 6H).

[0180] Peak2: LCMS: RT = 6.337 min, [M+H]+ = 676.0; 1H NMR (400 MHz, DMSO-d6) δ 12.40 (brs, 1H), 10.18 (d, J = 68.3 Hz, 1H), 9.27 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 26.7 Hz, 1H), 7.00 (t, J = 8.3 Hz, 1H), 6.96 (s, 2H), 6.82 (s, 1H), 5.77 (dd, J = 11.3, 5.0 Hz, 1H), 5.53 (q, J = 7.5 Hz, 1H), 3.81–3.60 (m, 2H), 3.32–3.13 (m, 2H), 2.92 (d, J = 10.4 Hz, 4H), 2.80 (dd, J = 16.1, 6.8 Hz, 1H), 2.44–2.30 (m, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.09–1.75 (m, 8H), 1.59–1.48 (m, 1H), 1.21–1.09 (m, 1H), 0.78 (dd, J = 8.7, 6.5 Hz, 6H).

[0181] Example 189

[0182] Synthesis of (S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-(S)-2-(5-(1-isopropylazetidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid

[0183]

[0184] Step A: Dissolve 5-(azetidin-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine (220 mg, 0.947 mmol) in dichloromethane (6 mL) at room temperature, add acetone (114 mg, 1.89 mmol) and glacial acetic acid (83 mg, 1.42 mmol), and add sodium triacetoxyborohydride (803 mg, 3.79 mmol) portionwise with stirring. Stir the reaction at room temperature for 1 hour. The reaction was monitored by LCMS and was found to be complete. Add water (20 mL), extract with ethyl acetate (20 mL × 3), wash twice with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting residue was purified by flash chromatography (mobile phase: 0.1% aqueous trifluoroacetic acid and acetonitrile) to give 200 mg of the target compound 5-(1-isopropylazetidin-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine as a yellow solid (yield: 76.96%). LCMS: RT = 6.318 min, [M+H]+ = 275.1.

[0185] Step B: Synthesis of 5-(1-isopropylazetidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol

[0186] Dissolve 5-(1-isopropylazetidin-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine (200 mg, 0.729 mmol) in acetic acid (2 mL) at room temperature, and add hydrobromic acid (0.5 mL) at room temperature. The reaction solution was stirred overnight at 40 °C until complete. The reaction solution was purified by flash chromatography (mobile phase: 0.1% aqueous trifluoroacetic acid and acetonitrile) to obtain 176 mg of orange-yellow solid 5-(1-isopropylazetidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol (yield: 92.74%). LCMS: RT = 0.642 min, [M+H] + = 261.1.

[0187] Step C: Synthesis of ethyl (S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(1-isopropylazetidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propionate

[0188] Dissolve 1'-cyclopropyl-4-(trifluoromethyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-ol (176 mg, 0.676 mmol) in acetonitrile (3 mL) solution at room temperature, and successively add ethyl (S)-3-((R)-2-bromo-4-methylpentanamido)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (364 mg, 0.676 mmol), potassium carbonate (280 mg, 2.03 mmol), and stir overnight at 50 °C until complete. The reaction solution was purified by flash chromatography (mobile phase: dichloromethane:methanol = 20:1) to obtain 335 mg of yellow oily liquid ethyl (S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(1-isopropylazetidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propionate (yield: 69.01%). LCMS: RT = 10.146 min, [M+H] + = 718.1.

[0189] Step D: Synthesis of (S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-(S)-2-(5-(1-isopropylazetidin-3-yl)-2-oxo-4-9(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid

[0190] At room temperature, ethyl (S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(1-isopropylazetidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propionate (225 mg, 0.313 mmol) and lithium hydroxide monohydrate (45 mg, 1.88 mmol) were dissolved in tetrahydrofuran (2 mL) and water (0.4 mL). The reaction mixture was stirred at 50 °C for 6 hours until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high performance liquid chromatography (trifluoroacetic acid) to give 52.74 mg of white solid (S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-(S)-2-(5-(1-isopropylazetidin-3-yl)-2-oxo-4-9(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (yield: 24.39%). LCMS: RT = 9.403 min, [M+H] + = 690.1; 1 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 10.11 (d, J = 78.3 Hz, 1H), 9.28 (d, J = 7.0 Hz, 1H), 7.93 (d, J = 66.9 Hz, 1H), 6.89 (s, 1H), 5.74 (dd, J = 10.3, 5.3 Hz, 1H), 5.54 (dd, J = 14.9, 7.5 Hz, 1H), 4.31 (s, 4H), 4.15–3.86 (m, 3H), 2.95 (dd, J = 16.0, 8.7 Hz, 1H), 2.80 (dd, J = 16.2, 6.8 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.02 (s, 1H), 1.93 (d, J = 2.4 Hz, 6H), 1.58 (s, 1H), 1.29–1.11 (m, 8H), 0.80 (dd, J = 10.1, 6.6 Hz, 6H); 19 19F NMR (377 MHz, DMSO-d6): δ -62.72, -63.05, -73.67, -117.96, -119.06.

[0191] Example 192

[0192] Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-2-(5-(1-isopropylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid

[0193]

[0194] Step A: Dissolve 5-(2,5-dihydro-1H-pyrrol-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine (600 mg, 2.457 mmol) in dichloromethane (15 mL) at room temperature. Add acetone (214 mg, 3.685 mmol), acetic acid (295 mg, 4.914 mmol), and sodium triacetoxyborohydride (2.083 g, 9.827 mmol) at room temperature. Stir the reaction mixture at room temperature for 1 hour until complete. Quench the reaction with sodium bicarbonate solution, then extract with dichloromethane (20 mL × 3) three times, dry over anhydrous sodium sulfate, filter off the insoluble solids, and concentrate under reduced pressure to obtain 596 mg of an orange-yellow liquid, 5-(1-isopropyl-2,5-dihydro-1H-pyrrol-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine (yield: 81.88%). LCMS: RT = 1.030 min, [M+H] + = 287.4.

[0195] Step B: Synthesis of 5-(1-isopropylpyrrolidin-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine

[0196] Dissolve 5-(1-isopropyl-2,5-dihydro-1H-pyrrol-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine (596 mg, 2.082 mmol) in methanol (15 mL) at room temperature. Add palladium on carbon (27 mg, 0.249 mmol) and acetic acid (138 mg, 2.290 mmol) at room temperature. After thoroughly displacing hydrogen, stir the reaction mixture at 50 °C for 4 hours until complete. Filter off the solid, and purify the remaining solution by flash chromatography (mobile phase: 0.1% aqueous trifluoroacetic acid and acetonitrile) to obtain 570 mg of an orange-yellow liquid, 5-(1-isopropylpyrrolidin-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine (yield: 94.96%). LCMS: RT = 6.662 min, [M+H] + = 289.1.

[0197] Step C: Synthesis of 5-(1-isopropylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol

[0198] At 0 °C, 5-(1-isopropylpyrrolidin-3-yl)-2-methoxy-4-(trifluoromethyl)pyridine (570 mg, 1.977 mmol) was dissolved in acetic acid (6.13 mL), and a 33 wt% hydrobromic acid - acetic acid solution (1.47 mL, 7.908 mmol) was added at room temperature. The reaction mixture was stirred at 50 °C overnight until complete. The solvent of the reaction mixture was removed by a freeze dryer to obtain 544 mg of an orange-yellow solid, 5-(1-isopropylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol (yield: 100.32%). LCMS: RT = 1.003 min, [M + H] + = 275.0.

[0199] Step D: Synthesis of ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-2-(5-(1-isopropylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propionate

[0200] At room temperature, 5-(1-isopropylpyrrolidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol (544 mg, 1.983 mmol) and ethyl (S)-3-((R)-2-bromo-4-methylpentanamido)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (1.068 g, 1.983 mmol) were dissolved in a mixed solvent of acetonitrile (8 mL) and water (4 mL), and potassium carbonate (685 mg, 4.958 mmol) was added. The reaction mixture was stirred at 90 °C overnight until complete. The reaction mixture was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane = 1 / 20) to obtain 430 mg of an orange-yellow solid, ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-2-(5-(1-isopropylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propionate (yield: 29.63%). LCMS: RT = 1.514 min, [M + H] + = 732.4.

[0201] Step E: Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-2-(5-(1-isopropylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid

[0202] At room temperature, ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-2-(5-(1-isopropylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propionate (430 mg, 0.588 mmol) and lithium hydroxide monohydrate (89 mg, 2.115 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL). The reaction mixture was stirred at room temperature overnight until the reaction was complete. The insoluble solids were filtered off, and the residual solution was purified by high performance liquid chromatography (trifluoroacetic acid) to give 60.95 mg of white solid (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-2-(5-(1-isopropylpyrrolidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propionic acid (yield: 14.73%) and 42.1 mg of chiral isomer. LCMS: RT = 9.433 min, [M+H] + = 704.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (d, J = 83.7 Hz, 1H), 9.27 (t, J = 8.1 Hz, 1H), 8.02 (d, J = 41.2 Hz, 1H), 7.03–6.94 (m, 3H), 6.84 (s, 1H), 5.75 (dd, J = 10.9, 4.9 Hz, 1H), 5.53 (dd, J = 14.6, 7.4 Hz, 1H), 3.79–3.61 (m, 2H), 3.56 (dd, J = 13.8, 6.9 Hz, 2H), 3.34–3.29 (m, 1H), 3.17 (dd, J = 21.2, 10.5 Hz, 1H), 2.94 (dd, J = 16.0, 8.6 Hz, 1H), 2.80 (dd, J = 16.1, 6.9 Hz, 1H), 2.39–2.30 (m, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.08–1.95 (m, 2H), 1.93 (s, 6H), 1.56 (d, J = 8.0 Hz, 1H), 1.31 (dd, J = 13.4, 7.2 Hz, 6H), 1.21–1.13 (m, 1H), 0.79 (dd, J = 9.8, 6.6 Hz, 6H); 19 F NMR (377 MHz, DMSO-d6): δ -61.88, -62.02, -73.79, -117.91, -117.93, -118.04, -118.06, -118.99, -119.01, -119.08, -119.10.

[0203] Example 204

[0204] Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpiperidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propanoic acid

[0205]

[0206] Step A: tert-Butyl 6'-methoxy-4'-(trifluoromethyl)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate

[0207] At room temperature, 5-bromo-2-methoxy-4-trifluoromethylpyridine (1.0 g, 3.92 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.333 g, 4.31 mmol) were dissolved in a mixed solvent of 1,4-dioxane (15.0 mL) and water (3.0 mL). At room temperature, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (126 mg, 0.16 mmol) and potassium phosphate (1.248 g, 5.88 mmol) were added. After replacing the reaction solution with argon, it was stirred at 90 °C for 5 h until the reaction was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (60 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residual solution was purified by flash chromatography (mobile phase: n-hexane / ethyl acetate = 4 / 1) to obtain 1.280 g of an orange-yellow solid, tert-butyl 6'-methoxy-4'-(trifluoromethyl)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate (yield: 85.5%). LCMS: RT = 2.291 min, [M+H]+ = 359.01.

[0208] Step B: Synthesis of 6'-methoxy-4'-(trifluoromethyl)-1,2,5,6-tetrahydro-3,3'-bipyridine

[0209] At room temperature, tert-butyl 6'-methoxy-4'-(trifluoromethyl)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate (1.280 g, 3.57 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred for 2 h until the reaction was complete. The reaction solution was directly concentrated by rotary evaporation to obtain 921 mg of orange-yellow oily liquid 6'-methoxy-4'-(trifluoromethyl)-1,2,5,6-tetrahydro-3,3'-bipyridine (crude yield calculated as 100.0%). LCMS: RT = 1.591 min, [M+H]+ = 259.11.

[0210] Step C: Synthesis of 6'-methoxy-1-methyl-4'-(trifluoromethyl)-1,2,5,6-tetrahydro-3,3'-bipyridine

[0211] At room temperature, 6'-methoxy-4'-(trifluoromethyl)-1,2,5,6-tetrahydro-3,3'-bipyridine (710 mg, 2.75 mmol), aqueous formaldehyde solution (310 mg, 4.13 mmol, wt% = 40%), and acetic acid (330 mg, 5.51 mmol) were dissolved in dichloromethane (10 mL) and stirred for 0.5 h. Then, sodium triacetoxyborohydride (2.331 g, 11.01 mmol) was added. The reaction solution was stirred at room temperature for 2 h until complete. The reaction solution was quenched with saturated sodium bicarbonate solution (30 mL), extracted three times with dichloromethane (60 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to directly obtain 486 mg of white solid 6'-methoxy-1-methyl-4'-(trifluoromethyl)-1,2,5,6-tetrahydro-3,3'-bipyridine (yield: 65.0%). LCMS: RT = 1.631 min, [M+H]+ = 273.02.

[0212] Step D: Synthesis of 2-methoxy-5-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridine

[0213] At room temperature, 6'-methoxy-1-methyl-4'-(trifluoromethyl)-1,2,5,6-tetrahydro-3,3'-bipyridine (300 mg, 1.10 mmol) was dissolved in methanol (10 mL), and Pd / C (90 mg, wt% = 50%) was added. The reaction solution was purged with hydrogen and stirred at 50 °C for 5 h until the reaction was complete. The reaction solution was filtered by suction, the filtrate was taken, and the filtrate was concentrated by rotary evaporation to obtain 187 mg of white transparent liquid 2-methoxy-5-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridine (yield: 61.92%). LCMS: RT = 2.001 min, [M+H]+ = 275.12.

[0214] Step E: Synthesis of 5-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol

[0215] At room temperature, hydrobromic acid aqueous solution (2 mL, wt% = 48%) was added to 2-methoxy-5-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridine (187 mg, 0.68 mmol), and the mixture was stirred at 65 °C overnight until the reaction was complete. The reaction solution was purified by flash chromatography (mobile phase: dichloromethane / methanol = 9 / 1) to obtain 177 mg of orange-yellow solid powder of 5-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol (crude yield calculated as 100.0%). LCMS: RT = 1.021 min, [M+H]+ = 261.22.

[0216] Step F: Synthesis of ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpiperidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propionate

[0217] At room temperature, (S)-ethyl 3-((R)-2-bromo-4-methylpentanamido)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (403 mg, 0.75 mmol) and 5-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridin-2-ol (177 mg, 0.68 mmol) were dissolved in acetonitrile (10 mL), then potassium carbonate (141 mg, 1.02 mmol) was added, and the mixture was stirred at 85 °C for 6 hours until complete. The reaction solution was purified by flash chromatography (mobile phase: n-hexane / ethyl acetate = 4 / 6) to obtain 171 mg of orange-yellow oily liquid of ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpiperidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propionate (yield: 35.05%). LCMS: RT = 2.041 min, [M+H]+ = 718.07.

[0218] Step G: Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpiperidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propanoic acid

[0219] At room temperature, ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)-3-((2S)-4-methyl-2-(5-(1-methylpiperidin-3-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)propionate (171 mg, 0.24 mmol) and lithium hydroxide monohydrate (41 mg, 0.96 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and 1 mL of methanol was added to assist dissolution. The reaction mixture was stirred at room temperature for 5 hours until the reaction was complete. Saturated ammonium chloride solution (15 mL) was added to adjust the pH to neutral, and then extracted three times with ethyl acetate (60 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The residue was purified by high performance liquid chromatography (trifluoroacetic acid) to obtain 42 mg of white solid Peak 1 (yield: 25.45%) and 22.5 mg of white solid Peak 2 (yield: 13.63%).

[0220] (Peak 1): RT = 1.912 min, [M+H]+ = 690.33;

[0221] (Peak 2): LCMS: RT = 1.951 min, [M+H]+ = 690.33; 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO) δ 9.25 (d, J = 6.9 Hz, 1H), 7.87 (s, 1H), 7.05–6.88 (m, 3H), 6.80 (s, 1H), 5.80–5.64 (m, 1H), 5.58–5.44 (m, 1H), 2.99–2.86 (m, 4H), 2.85–2.71 (m, 4H), 2.35–2.31 (m, 1H), 2.26 (s, 3H), 2.21 (s, 3H), 2.17–2.13 (m, 1H), 1.92 (s, 6H), 1.92–1.81 (m, 3H), 1.25–1.04 (m, 3H), 0.87–0.81 (m, 2H), 0.81–0.71 (m, 5H).

[0222] Comparative Example 1

[0223] Compound (S)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid

[0224]

[0225] Example 298 In Vitro Evaluation Experiment of the Inhibitory Activity of Human MAdCAM / α4β7 Integrin Binding

[0226] Use the TBS buffer containing 1% BSA, 1 mM Cacl2, 1 mM MgCl2, and 1 mM MnCl2 as the Washbuffer and the drug and antibody dilution buffer. Add 100 μL of the coating solution of recombinant human MAdCAM-1Fc chimera (purchased from R&D, 6056-MC-050) to a 96-well ELISA plate and incubate overnight at 4°C. Subsequently, wash the plate 3 times with the washing buffer, dry it by inversion, and then block it with the blocking solution (purchased from R&D, DY008) at 37°C for 1 h. Wash the plate 3 times with the washing buffer, dry it by inversion, add 50 μL of α4β7 integrin protein (purchased from R&D, 5397-A3-050), and add 50 μL of different concentrations of 2X compound, and incubate at room temperature for 2 h. After incubation, wash 3 times with the washing buffer, dry the plate by inversion, and then bind α4β7 protein with 100 μL of biotinylated anti-β7 antibody (purchased from R&D, BAF4669) and incubate at room temperature for 1 h. Wash 3 times with the washing buffer, dry the plate by inversion, and incubate with 100 μL of Streptavidin-HRP-labeled anti-β7 antibody in the dark at room temperature for 20 min. Wash 3 times with the washing buffer, dry the plate by inversion, add 100 uL of TMB for color development, incubate in the dark at room temperature for 20 min, then add 50 μL of the stop solution, and read the absorbance value (OD450) at a wavelength of 450 nm using an ELISA reader.

[0227] Calculate the compound inhibitors at different concentrations: Inhibition rate (%) = [1 - (OD450 Control - OD450 cpd ) / OD450 Control - OD450 blank )] * 100, where OD450 blank is the OD450 value of the well without compound and integrin protein, OD450 cpd is the OD450 value of the well with the test compound, and OD450 control is the OD450 value of the well without compound. Using the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, perform non-linear regression curve fitting to calculate the IC 50 value (Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))), and the test results are shown in Table 2.

[0228] Table 2 Inhibitory Activity of the Compounds of the Present Invention on MAdCAM / α4β7 Integrin Binding

[0229]

[0230]

[0231] Example 299 Evaluation Experiment on the Inhibitory Activity of the Invention against the Binding of Human VCAM-1 / α4β1 Integrin In Vitro

[0232] For the α4β1 integrin selective screening experiment, a TBS buffer containing 1% BSA, 1 mM Cacl2, 1 mM MgCl2, and 0.5 mM MnCl2 was used as the Wash buffer and the drug and antibody dilution buffer. 100 μl of the coating solution of recombinant human VCAM-1 Fc chimera was added to a 96-well microplate and incubated overnight at 4°C. Subsequently, it was washed 3 times with the washing buffer, blocked with the blocking solution, and incubated at 37°C for 1 h. After washing the plate and drying it, 50 μl of α4β1 integrin protein was added, and 50 μl of different concentrations of 2X compound was added, followed by incubation at room temperature for 2 h. After the incubation ended, the plate was washed and dried, and then 100 μl of biotinylated secondary antibody β1 that binds to α4β1 protein was added and incubated at room temperature for 1 h. After washing the plate and drying it, 100 μl of Streptavidin-HRP-labeled secondary antibody was added and incubated in the dark at room temperature for 20 min. After washing the plate and drying it, 100 μl of chromogenic solution was added for color development, and after incubating in the dark at room temperature for 20 min, 50 μl of stop solution was added. The absorbance value was read using a microplate reader at a wavelength of 450 nm. Calculate the compound inhibitor at different concentrations: Inhibition rate (%) = [1 - (FI Control - FI cpd ) / FI Control - FI blank )] * 100, where FI blank is the FI value of the well without compound and Jurkat E6.1 cells, FI cpd is the FI value of the well with the compound to be tested, and FI control is the FI value of the well without compound.

[0233] Calculate the compound inhibitor at different concentrations: Inhibition rate (%) = [1 - (OD450 Control - OD450 cpd ) / OD450 Control - OD450 blank )] * 100, where OD450 blank is the OD450 value of the well without compound and integrin protein, OD450 cpd is the OD450 value of the well with the compound to be tested, and OD450 control is the OD450 value of the well without compound. Taking the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, perform non-linear regression curve fitting to calculate IC 50Value (Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*HillSlope))), and the test results are shown in Table 3.

[0234] Table 3 Inhibitory Activity of the Compounds of the Invention against the Binding of VCAM-1 / α4β1 Integrin

[0235]

[0236] Example 300 Pharmacokinetic Experiment

[0237] 1 Experimental Materials

[0238] SD rats: male, 180 - 250 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0239] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), normal saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.

[0240] Instrument: Thermo Fisher LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[0241] 2 Experimental Methods

[0242] Weigh the compound and dissolve it in the DMSO-PEG-400-normal saline (5:60:35, v / v / v) system. After intravenous or oral administration to rats, 200 μL of venous blood is collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, 24 h (5 min is added for the iv group) into an EDTA-K2 anticoagulant tube, centrifuged at 12000 rpm for 2 min, and the plasma is frozen at -80 °C for later measurement. Weigh a certain amount of the test sample precisely and dissolve it in DMSO to 2 mg / mL as the stock solution. Accurately pipette an appropriate amount of the compound stock solution and dilute it with acetonitrile to prepare a standard series of solutions. Accurately pipette 20 μL of each of the above standard series of solutions, add 180 μL of blank plasma, vortex and mix well to prepare plasma samples with plasma concentrations equivalent to 10, 30, 100, 300, 1000, 3000, 10000, 30000 ng / mL. Each concentration is analyzed in duplicate to establish a standard curve. Take 30 μL of plasma (the plasma at 5 min, 15 min, 30 min, 1 h after intravenous administration is diluted 10 times), add diclofenac acetonitrile solution (internal standard, 50 ng / mL) to precipitate proteins, then add 100 μL of water, vortex and mix well, centrifuge at 4000 rpm for 5 min, and take the supernatant for LC-MS analysis. The LC-MS detection conditions are as follows:

[0243] Chromatographic column: Thermo Fisher HYPERSIL GOLD C-18 UPLC column, 100 * 2.1 mm, 1.7 μm.

[0244] Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 0.5 mL / min, gradient elution as shown in Table 4:

[0245] Table 4

[0246] 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％

[0247] 3 Data processing

[0248] After detecting the blood drug concentration by LC-MS, WinNonlin 6.1 software was used, and the pharmacokinetic parameters were calculated by the non-compartmental model method. The results are shown in Table 5.

[0249] Table 5: Pharmacokinetic results of the compounds of the present invention in rats

[0250]

[0251] From the experimental results in Table 5, it can be seen that compared with the compound of Comparative Example 1, the PK of the compound of the present invention in rats has slower metabolism in vivo, higher oral exposure and comparable bioavailability.

[0252] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A compound represented by general formula (I), or an isomer, a racemate, a prodrug, or a pharmaceutically acceptable salt thereof, characterized in that: in, R 0 is selected from hydrogen, alkyl, halogen; R 1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, alkynyl, alkylthio, alkylsulfonamide, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylacyl, substituted or unsubstituted -N(A 1 )(A 2 ), where A 1 and A 2 are independently selected from hydrogen, alkyl, or A 1 and A 2 Cyclize together to form a substituted or unsubstituted, saturated or unsaturated heterocycloalkyl, a substituted or unsubstituted 7-10 membered heterobicyclic ring, a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl; the substitution is selected from alkyl, halogen, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, oxo (=O), hydroxyl, halogen; R 2 is selected from hydrogen, alkyl, cycloalkyl, halogen, alkene, and halogenated alkene; R 3 is selected from alkyl, cycloalkyl, halogen; Each R 4 independently selected from hydrogen, halogen, alkyl, cyano, alkoxy, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl; R 5 Selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl; R 6 Selected from hydrogen, alkyl, R' and R" are independently selected from hydrogen, alkyl, halogen, haloalkyl, and alkoxy, or R' and R" are cyclized together to form a substituted cycloalkyl or heterocycloalkyl, wherein the substitution is selected from alkyl, halogen, and haloalkyl; Each R 7 independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, halocycloalkyl, or substituted or unsubstituted A ring, -(CH2) 1-5 N(R 8 )(R 9 )、-(CH2) 1-5 C(R 10 )(R 11 )、-(CH2) 1-5 C(R 12 )(R 13 )N(R 8 )(R 9 )、-C(R 12 )(R 13 )(CH2) 1-5 N(R 8 )(R 9 ), the substituent is selected from alkyl, halogen, haloalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oxo (=O), the substituent is one or more, and multiple adjacent substituents may form a cycloalkyl or heterocycloalkyl; Wherein, the A ring is selected from substituted or unsubstituted Among them, R 8 , R 9 independently selected from hydrogen, alkyl, or R 8 and R 9 Cyclize together to form a substituted or unsubstituted 4-6 membered heterocycloalkyl, wherein the substitution is selected from alkyl, alkoxy, hydroxy, halogen, and haloalkyl; The R 10 , R 11 Cyclize together to form substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein the substitution is selected from alkyl, halogen, haloalkyl; The R 12 , R 13 Cyclize together to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein the substitution is selected from alkyl and halogen; When R 1 When selected from hydrogen, alkyl, halogen, at least one of the R7 is independently selected from A ring, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, substituted -(CH2) 1-5 N(R 8 )(R 9 ), or substituted or unsubstituted -(CH2) 1-5 C(R 10 )(R 11 )、-(CH2) 1-5 C(R 12 )(R 13 )N(R 8 )(R 9 )、-C(R 12 )(R 13 )(CH2) 1-5 N(R 8 )(R 9 ), wherein the substitution is selected from alkyl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl; m and n are each independently 0, 1, 2, 3 or 4.

2. The compound according to claim 1, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The alkyl group is selected from C 1-6 The alkyl group, the C 1-6 The alkyl group is selected from the group consisting of 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, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutoxy, 1-ethylbutoxy; the alkoxyalkyl group is selected from C 14 Alkoxy C 14 The alkyl group is further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl; The olefin group is selected from C 2-6 Alkenyl, C 2-6 The alkenyl group is selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl. , 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl; The alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyhexyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, and hexyloxyhexyl; The alkynyl group is selected from C 2-6 The alkynyl group, the C 2-6 The alkynyl group is selected from ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl; The cycloalkyl group is selected from C 3-8 The cycloalkyl group, the C 3-8 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and the heterocycloalkyl group refers to at least one carbon atom on the cycloalkyl group being substituted by a heteroatom; The alkylcycloalkyl group refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by an alkyl group, and the cycloalkylalkyl group refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by a cycloalkyl group.

3. The compound according to claim 1, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The aryl group is selected from a five-membered ring and a six-membered ring; the heteroaryl group means that at least one carbon atom on the aryl group is replaced by a heteroatom, and the heteroatom is selected from nitrogen, oxygen, and sulfur, and the heteroatom is one or more.

4. The compound according to claim 1, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The halogen is selected from fluorine, chlorine, bromine and iodine; the haloalkyl refers to at least one hydrogen atom on the alkyl group being replaced by a halogen, the haloalkoxy refers to at least one hydrogen atom on the alkoxy group being replaced by a halogen, and the haloolefin refers to at least one hydrogen atom on the olefin group being replaced by a halogen.

5. The compound according to claim 1, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The 7-10 membered heterobicyclic ring is selected from:

6. The compound according to claim 1, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: A compound selected from the group consisting of the following structure (Ia), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof: Among them, R 0 , R 1 , R 2 , R 3 , R 4 , R 6 , R', R", R 7 and m and n are as defined above.

7. The compound according to claim 1, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: m is 2, 3 or 4, and n is 1, 2 or 3; R 0 is selected from hydrogen and fluorine; The R 1 is selected from hydrogen, methyl, ethyl, isopropyl, propyne, fluorine, chlorine, cyclopropyl, methoxy, Replaced by R 1 Selected from: The R 2 is selected from fluorine, chlorine, methyl, ethyl, and haloalkenyl; The R 3 is selected from methyl, chlorine, and fluorine; The R 4 is selected from hydrogen, methyl, fluorine, trifluoromethyl; The R 5 Selected from ethyl, propyl, The R 6 is selected from hydrogen, methyl, ethyl, isopropyl, Said R', R" are hydrogen or cyclized together to form a cyclopropyl; The R 7 is selected from fluorine, methyl, ethyl, isopropyl, cyclopropyl, methoxy, difluoromethylene, trifluoromethyl, When R 1 When selected from hydrogen, methyl, at least one of the R 7 are independently selected from cyclopropyl, methoxy, 8. The compound according to claim 1, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: Select from the structures shown in Table 1.

9. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the compound according to any one of claims 1 to 8, or an isomer, a racemate, a prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The medical use of the compound according to any one of claims 1 to 8, or its isomer, or its racemate, or its prodrug, or its pharmaceutically acceptable salt, specifically, its use in the preparation of a drug for treating a disease, wherein the disease is an α4β7-related disease, specifically selected from enteritis and the like.

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