WO2021204185A1 - Benzo[d]azepine derivative as inhibitor of aggrecanase-2, preparation method therefor, and pharmaceutical use thereof - Google Patents

Abstract

The present invention belongs to the field of chemical drug technology, and provides a benzo[d]azepine derivative as an inhibitor of aggrecanase-2, a preparation method therefor, and a pharmaceutical use thereof. The present invention specifically provides a series of inhibitors of aggrecanase-2 (ADAMTS-5), and especially provides a benzo[d]azepine derivative as an inhibitor of aggrecanase-2. The present invention also relates to pharmaceutical compositions comprising these compounds and uses of these compounds in drugs for treating diseases such as osteoarthritis.

Description

Benzo[D] azepine derivative proteoglycanase 2 inhibitor, preparation method and medical use thereof Technical field

The present invention belongs to the technical field of chemical medicines, and provides a benzo[D] azepine derivative proteoglycanase 2 inhibitor and its preparation method and medical use. Specifically, it relates to a series of proteoglycanase 2 (ADAMTS-5, Aggrecanase-2) inhibitors, especially an inhibitor of benzo[D] azepine derivatives proteoglycanase 2. The present invention also relates to a pharmaceutical composition containing these compounds and the use of the compounds in the treatment of diseases such as osteoarthritis.

Background technique

Osteoarthfitis (OA), also known as degenerative arthritis, is a degenerative disease in which joint pain is the main symptom caused by the fibrosis, chapped, ulcer, and loss of articular cartilage caused by multiple factors, which can cause patients The end result of the loss of exercise capacity and pain is often the need for total joint replacement, which is the most common disease among the elderly and obese. At present, the pathogenesis of OA has not been clearly studied. Its main causes include age, obesity and joint damage. Under the action of these factors, the disorder of cell metabolism in the joint tissues, cell signal transduction disorders, and catabolic pathways are activated.

Articular cartilage is mainly composed of cartilage cells and cartilage matrix. Articular cartilage cells account for only a small part of the total volume of articular cartilage, and most of them are composed of extracellular matrix. The extracellular matrix is composed of two macromolecular structures: collagen and proteoglycan. The main reason for the degradation of articular cartilage in bone and joint diseases is the degradation of collagen and proteoglycan of the extracellular matrix of articular cartilage. When the degradation of extracellular matrix and basement membrane components of articular cartilage by proteolytic enzymes is far greater than that of synthesis, changes in the structure of cartilage tissue and subchondral bone, it will lead to functional abnormalities in joint functions. Therefore, proteoglycanase is the development of OA Potential targets for therapeutic drugs.

Aggrecanase is a member of the ADAMTS family, which is a disintegrin and metalloprotease with a thrombospondin (TS) motif and consists of secreted zinc metalloprotease. Aggrecanase is the main protease responsible for aggrecan cleavage in the early stage of cartilage remodeling. Matrix metalloproteinases (MMP) begin to participate in this process during the development of the disease and continue the degradation of collagen. Therefore, aggrecanase activity is considered to be a sign of cartilage degradation during inflammatory joint diseases such as OA.

The ADAMTS family of secreted zinc metalloproteinases includes nineteen members that are known to bind and degrade the extrachondral matrix (ECM) components. Several members of the ADAMTS family have been found to lyse the main proteoglycan component of cartilage-aggrecan: ADAMTS-1, -4, -5, -8, -9, -15, -16, and -18. Since the expression and/or aggrecanase degradation activity of ADAMTS-1, -8, -9, -15, -16 and -18 are quite low, it is believed that ADAMTS-4 (agrecanase-1) and ADAMTS -5 (Aggrecanase-2) are the two main functional aggrecanases.

Aggrecanase 1 (ADAMTS-4) and aggrecanase 2 (ADAMTS-5) are two different aggrecanases isolated from cartilage. These two proteases specifically cleave the aggrecanase Glu373-Ala374 bond of the aggrecan core protein in the IGD region. Therefore, these proteases have received the most attention in the pathology of arthritis arthropathy because they are the most effective aggrecanase in vitro. The activity of these aggrecanases is critical to the metabolic balance between the synthesis and decomposition of aggrecan. In normal humans, the control mechanism of aggrecan catabolism may be related to endogenous inhibitors, such as the tissue inhibitor of matrix metalloproteinase (TIM-3) of aggrecanase. But in OA patients, the balance between the synthesis of TIMP-3 and ADAMTS-4 is disrupted, and the metabolism is greater than the synthesis. Some studies suggest that this may be due to the de novo synthesis of ADAMTS-4 or the activation of ADAMTS-4 and ADAMTS-5 after translation. By inhibiting ADAMTS-4 and ADAMTS-5, it can effectively prevent the degradation of local proteoglycans in OA cartilage and prevent cartilage degeneration.

Therefore, the present invention intends to discover new ADAMTS inhibitors, especially new compounds that have inhibitory activity against ADAMTS-5 and ADAMTS-4, have good biological properties, and can be safely applied to the human body. The present invention also provides It is a necessary tool for preventing and/or treating diseases involving cartilage degradation, especially osteoarthritis and/or rheumatoid arthritis.

Summary of the invention

In view of the problems existing in the prior art, the present invention provides a series of benzo[D]azepine derivatives, their preparation methods and their applications in medicine.

Specifically, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

The compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

in:

R ₁ and R _{2 are} selected from: hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, or

C _1-6 alkoxy;

R ₁ and R ₂ may be connected to the same carbon atom or different carbon atoms;

R _{3 is} selected from:

-hydrogen,

halogen,

Cyano,

C _1-6 alkyl group,

Halogenated C _1-6 alkyl group,

C _1-6 alkoxy group,

Halogenated C _1-6 alkoxy group,

Nitro,

Amide group,

Phenyl,

Halogenated phenyl,

A 5-10 membered monocyclic or fused bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a halogen optionally selected by one or more independently, C _1-6 alkyl, C _1-6 alkoxy substituted, or

-NR _9g R _9h ;

R _{4 is} selected from:

-hydrogen,

C _1-6 alkyl or it is optionally substituted with one or more independently selected R ₅ groups,

C _3-7 monocyclic cycloalkyl or it is optionally substituted with one or more independently selected R ₅ groups,

A 4-7 membered monocyclic heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S, or the monocyclic heterocycloalkyl is optionally selected by one or more independently selected C _{1 -6} alkyl, -C(=O)C _1-6 alkyl or -C(=O)OC _1-6 alkyl substituted,

Phenyl or it is optionally substituted with one or more independently selected R ₆ groups,

A phenyl group fused to a 5-6 membered monocyclic heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl group is optionally substituted by one or more A = O substitution, or

A 5-6 membered monocyclic heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O and S, or the monocyclic heteroaryl group is optionally selected by one or more independently selected R ₆ groups replace;

R _{5 is} selected from:

halogen,

Hydroxyl,

Cyano,

C _1-6 alkyl,

C _1-6 alkoxy or it is optionally _{substituted by C 1-6} alkoxy or phenyl,

C _1-6 thioalkoxy,

A 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from N, S, and O, or the monocyclic heterocycloalkyl group is optionally substituted by one or more halogens or -C( =0)OC _1-6 alkyl substitution,

Phenyl,

-S(=O) ₂ C _1-6 alkyl,

-C(=O)OR _7a ,

-C(=O)NR _7b R _7c ,

-NHC(=O)OR _7d ,

-NHC(=O)R _7e , or

-NR _8a R _8b ;

R _{6 is} selected from:

halogen,

Hydroxyl,

Cyano,

C _1-6 alkyl or it is optionally substituted with one or more independently selected halogen, -NR _9a R _9b or -C(=O)NR _9c R _9d ,

C _1-6 alkoxy or it is optionally _{substituted by -NR 9e} R _9f , or

-S(=O) ₂ C _1-6 alkyl;

R _7a , R _7b , R _7c , R _7d or R _{7e are} independently selected from:

-Hydrogen, or

-C _1-6 alkyl or optionally substituted by OH or C _1-6 alkoxy,

R _8a or R _{8b are} independently selected from:

-Hydrogen, or

-C _1-6 alkyl or optionally substituted by OH, C _1-6 alkoxy or phenyl;

R _9a , R _9b , R _9c , R _9d , R _9e , R _9f , R _9g or R _{9h are} independently selected from H or C _1-6 alkyl;

n = a natural number from 0 to 4;

A represents a 5-7 membered nitrogen heterocyclic ring.

Further selected from compounds of formula (Ia), (Ib), (Ic), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,

in:

R ₁ , R ₂ , R _1a , R _1b , R _2a , and R _{2b are} independently selected from: hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or hydroxy substituted C _{1 -6} alkyl;

R _{3 is} selected from:

-hydrogen,

halogen,

Cyano,

C _1-6 alkyl group,

Halogenated C _1-6 alkyl group,

C _1-6 alkoxy group,

Halogenated C _1-6 alkoxy group,

Nitro,

Amide group,

A 5-10 membered monocyclic or fused bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a halogen optionally selected by one or more independently, C _1-6 alkyl, C _1-6 alkoxy substituted, or

-NR _9g R _9h ;

R _{4 is} selected from:

-hydrogen,

-C _1-6 alkyl or it is optionally substituted with one or more independently selected R ₅ groups,

-C _3-7 monocyclic cycloalkyl or it is optionally substituted with one or more independently selected R ₅ groups,

A 4-7 membered monocyclic heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S, or the monocyclic heterocycloalkyl is optionally selected by one or more independently selected C _{1 -6} alkyl, -C(=O)C _1-6 alkyl or -C(=O)OC _1-6 alkyl substituted,

Phenyl or it is optionally substituted with one or more independently selected R ₆ groups,

A phenyl group fused to a 5-6 membered monocyclic heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl group is optionally substituted by one or more A = O substitution, or

A 5-6 membered monocyclic heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O and S, or the monocyclic heteroaryl group is optionally selected by one or more independently selected R ₆ groups replace;

R _{5 is} selected from:

halogen,

Hydroxyl,

Cyano,

C _1-6 alkyl,

C _1-6 alkoxy or it is optionally _{substituted by C 1-6} alkoxy or phenyl,

C _1-6 thioalkoxy,

A 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from N, S, and O, or the monocyclic heterocycloalkyl group is optionally substituted by one or more halogens or -C( =0)OC _1-6 alkyl substitution,

Phenyl,

-S(=O) ₂ C _1-6 alkyl,

-C(=O)OR _7a ,

-C(=O)NR _7b R _7c ,

-NHC(=O)OR _7d ,

-NHC(=O)R _7e , or

-NR _8a R _8b ;

R _{6 is} selected from:

halogen,

Hydroxyl,

Cyano,

C _1-6 alkyl or it is optionally substituted with one or more independently selected halogen, -NR _9a R _9b or -C(=O)NR _9c R _9d ,

C _1-6 alkoxy or it is optionally _{substituted by -NR 9e} R _9f , or

-S(=O) ₂ C _1-6 alkyl;

R _7a , R _7b , R _7c , R _7d or R _{7e are} independently selected from:

-Hydrogen, or

-C _1-6 alkyl or optionally substituted by OH or C _1-6 alkoxy,

R _8a or R _{8b are} independently selected from:

-Hydrogen, or

-C _1-6 alkyl or optionally substituted by OH, C _1-6 alkoxy or phenyl;

R _9a , R _9b , R _9c , R _9d , R _9e , R _9f , R _9g or R _{9h are} independently selected from H or C _1-6 alkyl;

n = a natural number from 0 to 4;

A represents a 5-7 membered nitrogen heterocyclic ring.

Furthermore, the compounds of formula (Iaa), (Ibb), (Icc), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,

in:

R _1a , R _1b , R _2a , R _2b , R ₁ , and R _{2 are} independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or hydroxy substituted C _{1- 6} 's alkyl group;

R _{3 is} selected from:

-hydrogen,

-halogen,

-Cyano,

-C _1-6 alkyl group,

-Halogenated C _1-6 alkyl group,

-C _1-6 alkoxy group,

-Halogenated C _1-6 alkoxy group,

-Nitro,

-Amido group,

-Phenyl, or

-Halophenyl;

n = a natural number from 0 to 4.

Furthermore, the compound of formula (Iaaa), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

in:

R _{1a is} selected from hydrogen or C _1-6 alkyl;

R _{1b is} selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or hydroxy substituted C _1-6 alkyl;

R _{3 is} selected from hydrogen, halogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, nitro Group, amido group, phenyl group, or halogenated phenyl group;

n = a natural number from 0 to 2.

Further, the compound of formula (Iaaaa), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

in:

R _{1a is} selected from hydrogen or C1-6 alkyl;

R _{1b is} selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, or hydroxy substituted C1-6 alkyl;

R3 is selected from hydrogen, halogen, cyano, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, nitro, amido, Phenyl, or halophenyl;

n = a natural number from 0 to 2.

Further, the halogen is fluorine, chlorine, bromine, or iodine; the C _1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isopropyl Butyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, cyclopentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl , Tert-hexyl, cyclohexyl; the C _1-6 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy Group, tert-butoxy, cyclobutoxy, n-pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, tert-pentyloxy, cyclopentyloxy, n-hexyloxy, isohexyloxy, New hexyloxy, secondary hexyloxy, tert-hexyloxy, cyclohexyloxy.

Furthermore, R ₁ and R _{1a are} independently selected from hydrogen and methyl; R ₂ and R _{2a are} independently selected from hydrogen, methyl, and ethyl; R _{3 is} selected from hydrogen, fluorine, chlorine, bromine, and phenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, n is selected from 0,1,2.

In one aspect, the present invention provides a pharmaceutically acceptable salt of the compound, and the pharmaceutically acceptable salt is selected from inorganic acid or organic acid salt.

In another aspect, the present invention provides a compound, which is one of the following structures:

Or its stereoisomers, tautomers, pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers.

In one aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The pharmaceutical composition may further comprise a pharmaceutically acceptable salt. At least one of acceptable carriers, excipients, diluents, adjuvants and vehicles.

In some embodiments, the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used for the treatment and/or prevention of proteoglycanase 2 inhibition related diseases The use of drugs.

Further, the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament refers to the prevention and/or treatment of inflammatory conditions and/or cartilage degradation and/or cartilage homeostasis destroy.

Further, the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine refers to the prevention and/or treatment of osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormal increase in bone turnover, periodontal disease, tooth loss, fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia Diseases such as hyperemia or multiple myeloma.

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable salt" as used herein is a derivative of the compound of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base.

The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.

The compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as deuterium (2H), iodine-125 (125I), or C-14 (14C). All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

The term "pharmaceutically acceptable carrier" refers to any preparation 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 has no toxic or side effects to the host or patient. Representative carriers include water and oil. , Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.

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

For drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat the target disorder, disease or condition.

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversion through the recombination of some bond-forming electrons. Specific examples of keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

The compounds of the present invention may 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, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.

The optically active (R)- and (S)-isomers, as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The 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), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).

"Optional" or "optionally" means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.

The term "C _1-6 alkyl" means an alkane composed of 1 to 6 carbons. Examples of this include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, and n-butyl. Base, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, cyclopentyl, n-hexyl, isohexyl, neohexyl , Sec-hexyl, tert-hexyl, cyclohexyl;

The term "halogenated C _1-6 alkyl" refers to the case where the hydrogen on the alkyl group may be replaced by one or more identical or different halogen atoms. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, trifluoromethyl, 1-chloroethyl, difluoromethyl, dichloroethyl, 2,2-difluoro Ethyl, 3,3,3-trifluoropropyl, 2-fluoro-2-methylpropyl, etc.

The term "hydroxy-substituted C _1-6 alkyl group" refers to the case where the hydrogen on the alkyl group may be replaced by one or more hydroxy groups. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, dimethylol, 2,2-dihydroxyethyl, 3,3,3 -Trihydroxypropyl, 1,3-dihydroxypropyl, etc.;

The term "C _1-6 alkoxy" means that the hydrogen on the alkyl group may be replaced by one or more oxygen atoms. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to methoxy, ethoxy, isopropoxy, etc.;

The term "halogenated C _1-6 alkoxy group" refers to the case where the hydrogen on the alkoxy group may be replaced by one or more identical or different halogen atoms. Where the alkoxy group has the meaning as described in the present invention, such examples include, but are not limited to, chloromethoxy, 1-fluoroethoxy, 1,2-fluoro-chloroethoxy, etc.;

The term "nitro" refers to -NO ₂ ;

The term "amido" means -CO-NH-;

The term "halogen" means fluorine, chlorine, bromine, and iodine.

The term "halogenated phenyl" refers to the situation where the hydrogen on the phenyl group can be replaced by one or more identical or different halogen atoms. Examples of this include, but are not limited to, dichlorophenyl, 3,4-dichlorophenyl.

"Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic hydrocarbyl ring structure having a specified number of ring atoms. The cycloalkyl group may have 3 to 10 carbon atoms, especially 3 to 7 carbon atoms. The cycloalkyl group includes, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

"Heteroaryl" means a monocyclic or fused polycyclic aromatic ring structure containing one or more heteroatoms independently selected from O, N, and S and a specified number of carbon atoms. Specifically, the aromatic ring structure may have 5 to 12 ring members, preferably 5 to 9 ring members. The heteroaryl group may be, for example, a five-membered or six-membered monocyclic ring or a fused two-membered ring formed from fused five-membered and six-membered rings or two fused six-membered rings or as another example of two fused five-membered rings.环结构。 Ring structure. Each ring may contain up to four heteroatoms generally selected from nitrogen, sulfur and oxygen. Heteroaryl rings usually contain up to 4 heteroatoms, more usually up to 3 heteroatoms, and more usually up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituents of the ring) will be less than five.

Examples of five-membered monocyclic heteroaryl groups include (but are not limited to) pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, Thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl. Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl. Specific examples of bicyclic heteroaryl groups containing six-membered rings fused to five-membered rings include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxanyl Azolyl, benzisoazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, purinyl (e.g. adenine, guanine) , Indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl and pyrazolopyridyl. Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, and cinnolinyl , Phthalazinyl, naphthyridinyl and pteridinyl. Specific heteroaryl groups are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl, and pyrazinyl.

Examples of representative heteroaryl groups include the following:

Wherein each Y is selected from NH, O, >C(=O), >SO ₂ and S.

A 5-6 membered monocyclic heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S. The fused phenyl group represents two adjacent carbon atoms of the heterocycloalkane and the benzene ring The two adjacent carbon atoms are fused.

As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic stable non-aromatic ring structure containing one or more heteroatoms independently selected from O, N, and S and a specified number of carbon atoms. The non-aromatic ring structure may have 4 to 10 ring members, especially 4 to 7 ring members. The fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocycles include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidine) Group, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydropyranyl), imidazoline, imidazolidine Ketones, oxazolines, thiazolines, 2-pyrazolines, pyrazolidines, piperazines, and N-alkylpiperazines, such as N-methylpiperazine. Other examples include thiomorpholine and its S-oxide and S,S-dioxide (especially thiomorpholine). Other examples include azetidine, piperidone, piperazinone and N-alkylpiperidines such as N-methylpiperidine. Specific examples of heterocycloalkyl and heterocycloalkyl fused phenyl groups are shown in the following illustrative examples:

Wherein each W is selected from CH ₂ , NH, O and S; and each Y is selected from NH, O, >C(=O), >SO ₂ and S.

As used herein, the term "nitrogen heterocycle" means that more than one carbon atom in a cycloalkyl group is replaced by a nitrogen atom.

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 combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.

Detailed ways

The present invention will be further described in detail below in conjunction with examples, but the implementation of the invention is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} The measurement of NMR was carried out with Bruker AVANCE-III nuclear magnetometer, and the measuring solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethylsilane (TMS).

MS is measured with ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).

High performance liquid chromatography (HPLC) analysis uses Thermo U3000 HPLC DAD high performance liquid chromatograph.

CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Yinlong HSGF ₂₅₄ or GF ₂₅₄ silica gel plate. The size of the silica gel plate used for thin layer chromatography (TLC) is 0.17mm～0.23mm, and the specification for thin layer chromatography separation and purification products is 0.4mm～0.5mm.

The silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.

Compound synthesis and characterization:

Example 1

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step A: Synthesis of (S)-5-(3-((R)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (30.0 mg, 0.14 mmol) (refer to patent CN201580070274 for synthesis method) and half Water green caseerin hydrochloride (75.0 mg, 0.16 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (94.0 μl) was added dropwise, and then Add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (30.0 mg, 0.16 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol) in sequence, Under the protection of N ₂ , the reaction was carried out at room temperature overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：56.9％)。LCMS:RT＝1.87min,[M-H] ^-＝388.13。 ¹H NMR(400MHz,DMSO)δ10.62(s,1H),7.74(s,0.5H),7.70(s,0.5H),7.26–7.08(m,3H),3.58–3.51(m,1H),3.51–3.45(m,1H),3.44–3.36(m,1H),3.23–3.11(m,1H),3.08–2.99(m,1H),2.96–2.88(m,1H),2.85–2.76(m,1H),2.42–2.29(m,1H),2.29–2.19(m,1H),2.02–1.94(m,1H),1.88–1.79(m,1H),1.22(d,J＝7.3Hz,1.5H),1.17(d,J＝7.1Hz,1.5H),1.12–1.00(m,1H),0.43(ddd,J＝13.5,9.1,4.6Hz,1H),0.36–0.26(m,2H),0.19–0.03(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 31.0 mg of white solid (S)-5-(3-((R)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 56.9%). LCMS: RT=1.87min, [MH] ^- =388.13. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 7.74 (s, 0.5H), 7.70 (s, 0.5H), 7.26-7.08 (m, 3H), 3.58-3.51 (m, 1H) ,3.51–3.45(m,1H), 3.44–3.36(m,1H), 3.23–3.11(m,1H), 3.08–2.99(m,1H), 2.96–2.88(m,1H), 2.85–2.76( m,1H),2.42–2.29(m,1H),2.29–2.19(m,1H),2.02–1.94(m,1H),1.88–1.79(m,1H),1.22(d,J=7.3Hz, 1.5H), 1.17(d,J=7.1Hz,1.5H),1.12–1.00(m,1H),0.43(ddd,J=13.5,9.1,4.6Hz,1H),0.36–0.26(m,2H) ,0.19–0.03(m,1H).

Example 2

Synthesis of 5-(3-(6-chloro-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 5-(3-(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4 -Diketone

At room temperature, 3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (20.0 mg, 0.10 mmol) and 6-chloro-1,2,3,4- Tetrahydroisoquinoline (14.4 mg, 0.10 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (94.0 μl) was added dropwise, and then added sequentially 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (30.0 mg, 0.16 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), N ₂ Under protection, react at room temperature overnight.

After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 11.2 mg of white solid 5-(3-(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2, 4-dione (yield: 31.3%). LCMS: RT=1.81 min, [M+H] ⁺ =362.21. ¹ H NMR(400MHz,DMSO)δ10.61(s,1H),7.73(s,0.5H),7.71(s,0.5H),7.38-7.20(m,3H),4.59(d,J=9.6Hz ,2H),3.73-3.56(m,2H),2.92-2.81(m,1H),2.80-2.72(m,1H),2.50-2.37(m,1H),2.37-2.25(m,1H),2.07 –1.90(m,2H), 1.19–1.04(m,1H), 0.51–0.38(m,1H), 0.40–0.24(m,2H), 0.21–0.05(m,1H).

Example 3

Synthesis of (S)-5-cyclopropyl-5-(3-(isoindol-2-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of (S)-5-cyclopropyl-5-(3-(isoindol-2-yl)-3-oxopropyl)imidazolidine-2,4-dione

At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (35.0 mg, 0.17 mmol) and isoindole hydrochloride (26.5 Mg, 0.17 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (82 μl) was added dropwise, and then 1-ethyl-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (47.0 mg, 0.25 mmol) and 1-hydroxybenzotriazole (3.3 mg, 0.02 mmol), under N ₂ protection, react at room temperature overnight.

After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 27.2 mg of white solid (S)-5-cyclopropyl-5-(3-(isoindol-2-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 50.9 %). LCMS: RT=1.95 min, [M+H] ⁺ =314.18. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 7.73 (s, 1H), 7.39-7.32 (m, 2H), 7.32-7.26 (m, 2H), 4.79 (s, 2H), 4.62 (s,2H),2.47-2.39(m,1H),2.33-2.25(m,1H),2.02(t,J=8.1Hz,2H),1.17-1.09(m,1H),0.4-0.43(m ,1H),0.41–0.32(m,2H),0.14-0.10(m,1H).

Example 4

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-7-bromo-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-2,2,2-三氟乙烷-1-酮 Step A: Synthesis of (R)-1-(8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

At zero degrees Celsius, add greencaserin hydrochloride hemihydrate (2.0 g, 4.15 mmol) to dichloromethane (20.0 ml), add pyridine (1.8 ml) and trifluoroacetic anhydride (1.5 ml) dropwise in turn, N ₂ Under protection, react at room temperature for 3.5 hours.

-3-基)-2,2,2-三氟乙烷-1-酮(收率：90.9％)。LCMS:RT＝2.16min,[M+H] ⁺＝292.03。 After the reaction was completed, aqueous hydrochloric acid solution (1.0 mol per liter, 10 ml) was added for quenching, the mixture was extracted with dichloromethane (50 ml × 3 times), the organic phases were combined, and the organic phase was first used with saturated brine (30 ml × 2 times) ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/20). 1.1 g of light yellow oil (R)-1-(8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (yield: 90.9%). LCMS: RT = 2.16 min, [M+H] ⁺ =292.03.

-3-基)-2,2,2-三氟乙烷-1-酮 Step B: Synthesis of (R)-1-(7-bromo-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

-3-基)-2,2,2-三氟乙烷-1-酮(600.0毫克，2.06毫摩尔)和N-溴代丁二酰亚胺(257.0毫克，1.44毫摩尔)加入二氯乙烷(6.0毫升)中，滴加三氟甲磺酸(253.0微升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the (R)-1-(8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (600.0 mg, 2.06 mmol) and N-bromosuccinimide (257.0 mg, 1.44 mmol) add dichloroethane In alkane (6.0 ml), trifluoromethanesulfonic acid (253.0 μl) was added dropwise, and the reaction was carried out at 75 degrees Celsius overnight under the protection of _{N 2.}

-3-基)-2,2,2-三氟乙烷-1-酮。LCMS:RT＝2.21min。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). Obtained 610.0 mg of a colorless oily mixture (R)-1-(7-bromo-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one. LCMS: RT = 2.21 min.

Step C: Synthesis of (R)-7-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-3-基)-2,2,2-三氟乙烷-1-酮(610.0毫克，1.65毫摩尔)加入甲醇(10.0毫升)中，滴加15％氢氧化钠水溶液(10.0微升)，室温反应2小时。 At room temperature, the (R)-1-(7-bromo-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (610.0 mg, 1.65 mmol) was added to methanol (10.0 ml), and 15% aqueous sodium hydroxide solution (10.0 μl) was added dropwise, React at room temperature for 2 hours.

(收率：9.5％)。LCMS:RT＝1.61min,[M+H] ⁺＝273.95。 After the reaction, the methanol was evaporated, ethyl acetate was dissolved, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 25% acetonitrile eluted in 15.10 minutes ; Detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 43.0 mg of white solid (R)-7-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 9.5%). LCMS: RT=1.61 min, [M+H] ⁺ =273.95.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step D: Synthesis of (S)-5-(3-((R)-7-bromo-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]nitrogen miscellaneous

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (30.0 mg, 0.14 mmol) and greencaserin hydrochloride hemihydrate (30.0 mg, 0.14 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (70.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (30.0 mg, 0.16 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：22.9％)。LCMS:RT＝1.94min,[M+H] ⁺＝468.02。 ¹H NMR(400MHz,DMSO)δ10.61(s,0.5H),10.60(s,0.5H),7.73(s,0.5H),7.69(s,0.5H),7.58(s,0.5H),7.55(s,0.5H),7.40(s,0.5H),7.38(s,0.5H),3.63–3.55(m,1H),3.54–3.43(m,1H),3.43–3.35(m,1H),3.23–3.10(m,1H),3.07–2.98(m,1H),2.98–2.87(m,1H),2.87–2.76(m,1H),2.44–2.32(m,1H),2.31–2.21(m,1H),1.93–1.79(m,2H),1.22(d,J＝7.0Hz,1.5H),1.16(d,J＝7.1Hz,1.5H),1.10–0.98(m,1H),0.49–0.36(m,1H),0.36–0.24(m,2H),0.15–0.04(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 15.0 mg of white solid (S)-5-(3-((R)-7-bromo-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d] Aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 22.9%). LCMS: RT=1.94 min, [M+H] ⁺ =468.02. ¹ H NMR (400MHz, DMSO) δ 10.61 (s, 0.5H), 10.60 (s, 0.5H), 7.73 (s, 0.5H), 7.69 (s, 0.5H), 7.58 (s, 0.5H), 7.55(s,0.5H),7.40(s,0.5H),7.38(s,0.5H),3.63-3.55(m,1H),3.54-3.43(m,1H),3.43-3.35(m,1H) , 3.23–3.10(m,1H),3.07–2.98(m,1H), 2.98–2.87(m,1H), 2.87–2.76(m,1H), 2.44–2.32(m,1H), 2.31–2.21( m,1H),1.93-1.79(m,2H),1.22(d,J=7.0Hz,1.5H),1.16(d,J=7.1Hz,1.5H),1.10-0.98(m,1H),0.49 –0.36(m,1H), 0.36–0.24(m,2H), 0.15–0.04(m,1H).

Example 5

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-8-chloro-9-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-2,2,2-三氟乙烷-1-酮 Step A: Synthesis of (R)-1-(8-chloro-9-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

-3-基)-2,2,2-三氟乙烷-1-酮(500.0毫克，1.72毫摩尔)和选择性氟试剂(790.0毫克，2.23毫摩尔)加入二氯乙烷(3.0毫升)中，滴加三氟甲磺酸(1.6毫升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the (R)-1-(8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (500.0 mg, 1.72 mmol) and selective fluorine reagent (790.0 mg, 2.23 mmol) were added to dichloroethane (3.0 mL) In the medium, trifluoromethanesulfonic acid (1.6 ml) was added dropwise, and the reaction was carried out at 75 degrees Celsius overnight under the protection of _{N 2.}

-3-基)-2,2,2-三氟乙烷-1-酮。LCMS:RT＝2.16min。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). Obtained 163.0 mg of white solid mixture (R)-1-(6-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one. LCMS: RT = 2.16 min.

Step B: Synthesis of (R)-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-3-基)-2,2,2-三氟乙烷-1-酮(163.0毫克，0.53毫摩尔)加入甲醇(5.0毫升)中，滴加15％氢氧化钠水溶液(5.0微升)，室温反应2小时。 At room temperature, the (R)-1-(6-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (163.0 mg, 0.53 mmol) was added to methanol (5.0 ml), and 15% aqueous sodium hydroxide solution (5.0 μl) was added dropwise, React at room temperature for 2 hours.

(收率：26.7％)。LCMS:RT＝1.59min,[M+H] ⁺＝214.03。 After the reaction, the methanol was evaporated, ethyl acetate was dissolved, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 20% acetonitrile eluted in 20.00 minutes ; Detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 30.2 mg of white solid (R)-6-fluoro-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 26.7%). LCMS: RT=1.59 min, [M+H] ⁺ =214.03.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step C: Synthesis of (S)-5-(3-((R)-8-chloro-9-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]nitrogen miscellaneous

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(30.2毫克，0.14毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(70.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚 胺盐酸盐(30.0毫克，0.16毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (30.0 mg, 0.14 mmol) and (R)-6-fluoro- 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

(30.2 mg, 0.14 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (70.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (30.0 mg, 0.16 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：19.3％)。LCMS:RT＝1.88min,[M+H] ⁺＝408.11。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 11.0 mg of white solid (S)-5-(3-((R)-6-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d] Aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 19.3%). LCMS: RT=1.88 min, [M+H] ⁺ =408.11.

Example 6

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-7-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-2,2,2-三氟乙烷-1-酮 Step A: Synthesis of (R)-1-(7-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

-3-基)-2,2,2-三氟乙烷-1-酮(500.0毫克，1.72毫摩尔)和选择性氟试剂(790.0毫克，2.23毫摩尔)加入二氯乙烷(3.0毫升)中，滴加三氟甲磺酸(1.60毫升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the (R)-1-(8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (500.0 mg, 1.72 mmol) and selective fluorine reagent (790.0 mg, 2.23 mmol) were added to dichloroethane (3.0 mL) In the medium, trifluoromethanesulfonic acid (1.60 ml) was added dropwise, and the reaction was carried out at 75 degrees Celsius overnight under the protection of _{N 2.}

-3-基)-2,2,2-三氟乙烷-1-酮。LCMS:RT＝2.16min。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). Obtained 163.0 mg of a white solid mixture (R)-1-(7-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one. LCMS: RT = 2.16 min.

Step B: Synthesis of (R)-7-fluoro-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-3-基)-2,2,2-三氟乙烷-1-酮(163.0毫克，0.53毫摩尔)加入甲醇(5.0毫升)中，滴加15％氢氧化钠水溶液(5.0微升)，室温反应2小时。 At room temperature, the (R)-1-(7-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (163.0 mg, 0.53 mmol) was added to methanol (5.0 ml), and 15% aqueous sodium hydroxide solution (5.0 μl) was added dropwise, React at room temperature for 2 hours.

(收率：23.8％)。LCMS:RT＝1.59min,[M+H] ⁺＝214.03。 After the reaction, the methanol was evaporated, ethyl acetate was dissolved, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 20% acetonitrile eluted in 22.50 minutes Out; detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 27.0 mg of white solid (R)-7-fluoro-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 23.8%). LCMS: RT=1.59 min, [M+H] ⁺ =214.03.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step C: Synthesis of (S)-5-(3-((R)-7-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]nitrogen miscellaneous

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(27.0毫克，0.13毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(63.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(27.0毫克，0.14毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (27.0 mg, 0.13 mmol) and (R)-7-fluoro- 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

(27.0 mg, 0.13 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (63.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (27.0 mg, 0.14 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：17.5％)。LCMS:RT＝1.88min,[M+H] ⁺＝408.15。 ¹H NMR(500MHz,DMSO)δ10.62(s,0.5H),10.60(s,0.5H),7.73(s,0.5H),7.69(s,0.5H),7.35(d,J＝7.7Hz,0.5H),7.33(d,J＝7.7Hz,0.5H),7.24(d,J＝10.3Hz,0.5H),7.22(d,J＝10.4Hz,0.5H),3.62–3.54(m,1H),3.53–3.45(m,1H),3.45–3.38(m,1H),3.23–3.11(m,1H),3.10–3.00(m,1H),3.00–2.88(m,1H),2.88–2.80(m,1H),2.41–2.31(m,1H),2.31–2.22(m,1H),2.03–1.95(m,1H),1.87–1.82(m,1H),1.22(d,J＝7.4Hz,1.5H),1.17(d,J＝7.1Hz,1.5H),1.09–1.02(m,1H),0.47–0.39(m,1H),0.38–0.27(m,2H),0.14–0.05(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 9.3 mg of white solid (S)-5-(3-((R)-7-fluoro-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d] Aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 17.5%). LCMS: RT=1.88 min, [M+H] ⁺ =408.15. ¹ H NMR(500MHz,DMSO)δ10.62(s,0.5H), 10.60(s,0.5H), 7.73(s,0.5H), 7.69(s,0.5H), 7.35(d,J=7.7Hz ,0.5H),7.33(d,J＝7.7Hz,0.5H),7.24(d,J＝10.3Hz,0.5H),7.22(d,J＝10.4Hz,0.5H),3.62–3.54(m, 1H), 3.53–3.45(m,1H), 3.45–3.38(m,1H), 3.23–3.11(m,1H), 3.10–3.00(m,1H), 3.00–2.88(m,1H), 2.88– 2.80(m,1H),2.41–2.31(m,1H),2.31–2.22(m,1H),2.03–1.95(m,1H),1.87–1.82(m,1H),1.22(d,J=7.4 Hz, 1.5H), 1.17 (d, J = 7.1 Hz, 1.5H), 1.09–1.02 (m, 1H), 0.47–0.39 (m, 1H), 0.38–0.27 (m, 2H), 0.14–0.05( m,1H).

Example 7

-3-基)丙基)咪唑烷-2,4-二酮 Synthesis of (S)-5-cyclopropyl-5-(3-oxo-3-(1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)propyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)丙基)咪唑烷-2,4-二酮 Step A: Synthesis of (S)-5-cyclopropyl-5-(3-oxo-3-(1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)propyl)imidazolidine-2,4-dione

(16.5毫克，0.09毫摩尔)加入N,N-二甲基甲酰胺(1.0毫升)中，滴加N,N-二异丙基乙胺(47.9微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(19.0毫克，0.10毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (20.0 mg, 0.09 mmol) and 2,3,4,5- Tetrahydro-1H-benzo[d]aza

(16.5 mg, 0.09 mmol) was added to N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (47.9 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (19.0 mg, 0.10 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)丙基)咪唑烷-2,4-二酮(收率：56.9％)。LCMS:RT＝1.77min,[M+H] ⁺＝342.24。 ¹H NMR(400MHz,DMSO)δ10.62(s,1H),7.72(s,1H),7.26–7.07(m,4H),3.62–3.46(m,4H),2.99–2.75(m,4H),2.50–2.38(m,1H),2.36–2.26(m,1H),2.06–1.91(m,2H),1.18–1.02(m,1H),0.51–0.42(m,1H),0.40–0.24(m,2H),0.20–0.05(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 17.0 mg of white solid (S)-5-cyclopropyl-5-(3-oxo-3-(1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)propyl)imidazolidine-2,4-dione (yield: 56.9%). LCMS: RT=1.77 min, [M+H] ⁺ =342.24. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 7.72 (s, 1H), 7.26-7.07 (m, 4H), 3.62-3.46 (m, 4H), 2.99-2.75 (m, 4H) , 2.50–2.38(m,1H), 2.36–2.26(m,1H), 2.06–1.91(m,2H), 1.18–1.02(m,1H), 0.51–0.42(m,1H), 0.40–0.24( m,2H),0.20–0.05(m,1H).

Example 8

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (5S)-5-(3-(6-bromo-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of N-(2-bromophenethyl)-2-chloropropionamide

At zero degrees Celsius, add 2-(2-bromophenyl)ethyl-1-amine (1.0 g, 5.0 mmol) to dichloromethane (25.0 ml), and add N,N-diisopropylethylamine dropwise in turn (1.3 ml) and 2-chloropropionyl chloride (590.0 μl), under N ₂ protection, react at room temperature for 1 hour.

After the reaction was completed, it was quenched by adding water, the mixed solution was extracted with dichloromethane (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 1.38 g of light yellow oily N-(2-bromophenethyl)-2-chloropropionamide was obtained (yield: 95.0%). LCMS: RT=1.97 min, [M+H] ⁺ = 290.10.

-2-酮 Step B: Synthesis of 6-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

At room temperature, anhydrous aluminum trichloride (1.58 g, 11.90 mmol), under N ₂ protection, react at 165 degrees Celsius for 2 hours.

-2-酮(收率：64.4％)。LCMS:RT＝1.84min,[M+H] ⁺＝254.00。 After the reaction was completed, it was cooled to room temperature, quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then washed with anhydrous Dry over sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtained 780.0 mg of yellow solid 6-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one (yield: 64.4%). LCMS: RT=1.84 min, [M+H] ⁺ =254.00.

Step C: Synthesis of 6-bromo-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-2-酮(780.0毫克，3.06毫摩尔)的四氢呋喃(10毫升)中，滴加硼烷四氢呋喃溶液(12.2毫升，1.0摩尔每升)，N ₂保护下，60摄氏度搅拌2小时。 At zero degrees Celsius, it contains 6-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-ketone (780.0 mg, 3.06 mmol) in tetrahydrofuran (10 mL), borane tetrahydrofuran solution (12.2 mL, 1.0 mol per liter) was added dropwise, and stirred at 60 degrees Celsius for 2 hours under the protection of _{N 2.}

，无需纯化，直接用于下一步反应。LCMS:RT＝1.58min,[M+H] ⁺＝241.97。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 180.0 mg of yellow solid 6-bromo-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

, Without purification, directly used in the next reaction. LCMS: RT=1.58 min, [M+H] ⁺ =241.97.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step D: Synthesis of (5S)-5-(3-(6-bromo-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(30.0毫克，0.14毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(82微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(47.0毫克，0.17毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (35.0 mg, 0.16 mmol) and 6-bromo-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(30.0 mg, 0.14 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (82 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (47.0 mg, 0.17 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：20.9％)。LCMS:RT＝1.88min,[M+H] ⁺＝434.15。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 14.5 mg of white solid (5S)-5-(3-(6-bromo-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 20.9%). LCMS: RT=1.88 min, [M+H] ⁺ =434.15.

Examples 9 and 10

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(S)-5-(3-((R)-6-氯-1-甲基-1,2,4,5-四氢-3H-苯并[d]氮杂

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((S)-6-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-6-chloro-1-methyl -1,2,4,5-Tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of N-(2-chlorophenethyl)-2-chloropropionamide

At zero degrees Celsius, add 2-(2-chlorophenyl)ethyl-1-amine (790.0 mg, 5.08 mmol) to dichloromethane (25.0 ml), and add N,N-diisopropylethylamine dropwise in turn (1.3 ml) and 2-chloropropionyl chloride (600.0 μl), under N ₂ protection, react at room temperature for 1 hour.

After the reaction was completed, it was quenched by adding water, the mixed solution was extracted with dichloromethane (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 1.20 g of light yellow oily N-(2-chlorophenethyl)-2-chloropropionamide was obtained (yield: 97.6%). LCMS: RT=1.98 min, [M+H] ⁺ =246.70.

-2-酮 Step B: Synthesis of 6-chloro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

At room temperature, anhydrous aluminum trichloride (1.63 g, 12.20 mmol), under N ₂ protection, react at 165 degrees Celsius for 2 hours.

-2-酮(收率：40.0％)。LCMS:RT＝1.84min,[M+H] ⁺＝210.10。 After the reaction was completed, it was cooled to room temperature, quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then washed with anhydrous Dry over sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtained 410.0 mg of yellow solid 6-chloro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one (yield: 40.0%). LCMS: RT=1.84 min, [M+H] ⁺ =210.10.

Step C: Synthesis of 6-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-2-酮(410.0毫克，1.95毫摩尔)的四氢呋喃(10毫升)中，滴加硼烷四氢呋喃溶液(7.8毫升，1.0摩尔每升)，N ₂保护下，45摄氏度搅拌2小时。 At zero degrees Celsius, it contains 6-chloro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-ketone (410.0 mg, 1.95 mmol) in tetrahydrofuran (10 mL), borane tetrahydrofuran solution (7.8 mL, 1.0 mol per liter) was added dropwise, under N ₂ protection, and stirred at 45 degrees Celsius for 2 hours.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.54min,[M+H] ⁺＝196.10。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 25.0 mg of yellow solid 6-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

, Without purification, directly used in the next reaction. LCMS: RT=1.54 min, [M+H] ⁺ =196.10.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(S)-5-(3-((R)-6-氯-1-甲基-1,2,4,5-四氢-3H-苯并[d]氮杂

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step D: Synthesis of (S)-5-(3-((S)-6-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-6-chloro-1-methyl -1,2,4,5-Tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(25.0毫克，0.10毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(49.6微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(23.0毫克，0.12毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (21.2 mg, 0.10 mmol) and 6-chloro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(25.0 mg, 0.10 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (49.6 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (23.0 mg, 0.12 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：26.5％)和10.0毫克白色固体(S)-5-(3-((R)-6-氯-1-甲基-1,2,4,5-四氢-3H-苯并[d]氮杂

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：23.0％)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 30% acetonitrile eluted in 17.50 minutes Out; detection wavelength: 200nm. After purification, it was lyophilized to obtain 11.5 mg of white solid (S)-5-(3-((S)-6-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d ]Aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 26.5%) and 10.0 mg of white solid (S)-5-(3-(( R)-6-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 23.0%).

Example 9: LCMS: RT=1.88 min, [M+H] ⁺ =390.23. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 0.5H), 10.60 (s, 0.5H), 7.76 (s, 0.5H), 7.67 (s, 0.5H), 7.35-7.26 (m, 1H) ,7.20--7.10(m,2H), 3.86--3.78(m,1H), 3.78--3.69(m,1H), 3.65--3.59(m,1H), 3.43--3.29(m,1H), 3.29--3.20( m,1H), 3.20–3.08(m,1H), 2.96–2.76(m,1H), 2.33–2.20(m,1H), 2.20–2.07(m,1H), 1.99–1.83(m,1H), 1.83–1.71(m,1H), 1.17(dd,J=6.9,2.0Hz,1.5H), 1.13(d,J=6.7Hz,1.5H), 1.08–0.99(m,1H), 0.52–0.37( m,1H),0.37–0.18(m,2H),0.18–0.03(m,1H).

Example 10: LCMS: RT=1.90 min, [M+H] ⁺ =390.23. ¹ H NMR (500MHz, DMSO) δ 10.61 (s, 0.5H), 10.59 (s, 0.5H), 7.73 (d, J = 6.9 Hz, 0.5H), 7.68 (s, 0.5H), 7.25-7.11 (m,3H), 3.62--3.52(m,1H), 3.52--3.43(m,1H), 3.43--3.30(m,1H), 3.23--3.09(m,1H), 3.09--2.99(m,1H) , 2.96–2.86(m,1H), 2.85–2.78(m,1H), 2.44–2.29(m,1H), 2.29–2.16(m,1H), 2.03–1.92(m,1H), 1.88–1.79( m,1H),1.22(d,J=2.8Hz,1.5H),1.16(d,J=7.1Hz,1.5H),1.09–0.99(m,1H),0.42(d,J=5.0Hz,1H ), 0.38–0.26 (m, 2H), 0.14–0.04 (m, 1H).

Example 11

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((S)-7-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of N-(3-chlorophenethyl)-2-chloropropionamide

At zero degrees Celsius, add 2-(3-chlorophenyl)ethyl-1-amine (790.0 mg, 5.08 mmol) to dichloromethane (25.0 ml), and add N,N-diisopropylethylamine dropwise successively (1.3 ml) and 2-chloropropionyl chloride (600.0 μl), under N ₂ protection, react at room temperature for 1 hour.

After the reaction was completed, it was quenched by adding water, the mixed solution was extracted with dichloromethane (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 1.20 g of light yellow oily N-(3-chlorophenethyl)-2-chloropropionamide was obtained (yield: 97.6%). LCMS: RT=1.99 min, [M+H] ⁺ =246.53.

-2-酮 Step B: Synthesis of 7-chloro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

At room temperature, anhydrous aluminum trichloride (1.63 g, 12.20 mmol), under N ₂ protection, react at 165 degrees Celsius for 2 hours.

-2-酮(收率：87.8％)。LCMS:RT＝1.82min,[M+H] ⁺＝210.13。 After the reaction was completed, it was cooled to room temperature, quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then washed with anhydrous Dry over sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtained 900.0 mg of yellow solid 7-chloro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one (yield: 87.8%). LCMS: RT=1.82 min, [M+H] ⁺ =210.13.

Step C: Synthesis of 7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-2-酮(900.0毫克，4.29毫摩尔)的四氢呋喃(20毫升)中，滴加硼烷四氢呋喃溶液(17.1毫升，1.0摩尔每升)，N ₂保护下，45摄氏度搅拌2小时。 At zero degrees Celsius, to contain 7-chloro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one (900.0 mg, 4.29 mmol) in tetrahydrofuran (20 mL), borane tetrahydrofuran solution (17.1 mL, 1.0 mol per liter) was added dropwise, under N ₂ protection, and stirred at 45 degrees Celsius for 2 hours.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.56min,[M+H] ⁺＝196.12。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 64.0 mg of yellow solid 7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

, Without purification, directly used in the next reaction. LCMS: RT=1.56 min, [M+H] ⁺ =196.12.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step D: Synthesis of (S)-5-(3-((S)-7-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(30.0毫克，0.15毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中， 滴加N,N-二异丙基乙胺(74.4微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(43.0毫克，0.23毫摩尔)和1-羟基苯并三唑(2.7毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (31.8 mg, 0.15 mmol) and 7-chloro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(30.0 mg, 0.15 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (74.4 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (43.0 mg, 0.23 mmol) and 1-hydroxybenzotriazole (2.7 mg, 0.02 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：23.1％)。LCMS:RT＝1.86min,[M+H] ⁺＝390.23。 ¹H NMR(500MHz,DMSO)δ10.60(s,0.5H),10.57(s,0.5H),7.72(d,J＝11.0Hz,0.5H),7.66(d,J＝13.0Hz,0.5H),7.33–7.26(m,1H),7.21–7.10(m,2H),3.76–3.70(m,1H),3.67–3.59(m,1H),3.60–3.53(m,1H),3.51–3.40(m,1H),3.38–3.27(m,1H),3.27–3.19(m,1H),3.19–3.06(m,1H),2.38–2.24(m,1H),2.22–2.11(m,1H),1.99–1.85(m,1H),1.80–1.72(m,1H),1.16(dd,J＝6.9,2.4Hz,1.5H),1.12(d,J＝6.8Hz,1.5H),1.07–0.97(m,1H),0.44–0.37(m,1H),0.36–0.24(m,2H),0.10–0.03(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 32% acetonitrile eluted in 16.50 minutes Out; detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 13.5 mg of white solid (S)-5-(3-((S)-7-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[ d]Aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 23.1%). LCMS: RT=1.86 min, [M+H] ⁺ =390.23. ¹ H NMR(500MHz,DMSO)δ10.60(s,0.5H), 10.57(s,0.5H), 7.72(d,J=11.0Hz,0.5H), 7.66(d,J=13.0Hz,0.5H ), 7.33–7.26(m,1H), 7.21–7.10(m,2H), 3.76–3.70(m,1H), 3.67–3.59(m,1H), 3.60–3.53(m,1H), 3.51–3.40 (m,1H), 3.38–3.27(m,1H), 3.27–3.19(m,1H), 3.19–3.06(m,1H), 2.38–2.24(m,1H), 2.22–2.11(m,1H) ,1.99–1.85(m,1H),1.80–1.72(m,1H), 1.16(dd,J=6.9,2.4Hz,1.5H), 1.12(d,J=6.8Hz,1.5H),1.07–0.97 (m,1H), 0.44–0.37(m,1H), 0.36–0.24(m,2H), 0.10–0.03(m,1H).

Example 12

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-7-bromo-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 2-chloro-N-phenethyl propionamide

At zero degrees Celsius, add 2-phenylethyl-1-amine (1.50 g, 12.4 mmol) to dichloromethane (30.0 ml), and add N,N-diisopropylethylamine (1.3 ml) and 2-Chloropropionyl chloride (600.0 microliters), under N ₂ protection, react at room temperature for 1 hour.

After the reaction was completed, it was quenched by adding water, the mixed solution was extracted with dichloromethane (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 1.00 g of light yellow oily 2-chloro-N-phenethylpropionamide was obtained (yield: 38.1%). LCMS: RT=1.96 min, [M+H] ⁺ =212.32.

-2-酮 Step B: Synthesis of 1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

At room temperature, anhydrous aluminum trichloride (1.47 g, 11.80 mmol) was added to o-dichlorobenzene (2.4 mL) containing 2-chloro-N-phenethylpropionamide (1.00 g, 4.72 mmol), Under the protection of N ₂ , react at 165 degrees Celsius for 2 hours.

-2-酮(收率：48.1％)。LCMS:RT＝1.80min,[M+H] ⁺＝176.20。 After the reaction was completed, cooled to room temperature, quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then with anhydrous Dry over sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 400.0 mg of yellow solid 1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one (yield: 48.1%). LCMS: RT=1.80 min, [M+H] ⁺ =176.20.

-2-酮 Step C: Synthesis of (S)-7-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

-2-酮(400.0毫克，2.27毫摩尔)和N-溴代丁二酰亚胺(404.0毫克，2.27毫摩尔)加入二氯乙烷(11.4毫升)中，滴加三氟甲磺酸(455微升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the 1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one (400.0 mg, 2.27 mmol) and N-bromosuccinimide (404.0 mg, 2.27 mmol) were added to dichloroethane (11.4 mL), and trifluoromethanesulfonic acid (455 Microliter), _{under the protection of N 2} , react at 75 degrees Celsius overnight.

-2-酮(收率：86.3％)。LCMS:RT＝1.83min,[M+H] ⁺＝254.35。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (30 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 28% acetonitrile eluted in 17.50 minutes Out; detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 500.0 mg of white solid (S)-7-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one (yield: 86.3%). LCMS: RT=1.83 min, [M+H] ⁺ =254.35.

Step D: Synthesis of (S)-7-bromo-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-2-酮(500.0毫克，1.96毫摩尔)的四氢呋喃(9.2毫升)中，滴加硼烷四氢呋喃溶液(3.9毫升，1.0摩尔每升)，N ₂保护下，45摄氏度搅拌2小时。 At zero degrees Celsius, to contain (S)-7-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-ketone (500.0 mg, 1.96 mmol) in tetrahydrofuran (9.2 mL), borane tetrahydrofuran solution (3.9 mL, 1.0 mol per liter) was added dropwise, under N ₂ protection, and stirred at 45 degrees Celsius for 2 hours.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] ⁺＝240.10。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 79.0 mg of yellow solid (S)-7-bromo-1-methyl-2,3,4,5-tetrahydro-1H-benzo[ d]Aza

, Without purification, directly used in the next reaction. LCMS: RT=1.59 min, [M+H] ⁺ =240.10.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step E: Synthesis of (S)-5-(3-((R)-7-bromo-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(79.0毫克，0.33毫摩尔)加入N,N-二甲基甲酰胺(1.6毫升)中，滴加N,N-二异丙基乙胺(82微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(47.0毫克，0.25毫摩尔)和1-羟基苯并三唑(2.7毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (70.0 mg, 0.33 mmol) and (S)-7-bromo- 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

(79.0 mg, 0.33 mmol) was added to N,N-dimethylformamide (1.6 mL), N,N-diisopropylethylamine (82 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride (47.0 mg, 0.25 mmol) and 1-hydroxybenzotriazole (2.7 mg, 0.02 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：17.4％)。LCMS:RT＝1.88min,[M+H] ⁺＝434.16。 ¹H NMR(400MHz,DMSO)δ10.61(s,0.5H),10.59(s,0.5H),7.74(d,J＝5.7Hz,0.5H),7.68(s,0.5H),7.36–7.26(m,2H),7.08(t,J＝8.2Hz,1H),3.51–3.44(m,1H),3.44–3.39(m,1H),3.39–3.32(m,1H),3.18–3.09(m,1H),3.05–2.95(m,1H),2.95–2.84(m,1H),2.84–2.75(m,1H),2.37–2.27(m,1H), 2.27–2.13(m,1H),1.92–1.84(m,1H),1.84–1.76(m,1H),1.20(d,J＝2.2Hz,1.5H),1.15(d,J＝7.1Hz,1.5H),1.08–1.00(m,1H),0.47–0.37(m,1H),0.37–0.24(m,2H),0.12–0.02(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 25.0 mg of white solid (S)-5-(3-((R)-7-bromo-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 17.4%). LCMS: RT=1.88 min, [M+H] ⁺ =434.16. ¹ H NMR (400MHz, DMSO) δ 10.61 (s, 0.5H), 10.59 (s, 0.5H), 7.74 (d, J = 5.7 Hz, 0.5H), 7.68 (s, 0.5H), 7.36-7.26 (m,2H),7.08(t,J=8.2Hz,1H),3.51–3.44(m,1H),3.44–3.39(m,1H),3.39–3.32(m,1H),3.18–3.09(m ,1H),3.05–2.95(m,1H), 2.95–2.84(m,1H), 2.84–2.75(m,1H), 2.37–2.27(m,1H), 2.27–2.13(m,1H),1.92 –1.84(m,1H),1.84–1.76(m,1H), 1.20(d,J=2.2Hz,1.5H), 1.15(d,J=7.1Hz,1.5H), 1.08–1.00(m,1H ), 0.47–0.37(m,1H), 0.37–0.24(m,2H), 0.12–0.02(m,1H).

Example 13

-3-基)-3-氧丙基)咪唑啉-2,4-二酮 Synthesis of (5S)-5-cyclopropyl-5-(3-(6-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazoline-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 2-chloro-N-(2-fluorophenethyl)propionamide

At zero degrees Celsius, add 2-(2-fluorophenyl)ethyl-1-amine (1.0 g, 7.19 mmol) to dichloromethane (30.0 ml), and add N,N-diisopropylethylamine dropwise successively (1.8 ml) and 2-chloropropionyl chloride (852 μl), under N ₂ protection, react at room temperature for 1.5 hours.

After the reaction was completed, it was quenched by adding water, the mixed solution was extracted with dichloromethane (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/4). 1.6 g of yellow oily 2-chloro-N-(2-fluorophenethyl)propionamide was obtained (yield: 96.3%).

Step B: Synthesis of 6-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza-2-one

At room temperature, add 2-chloro-N-(2-fluorophenethyl) (1.6 g, 7.10 mmol) propionamide to 1,2-dichlorobenzene (3.2 ml), and finally add aluminum trichloride (2.3 G), _{under the protection of N 2} , react at 160 degrees Celsius for 5 hours.

After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 734.0 mg of yellow oily 6-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza-2-one was obtained (yield: 53.3%). LCMS: RT=1.73min, [M+H] ⁺ =194.12.

Step C: Synthesis of 6-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

At room temperature, add 6-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza-2-one (734 mg, 3.79 mmol) to borane tetrahydrofuran complex In the compound (17.1 ml), _{under the protection of N 2} , the reaction was carried out at 45 degrees Celsius overnight.

(收率：87.9％)。LCMS:RT＝1.49min,[M+H] ⁺＝180.17。 After the reaction is over, cool to room temperature, add methanol dropwise until no bubbles are generated, and then quench by adding water. The mixture is extracted with ethyl acetate (20 ml × 3 times), and the organic phases are combined. The organic phase is first used with saturated brine (20 ml × 2 times) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The resulting residue was used directly in the next reaction. Obtained 600.0 mg of yellow oil 6-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 87.9%). LCMS: RT=1.49 min, [M+H] ⁺ = 180.17.

-3-基)-3-氧丙基)咪唑啉-2,4-二酮 Step D: Synthesis of (5S)-5-cyclopropyl-5-(3-(6-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazoline-2,4-dione

(178.0毫克，0.96毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(94.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(30.0毫克，0.16毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (35.0 mg, 0.16 mmol) and 6-fluoro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(178.0 mg, 0.96 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (94.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (30.0 mg, 0.16 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)咪唑啉-2,4-二酮(收率：67.8％)。LCMS:RT＝1.81min,[M+H] ⁺＝374.14。 ¹H NMR(400MHz,DMSO)δ10.62(s,0.5H),10.60(s,0.5H),7.76(s,0.5H),7.68(s,0.5H),7.19–7.11(m,1H),7.07–6.95(m,2H),3.68–3.60(m,1H),3.60–3.54(m,1H),3.52–3.41(m,1H),3.39–3.30(m,1H),3.28–3.17(m,1H),3.18–3.05(m,1H),2.94–2.79(m,1H),2.41–2.29(m,1H),2.27–2.11(m,1H),2.04–1.89(m,1H),1.89–1.77(m,1H),1.16(dd,J＝6.7,2.6Hz,1.5H),1.11(d,J＝7.1Hz,1.5H),1.07–1.00(m,1H),0.48–0.37(m,1H),0.37–0.26(m,2H),0.14–0.03(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 13% acetonitrile eluted in 16.10 minutes Out; detection wavelength: 220nm. After purification, it was freeze-dried at low temperature to obtain 26.28 mg of white solid (5S)-5-cyclopropyl-5-(3-(6-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzene And [d]aza

-3-yl)-3-oxopropyl)imidazoline-2,4-dione (yield: 67.8%). LCMS: RT=1.81 min, [M+H] ⁺ =374.14. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 0.5H), 10.60 (s, 0.5H), 7.76 (s, 0.5H), 7.68 (s, 0.5H), 7.19-7.11 (m, 1H) ,7.07–6.95(m,2H), 3.68–3.60(m,1H), 3.60–3.54(m,1H), 3.52–3.41(m,1H), 3.39–3.30(m,1H), 3.28–3.17( m,1H), 3.18–3.05(m,1H), 2.94–2.79(m,1H), 2.41–2.29(m,1H), 2.27–2.11(m,1H), 2.04–1.89(m,1H), 1.89–1.77 (m, 1H), 1.16 (dd, J = 6.7, 2.6 Hz, 1.5H), 1.11 (d, J = 7.1 Hz, 1.5H), 1.07–1.00 (m, 1H), 0.48–0.37 ( m,1H),0.37–0.26(m,2H),0.14–0.03(m,1H).

Example 14

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-7,8-dichloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-2,2,2-三氟乙烷-1-酮 Step A: Synthesis of (R)-1-(7,8-Dichloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

-3-基)-2,2,2-三氟乙烷-1-酮(600.0毫克，2.06毫摩尔)和N-氯代丁二酰亚胺(289.0毫克，2.23毫摩尔)加入二氯乙烷(10.0毫升)中，滴加三氟甲磺酸(380.0微升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the (R)-1-(8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (600.0 mg, 2.06 mmol) and N-chlorosuccinimide (289.0 mg, 2.23 mmol) add dichloroethane In the alkane (10.0 ml), trifluoromethanesulfonic acid (380.0 μl) was added dropwise, _{under the protection of N 2} , the reaction was carried out at 75 degrees Celsius overnight.

-3-基)-2,2,2-三氟乙烷-1-酮。LCMS:RT＝2.16min。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). Obtained 480.0 mg of a white solid mixture (R)-1-(7,8-dichloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one. LCMS: RT = 2.16 min.

Step B: Synthesis of (R)-7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-3-基)-2,2,2-三氟乙烷-1-酮(480.0毫克，1.47毫摩尔)加入甲醇(10.0毫升)中，滴加15％氢氧化钠水溶液(10.0微升)，室温反应2小时。 At room temperature, the (R)-1-(7,8-dichloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (480.0 mg, 1.47 mmol) was added to methanol (10.0 mL), and 15% aqueous sodium hydroxide solution (10.0 μl) was added dropwise, React at room temperature for 2 hours.

(收率：15.7％)。LCMS:RT＝1.65min,[M+H] ⁺＝229.96。 After the reaction, the methanol was evaporated, ethyl acetate was dissolved, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows. Column: Agilent 5Prep-C18 100mm×30mm 5μM; Mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; Flow rate: 20 ml/min; Gradient: eluted from 20% acetonitrile in 16.00 minutes ; Detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 30.0 mg of white solid (R)-7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 15.7%). LCMS: RT=1.65 min, [M+H] ⁺ =229.96.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step C: Synthesis of (S)-5-(3-((R)-7,8-dichloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(30.0毫克，0.13毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(65.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(27.0毫克，0.14毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (31.0 mg, 0.15 mmol) and (R)-7,8- Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

(30.0 mg, 0.13 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (65.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (27.0 mg, 0.14 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：30.8％)。LCMS:RT＝1.93min,[M+H] ⁺＝424.17。 ¹H NMR(400MHz,DMSO)δ10.62(s,0.5H),10.60(s,0.5H),7.73(s,0.5H),7.69(s,0.5H),7.44(d,J＝11.2Hz,1H),7.40(d,J＝10.3Hz,1H),3.63–3.55(m,1H),3.55–3.46(m,1H),3.45–3.37(m,1H),3.22–3.10(m,1H),3.10–2.97(m,1H),2.97–2.89(m,1H),2.89–2.77(m,1H),2.42–2.32(m,1H),2.32–2.17(m,1H),2.03–1.92(m,1H),1.89–1.78(m,1H),1.22(d,J＝7.4Hz,1.5H),1.16(d,J＝7.1Hz,1.5H),1.10–1.00(m,1H),0.46–0.36(m,1H),0.36–0.25(m,2H),0.17–0.02(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 17.0 mg of white solid (S)-5-(3-((R)-7,8-dichloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]nitrogen miscellaneous

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 30.8%). LCMS: RT=1.93 min, [M+H] ⁺ =424.17. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 0.5H), 10.60 (s, 0.5H), 7.73 (s, 0.5H), 7.69 (s, 0.5H), 7.44 (d, J = 11.2Hz) ,1H),7.40(d,J=10.3Hz,1H),3.63–3.55(m,1H),3.55–3.46(m,1H),3.45–3.37(m,1H),3.22–3.10(m,1H) ), 3.10–2.97(m,1H), 2.97–2.89(m,1H), 2.89–2.77(m,1H), 2.42–2.32(m,1H), 2.32–2.17(m,1H), 2.03–1.92 (m,1H),1.89–1.78(m,1H),1.22(d,J=7.4Hz,1.5H), 1.16(d,J=7.1Hz,1.5H), 1.10–1.00(m,1H), 0.46–0.36(m,1H), 0.36–0.25(m,2H), 0.17–0.02(m,1H).

Example 15

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Synthesis of (5S)-5-cyclopropyl-5-(3-(1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-2-酮(344.96毫克，1.96毫摩尔)的四氢呋喃(9.2毫升)中，滴加硼烷四氢呋喃溶液(3.9毫升，1.0摩尔每升)，N ₂保护下，45摄氏度搅拌2小时。 At zero degrees Celsius, it contains 1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-ketone (344.96 mg, 1.96 mmol) in tetrahydrofuran (9.2 mL), borane tetrahydrofuran solution (3.9 mL, 1.0 mol per liter) was added dropwise, and the mixture was stirred at 45 degrees Celsius for 2 hours under the protection of _{N 2.}

，无需纯化，直接用于下一步反应。LCMS:RT＝1.55min,[M+H] ⁺＝162.20。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure to obtain 79.0 mg of yellow solid 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

, Without purification, directly used in the next reaction. LCMS: RT=1.55 min, [M+H] ⁺ =162.20.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Step B: Synthesis of (5S)-5-cyclopropyl-5-(3-(1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

(53.13毫克，0.33毫摩尔)加入N,N-二甲基甲酰胺(1.6毫升)中，滴加N,N-二异丙基乙胺(82微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(47.0毫克，0.25毫摩尔)和1-羟基苯并三唑(2.7毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (70.0 mg, 0.33 mmol) and (S)-7-bromo- 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

(53.13 mg, 0.33 mmol) was added to N,N-dimethylformamide (1.6 mL), N,N-diisopropylethylamine (82 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (47.0 mg, 0.25 mmol) and 1-hydroxybenzotriazole (2.7 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：33.7％)。LCMS:RT＝1.80min,[M+H] ⁺＝354.26。 ¹H NMR(400MHz,DMSO)δ10.61(s,0.5H),10.60(s,0.5H),7.74(d,J＝3.1Hz,0.5H),7.69(s,0.5H),7.18–7.08(m,4H),3.63–3.51(m,1H),3.51–3.42(m,1H),3.41–3.31(m,1H),3.19–3.09(m,1H), 3.09–2.98(m,1H),2.98(s,1H),2.98–2.85(m,1H),2.41–2.29(m,1H),2.30–2.17(m,1H),1.92–1.84(m,1H),1.84–1.75(m,1H),1.22(dd,J＝7.1,1.9Hz,1.5H),1.16(d,J＝7.2Hz,1.5H),1.09–0.99(m,1H),0.47–0.38(m,1H),0.36–0.24(m,2H),0.15–0.03(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 35.0 mg of white solid (5S)-5-cyclopropyl-5-(3-(1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 33.7%). LCMS: RT=1.80 min, [M+H] ⁺ =354.26. ¹ H NMR (400MHz, DMSO) δ 10.61 (s, 0.5H), 10.60 (s, 0.5H), 7.74 (d, J = 3.1 Hz, 0.5H), 7.69 (s, 0.5H), 7.18-7.08 (m,4H),3.63-3.51(m,1H),3.51-3.42(m,1H),3.41-3.31(m,1H),3.19-3.09(m,1H), 3.09-2.98(m,1H) ,2.98(s,1H),2.98–2.85(m,1H),2.41–2.29(m,1H),2.30–2.17(m,1H),1.92–1.84(m,1H),1.84–1.75(m, 1H), 1.22(dd,J=7.1,1.9Hz,1.5H), 1.16(d,J=7.2Hz,1.5H), 1.09–0.99(m,1H),0.47–0.38(m,1H),0.36 –0.24(m,2H),0.15–0.03(m,1H).

Example 16

-3-基)-3-氧丙基)咪唑啉-2,4-二酮 Synthesis of (5S)-5-cyclopropyl-5-(3-(7-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazoline-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 2-chloro-N-(3-fluorophenethyl)propionamide

At zero degrees Celsius, add 2-(3-fluorophenyl)ethyl-1-amine (1.0 g, 7.19 mmol) to dichloromethane (30.0 ml), and add N,N-diisopropylethylamine dropwise in turn (1.8 ml) and 2-chloropropionyl chloride (852 μl), under N ₂ protection, react at room temperature for 1.5 hours.

After the reaction was completed, it was quenched by adding water, the mixed solution was extracted with dichloromethane (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/4). 1.4 g of yellow oily 2-chloro-N-(3-fluorophenethyl)propionamide was obtained (yield: 85.0%).

-2-酮 Step B: Synthesis of 7-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

At room temperature, add 2-chloro-N-(3-fluorophenethyl)propionamide (1.4 g, 6.1 mmol) to 1,4-dichlorobenzene (3.2 ml), and finally add aluminum trichloride (2.2 G), _{under the protection of N 2} , react at 160 degrees Celsius for 5 hours.

-2-酮(收率：76.3％)。LCMS:RT＝1.73min,[M+H] ⁺＝194.12。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 901.0 mg of yellow oily 7-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one (yield: 76.3%). LCMS: RT=1.73min, [M+H] ⁺ =194.12.

Step C: Synthesis of 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

At room temperature, add 7-fluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza-2-one (900.0 mg, 4.66 mmol) to borane tetrahydrofuran complex In the compound (18.6 ml), _{under the protection of N 2} , the reaction was carried out at 45 degrees Celsius overnight.

(收率：62.6％)。LCMS:RT＝1.49min,[M+H] ⁺＝180.17。 After the reaction is over, cool to room temperature, add methanol dropwise until no bubbles are generated, then add water to quench, the mixture is extracted with ethyl acetate (20 ml × 3 times), the organic phases are combined, and the organic phase is first used with saturated brine (20 ml × 2 times) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The resulting residue was used directly in the next reaction. Obtained 530.0 mg of yellow oily 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 62.6%). LCMS: RT=1.49 min, [M+H] ⁺ = 180.17.

-3-基)-3-氧丙基)咪唑啉-2,4-二酮 Step D: Synthesis of (5S)-5-cyclopropyl-5-(3-(7-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazoline-2,4-dione

(178.0毫克，0.96毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(94.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(30.0毫克，0.16毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (30.0 mg, 0.14 mmol) and 7-fluoro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(178.0 mg, 0.96 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (94.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (30.0 mg, 0.16 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)咪唑啉-2,4-二酮(收率：26.6％)。LCMS:RT＝1.81min,[M+H] ⁺＝374.14。 ¹H NMR(400MHz,DMSO)δ10.63(s,0.5H),10.61(s,0.5H),7.75(s,0.5H),7.71(s,0.5H),7.23–7.12(m,1H),7.05–6.89(m,2H),3.55–3.48(m,1H),3.55–3.46(m,1H),3.42–3.38(m,1H),3.21–3.11(m,1H),3.11–2.97(m,1H),2.97–2.86(m,1H),2.86–2.74(m,1H),2.44–2.34(m,1H),2.30–2.17(m,1H),2.10–1.95(m,1H),1.88–1.81(m,1H),1.26–1.22(m,1.5H),1.21–1.15(m,1.5H),1.10–1.04(m,1H),0.49–0.39(m,1H),0.39–0.24(m,2H),0.14–0.05(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 13% acetonitrile eluted in 16.10 minutes Out; detection wavelength: 220nm. After purification, it was freeze-dried at low temperature to obtain 11.95 mg of white solid (5S)-5-cyclopropyl-5-(3-(7-fluoro-1-methyl-1,2,4,5-tetrahydro-3H-benzene) And [d]aza

-3-yl)-3-oxopropyl)imidazoline-2,4-dione (yield: 26.6%). LCMS: RT=1.81 min, [M+H] ⁺ =374.14. ¹ H NMR (400MHz, DMSO) δ 10.63 (s, 0.5H), 10.61 (s, 0.5H), 7.75 (s, 0.5H), 7.71 (s, 0.5H), 7.23-7.12 (m, 1H) ,7.05--6.89(m,2H),3.55--3.48(m,1H),3.55--3.46(m,1H),3.42--3.38(m,1H),3.21--3.11(m,1H),3.11-2.97( m,1H), 2.97–2.86(m,1H), 2.86–2.74(m,1H), 2.44–2.34(m,1H), 2.30–2.17(m,1H), 2.10–1.95(m,1H), 1.88–1.81(m,1H), 1.26–1.22(m,1.5H), 1.21–1.15(m,1.5H), 1.10–1.04(m,1H), 0.49–0.39(m,1H), 0.39–0.24 (m, 2H), 0.14–0.05 (m, 1H).

Example 17

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 1,5-dihydrobenzo[d]oxapine-2,4-dione

At room temperature, add phthalic acid (20.0 g, 0.10 mol) to toluene (200.0 ml), and add thionyl chloride (8.97 ml) and 5 drops of N,N-dimethylformamide dropwise under an ice bath. Under the protection of N ₂ , the reaction was refluxed for 24 hours.

After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain 17.5 g of black solid 1,5-dihydrobenzo[d]oxapine-2,4-dione, which was directly used in the next reaction without purification. LCMS: RT=1.79 min.

Step B: Synthesis of (R)-2-(2-(2-(((2-hydroxy-1-phenylethyl)amino)-2-oxoethyl)phenyl)acetic acid

At room temperature, 1,5-dihydrobenzo[d]oxapine-2,4-dione (17.5g, 0.1mol) was added to dichloromethane (200.0ml), and triethylamine (13.8 ML) and D-phenylglycinol (13.6 g, 0.1 mol) in dichloromethane (200.0 mL), react at room temperature for 3 hours.

After the reaction is over, dichloromethane is diluted, extracted with aqueous sodium hydroxide solution (0.15 mole per liter, 200 ml×4 times), the water layers are combined, the pH of the water layer is adjusted to 3, and then dichloromethane (200 ml×3 times) After extraction, the organic layers were combined. The organic layer was washed with saturated brine (300 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 10.2 g of yellow solid (R)-2-(2-(2) -(((2-Hydroxy-1-phenylethyl)amino)-2-oxoethyl)phenyl)acetic acid, without purification, directly used in the next reaction. LCMS:RT=1.70min, [M+ H] ⁺ =314.14.

Step C: Synthesis of methyl (R)-2-(2-(2-(((2-hydroxy-1-phenylethyl)amino)-2-oxoethyl)phenyl)acetate

Under an ice bath, add (R)-2-(2-(2-(((2-hydroxy-1-phenylethyl)amino)-2-oxoethyl)phenyl)acetic acid (10.2 g, 32.4 mmol) of methanol (800.0 ml) was added dropwise trimethylchlorosilane (12.4 ml), and the reaction was carried out at room temperature for 3 hours under the protection of _{N 2.}

After the reaction is over, the methanol is evaporated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/2). Obtain 4.0 g of white solid (R)-2-(2-(2-(((2-hydroxy-1-phenylethyl)amino)-2-oxoethyl)phenyl)acetate (yield : 30.8%). LCMS: RT=1.93 min, [M+H] ⁺ =424.17.

Step D: Synthesis of (R)-2-(2-(2-oxo-2-((1-phenyl-2-((triisopropylsilyl)oxy)ethyl)amino)ethyl )Phenyl)methyl acetate

At room temperature, add methyl (R)-2-(2-(2-(((2-hydroxy-1-phenylethyl)amino)-2-oxoethyl)phenyl)acetate (1.0 g , 3.1 mmol) and imidazole (682.6 mg, 7.8 mmol) in N,N-dimethylformamide (10.0 mL), add triisopropylchlorosilane (1.0 mL) dropwise, under N ₂ protection, at room temperature React overnight.

After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2). Obtain 1.0 g of yellow oil (R)-2-(2-(2-oxo-2-((1-phenyl-2-((triisopropylsilyl)oxy)ethyl)amino) (Ethyl)phenyl)methyl acetate (yield: 66.7%). LCMS: RT = 2.45 min, [M+H] ⁺ =484.31.

Step E: Synthesis of (R)-2-(2-(2-hydroxyethyl)phenyl)-N-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl) Acetamide

At room temperature, add (R)-2-(2-(2-oxo-2-((1-phenyl-2-((triisopropylsilyl)oxy)ethyl)amino) ethyl Into tetrahydrofuran (10.0 ml) of methyl phenyl)acetate (1.0 g, 2.1 mmol), lithium borohydride (911.4 mg, 21.0 mmol) was added, and the reaction was carried out at 70 degrees Celsius for 4 hours under the protection of _{N 2.}

After the reaction is complete, it is quenched by adding saturated ammonium chloride solution, the mixture is extracted with ethyl acetate (30 ml×3 times), and the organic phases are combined. The organic phase is washed with saturated brine (30 ml×2 times), and then It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 765.6 mg of yellow oil (R)-2-(2-(2-hydroxyethyl)phenyl)-N-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl Yl)acetamide (yield: 80.0%). LCMS: RT = 2.37 min, [M+H] ⁺ =456.32.

Step F: Synthesis of (R)-2-(2-(2-oxoethyl)phenyl)-N-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl )Acetamide

At zero degrees Celsius, add (R)-2-(2-(2-hydroxyethyl)phenyl) dropwise to methylene chloride (10.0 ml) containing Dess-Martin oxidant (1.1 g, 1.7 mmol) -N-(1-Phenyl-2-((triisopropylsilyl)oxy)ethyl)acetamide (765.6 mg, 1.7 mmol) in dichloromethane (10.0 ml), protected by _{N 2} , React at room temperature for 1 hour.

After the reaction is over, add 50 ml of dichloromethane and sodium hydroxide aqueous solution (1.0 moles per liter, 2.0 ml), stir for 15 minutes, separate the organic phase, and use sodium hydroxide aqueous solution (1.0 moles per liter, 20.0 ml× 1 time) washing, and then extracting the aqueous phase with dichloromethane (50.0 ml×3 times), combining the organic phases, drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 634.8 mg of yellow oil (R)-2-(2-(2-oxoethyl)phenyl)phenyl)-N-(1-phenyl-2-((triisopropylsilyl) (Oxy)ethyl)acetamide (yield: 82.3%). LCMS: RT = 2.43 min, [M+H] ⁺ =454.29.

Step G: Synthesis of (R)-2-(2-(2,2-dimethoxyethyl)phenyl)-N-(2-hydroxy-1-phenylethyl)acetamide

At room temperature, add (R)-2-(2-(2-oxoethyl)phenyl)phenyl)-N-(1-phenyl-2-((triisopropylsilyl)oxy ) Ethyl)acetamide (634.8 mg, 1.4 mmol) was added to the methanol solution of hydrochloric acid (mass fraction: 1.0%, 50.0 ml), and reacted overnight at room temperature under the protection of _{N 2.}

After the reaction is over, add saturated sodium bicarbonate aqueous solution to the reaction solution until no bubbles emerge, then extract the aqueous phase with ethyl acetate (50.0 ml×3 times), combine the organic phases, and then wash with saturated sodium bicarbonate and water. Once, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2). Obtain 323.1 mg of yellow oil (R)-2-(2-(2,2-dimethoxyethyl)phenyl)-N-(2-hydroxy-1-phenylethyl)acetamide (yield : 67.2%). LCMS: RT=1.81 min, [M-OCH ₃ ] ^- =312.27.

Step H: Synthesis of (3R,11'S)-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]aza-5(6H)-one )

At zero degrees Celsius, it contains (R)-2-(2-(2,2-dimethoxyethyl)phenyl)-N-(2-hydroxy-1-phenylethyl)acetamide (323.1 mg , 0.9 mmol) in chloroform (10.0 ml), add 1 drop of concentrated hydrochloric acid dropwise, _{under the protection of N 2} , and react overnight at zero degrees Celsius.

After the reaction was completed, the reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/5). Obtained 177.0 mg of white solid (3R,11'S)-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]aza-5(6H)- Ketone (yield: 70.4%). LCMS: RT=1.95 min, [M+H] ⁺ =280.19.

Step I: Synthesis of (3R,6R,11'S)-6-methyl-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]aza -5(6H)-ketone)

At zero degrees Celsius, it contains (3R,11'S)-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]aza-5(6H) -Ketone (87.0 mg, 0.3 mmol) in tetrahydrofuran (16.0 ml), dropwise add lithium diisopropylamide (311.0 μl), _{under the protection of N 2} , keep stirring at this temperature for 1 hour, and then add dropwise to it Iodomethane (30.0 microliters) was kept at this temperature and reacted for 3 hours.

After the reaction was completed, it was quenched by adding saturated ammonium chloride solution, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/4). Obtain 80.0 mg of white solid (3R,6R,11'S)-6-methyl-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]nitrogen Hetero-5(6H)-one (yield: 90.1%). LCMS: RT = 2.02 min, [M+H] ⁺ =294.19.

Step J: Synthesis of (R)-2-((R)-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza-3-yl)-2-phenyl Ethan-1-ol

At zero degrees Celsius, dissolve anhydrous aluminum chloride (33.0 mg, 0.3 mmol) in tetrahydrofuran (2.0 ml), stir for 5 minutes, add lithium aluminum tetrahydrofuran solution in tetrahydrofuran (1.0 mole per liter, 820.0 microliters), Stir at room temperature for 20 minutes, then reduce the reaction solution to zero degrees Celsius, and add (3R,6R,11'S)-6-methyl-3-phenyl-2,3,11,11'-tetrahydrobenzo[ d] Oxazolo[3,2-a]aza-5(6H)-one (80.0 mg, 0.3 mmol) in tetrahydrofuran (5.0 mL), and react at this temperature for 2 hours.

After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 75.0 mg of colorless oil (R)-2-((R)-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza-3-yl)-2 -Phenylethyl-1-ol (yield: 88.7%). LCMS: RT=1.61 min, [M+H] ⁺ =282.26.

Step K: Synthesis of (R)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

At room temperature, it contains (R)-2-((R)-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza-3-yl)-2-benzene Ethyl-1-ol (75.0 mg, 0.3 mmol) in methanol (10.0 mL), add ammonium formate (190.0 mg, 3.0 mmol) and palladium on carbon (7.5 mg), under N ₂ protection, react at 65 degrees Celsius 3 Hour.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.45min,[M+H] ⁺＝162.19。 After the reaction is over, the palladium carbon is filtered, the filter cake is washed with methanol, the filtrate is concentrated under reduced pressure, and dried to obtain 26.0 mg of (R)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]nitrogen miscellaneous

, Without purification, directly used in the next reaction. LCMS: RT=1.45 min, [M+H] ⁺ =162.19.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step L: Synthesis of (S)-5-(3-((R)-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(26.0毫克，0.18毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(80.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(34.0毫克，0.2毫摩尔)和1-羟基苯并三唑(4.0毫克，0.03毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (42.4 mg, 0.2 mmol) and (R)-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(26.0 mg, 0.18 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (80.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (34.0 mg, 0.2 mmol) and 1-hydroxybenzotriazole (4.0 mg, 0.03 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：33.8％)。LCMS:RT＝1.79min,[M+H] ⁺＝356.26。 ¹H NMR(400MHz,DMSO)δ10.61(s,0.5H),10.60(s,0.5H),7.73(s,0.5H),7.69(s,0.5H),7.21–7.05(m,4H),3.75–3.62(m,1H),3.62–3.52(m,1H),3.50–3.39(m,1H),3.19–3.08(m,1H),3.08–2.97(m,1H),2.97–2.88(m,1H),2.86–2.75(m,1H),2.44–2.31(m,1H),2.32–2.16(m,1H),1.95–1.75(m,2H),1.23(d,J＝7.2Hz,1.5H),1.17(d,J＝7.2Hz,1.5H),1.11–0.99(m,1H),0.51–0.38(m,1H),0.38–0.25(m,2H),0.16–0.04(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 24.0 mg of white solid (S)-5-(3-((R)-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 33.8%). LCMS: RT=1.79 min, [M+H] ⁺ =356.26. ¹ H NMR (400MHz, DMSO) δ 10.61 (s, 0.5H), 10.60 (s, 0.5H), 7.73 (s, 0.5H), 7.69 (s, 0.5H), 7.21-7.05 (m, 4H) ,3.75-3.62(m,1H),3.62-3.52(m,1H),3.50-3.39(m,1H),3.19-3.08(m,1H),3.08-2.97(m,1H),2.97-2.88( m,1H), 2.86–2.75(m,1H), 2.44–2.31(m,1H), 2.32–2.16(m,1H), 1.95–1.75(m,2H), 1.23(d,J=7.2Hz, 1.5H), 1.17(d,J=7.2Hz,1.5H), 1.11–0.99(m,1H), 0.51–0.38(m,1H), 0.38–0.25(m,2H),0.16–0.04(m, 1H).

Example 18

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((R)-1-ethyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of (3R,6R,11'S)-6-ethyl-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]aza -5(6H)-ketone)

At zero degrees Celsius, it contains (3R,11'S)-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]aza-5(6H) -Ketone (87.0 mg, 0.3 mmol) in tetrahydrofuran (16.0 ml), dropwise add lithium diisopropylamide (311.0 μl), _{under the protection of N 2} , keep stirring at this temperature for 1 hour, and then add dropwise to it Iodoethane (35.5 microliters), keep the temperature for 3 hours.

After the reaction was completed, it was quenched by adding saturated ammonium chloride solution, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/4). Obtain 70.0 mg of white solid (3R,6R,11'S)-6-ethyl-3-phenyl-2,3,11,11'-tetrahydrobenzo[d]oxazolo[3,2-a]nitrogen Hetero-5(6H)-one (yield: 75.9%). LCMS: RT = 2.05 min, [M+H] ⁺ =308.25.

Step B: Synthesis of (R)-2-((R)-1-ethyl-1,2,4,5-tetrahydro-3H-benzo[d]aza-3-yl)-2-phenyl Ethan-1-ol

At zero degrees Celsius, dissolve anhydrous aluminum chloride (26.7 mg, 0.2 mmol) in tetrahydrofuran (2.0 mL), stir for 5 minutes, add lithium tetrahydroaluminum lithium tetrahydrofuran solution (1.0 mol per liter, 684.0 microliters), Stir at room temperature for 20 minutes, then reduce the reaction solution to zero degrees Celsius, and add (3R,6R,11'S)-6-ethyl-3-phenyl-2,3,11,11'-tetrahydrobenzo[ d] Oxazolo[3,2-a]aza-5(6H)-one (70.0 mg, 0.2 mmol) in tetrahydrofuran (5.0 mL), and react at this temperature for 2 hours.

After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 45.0 mg of colorless oil (R)-2-((R)-1-ethyl-1,2,4,5-tetrahydro-3H-benzo[d]aza-3-yl)-2 -Phenylethyl-1-ol (yield: 76.2%). LCMS: RT=1.65 min, [M+H] ⁺ =296.28.

Step C: Synthesis of (R)-1-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

At room temperature, it contains (R)-2-((R)-1-ethyl-1,2,4,5-tetrahydro-3H-benzo[d]aza-3-yl)-2-benzene Ethan-1-ol (45.0 mg, 0.2 mmol) in methanol (10.0 ml), ammonium formate (126.2 mg, 2.0 mmol) and palladium on carbon (45.0 mg) were added, _{under the protection of N 2} and reacted at 65 degrees Celsius for 3 Hour.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.50min,[M+H] ⁺＝176.18。 After the reaction is over, the palladium carbon is filtered, the filter cake is washed with methanol, the filtrate is concentrated under reduced pressure, and dried to obtain 25.0 mg of (R)-1-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]nitrogen miscellaneous

, Without purification, directly used in the next reaction. LCMS: RT=1.50min, [M+H] ⁺ =176.18.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step D: Synthesis of (S)-5-(3-((R)-1-ethyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(25.0毫克，0.14毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升) 中，滴加N,N-二异丙基乙胺(64.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(27.0毫克，0.14毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (42.4 mg, 0.2 mmol) and (R)-1-ethyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(25.0 mg, 0.14 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (64.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (27.0 mg, 0.14 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：40.6％)。LCMS:RT＝1.85min,[M+H] ⁺＝370.27。 ¹H NMR(400MHz,DMSO)δ10.60(s,1H),7.73(s,0.5H),7.68(s,0.5H),7.22–6.99(m,4H),4.07–3.88(m,1H),3.85–3.71(m,1H),3.68–3.48(m,1H),3.23(t,J＝11.9Hz,1H),3.10–3.01(m,1H),2.99–2.88(m,1H),2.89–2.77(m,1H),2.44–2.29(m,1H),2.29–2.18(m,1H),1.92–1.74(m,2H),1.65–1.59(m,1H),1.57–1.47(m,1H),1.11–0.99(m,1H),0.82(t,J＝7.3Hz,3H),0.51–0.36(m,1H),0.39–0.27(m,2H),0.15–0.04(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 21.0 mg of white solid (S)-5-(3-((R)-1-ethyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 40.6%). LCMS: RT=1.85 min, [M+H] ⁺ =370.27. ¹ H NMR (400MHz, DMSO) δ 10.60 (s, 1H), 7.73 (s, 0.5H), 7.68 (s, 0.5H), 7.22-6.99 (m, 4H), 4.07-3.88 (m, 1H) ,3.85–3.71(m,1H), 3.68–3.48(m,1H), 3.23(t,J=11.9Hz,1H), 3.10–3.01(m,1H), 2.99–2.88(m,1H), 2.89 --2.77 (m, 1H), 2.44 - 2.29 (m, 1H), 2.29 - 2.18 (m, 1H), 1.92 - 1.74 (m, 2H), 1.65 - 1.59 (m, 1H), 1.57 - 1.47 (m, 1H),1.11–0.99(m,1H),0.82(t,J=7.3Hz,3H),0.51–0.36(m,1H),0.39–0.27(m,2H),0.15–0.04(m,1H) .

Example 19

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-(6-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-2,2,2-三氟乙烷-1-酮 Step A: Synthesis of 1-(1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

At zero degrees Celsius, add 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (300.0 g, 1.63 mmol) to dichloromethane (16.3 ml), and then add pyridine dropwise. (394 microliters) and trifluoroacetic anhydride (346 microliters), under N ₂ protection, react at room temperature for 3.5 hours.

-3-基)-2,2,2-三氟乙烷-1-酮(收率：68.1％)。LCMS:RT＝2.05min。 After the reaction was completed, aqueous hydrochloric acid solution (1.0 mol per liter, 10 ml) was added for quenching, the mixture was extracted with dichloromethane (50 ml × 3 times), the organic phases were combined, and the organic phase was first used with saturated brine (30 ml × 2 times) ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/20). Obtained 270.0 mg of white solid 1-(1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one (yield: 68.1%). LCMS: RT = 2.05 min.

-3-基)-2,2,2-三氟乙烷-1-酮 Step B: Synthesis of 1-(6-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

-3-基)-2,2,2-三氟乙烷-1-酮(205.0毫克，0.84毫摩尔)和N-氯代丁二酰亚胺(118.0毫克，0.89毫摩尔)加入二氯乙烷(8.4毫升)中，滴加三氟甲磺酸(149微升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the 1-(1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (205.0 mg, 0.84 mmol) and N-chlorosuccinimide (118.0 mg, 0.89 mmol) add dichloroethane In the alkane (8.4 ml), trifluoromethanesulfonic acid (149 μl) was added dropwise, and the reaction was carried out at 75 degrees Celsius overnight under the protection of _{N 2.}

-3-基)-2,2,2-三氟乙烷-1-酮(收率：85.7％)。LCMS:RT＝2.14min。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 25% acetonitrile in 18.10 minutes Out; detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 200.0 mg of white solid mixture 1-(6-chloro-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one (yield: 85.7%). LCMS: RT = 2.14 min.

Step C: Synthesis of 6-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-3-基)-2,2,2-三氟乙烷-1-酮(200.0毫克，0.72毫摩尔)加入甲醇(10.0毫升)中，滴加15％氢氧化钠水溶液(10.0微升)，室温反应2小时。 At room temperature, the 1-(6-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (200.0 mg, 0.72 mmol) was added to methanol (10.0 mL), and 15% aqueous sodium hydroxide solution (10.0 μl) was added dropwise, React at room temperature for 2 hours.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.53min,[M+H] ⁺＝182.29。 When the reaction is over, the methanol is evaporated, ethyl acetate is dissolved, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 27.3 mg of yellow solid 6-chloro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

, Without purification, directly used in the next reaction. LCMS: RT=1.53 min, [M+H] ⁺ =182.29.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step D: Synthesis of (S)-5-(3-(6-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(27.3毫克，0.15毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(65.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(27.0毫克，0.14毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (31.0 mg, 0.15 mmol) and 6-chloro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(27.3 mg, 0.15 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (65.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (27.0 mg, 0.14 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：70.4％)。LCMS:RT＝1.81min,[M+H] ⁺＝376.20。 ¹H NMR(400MHz,DMSO)δ10.60(s,1H),7.70(s,1H),7.29(dd,J＝8.4,4.8Hz,1H),7.17–7.09(m,2H),3.66–3.47(m,4H),3.17–2.84(m,4H),2.43–2.31(m,1H),2.29–2.15(m,1H),1.93–1.82(m,2H),1.13–1.01(m,1H),0.49–0.38(m,1H),0.40–0.26(m,2H),0.13–0.01(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 39.8 mg of white solid (S)-5-(3-(6-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 70.4%). LCMS: RT=1.81 min, [M+H] ⁺ =376.20. ¹ H NMR (400MHz, DMSO) δ 10.60 (s, 1H), 7.70 (s, 1H), 7.29 (dd, J = 8.4, 4.8 Hz, 1H), 7.17-7.09 (m, 2H), 3.66-3.47 (m,4H),3.17-2.84(m,4H),2.43--2.31(m,1H),2.29-2.15(m,1H),1.93-1.82(m,2H),1.13-1.01(m,1H) , 0.49–0.38(m,1H), 0.40–0.26(m,2H), 0.13–0.01(m,1H).

Example 20

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-(7-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-2,2,2-三氟乙烷-1-酮 Step A: Synthesis of 1-(7-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

-3-基)-2,2,2-三氟乙烷-1-酮(205.0毫克，0.84毫摩尔)和N-氯代丁二酰亚胺(118.0毫克，0.89毫摩尔)加入二氯乙烷(8.4毫升)中，滴加三氟甲磺酸(149微升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the 1-(1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (205.0 mg, 0.84 mmol) and N-chlorosuccinimide (118.0 mg, 0.89 mmol) add dichloroethane In the alkane (8.4 ml), trifluoromethanesulfonic acid (149 μl) was added dropwise, and the reaction was carried out at 75 degrees Celsius overnight under the protection of _{N 2.}

-3-基)-2,2,2-三氟乙烷-1-酮(收率：85.7％)。LCMS:RT＝2.15min。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 25% acetonitrile in 19.20 minutes Out; detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 200.0 mg of white solid 1-(7-chloro-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one (yield: 85.7%). LCMS: RT = 2.15 min.

Step B: Synthesis of 7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-3-基)-2,2,2-三氟乙烷-1-酮(200.0毫克，0.72毫摩尔)加入甲醇(10.0毫升)中，滴加15％氢氧化钠水溶液(10.0微升)，室温反应2小时。 At room temperature, the 1-(7-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (200.0 mg, 0.72 mmol) was added to methanol (10.0 mL), and 15% aqueous sodium hydroxide solution (10.0 μl) was added dropwise, React at room temperature for 2 hours.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.54min,[M+H] ⁺＝182.10。 After the reaction is over, the methanol is evaporated, ethyl acetate is dissolved, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 27.3 mg of yellow solid 7-chloro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

, Without purification, directly used in the next reaction. LCMS: RT=1.54 min, [M+H] ⁺ =182.10.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step C: Synthesis of (S)-5-(3-(7-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(27.3毫克，0.15毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(65.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(27.0毫克，0.14毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (31.0 mg, 0.15 mmol) and 7-chloro-1-methyl -2,3,4,5-tetrahydro-1H-benzo[d]aza

(27.3 mg, 0.15 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (65.0 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (27.0 mg, 0.14 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：66.8％)。LCMS:RT＝1.83min,[M-H] ^-＝374.18。 ¹H NMR(400MHz,DMSO)δ10.61(s,1H),7.71(s,1H),7.25(d,J＝10.9Hz,1H),7.20–7.14(m,2H),3.59–3.46(m,4H),2.85(dd,J＝32.5,5.4Hz,4H),2.45–2.32(m,1H),2.32–2.22(m,1H),1.97–1.86(m,2H),1.14–0.98(m,1H),0.50–0.36(m,1H),0.37–0.22(m,2H),0.13–0.03(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 37.5 mg of white solid (S)-5-(3-(7-chloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 66.8%). LCMS: RT=1.83 min, [MH] ^- =374.18. ¹ H NMR (400MHz, DMSO) δ 10.61 (s, 1H), 7.71 (s, 1H), 7.25 (d, J = 10.9 Hz, 1H), 7.20-7.14 (m, 2H), 3.59-3.46 (m ,4H), 2.85(dd,J=32.5,5.4Hz,4H), 2.45–2.32(m,1H), 2.32–2.22(m,1H),1.97–1.86(m,2H),1.14–0.98(m ,1H),0.50–0.36(m,1H),0.37–0.22(m,2H),0.13–0.03(m,1H).

Example 21

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-(6,9-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

-3-基)-2,2,2-三氟乙烷-1-酮 Step A: Synthesis of 1-(6,9-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one

-3-基)-2,2,2-三氟乙烷-1-酮(210.0毫克，0.86毫摩尔)和N-氯代丁二酰亚胺(230.6毫克，1.73毫摩尔)加入二氯乙烷(10毫升)中，滴加三氟甲磺酸(152微升)，N ₂保护下，75摄氏度反应过夜。 At room temperature, the 1-(1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (210.0 mg, 0.86 mmol) and N-chlorosuccinimide (230.6 mg, 1.73 mmol) add dichloroethane In alkane (10 ml), trifluoromethanesulfonic acid (152 μl) was added dropwise, and the reaction was carried out at 75 degrees Celsius overnight under the protection of _{N 2.}

-3-基)-2,2,2-三氟乙烷-1-酮(收率：76.5％)。LCMS:RT＝2.17min。 After the reaction is complete, cool to room temperature, dilute with ethyl acetate, quench with water, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and wash the organic phase with saturated brine (20 ml×2 times) , And then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 25% acetonitrile in 21.15 minutes Out; detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 205.3 mg of white solid 1-(6,9-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]azepine

-3-yl)-2,2,2-trifluoroethane-1-one (yield: 76.5%). LCMS: RT = 2.17 min.

Step B: Synthesis of 6,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-3-基)-2,2,2-三氟乙烷-1-酮(205.3毫克，0.66毫摩尔)加入甲醇(10.0毫升)中，滴加15％氢氧化钠水溶液(10.0微升)，室温反应2小时。 At room temperature, the 1-(6,9-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-2,2,2-trifluoroethane-1-one (205.3 mg, 0.66 mmol) was added to methanol (10.0 ml), and 15% aqueous sodium hydroxide solution (10.0 μl) was added dropwise, React at room temperature for 2 hours.

，无需纯化，直接用于下一步反应。LCMS:RT＝1.57min,[M+H] ⁺＝217.30。 When the reaction is over, the methanol is evaporated, ethyl acetate is dissolved, washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 28.5 mg of yellow solid 6,9-dichloro- 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

, Without purification, directly used in the next reaction. LCMS: RT=1.57 min, [M+H] ⁺ =217.30.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step C: Synthesis of (S)-5-(3-(6,9-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(28.5毫克，0.13毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(56.5微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(27.0毫克，0.14毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (27.0 mg, 0.13 mmol) and 6,9-dichloro-1 -Methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

(28.5 mg, 0.13 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (56.5 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (27.0 mg, 0.14 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：66.0％)。LCMS:RT＝1.88min,[M+H] ⁺＝410.15。 ¹H NMR(400MHz,DMSO)δ10.60(s,1H),7.69(s,1H),7.34(s,2H),3.64–3.50(m,4H),3.24–3.07(m,4H),2.37–2.25(m,1H),2.24–2.11(m,1H),2.05–1.87(m,2H),1.09–0.98(m,1H),0.47–0.36(m,1H),0.36–0.25(m,2H),0.12–0.01(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 35.2 mg of white solid (S)-5-(3-(6,9-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 66.0%). LCMS: RT=1.88 min, [M+H] ⁺ =410.15. ¹ H NMR (400MHz, DMSO) δ 10.60 (s, 1H), 7.69 (s, 1H), 7.34 (s, 2H), 3.64-3.50 (m, 4H), 3.24-3.07 (m, 4H), 2.37 --2.25(m,1H),2.24–2.11(m,1H),2.05–1.87(m,2H),1.09–0.98(m,1H),0.47–0.36(m,1H),0.36–0.25(m, 2H), 0.12–0.01 (m, 1H).

Example 22

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-((S)-8-chloro-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of (S)-2-(4-chlorophenyl)-N-(1-hydroxypropan-2-yl)acetamide

At room temperature, add 2-(4-chlorophenyl) acetic acid (1.0 g, 5.86 mmol) and L-2-aminopropan-1-ol (462.0 mg, 6.16 mmol) to N,N-dimethylformaldehyde To the amide (15.0 ml), add N,N-diisopropylethylamine (1.45 ml) dropwise, and then add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride one by one (1.35 g, 7.03 mmol) and 1-hydroxybenzotriazole (79.0 mg, 0.59 mmol), under N ₂ protection, react at room temperature overnight.

After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/20). 1.27 g of white solid (S)-2-(4-chlorophenyl)-N-(1-hydroxypropan-2-yl)acetamide was obtained (yield: 95.5%). LCMS: RT=1.57 min, [M+H] ⁺ =228.20.

Step B: Synthesis of (S)-2-(4-chlorophenyl)-N-(1-chloropropan-2-yl)acetamide

At room temperature, (S)-2-(4-chlorophenyl)-N-(1-hydroxypropan-2-yl)acetamide (1.27 g, 5.59 mmol) was added to chloroform (10.0 ml) and added dropwise A chloroform solution (5.0 ml) of thionyl chloride (565.0 microliters) was reacted at 40 degrees Celsius for 4 hours under the protection of _{N 2.}

After the reaction was over, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 1.04 g of white solid (S)-2-(4-chlorophenyl)-N-(1-chloropropan-2-yl)acetamide was obtained (yield: 95.5%). LCMS: RT=1.66 min, [M+H] ⁺ =246.09.

-2-酮 Step C: Synthesis of (S)-8-chloro-4-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

At room temperature, add o-dichlorobenzene (2.1 mL) containing (S)-2-(4-chlorophenyl)-N-(1-chloropropan-2-yl)acetamide (1.04 g, 4.23 mmol) Anhydrous aluminum trichloride (1.40 g, 10.53 mmol) was added to the mixture, and the reaction was carried out at 165 degrees Celsius for 2 hours under the protection of _{N 2.}

-2-酮(收率：40.3％)。LCMS:RT＝1.81min,[M+H] ⁺＝210.08。 After the reaction was completed, it was cooled to room temperature, quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then washed with anhydrous Dry over sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/20). Obtained 360.0 mg of colorless liquid (S)-8-chloro-4-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one (yield: 40.3%). LCMS: RT=1.81 min, [M+H] ⁺ =210.08.

Step D: Synthesis of (S)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-2-酮(360.0毫克，1.72毫摩尔)的四氢呋喃(3.0毫升)中，滴加硼烷四氢呋喃溶液(4.3毫升，4.3摩尔每升)，N ₂保护下，45摄氏度搅拌2小时。 At zero degrees Celsius, it contains (S)-8-chloro-4-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

In tetrahydrofuran (3.0 ml) of -2-one (360.0 mg, 1.72 mmol), borane tetrahydrofuran solution (4.3 ml, 4.3 mol per liter) was added dropwise, and the mixture was stirred at 45 degrees Celsius for 2 hours under the protection of _{N 2.}

，无需纯化，直接用于下一步反应。LCMS:RT＝1.54min,[M+H] ⁺＝196.15。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 33.0 mg of yellow solid (S)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-benzo[ d]Aza

, Without purification, directly used in the next reaction. LCMS: RT=1.54 min, [M+H] ⁺ =196.15.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step E: Synthesis of (S)-5-(3-((S)-8-chloro-2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(33.0毫克，0.11毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(37微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(32.0毫克，0.17毫摩尔)和1-羟基苯并三唑(3.0毫克，0.03毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (23.3 mg, 0.15 mmol) and (S)-8-chloro- 2-Methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

(33.0 mg, 0.11 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (37 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (32.0 mg, 0.17 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.03 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：23.8％)。LCMS:RT＝1.89min,[M-H] ^-＝388.25。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: Agilent 5Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: 32% acetonitrile eluted in 16.30 minutes Out; detection wavelength: 200nm. After purification, it was freeze-dried at low temperature to obtain 10.2 mg of white solid (S)-5-(3-((S)-8-chloro-2-methyl-1,2,4,5-tetrahydro-3H-benzo[ d]Aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 23.8%). LCMS: RT=1.89 min, [MH] ^- =388.25.

Example 23

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Synthesis of (S)-5-(3-(2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 2-(2-(2-oxopropyl)phenyl)acetic acid

At zero degrees Celsius, to tetrahydrofuran (50 ml) containing phthalic acid (2.0 mg, 10.09 mmol), add methyl lithium tetrahydrofuran solution (15.0 ml, 3.5 moles per liter) dropwise, under N ₂ protection, at 0 degrees Celsius Stir overnight.

After the reaction was completed, aqueous hydrochloric acid solution (1.0 mol per liter, 10 ml) was added to quench, the mixture was extracted with ethyl acetate (20 ml × 3 times), and the organic phases were combined, and the organic phase was first used with saturated brine (20 ml × 2 times) ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtained 870.0 mg of yellow solid 2-(2-(2-oxopropyl)phenyl)acetic acid (yield: 45.9%). LCMS: RT=1.44min, [MH] ^- =191.23.

-2-酮 Step B: Synthesis of 4-methyl-1,3-dihydro-2H-benzo[d]aza

-2-one

At room temperature, add 2-(2-(2-oxopropyl)phenyl)acetic acid (870.0 mg, 4.64 mmol) and ammonium acetate (714.0 mg, 9.27 mmol) to toluene (12.0 mL), microwave at 120 degrees Celsius React for 2 hours.

-2-酮(收率：43.3％)。LCMS:RT＝1.78min,[M+H] ⁺＝174.15。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/50). Obtained 348.0 mg of yellow solid 4-methyl-1,3-dihydro-2H-benzo[d]aza

-2-one (yield: 43.3%). LCMS: RT=1.78 min, [M+H] ⁺ =174.15.

-2-酮 Step C: Synthesis of 4-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-one

-2-酮(348.0毫克，2.01毫摩尔)的甲醇(20.0毫升)和水(5.0毫升)的混合溶液中，加入甲酸铵(640.0毫克，10.05毫摩尔)和钯碳(20.0毫克)，N ₂保护下，75摄氏度反应6小时。 At room temperature, add 4-methyl-1,3-dihydro-2H-benzo[d]aza

To a mixed solution of -2-one (348.0 mg, 2.01 mmol) in methanol (20.0 mL) and water (5.0 mL), ammonium formate (640.0 mg, 10.05 mmol) and palladium on carbon (20.0 mg) were added, N ₂ Under protection, react at 75 degrees Celsius for 6 hours.

-2-酮，无需纯化，直接用于下一步反应。LCMS:RT＝1.78min,[M+H] ⁺＝176.17。 After the reaction is over, the palladium carbon is filtered, the filter cake is washed with methanol, the filtrate is concentrated under reduced pressure and dried to obtain 347.0 mg of yellow solid 4-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine

-2-one, without purification, directly used in the next reaction. LCMS: RT=1.78 min, [M+H] ⁺ =176.17.

Step D: Synthesis of 2-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aza

-2-酮(347.0毫克，1.94毫摩尔)的四氢呋喃(10.0毫升)中，滴加硼烷四氢呋喃溶液(6.8毫升，1.0摩尔每升)，N ₂保护下，45摄氏度搅拌2小时。 At zero degrees Celsius, it contains 4-methyl-1,3,4,5-tetrahydro-2H-benzo[d]aza

-2-ketone (347.0 mg, 1.94 mmol) in tetrahydrofuran (10.0 mL), borane tetrahydrofuran solution (6.8 mL, 1.0 mol per liter) was added dropwise, and the mixture was stirred at 45 degrees Celsius for 2 hours under the protection of _{N 2.}

，无需纯化，直接用于下一步反应。LCMS:RT＝1.54min,[M+H] ⁺＝162.13。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 200.0 mg of pale yellow solid 2-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

, Without purification, directly used in the next reaction. LCMS: RT=1.54 min, [M+H] ⁺ =162.13.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮 Step E: Synthesis of (S)-5-(3-(2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

(26.6毫克，0.17毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(82微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(47.0毫克，0.25毫摩尔)和1-羟基苯并三唑(3.3毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (35.0 mg, 0.17 mmol) and 2-methyl-2,3 ,4,5-Tetrahydro-1H-benzo[d]aza

(26.6 mg, 0.17 mmol) was added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (82 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride (47.0 mg, 0.25 mmol) and 1-hydroxybenzotriazole (3.3 mg, 0.02 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：48.9％)。LCMS:RT＝1.78min,[M-H] ^-＝354.24。 ¹H NMR(400MHz,DMSO)δ10.62(s,0.5H),10.59(s,0.5H),7.72(s,0.5H),7.69(s,0.5H),7.21–7.03(m,4H),3.82–3.67(m,1H),3.50–3.44(m,1H),3.43–3.33(m,1H),3.05–2.77(m,4H),2.36–2.20(m,1H),2.21–2.01(m,1H),1.97–1.82(m,1H),1.83–1.56(m,1H),1.06(m,1.5H),0.98–0.92(m,1.5H),0.90–0.8(m,1H),0.46–0.36(m,1H),0.36–0.18(m,2H),0.15–0.01(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 29.5 mg of white solid (S)-5-(3-(2-methyl-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 48.9%). LCMS: RT=1.78 min, [MH] ^- =354.24. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 0.5H), 10.59 (s, 0.5H), 7.72 (s, 0.5H), 7.69 (s, 0.5H), 7.21-7.03 (m, 4H) ,3.82–3.67(m,1H), 3.50–3.44(m,1H), 3.43–3.33(m,1H), 3.05–2.77(m,4H), 2.36–2.20(m,1H),2.21–2.01( m,1H),1.97-1.82(m,1H),1.83-1.56(m,1H),1.06(m,1.5H),0.98-0.92(m,1.5H),0.90-0.8(m,1H), 0.46–0.36(m,1H), 0.36–0.18(m,2H), 0.15–0.01(m,1H).

Example 24

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Synthesis of (S)-5-cyclopropyl-5-(3-(7-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of 2,2'-(4-nitro-1,2-phenylene)diacetic acid

At zero degrees Celsius, to concentrated sulfuric acid (100 mL) containing o-diphenylacetic acid (20.0 g, 103.0 mmol), concentrated nitric acid (5.1 mL) was added dropwise, and _{under the protection of N 2} , the temperature was kept and stirred for 1.5 hours.

After the reaction, the reaction solution was poured into a large amount of ice water, stirred for 10 minutes, the mixture was extracted with ethyl acetate (200 ml×3 times), the organic phases were combined, and the organic phase was washed with saturated brine (200 ml×2 times) Then, it was dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 16.0 g of yellow solid 2,2'-(4-nitro-1,2-phenylene)diacetic acid (yield: 65.9%). LCMS: RT=1.61 min, [MH] ^- =238.13.

Step B: Synthesis of 2,2'-(4-nitro-1,2-phenylene)bis(ethane-1-ol)

At zero degrees Celsius, to tetrahydrofuran (100 ml) containing 2,2'-(4-nitro-1,2-phenylene) diacetic acid (10.0 g, 41.8 mmol), add borane tetrahydrofuran solution ( 168.0 ml, 1.0 mole per liter), _{under the protection of N 2} , keep the temperature and stir for 2 hours.

After the reaction is over, add water slowly to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixture is extracted with ethyl acetate (100 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (100 ml×2). Times) washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 6.8 grams of yellow solid 2,2'-(4-nitro-1,2-phenylene)bis(ethane-1-ol)( Yield: 77.0%). LCMS: RT=1.61 min.

Step C: Synthesis of 7-nitro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

At zero degrees Celsius, it contains 2,2'-(4-nitro-1,2-phenylene) bis(ethane-1-ol) (6.8 g, 32.2 mmol), trifluoromethanesulfonamide (7.2 g , 48.3 mmol), triphenylphosphine (16.9 g, 64.5 mmol) in tetrahydrofuran (100 ml), add dropwise diethyl azodicarboxylate (10.2 ml), under N ₂ protection, and stir at room temperature for 2 hours.

(收率：95.9％)。LCMS:RT＝2.05min,[M-H] ^-＝323.17。 The reaction is over, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtain 10.0 grams of yellow solid 7-nitro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

(Yield: 95.9%). LCMS: RT = 2.05 min, [MH] ^- = 323.17.

-7-胺 Step D: Synthesis of 3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine

(10.0克，30.9毫摩尔)和氯化铵(8.2克，154.5毫摩尔)的乙醇水混合溶液(120毫升，乙醇：水＝5:1)中，加入还原铁粉(6.9克，123.6毫摩尔)，N ₂保护下，80摄氏度反应1小时。 At room temperature, add 7-nitro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

(10.0 g, 30.9 mmol) and ammonium chloride (8.2 g, 154.5 mmol) in ethanol water mixed solution (120 ml, ethanol: water = 5:1), add reduced iron powder (6.9 g, 123.6 mmol) ), under N ₂ protection, react at 80 degrees Celsius for 1 hour.

-7-胺(收率：74.6％)。LCMS:RT＝1.82min,[M+H] ⁺＝295.13。 After the reaction is complete, cool to room temperature, add 200 ml of dichloromethane to dilute, filter with suction, wash the filter cake with dichloromethane, extract the filtrate with dichloromethane (100 ml×3 times), combine the organic phases, and use saturated salt for the organic phase. Wash with water (100 ml×2 times), then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure to obtain 6.8 g of yellow solid 3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro -1H-benzo[d]aza

-7-amine (yield: 74.6%). LCMS: RT=1.82 min, [M+H] ⁺ =295.13.

Step E: Synthesis of 7-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-胺(300.0毫克，1.0毫摩尔)的浓盐酸(5毫升)中，缓慢滴加亚硝酸钠水溶液(75.9毫克，1.1毫摩尔，1.0毫升水)，滴毕，N ₂保护下保持该温度反应1小时后，缓慢滴加四氟硼酸(954.5微升)，保持该温度继续搅拌2小时。 At zero degrees Celsius, to contain 3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine (300.0 mg, 1.0 mmol) in concentrated hydrochloric acid (5 mL), slowly dropwise add sodium nitrite aqueous solution (75.9 mg, 1.1 mmol, 1.0 mL water), after dripping, keep the solution under the protection of _{N 2} After reacting at the temperature for 1 hour, tetrafluoroboric acid (954.5 microliters) was slowly added dropwise, and stirring was continued for 2 hours while maintaining the temperature.

After the reaction was completed, suction filtration, the filter cake was washed with ice water, and the filter cake was vacuum dried to obtain 300 mg of white solid diazonium tetrafluoroborate, LCMS:RT=1.52 min.

The solid obtained from the appeal was put into an eggplant-shaped bottle and pyrolyzed at 110 degrees Celsius for 30 minutes.

，无需纯化，直接用于下一步反应。LCMS:RT＝2.31min。 After the reaction is over, 250 mg of crude product is obtained as a brown solid 7-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

, Without purification, directly used in the next reaction. LCMS: RT = 2.31 min.

Step F: Synthesis of 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

(250毫克，0.8毫摩尔)的甲苯(3毫升)中，缓慢滴加红铝的甲苯溶液(2.3毫升，3.5摩尔每升)，滴毕，N ₂保护下室温反应3小时。 At zero degrees Celsius, to contain 3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

(250 mg, 0.8 mmol) of toluene (3 mL), slowly add red aluminum toluene solution (2.3 mL, 3.5 mol per liter) dropwise, after dripping, react at room temperature under _{N 2 protection for 3 hours.}

(收率：64.0％)。LCMS:RT＝0.28min,[M+H] ⁺＝166.14。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/5). Obtain 85.0 mg of white solid 7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 64.0%). LCMS: RT=0.28 min, [M+H] ⁺ =166.14.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Step G: Synthesis of (S)-5-cyclopropyl-5-(3-(7-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

(99.6毫克，0.60毫摩尔)加入N,N-二甲基甲酰胺(4毫升)中，滴加N,N-二异丙基乙胺(299微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(126.5毫克，0.66毫摩尔)和1-羟基苯并三唑(12.2毫克，0.09毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (128.0 mg, 0.60 mmol) and 7-fluoro-2,3, 4,5-Tetrahydro-1H-benzo[d]aza

(99.6 mg, 0.60 mmol) was added to N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (299 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (126.5 mg, 0.66 mmol) and 1-hydroxybenzotriazole (12.2 mg, 0.09 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：43.6％)。LCMS:RT＝1.77min,[M+H] ⁺＝360.26。 ¹H NMR(400MHz,DMSO)δ10.61(s,1H),7.71(s,1H),7.18(dd,J＝14.1,8.0Hz,1H),7.02(td,J＝10.6,1.4Hz,1H),6.94(t,J＝8.6Hz,1H),3.65–3.42(m,4H),2.86(d,J＝33.7Hz,4H),2.50–2.36(m,1H),2.37–2.18(m,1H),2.04–1.82(m,2H),1.18–1.01(m,1H),0.52–0.40(m,1H),0.39–0.24(m,2H),0.20–0.02(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 94.0 mg of white solid (S)-5-cyclopropyl-5-(3-(7-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 43.6%). LCMS: RT=1.77 min, [M+H] ⁺ =360.26. ¹ H NMR (400MHz, DMSO) δ 10.61 (s, 1H), 7.71 (s, 1H), 7.18 (dd, J = 14.1, 8.0 Hz, 1H), 7.02 (td, J = 10.6, 1.4 Hz, 1H ), 6.94(t,J=8.6Hz,1H), 3.65–3.42(m,4H), 2.86(d,J=33.7Hz,4H), 2.50–2.36(m,1H), 2.37–2.18(m, 1H), 2.04–1.82(m,2H), 1.18–1.01(m,1H), 0.52–0.40(m,1H), 0.39–0.24(m,2H), 0.20–0.02(m,1H).

Example 25

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Synthesis of (S)-5-cyclopropyl-5-(3-(7-chloro-8-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

-7-基)乙酰胺 Step A: Synthesis of N-(3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide

-7-胺(2.5克，8.5毫摩尔)的二氯甲烷(30毫升)中，滴加三乙胺(2.9毫升)和乙酰氯(0.9毫升)，N ₂保护下，保持该温度下搅拌30分钟。 At zero degrees Celsius, to contain 3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine (2.5 g, 8.5 mmol) in dichloromethane (30 ml), add triethylamine (2.9 ml) and acetyl chloride (0.9 ml) dropwise, _{under the protection of N 2} and keep stirring at this temperature for 30 minute.

-7-基)乙酰胺(收率：87.5％)。LCMS:RT＝1.93min,[M+H] ⁺＝337.14。 After the reaction was completed, it was quenched by adding water, the mixed solution was extracted with dichloromethane (50 ml × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml × 2 times), and then dried with anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtain 2.5 g of yellow solid N-(3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (yield: 87.5%). LCMS: RT=1.93 min, [M+H] ⁺ =337.14.

-7-基)乙酰胺 Step B: Synthesis of N-(8-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide

-7-基)乙酰胺(2.5克，7.4毫摩尔)的N,N-二甲基甲酰胺(30毫升)中，加入N-氯代丁二酰亚胺(1.1毫克，8.2毫摩尔)，N ₂保护下，100摄氏度反应2小时。 At room temperature, add N-(3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (2.5 g, 7.4 mmol) in N,N-dimethylformamide (30 mL) was added N-chlorosuccinimide (1.1 mg, 8.2 mmol), Under the protection of N ₂ , the reaction was carried out at 100 degrees Celsius for 2 hours.

-7-基)乙酰胺(收率：32.1％)。LCMS:RT＝1.98min,[M+H] ⁺＝371.11。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2). Obtain 880.0 mg of white solid N-(8-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (yield: 32.1%). LCMS: RT=1.98 min, [M+H] ⁺ =371.11.

-7-胺 Step C: Synthesis of 8-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine

-7-基)乙酰胺(880.0毫克，2.4毫摩尔)加入6摩尔每升的盐酸水溶液(20毫升)中，N ₂保护下，100摄氏度反应5小时。 At room temperature, N-(8-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (880.0 mg, 2.4 mmol) was added to 6 moles of hydrochloric acid aqueous solution (20 ml) per liter, and the reaction was carried out at 100 degrees Celsius for 5 hours under the protection of _{N 2.}

-7-胺(收率：88.1％)。LCMS:RT＝2.07min,[M+H] ⁺＝329.28。 ¹H NMR(400MHz,DMSO)δ7.00(s,1H),6.60(s,1H),5.21(s,2H),3.80-3.30(brs,4H),2.8-2.82(m,4H)。 At the end of the reaction, adjust the pH to 10 with saturated aqueous sodium hydroxide solution under ice bath, extract the mixture with ethyl acetate (30 ml×3 times), combine the organic phases, and use saturated brine (20 ml×2 times). ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2). Obtained 695.0 mg of white solid 8-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

-7-amine (yield: 88.1%). LCMS: RT = 2.07 min, [M+H] ⁺ =329.28. ¹ H NMR (400MHz, DMSO) δ 7.00 (s, 1H), 6.60 (s, 1H), 5.21 (s, 2H), 3.80-3.30 (brs, 4H), 2.8-2.82 (m, 4H).

Step D: Synthesis of 7-chloro-8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-胺(300.0毫克，0.9毫摩尔)的浓盐酸(5毫升)中，缓慢滴加亚硝酸钠水溶液(69.0毫克，1.0毫摩尔，1.0毫升水)，滴毕，N ₂保护下保持该温度反应1小时后，缓慢滴加四氟硼酸(870微升)，保持该温度继续搅拌2小时。 At zero degrees Celsius, it contains 8-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine (300.0 mg, 0.9 mmol) in concentrated hydrochloric acid (5 ml), slowly dropwise add sodium nitrite aqueous solution (69.0 mg, 1.0 mmol, 1.0 ml of water), after dripping, keep it under the protection of _{N 2} After reacting at the temperature for 1 hour, tetrafluoroboric acid (870 microliters) was slowly added dropwise, and the temperature was kept at this temperature and stirring was continued for 2 hours.

After the reaction was completed, suction filtration, the filter cake was washed with ice water, and the filter cake was vacuum dried to obtain 300 mg of white solid diazonium tetrafluoroborate, LCMS:RT=1.51 min.

The solid obtained above was dissolved in o-dichlorobenzene (5 ml) and pyrolyzed at 170 degrees Celsius for 1 hour. At the end of the reaction, the reaction solution does not need to be purified and is directly used in the next reaction. LCMS: RT = 2.32 min.

Step E: Synthesis of 7-chloro-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

At zero degrees Celsius, slowly add a toluene solution of red aluminum (2.7 ml, 3.5 moles per liter) dropwise to the above reaction solution. After the drop, the reaction was carried out at room temperature under the protection of _{N 2 for 3 hours.}

(收率：33.1％)。LCMS:RT＝1.56min,[M+H] ⁺＝200.11。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/5). Obtained 60.0 mg of white solid 7-chloro-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 33.1%). LCMS: RT=1.56 min, [M+H] ⁺ =200.11.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Step F: Synthesis of (S)-5-cyclopropyl-5-(3-(7-chloro-8-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

(60.0毫克，0.3毫摩尔)加入N,N-二甲基甲酰胺(3毫升)中，滴加N,N-二异丙基乙胺(149微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(63.3毫克，0.33毫摩尔)和1-羟基苯并三唑(6.7毫克，0.05毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (63.7 mg, 0.3 mmol) and 7-chloro-8-fluoro- 2,3,4,5-Tetrahydro-1H-benzo[d]aza

(60.0 mg, 0.3 mmol) was added to N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (149 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride (63.3 mg, 0.33 mmol) and 1-hydroxybenzotriazole (6.7 mg, 0.05 mmol), _{react under N 2} protection at room temperature overnight.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：33.9％)。LCMS:RT＝1.85min,[M+H] ⁺＝394.19。 ¹H NMR(400MHz,DMSO)δ10.61(s,1H),7.71(s,1H),7.40(dd,J＝12.3,7.7Hz,1H),7.25(t,J＝10.9Hz,1H),3.57-3.52(m,4H),2.92-2.83(m,4H),2.52–2.35(m,1H),2.35–2.18(m,1H),2.06–1.82(m,2H),1.13-1.06(m,1H),0.55–0.39(m,1H),0.39–0.21(m,2H),0.18–0.00(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 40.0 mg of white solid (S)-5-cyclopropyl-5-(3-(7-chloro-8-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 33.9%). LCMS: RT=1.85 min, [M+H] ⁺ =394.19. ¹ H NMR (400MHz, DMSO) δ 10.61 (s, 1H), 7.71 (s, 1H), 7.40 (dd, J = 12.3, 7.7 Hz, 1H), 7.25 (t, J = 10.9 Hz, 1H), 3.57-3.52 (m, 4H), 2.92-2.83 (m, 4H), 2.52-2.35 (m, 1H), 2.35-2.18 (m, 1H), 2.06-1.82 (m, 2H), 1.13-1.06 (m ,1H),0.55–0.39(m,1H),0.39–0.21(m,2H),0.18–0.00(m,1H).

Example 26

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Synthesis of (S)-5-cyclopropyl-5-(3-(6-chloro-7-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

-7-基)乙酰胺 Step A: Synthesis of N-(6-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide

-7-基)乙酰胺(2.5克，7.4毫摩尔)的N,N-二甲基甲酰胺(30毫升)中，加入N-氯代丁二酰亚胺(1.1毫克，8.2毫摩尔)，N ₂保护下，100摄氏度反应2小时。 At room temperature, add N-(3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (2.5 g, 7.4 mmol) in N,N-dimethylformamide (30 mL) was added N-chlorosuccinimide (1.1 mg, 8.2 mmol), Under the protection of N ₂ , the reaction was carried out at 100 degrees Celsius for 2 hours.

-7-基)乙酰胺(收率：5.1％)。LCMS:RT＝1.98min,[M+H] ⁺＝371.11。 ¹H NMR(400MHz,DMSO)δ9.47(s,1H),7.49(d,J＝8.2Hz,1H),7.14(d,J＝8.2Hz,1H),3.90-3.45(m,4H),3.35-3.15(m,2H),3.07(t,J＝5.3Hz,2H),2.08(s,3H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2). Obtain 140.0 mg of white solid N-(6-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (yield: 5.1%). LCMS: RT=1.98 min, [M+H] ⁺ =371.11. ¹ H NMR(400MHz,DMSO)δ9.47(s,1H), 7.49(d,J=8.2Hz,1H), 7.14(d,J=8.2Hz,1H), 3.90-3.45(m,4H), 3.35-3.15 (m, 2H), 3.07 (t, J=5.3 Hz, 2H), 2.08 (s, 3H).

-7-胺 Step B: Synthesis of 6-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine

-7-基)乙酰胺(140.0毫克，0.38毫摩尔)加入6摩尔每升的盐酸水溶液(5.0毫升)中，N ₂保护下，100摄氏度反应5小时。 At room temperature, the N-(6-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (140.0 mg, 0.38 mmol) was added to 6 moles of hydrochloric acid aqueous solution (5.0 ml) per liter, and the reaction was carried out at 100 degrees Celsius for 5 hours under the protection of _{N 2.}

-7-胺(收率：84.2％)。LCMS:RT＝2.07min,[M+H] ⁺＝329.10。 After the reaction is over, adjust the pH to 10 with saturated aqueous sodium hydroxide solution under ice bath, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and use saturated brine (20 ml×2 times). ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2). Obtain 105.0 mg of white solid 6-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine (yield: 84.2%). LCMS: RT = 2.07 min, [M+H] ⁺ =329.10.

Step C: Synthesis of 6-chloro-7-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-胺(105.0毫克，0.32毫摩尔)的浓盐酸(3毫升)中，缓慢滴加亚硝酸钠水溶液(24.3毫克，0.35毫摩尔，1.0毫升水)，滴毕，N ₂保护下保持该温度反应1小时后，缓慢滴加四氟硼酸(305微升)，保持该温度继续搅拌2小时。 At zero degrees Celsius, adding 6-chloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine (105.0 mg, 0.32 mmol) in concentrated hydrochloric acid (3 ml), slowly dropwise add sodium nitrite aqueous solution (24.3 mg, 0.35 mmol, 1.0 ml of water), after dripping, keep it under the protection of _{N 2} After reacting at the temperature for 1 hour, tetrafluoroboric acid (305 microliters) was slowly added dropwise, and stirring was continued for 2 hours while maintaining the temperature.

After the reaction was completed, suction filtration, the filter cake was washed with ice water, and the filter cake was vacuum dried to obtain 100 mg of white solid diazonium tetrafluoroborate, LCMS:RT=1.51 min.

The solid obtained above was dissolved in o-dichlorobenzene (3 ml) and pyrolyzed at 170 degrees Celsius for 1 hour. At the end of the reaction, the reaction solution does not need to be purified and is directly used in the next reaction. LCMS: RT = 2.32 min.

Step E: Synthesis of 6-chloro-7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

At zero degrees Celsius, slowly add a toluene solution of red aluminum (864 microliters, 3.5 moles per liter) dropwise to the above reaction solution. After the dripping is completed, react at room temperature under _{N 2 protection for 3 hours.}

(收率：41.7％)。LCMS:RT＝1.56min,[M+H] ⁺＝200.12。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/5). Obtained 25.0 mg of white solid 6-chloro-7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

(Yield: 41.7%). LCMS: RT=1.56 min, [M+H] ⁺ =200.12.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Step F: Synthesis of (S)-5-cyclopropyl-5-(3-(6-chloro-7-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

(25.0毫克，0.13毫摩尔)加入N,N-二甲基甲酰胺(3毫升)中，滴加N,N-二异丙基乙胺(64微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(63.3毫克，0.14毫摩尔)和1-羟基苯并三唑(2.7毫克，0.02毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (27.6 mg, 0.13 mmol) and 6-chloro-7-fluoro- 2,3,4,5-Tetrahydro-1H-benzo[d]aza

(25.0 mg, 0.13 mmol) was added to N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (64 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (63.3 mg, 0.14 mmol) and 1-hydroxybenzotriazole (2.7 mg, 0.02 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：44.9％)。LCMS:RT＝1.84min,[M+H] ⁺＝394.15。 ¹H NMR(400MHz,DMSO)δ10.60(s,1H),7.71(s,0.5H),7.70(s,0.5H),7.25–7.12(m,2H),3.58(ddd,J＝17.4,10.7,5.2Hz,4H),3.01(ddd,J＝41.5,24.0,18.7Hz,4H),2.50–2.32(m,1H),2.34–2.19(m,1H),2.01–1.79(m,2H),1.07(dt,J＝10.1,4.1Hz,1H),0.56–0.41(m,1H),0.40–0.23(m,2H),0.19–0.02(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 23.0 mg of white solid (S)-5-cyclopropyl-5-(3-(6-chloro-7-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 44.9%). LCMS: RT=1.84 min, [M+H] ⁺ =394.15. ¹ H NMR(400MHz,DMSO)δ10.60(s,1H),7.71(s,0.5H),7.70(s,0.5H),7.25-7.12(m,2H),3.58(ddd,J=17.4, 10.7,5.2Hz,4H),3.01(ddd,J=41.5,24.0,18.7Hz,4H), 2.50–2.32(m,1H), 2.34–2.19(m,1H), 2.01–1.79(m,2H) , 1.07 (dt, J = 10.1, 4.1 Hz, 1H), 0.56-0.41 (m, 1H), 0.40-0.23 (m, 2H), 0.19-0.02 (m, 1H).

Examples 27 and 28

-3-基)-3-氧丙基)咪唑烷-2,4-二酮和(S)-5-环丙基-5-(3-(7-(2,3-二氯苯基)-8-氟-1,2,4,5-四氢-3H-苯并[d]氮杂

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Synthesis of (S)-5-cyclopropyl-5-(3-(7-(3,4-dichlorophenyl)-8-fluoro-1,2,4,5-tetrahydro-3H-benzo[ d]Aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione and (S)-5-cyclopropyl-5-(3-(7-(2,3-dichlorophenyl) -8-Fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

-7-基)乙酰胺 Step A: Synthesis of N-(8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide

-7-基)乙酰胺(1.70克，5.04毫摩尔)的N,N-二甲基甲酰胺(30毫升)中，加入1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸盐)(2.14克，6.05毫摩尔)，N ₂保护下，120摄氏度反应16小时。 At room temperature, add N-(3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (1.70 g, 5.04 mmol) in N,N-dimethylformamide (30 mL), add 1-chloromethyl-4-fluoro-1,4-diazide Cyclo 2.2.2 octane bis (tetrafluoroborate) (2.14 g, 6.05 mmol), under N ₂ protection, reacted at 120 degrees Celsius for 16 hours.

-7-基)乙酰胺(收率：7.3％)。LCMS:RT＝1.95min,[M+H] ⁺＝355.15。 The reaction solution was quenched by adding 200 ml of water, the mixture was extracted with ethyl acetate (50 ml × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml × 2 times), and then dried over anhydrous sodium sulfate ,concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2). Obtain 130.0 mg of white solid N-(8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (yield: 7.3%). LCMS: RT=1.95 min, [M+H] ⁺ =355.15.

-7-胺 Step B: Synthesis of 8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine

-7-基)乙酰胺(130毫克，0.37毫摩尔)溶解于3毫升乙醇中，加入12摩尔每升的浓盐酸(1毫升)中，N ₂保护下，100摄氏度反应1小时。 At room temperature, the N-(8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-yl)acetamide (130 mg, 0.37 mmol) was dissolved in 3 ml of ethanol, 12 moles per liter of concentrated hydrochloric acid (1 ml) was added, and the reaction was carried out at 100 degrees Celsius for 1 hour under the protection of _{N 2.}

-7-胺(收率：82.6％)。 At the end of the reaction, adjust the pH to 10 with saturated aqueous sodium hydroxide solution under ice bath, extract the mixture with ethyl acetate (30 ml×3 times), combine the organic phases, and use saturated brine (20 ml×2 times). ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/2) to obtain 100.0 mg of white solid 8-fluoro-3-((trifluoromethyl)sulfonyl)-2, 3,4,5-Tetrahydro-1H-benzo[d]aza

-7-amine (yield: 82.6%).

-7-重氮氟硼酸盐 Step C: Synthesis of 8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-diazofluoroborate

-7-胺(100毫克，0.32毫摩尔)的浓盐酸(3毫升)中，缓慢滴加亚硝酸钠水溶液(26.0毫克，0.38毫摩尔，1.0毫升水)，滴毕，N ₂保护下保持该温度反应1小时后，缓慢滴加四氟硼酸(1.86克，48％)，保持该温度继续搅拌2小时。反应结束，抽滤，滤饼用冰水洗涤，滤饼真空干燥得110.0毫克白色固体8-氟-3-((三氟甲基)磺酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂

-7-重氮氟硼酸盐(收率：83.5％)。LCMS:RT＝1.51min。 At zero degrees Celsius, it contains 8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-amine (100 mg, 0.32 mmol) in concentrated hydrochloric acid (3 ml), slowly dropwise add sodium nitrite aqueous solution (26.0 mg, 0.38 mmol, 1.0 ml of water), after dripping, keep it under the protection of _{N 2} After reacting at the temperature for 1 hour, tetrafluoroboric acid (1.86 g, 48%) was slowly added dropwise, and stirring was continued for 2 hours while maintaining the temperature. After the reaction was completed, the filter cake was washed with ice water, and the filter cake was vacuum dried to obtain 110.0 mg of white solid 8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[d]aza

-7-diazofluoroborate (yield: 83.5%). LCMS: RT=1.51 min.

和7-(2,3-二氯苯基)-8-氟-2,3,4,5-四氢-1H-苯并[d]氮杂

Step D: Synthesis of 7-(3,4-dichlorophenyl)-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

And 7-(2,3-dichlorophenyl)-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-重氮氟硼酸盐(110毫克，)溶于邻二氯苯(5毫升)中，170摄氏度加热反应1小时。反应结束，反应液无需纯化。零摄氏度下，向上诉反应液中，缓慢滴加红铝的甲苯溶液(0.50毫升，3.5摩尔每升)，滴毕，N ₂保护下室温反应3小时。 The 8-fluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

-7-diazofluoroborate (110 mg,) was dissolved in o-dichlorobenzene (5 ml), and the reaction was heated at 170 degrees Celsius for 1 hour. At the end of the reaction, the reaction solution does not need to be purified. At zero degrees Celsius, slowly add a toluene solution of red aluminum (0.50 ml, 3.5 moles per liter) dropwise to the above reaction solution. After the dripping is completed, react at room temperature under the protection of _{N 2 for 3 hours.}

和7-(2,3-二氯苯基)-8-氟-2,3,4,5-四氢-1H-苯并[d]氮杂

的混合物。LCMS:RT＝1.73min,[M+H] ⁺＝310.10。 After the reaction, the reaction solution was slowly poured into ice water until no bubbles were generated, washed with 5% sodium hydroxide solution until clear, the mixed solution was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. It was washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/5). Obtained 47.0 mg of white solid 7-(3,4-dichlorophenyl)-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

And 7-(2,3-dichlorophenyl)-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

mixture. LCMS: RT=1.73min, [M+H] ⁺ =310.10.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮和(S)-5-环丙基-5-(3-(7-(2,3-二氯苯基)-8-氟-1,2,4,5-四氢-3H-苯并[d]氮杂

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Step E: Synthesis of (S)-5-cyclopropyl-5-(3-(7-(3,4-dichlorophenyl)-8-fluoro-1,2,4,5-tetrahydro-3H- Benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione and (S)-5-cyclopropyl-5-(3-(7-(2,3-dichlorophenyl) -8-Fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

和7-(2,3-二氯苯基)-8-氟-2,3,4,5-四氢-1H-苯并[d]氮杂

的混合物(47.0毫克，0.16毫摩尔)和(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(34.0毫克，0.16毫摩尔)溶解于N,N-二甲基甲酰胺(5毫升)中，滴加N,N-二异丙基乙胺(62毫克，0.483毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(34.0毫克，0.18毫摩尔)和1-羟基苯并三唑(3.2毫克，0.03毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, the 7-(3,4-dichlorophenyl)-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

And 7-(2,3-dichlorophenyl)-8-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

The mixture (47.0 mg, 0.16 mmol) and (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (34.0 mg, 0.16 mmol) were dissolved in To N,N-dimethylformamide (5ml), add N,N-diisopropylethylamine (62mg, 0.483mmol) dropwise, and then add 1-ethyl-(3-dimethylformamide) dropwise. Aminopropyl) carbodiimide hydrochloride (34.0 mg, 0.18 mmol) and 1-hydroxybenzotriazole (3.2 mg, 0.03 mmol) were reacted overnight at room temperature under _{N 2 protection.}

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(LCMS:RT＝2.01min,[M+H] ⁺＝504.20)和16.0毫克(S)-5-环丙基-5-(3-(7-(2,3-二氯苯基)-8-氟-1,2,4,5-四氢-3H-苯并[d]氮杂

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(LCMS:RT＝2.08min,[M+H] ⁺＝504.20)。 The reaction solution was poured into water, the mixed solution was extracted with ethyl acetate (30 ml × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml × 2 times), then dried with anhydrous sodium sulfate and concentrated . The obtained crude product was separated and purified by prep-HPLC (TFA) to obtain 14.0 mg of (S)-5-cyclopropyl-5-(3-(7-(3,4-dichlorophenyl)-8-fluoro-1,2 ,4,5-Tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (LCMS:RT＝2.01min, [M+H] ⁺ =504.20) and 16.0 mg (S)-5-cyclopropyl -5-(3-(7-(2,3-Dichlorophenyl)-8-fluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (LCMS: RT = 2.08 min, [M+H] ⁺ =504.20).

Example 27: ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 7.80 (s, 1H), 7.78-7.66 (m, 2H), 7.55 (d, J = 8.2 Hz, 1H), 7.43 -7.40(m,1H), 7.19(t,J=12.1Hz,1H), 3.69–3.47(m,4H), 3.03–2.82(m,4H), 2.47-2.43(m,1H), 2.37-2.29 (m, 1H), 2.02-1.95 (m, 2H), 1.31-1.19 (m, 1H), 1.14-1.06 (m, 1H), 0.54-0.25 (m, 3H), 0.13-0.09m, 1H).

Example 28: ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 7.74-7.71 (m, 2H), 7.50-7.43 (m, 1H), 7.42-7.34 (m, 1H), 7.25- 7.11(m,2H), 3.66-3.51(m,4H), 2.97-2.87(m,4H), 2.50-2.41(m,1H), 2.39-2.24(m,1H), 2.07-1.88(m,2H) ),1.26-1.24(m,1H),1.14-1.07(m,1H),0.46–0.32(m,3H),0.18–0.06(m,1H).

Example 29

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Synthesis of (S)-5-cyclopropyl-5-(3-(7,8-difluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of (4,5-difluoro-1,2-phenylene)dimethanol

At zero degrees Celsius, to tetrahydrofuran (25 ml) containing 4,5-difluorophthalic acid (2.50 g, 12.37 mmol), borane tetrahydrofuran solution (50.0 ml, 1.0 mole per liter), N ₂ Under protection, keep the temperature and stir for 1.5 hours.

At the end of the reaction, the reaction solution was slowly poured into ice water and stirred until no bubbles were generated. The mixture was extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 ml×2 times). , And then dried with anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/1). 1.60 g of white solid (4,5-difluoro-1,2-phenylene)dimethanol was obtained (yield: 74.4%).

Step B: Synthesis of 1,2-bis(bromomethyl)-4,5-difluorobenzene

At zero degrees Celsius, to (4,5-difluoro-1,2-phenylene)dimethanol (1.60 g, 9.19 mmol) in tetrahydrofuran (40.0 ml) was added triphenylphosphine (7.22 g, 27.6 Millimoles), carbon tetrabromide (6.70 g, 20.2 mmol) was added under ice bath, and under N ₂ protection, the temperature was kept and stirred for 1 hour.

After the reaction was completed, the reaction solution was slowly poured into ice water, the mixed solution was extracted with ethyl acetate (50 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=0/1). 1.90 g of colorless liquid 1,2-bis(bromomethyl)-4,5-difluorobenzene was obtained (yield: 69.3%).

Step C: Synthesis of (4,5-difluoro-1,2-phenylene) diacetonitrile

At zero degrees Celsius, to acetonitrile (20 ml) containing 1,2-bis(bromomethyl)-4,5-difluorobenzene (1.90 g, 6.35 mmol), add trimethylsilyl cyanide (1.92 ml) dropwise ) And a tetrahydrofuran solution of tetrabutylammonium fluoride (14.6 ml, 1.0 mole per liter), _{under the protection of N 2} , stirring at 80 degrees Celsius for 20 minutes.

At the end of the reaction, the reaction solution was poured into sodium bicarbonate solution, the mixed solution was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 1.10 g of light green solid 2,2'-(4,5-difluoro-1,2-phenylene)diacetonitrile was obtained (yield: 90.9%).

Step D: Synthesis of 2,2'-(4,5-difluoro-1,2-phenylene)diacetic acid

At room temperature, 2,2'-(4,5-difluoro-1,2-phenylene) diacetonitrile (1.1 g, 5.75 mmol) was added to concentrated hydrochloric acid (10 ml), under N ₂ protection, 100 Reaction in degrees Celsius for 2 hours.

After the reaction was over, the reaction solution was slowly poured into ice water, the mixed solution was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain 1.20 g of white solid 2,2'-(4 ,5-Difluoro-1,2-phenylene)diacetic acid (yield: 90.7%). LCMS: RT=1.64min, [MH] ^- =229.11.

Step E: Synthesis of 2,2'-(4,5-difluoro-1,2-phenylene)bis(ethane-1-ol)

At zero degrees Celsius, to tetrahydrofuran (15 ml) containing 2,2'-(4,5-difluoro-1,2-phenylene)diacetic acid (1.20 g, 5.22 mmol), add borane tetrahydrofuran dropwise The solution (20.8 ml, 1.0 mole per liter), _{under the protection of N 2} , was kept at this temperature and stirred for 1 hour.

At the end of the reaction, the reaction solution was slowly poured into ice water and stirred until no bubbles were generated. The mixed solution was extracted with ethyl acetate (30 ml×2 times), and the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated. 0.90 g of light yellow solid 2,2'-(4,5-difluoro-1,2-phenylene)bis(ethane-1-ol) was obtained (yield: 94.8%).

Step F: Synthesis of 7,8-difluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

Containing 2,2'-(4,5-difluoro-1,2-phenylene) bis(ethane-1-ol) (0.40 g, 1.98 mmol), trifluoromethanesulfonamide (442 mg, 2.97 In tetrahydrofuran (10 ml), triphenylphosphine (1.04 g, 3.96 mmol), diethyl azodicarboxylate (623 μl) was added dropwise, under N ₂ protection, and stirred at room temperature for 2 hours.

(收率：71.7％)。LCMS:RT＝2.12min。 After the reaction was completed, the residue obtained by spin-drying the reaction solution was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane = 1/20). Obtained 447.0 mg of yellow solid 7,8-difluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 71.7%). LCMS: RT = 2.12 min.

Step G: Synthesis of 7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza

(447毫克，1.42毫摩尔)的甲苯(10毫升)中，缓慢滴加红铝的甲苯溶液(4.0毫升，3.5摩尔每升)，滴毕，N ₂保护下室温反应1.5小时。 At zero degrees Celsius, it contains 7,8-difluoro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

(447 mg, 1.42 mmol) of toluene (10 mL) was slowly added dropwise a toluene solution of red aluminum (4.0 mL, 3.5 moles per liter), after dripping, the reaction was carried out at room temperature under _{N 2 protection for 1.5 hours.}

(粗品)。LCMS:RT＝0.63min,[M+H] ⁺＝184.18。 At the end of the reaction, the reaction solution was slowly poured into ice water until no bubbles were generated, washed with 5% sodium hydroxide solution until clear, the mixed solution was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, and anhydrous sulfuric acid was used. The sodium was dried and concentrated to obtain 254.0 mg of transparent oily 7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Crude). LCMS: RT=0.63 min, [M+H] ⁺ =184.18.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Step H: Synthesis of (S)-5-cyclopropyl-5-(3-(7,8-difluoro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

(254毫克，1.38毫摩尔)加入N,N-二甲基甲酰胺(15毫升)中， 滴加N,N-二异丙基乙胺(537毫克，4.16毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(290毫克，1.52毫摩尔)和1-羟基苯并三唑(28.0毫克，0.207毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (293 mg, 1.38 mmol) and 7,8-difluoro-2 ,3,4,5-Tetrahydro-1H-benzo[d]aza

(254 mg, 1.38 mmol) was added to N,N-dimethylformamide (15 mL), N,N-diisopropylethylamine (537 mg, 4.16 mmol) was added dropwise, and then 1- Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (290 mg, 1.52 mmol) and 1-hydroxybenzotriazole (28.0 mg, 0.207 mmol), under N ₂ protection , React overnight at room temperature.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：47.9％)。LCMS:RT＝1.79min,[M+H] ⁺＝378.22。 ¹H NMR(400MHz,DMSO)δ(ppm)10.61(s,1H),7.71(s,1H),7.26(td,J＝11.5,8.5Hz,2H),3.56-3.50(m,4H),2.90-2.80(m,4H),2.47-2.39(m,1H)2.32-2.25(m,1H),1.99-1.88(m,2H),1.12-1.05(m,1H),0.48-0.41(m,1H),0.39-0.28(m,2H),0.13-0.07(m,1H)。 The reaction solution was poured into water, the mixed solution was extracted with ethyl acetate (50 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was separated and purified by prep-HPLC (TFA) to obtain 250.0 mg of white solid (S)-5-cyclopropyl-5-(3-(7,8-difluoro-1,2,4,5-tetrahydro- 3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 47.9%). LCMS: RT=1.79 min, [M+H] ⁺ =378.22. ¹ H NMR (400MHz, DMSO) δ (ppm) 10.61 (s, 1H), 7.71 (s, 1H), 7.26 (td, J = 11.5, 8.5 Hz, 2H), 3.56-3.50 (m, 4H), 2.90 -2.80(m,4H),2.47-2.39(m,1H)2.32-2.25(m,1H),1.99-1.88(m,2H),1.12-1.05(m,1H),0.48-0.41(m,1H) ), 0.39-0.28 (m, 2H), 0.13-0.07 (m, 1H).

Example 30

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Synthesis of (S)-5-cyclopropyl-5-(3-(6,7-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

The specific synthesis route is as follows:

Step A: Synthesis of (4,5-dichloro-1,2-phenylene)dimethanol

At zero degrees Celsius, to tetrahydrofuran (20.0 ml) containing 4,5-dichlorophthalic acid (2.0 g, 8.5 mmol), borane tetrahydrofuran solution (34.0 ml, 1.0 mole per liter), N ₂ Under protection, keep stirring at this temperature for 2 hours.

At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixture is extracted with ethyl acetate (50 ml×3 times), and the organic phases are combined. Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/1). 1.65 g of white solid (4,5-dichloro-1,2-phenylene)dimethanol was obtained (yield: 93.8%). LCMS: RT = 2.24 min.

Step B: Synthesis of 1,2-bis(bromomethyl)-4,5-dichlorobenzene

At zero degrees Celsius, to (4,5-dichloro-1,2-phenylene)dimethanol (1.65 g, 8.0 mmol) in tetrahydrofuran (40.0 ml) was added triphenylphosphine (6.29 g, 24.0 Millimoles), carbon tetrabromide (5.84 g, 17.6 mmol) was added under ice bath, and under N ₂ protection, the temperature was kept and stirred for 1 hour.

After the reaction is over, suction filtration, the filtrate is concentrated under reduced pressure, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=0/1). 2.18 g of colorless liquid 1,2-bis(bromomethyl)-4,5-dichlorobenzene was obtained (yield: 81.9%). LCMS: RT = 2.24 min.

Step C: Synthesis of 2,2'-(4,5-dichloro-1,2-phenylene) diacetonitrile

At zero degrees Celsius, to acetonitrile (25 ml) containing 1,2-bis(bromomethyl)-4,5-dichlorobenzene (2.18 g, 6.5 mmol), add trimethylsilyl cyanide (1.9 ml ) And a tetrahydrofuran solution of tetrabutylammonium fluoride (14.7 ml, 1.0 mole per liter), _{under the protection of N 2} , stirring at 82 degrees Celsius for 20 minutes.

After the reaction was over, it was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 1.1 g of dark green solid 2,2'-(4,5-dichloro-1,2-phenylene)diacetonitrile was obtained (yield: 75.2%). LCMS: RT=1.96 min, [MH] ^- =223.06.

Step D: Synthesis of 2,2'-(4,5-dichloro-1,2-phenylene) diacetic acid

At room temperature, 2,2'-(4,5-dichloro-1,2-phenylene) diacetonitrile (1.1 g, 4.89 mmol) was added to concentrated hydrochloric acid (20 ml), under N ₂ protection, 100 Reaction in degrees Celsius for 3 hours.

After the reaction was completed, cooled to room temperature, filtered with suction, the filter cake was washed with water, and dried under vacuum at 40 degrees Celsius to obtain 820.0 mg of white solid 2,2'-(4,5-dichloro-1,2-phenylene) diacetic acid Rate: 63.7%). LCMS: RT=1.76 min, [MH] ^- =261.98.

Step E: Synthesis of 2,2'-(4,5-dichloro-1,2-phenylene)bis(ethane-1-ol)

At zero degrees Celsius, to tetrahydrofuran (5.0 ml) containing 2,2'-(4,5-dichloro-1,2-phenylene)diacetic acid (820.0 mg, 3.1 mmol), add borane tetrahydrofuran dropwise The solution (7.6 ml, 1.0 mole per liter), _{under the protection of N 2} , was kept at this temperature and stirred for 1 hour.

At the end of the reaction, add water slowly to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixture is extracted with ethyl acetate (30 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (30 ml×2) Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. Obtained 700.0 mg of yellow solid 2,2'-(4,5-dichloro-1,2-phenylene)bis(ethane-1-ol) (yield: 96.1%). LCMS: RT=1.77 min.

Step F: Synthesis of 7,8-dichloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza

At zero degrees Celsius, it contains 2,2'-(4,5-dichloro-1,2-phenylene) bis(ethane-1-ol) (400.0 mg, 1.70 mmol), trifluoromethanesulfonamide ( 380.0 mg, 2.55 mmol), triphenylphosphine (890.8 mg, 3.40 mmol) in tetrahydrofuran (5 mL), add diethyl azodicarboxylate (535 μl) dropwise, under N ₂ protection, and stir at room temperature 2 hours.

(收率：65.1％)。LCMS:RT＝2.21min。 The reaction is over, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtained 385.0 yellow solid 7,8-dichloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 65.1%). LCMS: RT = 2.21 min.

Step G: Synthesis of 7,8-dichloro-2,3,4,5-tetrahydro-1H-benzo[d]aza

(385.0毫克，1.11毫摩尔)的甲苯(5毫升)中，缓慢滴加红铝的甲苯溶液(3.2毫升，3.5摩尔每升)，滴毕，N ₂保护下室温反应1小时。 At zero degrees Celsius, it contains 7,8-dichloro-3-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(385.0 mg, 1.11 mmol) of toluene (5 mL), slowly add a toluene solution of red aluminum (3.2 mL, 3.5 mol per liter) dropwise, after dripping, react at room temperature under _{N 2 protection for 1 hour.}

(收率：83.4％)。LCMS:RT＝1.57min,[M+H] ⁺＝216.11。 At the end of the reaction, slowly add water to the reaction solution at zero degrees Celsius until no bubbles are generated. The mixed solution is extracted with ethyl acetate (20 ml×3 times), and the organic phases are combined. The organic phase is first saturated with brine (20 ml×2). Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/5). Obtained 200.0 mg of white solid 7,8-dichloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(Yield: 83.4%). LCMS: RT=1.57 min, [M+H] ⁺ =216.11.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮 Step H: Synthesis of (S)-5-cyclopropyl-5-(3-(7,8-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

(200.0毫克，0.93毫摩尔)加入N,N-二甲基甲酰胺(4毫升)中，滴加N,N-二异丙基乙胺(459微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(195.2毫克，1.02毫摩尔)和1-羟基苯并三唑(18.8毫克，0.14毫摩尔)，N ₂保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (196.48 mg, 0.93 mmol) and 7,8-dichloro-2 ,3,4,5-Tetrahydro-1H-benzo[d]aza

(200.0 mg, 0.93 mmol) was added to N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (459 μl) was added dropwise, and then 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (195.2 mg, 1.02 mmol) and 1-hydroxybenzotriazole (18.8 mg, 0.14 mmol), reacted at room temperature under _{N 2 protection} overnight.

-3-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：72.1％)。LCMS:RT＝1.88min,[M+H] ⁺＝410.19。 ¹H NMR(400MHz,DMSO)δ10.62(s,1H),7.72(s,1H),7.48(s,1H),7.45(s,1H),3.57–3.51(m,4H),2.92–2.81(m,4H),2.49–2.37(m,1H),2.36–2.25(m,1H),1.95-1.90(m,2H),1.17–1.00(m,1H),0.48–0.40(m,1H),0.39–0.30(m,2H),0.11-0.08(m,1H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried over anhydrous sodium sulfate. Finally, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 275.0 mg of white solid (S)-5-cyclopropyl-5-(3-(7,8-dichloro-1,2,4,5-tetrahydro-3H-benzo[d]aza

-3-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 72.1%). LCMS: RT=1.88 min, [M+H] ⁺ =410.19. ¹ H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 7.72 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 3.57-3.51 (m, 4H), 2.92-2.81 (m,4H), 2.49–2.37(m,1H), 2.36–2.25(m,1H), 1.95-1.90(m,2H), 1.17–1.00(m,1H), 0.48–0.40(m,1H) ,0.39–0.30(m,2H),0.11-0.08(m,1H).

Example 31 Enzyme Level Experimental Test

31.1 Inhibitory activity of compounds on human ADAMTS5

(1) Main experimental materials

Enzyme: human ADAMTS5 (R&D systems, article number: 2198-AD);

Substrate: WAAG-3R (Anaspec, catalog number: 60431-1);

Detection buffer: 50mM Tris, 100mM NaCl, 5mM CaCl2, 0.05% Brij35, pH 7.5

Compound: The compound of the present invention and the compound of Example 255 in the prior art CN201580070274.0

(2) Experimental steps

The compound was dissolved in DMSO to prepare a 30 or 100 mM stock solution. Set up 8 concentration gradients during detection, first adjust the concentration of the stock solution to 3 or 3.33mM with DMSO to obtain the highest concentration, and use DMSO to dilute the highest concentration by 1/3 to obtain the remaining 7 concentrations. Then take 2μl from a series of DMSO dilutions and add 198μl buffer to obtain serial dilutions of the compound with the highest concentration of 30 or 33.3μM.

Add 5μl of human ADAMTS5 enzyme solution (30μg/ml) and 5μl of compound serial dilutions to a 384-well plate (CISBIO, catalog number: 6008280), and incubate at 37°C for 30min, then add 5μl of buffer diluted substrate ( 75μM) to initiate the reaction. At 37°C, use FLUOstar Omega (BMG LABTECH) to read the fluorescence for 30 min (excitation wavelength 355nm, emission wavelength 460nm).

(3) Data processing

Taking the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, the IC50 value was calculated using GraphPad 6 fitting.

Table 1 The efficacy of the compounds of the present invention on human ADAMTS5

Note: n represents the number of test repetitions.

31.2. Inhibitory activity of compounds on human ADAMTS4

(1) Main experimental materials

Enzyme: human ADAMTS4 (R&D systems, article number: 4307-AD);

Substrate: WAAG-3R (Anaspec, catalog number: 60431-1);

Detection buffer: 50mM HEPES, 50mM NaCl, 1mM CaCl2, 0.05% Brij-35, pH 7.5;

Compound: The compound of the present invention and the compound of Example 255 in the prior art CN201580070274.0.

(2) Experimental steps

The compound was dissolved in DMSO to prepare a 30 or 100 mM stock solution. Set up 8 concentration gradients during detection, first adjust the concentration of the stock solution to 3 or 3.33mM with DMSO to obtain the highest concentration, and use DMSO to dilute the highest concentration by 1/3 to obtain the remaining 7 concentrations. Then take 2μl from a series of DMSO dilutions and add 198μl buffer to obtain serial dilutions of the compound with the highest concentration of 30 or 33.3μM.

Add 5μl of human ADAMTS4 enzyme solution (30μg/ml) and 5μl of compound serial dilutions to a 384-well plate (CISBIO, catalog number: 6008280), and incubate at 37°C for 30min, then add 5μl of buffer diluted substrate ( 75μM) to initiate the reaction. At 37°C, use FLUOstar Omega (BMG LABTECH) to read the fluorescence for 30 minutes (excitation wavelength 355nm, emission wavelength 460nm).

(3) Data processing

Taking the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, the IC50 value was calculated using GraphPad 6 fitting.

Table 2 The efficacy of the compounds of the present invention on human ADAMTS4

31.3 Inhibitory activity of the compound against human MMP-2

(1) Experimental materials

Enzyme: human MMP-2 (R&D systems, product number: 902-MP);

Substrate: MCA-Lys-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH2 (R&D systems, item number: ES010);

Detection buffer: 50mM Tris, 10mM CaCl2, 150mM NaCl, 0.05% (w/v) Brij-35, pH 7.5 (TCNB).

Compound: The compound of the present invention and the compound of Example 255 in the prior art CN201580070274.0.

(2) Experimental steps

The compound is dissolved in DMSO to prepare a 30 or 100 mM stock solution, and 8 concentration gradients are set during detection. First, adjust the concentration of the stock solution to 30 or 33.3 mM with DMSO to obtain the highest concentration. Use DMSO to reduce the highest concentration to 1/3 The remaining 7 concentrations were obtained by gradient dilution. Then take 2μl from a series of DMSO dilutions and add 198μl buffer to obtain the working solution to obtain the compound serial dilution with the highest concentration of 300 or 333.3μM.

Add 5μl of human MMP-2 enzyme solution (0.3μg/ml, incubate with 1mM APMA in advance for 1h activation at 37°C) and 5μl of serial dilutions of the compound into a 384-well plate (CISBIO, catalog number: 6008280), and incubate at 37°C 20min, then add 5μl of buffer diluted substrate (30μM) to initiate the reaction. At 37℃, use FLUOstar Omega (BMG LABTECH) to read the fluorescence for 20min (excitation wavelength 340nm, emission wavelength 420nm).

(3) Data processing

Taking the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, the IC50 value was calculated using GraphPad 6 fitting.

Table 6 The efficacy of the compounds of the present invention on human MMP-2

Conclusion: It can be seen from the above test results that the compound of the present invention has better inhibitory activity on human ADAMTS4 and ADAMTS5, and the compound of the present invention has better selectivity for MMP2 compared with the compound of Example 255 in the prior art CN201580070274.0 .

Test Example 32: Investigation of rat pharmacokinetic characteristics of the compound of the present invention

32.1 Experimental materials

SD rats: male, 180-250g, purchased from Guangdong Medical Experimental Animal Center.

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

Instrument: Thermo Fisher LC-MS (U300UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

Compound: The compound of the present invention and the compound of Example 255 in the prior art CN201580070274.0

32.2. Experimental method

Weigh the compound and dissolve it in the DMSO-PEG-400-physiological saline (5:60:35, v/v/v) system. After intravenous or intragastric administration of the rat, at 5min, 15min, 30min, 1h, 2h, 200μL of venous blood was collected at 5h, 7h, and 24h in a heparinized EP tube, centrifuged at 12000rpm for 2min, and the plasma was frozen at -80°C for testing. Accurately weigh a certain amount of the test substance and dissolve it to 1 mg/mL in DMSO as a stock solution. Accurately draw an appropriate amount of compound stock solution and add acetonitrile to dilute to prepare a standard series solution. Accurately draw 20μL of each of the above-mentioned standard series solutions, add 180μL of blank plasma, vortex to mix, and prepare plasma samples equivalent to plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000 ng/mL. Perform two-sample analysis for one concentration and establish a standard curve. Take 20μL of plasma (5min, 15min, 30min, 1h plasma diluted 10 times for intravenous administration), add internal standard propranolol (5ng/mL) acetonitrile solution 200μL, vortex and mix well, centrifuge at 4000rpm for 5min, take the supernatant LC -MS analysis. The LC-MS detection conditions are as follows:

Chromatographic column: Thermo Fisher HYPERSIL GOLD C-18 UPLC column, 100*2.1mm, 1.9μm.

Mobile phase: water (0.1% formic acid)-acetonitrile for gradient elution as shown in the table below

Time (min) Water (containing 0.1% formic acid) Acetonitrile 0 90% 10% 0.6 90% 10% 1 10% 90% 2.6 10% 90% 2.61 90% 10% 4 90% 10%

32.3. Data Processing

After LC-MS detected the blood drug concentration, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The results are shown in Table 11. Table 11 Rat pharmacokinetic parameters (IV and PO administration) of the compounds of the present invention.

Table 11 Rat pharmacokinetic parameters of the compound of the present invention (IV and PO administration)

Conclusion: The compound of the present invention is well absorbed after oral administration in rats, and the oral bioavailability is good.

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, etc. made without departing from the spirit and principle of the present invention Simplified, all should be equivalent replacement methods, and they are all included in the protection scope of the present invention.

Claims (15)

The compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

in: R ₁ and R _{2 are} selected from: hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, or C _1-6 alkoxy; R ₁ and R ₂ may be connected to the same carbon atom or different carbon atoms; R _{3 is} selected from: -hydrogen, halogen, Cyano, C _1-6 alkyl group, Halogenated C _1-6 alkyl group, C _1-6 alkoxy group, Halogenated C _1-6 alkoxy group, Nitro, Amide group, Phenyl, Halogenated phenyl, A 5-10 membered monocyclic or fused bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a halogen optionally selected by one or more independently, C _1-6 alkyl, C _1-6 alkoxy substituted, or -NR _9g R _9h ; R _{4 is} selected from: -hydrogen, C _1-6 alkyl or it is optionally substituted with one or more independently selected R ₅ groups, C _3-7 monocyclic cycloalkyl or it is optionally substituted with one or more independently selected R ₅ groups, A 4-7 membered monocyclic heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S, or the monocyclic heterocycloalkyl is optionally selected by one or more independently selected C _{1 -6} alkyl, -C(=O)C _1-6 alkyl or -C(=O)OC _1-6 alkyl substituted, Phenyl or it is optionally substituted with one or more independently selected R ₆ groups, A phenyl group fused to a 5-6 membered monocyclic heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl group is optionally substituted by one or more A = O substitution, or A 5-6 membered monocyclic heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O and S, or the monocyclic heteroaryl group is optionally selected by one or more independently selected R ₆ groups replace; R _{5 is} selected from: halogen, Hydroxyl, Cyano, C _1-6 alkyl, C _1-6 alkoxy or it is optionally _{substituted by C 1-6} alkoxy or phenyl, C _1-6 thioalkoxy, A 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from N, S, and O, or the monocyclic heterocycloalkyl group is optionally substituted by one or more halogens or -C( =0)OC _1-6 alkyl substitution, Phenyl, -S(=O) ₂ C _1-6 alkyl, -C(=O)OR _7a , -C(=O)NR _7b R _7c , -NHC(=O)OR _7d , -NHC(=O)R _7e , or -NR _8a R _8b ; R _{6 is} selected from: halogen, Hydroxyl, Cyano, C _1-6 alkyl or it is optionally substituted with one or more independently selected halogen, -NR _9a R _9b or -C(=O)NR _9c R _9d , C _1-6 alkoxy or it is optionally _{substituted by -NR 9e} R _9f , or -S(=O) ₂ C _1-6 alkyl; R _7a , R _7b , R _7c , R _7d or R _{7e are} independently selected from: -Hydrogen, or -C _1-6 alkyl or optionally substituted by OH or C _1-6 alkoxy, R _8a or R _{8b are} independently selected from: -Hydrogen, or -C _1-6 alkyl or optionally substituted by OH, C _1-6 alkoxy or phenyl; R _9a , R _9b , R _9c , R _9d , R _9e , R _9f , R _9g or R _{9h are} independently selected from H or C _1-6 alkyl; n = a natural number from 0 to 4; A represents a 5-7 membered nitrogen heterocyclic ring. The compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound is selected from compounds of formula (Ia), (Ib), (Ic) ,

in: R ₁ , R ₂ , R _1a , R _1b , R _2a , and R _{2b are} independently selected from: hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or hydroxy substituted C _{1 -6} alkyl; R _{3 is} selected from: -hydrogen, halogen, Cyano, C _1-6 alkyl group, Halogenated C _1-6 alkyl group, C _1-6 alkoxy group, Halogenated C _1-6 alkoxy group, Nitro, Amide group, A 5-10 membered monocyclic or fused bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a halogen optionally selected by one or more independently, C _1-6 alkyl, C _1-6 alkoxy substituted, or -NR _9g R _9h ; R _{4 is} selected from: -hydrogen, -C _1-6 alkyl or it is optionally substituted with one or more independently selected R ₅ groups, -C _3-7 monocyclic cycloalkyl or it is optionally substituted with one or more independently selected R ₅ groups, A 4-7 membered monocyclic heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S, or the monocyclic heterocycloalkyl is optionally selected by one or more independently selected C _{1 -6} alkyl, -C(=O)C _1-6 alkyl or -C(=O)OC _1-6 alkyl substituted, Phenyl or it is optionally substituted with one or more independently selected R ₆ groups, A phenyl group fused to a 5-6 membered monocyclic heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl group is optionally substituted by one or more A = O substitution, or A 5-6 membered monocyclic heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O and S, or the monocyclic heteroaryl group is optionally selected by one or more independently selected R ₆ groups replace; R _{5 is} selected from: halogen, Hydroxyl, Cyano, C _1-6 alkyl, C _1-6 alkoxy or it is optionally _{substituted by C 1-6} alkoxy or phenyl, C _1-6 thioalkoxy, A 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from N, S, and O, or the monocyclic heterocycloalkyl group is optionally substituted by one or more halogens or -C( =0)OC _1-6 alkyl substitution, Phenyl, -S(=O) ₂ C _1-6 alkyl, -C(=O)OR _7a , -C(=O)NR _7b R _7c , -NHC(=O)OR _7d , -NHC(=O)R _7e , or -NR _8a R _8b ; R _{6 is} selected from: halogen, Hydroxyl, Cyano, C _1-6 alkyl or it is optionally substituted with one or more independently selected halogen, -NR _9a R _9b or -C(=O)NR _9c R _9d , C _1-6 alkoxy or it is optionally _{substituted by -NR 9e} R _9f , or -S(=O) ₂ C _1-6 alkyl; R _7a , R _7b , R _7c , R _7d or R _{7e are} independently selected from: -Hydrogen, or -C _1-6 alkyl or optionally substituted by OH or C _1-6 alkoxy, R _8a or R _{8b are} independently selected from: -Hydrogen, or -C _1-6 alkyl or optionally substituted by OH, C _1-6 alkoxy or phenyl; R _9a , R _9b , R _9c , R _9d , R _9e , R _9f , R _9g or R _{9h are} independently selected from H or C _1-6 alkyl; n = a natural number from 0 to 4; A represents a 5-7 membered nitrogen heterocyclic ring. The compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound is selected from compounds of formula (Iaa), (Ibb), (Icc) ,

in: R _1a , R _1b , R _2a , R _2b , R ₁ , and R _{2 are} independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or hydroxy substituted C _{1- 6} 's alkyl group; R _{3 is} selected from: -hydrogen, -halogen, -Cyano, -C _1-6 alkyl group, -Halogenated C _1-6 alkyl group, -C _1-6 alkoxy group, -Halogenated C _1-6 alkoxy group, -Nitro, -Amido group, -Phenyl, or -Halophenyl; n = a natural number from 0 to 4. The compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound is selected from compounds of formula (Iaaa),

in: R _{1a is} selected from hydrogen or C _1-6 alkyl; R _{1b is} selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, or hydroxy substituted C _1-6 alkyl; R _{3 is} selected from hydrogen, halogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, nitro Group, amido group, phenyl group, or halogenated phenyl group; n = a natural number from 0 to 2. The compound according to claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from a compound of formula (Iaaaa),

in: R _{1a is} selected from hydrogen or C1-6 alkyl; R _{1b is} selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, or hydroxy substituted C1-6 alkyl; R3 is selected from hydrogen, halogen, cyano, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, nitro, amido, Phenyl, or halophenyl; n = a natural number from 0 to 2. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the halogen is fluorine, chlorine, bromine, or iodine. The halogen is substituted by halogen; the C _1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl Base, cyclobutyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, cyclopentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, cyclohexyl; The C _1-6 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutyl Oxy, n-pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, tert-pentyloxy, cyclopentyloxy, n-hexyloxy, isohexyloxy, neohexyloxy, sec-hexyloxy , Tert-hexyloxy, cyclohexyloxy. The compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: R _{1 is} selected from hydrogen and methyl; R _{2 is} selected from hydrogen, methyl and ethyl; R _{3 is} selected from hydrogen, fluorine, chlorine, bromine, phenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl; n is selected from 0, 1, 2. The compound according to claim 4 or 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: R _{1a is} selected from hydrogen and methyl; R _{2b is} selected from hydrogen, methyl and ethyl; R _{3 is} selected from hydrogen, fluorine, chlorine, bromine, phenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl; n is selected from 0, 1, 2. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from inorganic acids or Organic acids form salts. The compound according to any one of claims 1-9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that it is selected from the following compounds:

A pharmaceutical composition, characterized by comprising the compound of any one of the preceding claims 1-10, or its stereoisomers, tautomers, pharmaceutically acceptable salts and more than one pharmaceutically acceptable compound. Accepted carrier. The compound according to any one of claims 1-10, or its stereoisomers, tautomers, or pharmaceutically acceptable salts are used for the treatment and/or prevention of proteoglycanase 2 inhibition related diseases Drug use. The use of the pharmaceutical composition according to claim 11 in the preparation of a medicament for the treatment and/or prevention of proteoglycanase 2 inhibiting related diseases. The use according to claim 11 or 12, wherein the disease involves inflammatory conditions and/or cartilage degradation and/or cartilage homeostasis destruction. The use according to claim 11 or 12, wherein the disease is osteoporosis, glucocorticoid-induced osteoporosis, Paget’s disease, abnormal increase in bone turnover, periodontal disease, tooth loss, fracture, class Rheumatoid arthritis, osteoarthritis, osteolysis around the prosthesis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia, or multiple myeloma.