Tricyclic derivatives, their preparation methods and their pharmaceutical applications

Abstract

A tricyclic fused derivative, a preparation method thereof and a medical application thereof, which relate to the technical field of chemical drugs. The tricyclic fused derivative is an inhibitor of aggrecanase-2 (ADAMTS-5). A pharmaceutical composition containing these compounds and the use of the compounds in the preparation of drugs for treating diseases such as osteoarthritis.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and relates to tricyclic derivatives, a preparation method thereof and pharmaceutical applications thereof. Specifically, the derivatives are inhibitors of aggrecanase-2 (ADAMTS-5, Aggrecanase-2). The present invention also relates to pharmaceutical compositions containing these compounds and uses of the compounds in medicaments for treating diseases such as osteoarthritis. Background Art

[0002] Osteoarthritis (OA), also known as degenerative arthritis, is a degenerative disease mainly characterized by joint pain caused by fibrosis, cracking, ulceration and loss of articular cartilage due to multiple factors. It can cause loss of motor ability and pain in patients, and the ultimate result often requires total joint replacement. It is the most common disease in the elderly and obese. At present, the pathogenesis of OA has not been clearly studied. Its main causes include age, obesity and joint injury. Under the action of these factors, the cell metabolism in joint tissues is disordered, cell signal transduction is dysregulated, and catabolic pathways are activated.

[0003] Articular cartilage is mainly composed of chondrocytes and cartilage matrix. Among them, chondrocytes in articular cartilage only account for a small part of the total volume of articular cartilage, and most of it is composed of extracellular matrix. The extracellular matrix consists of two macromolecular structures: collagen and proteoglycan. The main reason for the degradation of articular cartilage in osteoarticular diseases is the degradation of collagen and proteoglycan in the extracellular matrix of articular chondrocytes. When the degradation of the extracellular matrix and basement membrane components of articular chondrocytes by proteolytic enzymes is much greater than the synthesis, and the structure of cartilage tissue and subchondral bone changes, it will lead to abnormal joint function. Therefore, aggrecanase is a potential target for developing OA treatment drugs.

[0004] Aggrecanase is a member of the ADAMTS family. It is a disintegrin and metalloproteinase with thrombospondin (TS) motifs and consists of secreted zinc metalloproteinases. Aggrecanase is the main protease responsible for aggrecan cleavage in the early stage of cartilage remodeling. Matrix metalloproteinase (MMP) starts to participate in this process during disease development and continues the degradation of collagen. Therefore, aggrecanase activity is considered a marker of cartilage degradation during inflammatory joint diseases such as OA.

[0005] The ADAMTS family of secreted zinc metalloproteinases includes nineteen members known to bind to and degrade components of the extracellular cartilage matrix (ECM). Several members of the ADAMTS family have been found to cleave aggrecan, the major proteoglycan component of cartilage: 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 rather low, it is believed that ADAMTS-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) are the two major functional aggrecanases.

[0006] Cartilage aggrecanase 1 (ADAMTS-4) and cartilage aggrecanase 2 (ADAMTS-5) are two different cartilage aggrecanases isolated successively from cartilage. These two proteases specifically cleave the aggrecan Glu373-Ala374 bond in the IGD region of the aggrecan core protein. Therefore, these proteases have received the most attention in the pathology of arthritic joint diseases because they are the most effective aggrecanases in vitro. The activity of these aggrecanases is crucial for the metabolic balance between the synthesis and degradation of aggrecan. In normal human bodies, the control mechanism of aggrecan catabolism may be related to endogenous inhibitors such as tissue inhibitor of metalloproteinase-3 (TIM-3) of aggrecanase. However, the balance between TIMP-3 and ADAMTS-4 synthesis is disrupted in OA patients, and catabolism is greater than anabolism. Some studies believe that this may be due to de novo synthesis of ADAMTS-4 or post-translational activation of ADAMTS-4 and ADAMTS-5. By inhibiting ADAMTS-4 and ADAMTS-5, the degradation of proteoglycans in OA cartilage can be effectively prevented, and the degeneration of cartilage can be prevented.

[0007] Therefore, the present invention aims to discover new ADAMTS inhibitors, particularly new compounds that have inhibitory activity against ADAMTS-5 and ADAMTS-4 and have good biological properties and can be safely applied to the human body. The present invention also provides the necessary tools for preventing and / or treating diseases involving cartilage degeneration, particularly osteoarthritis and / or rheumatoid arthritis. Summary of the Invention

[0008] In view of the problems existing in the prior art, the present invention provides a series of benzotricyclic derivatives, their preparation methods, and their applications in medicine.

[0009] Specifically, the present invention provides a series of tricyclic fused derivatives selected from tricyclic fused derivatives of formula (I), (II), (III), (VI) or their stereoisomers, tautomers, pharmaceutically acceptable salts:

[0010]

[0011] Wherein:

[0012] X is selected from carbon, nitrogen;

[0013] Y is selected from carbon, nitrogen, oxygen;

[0014] Z is selected from carbon, nitrogen, oxygen;

[0015] T 1 、T 2 、T 3 、T 4 are each independently selected from carbon, nitrogen, sulfur;

[0016] represents a single bond or a double bond;

[0017] Wherein, there are no substituents on ring A and ring B, or one or more hydrogens on ring A and / or ring B are independently substituted by one or more halogens, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy;

[0018] Ring C is substituted by one or more R 1 , R 1 is selected from:

[0019] hydrogen,

[0020] halogen,

[0021] cyano,

[0022] C 1-6 alkyl,

[0023] halo-C 1-6 alkyl,

[0024] C 1-6 alkoxy,

[0025] halo-C 1-6 alkoxy,

[0026] nitro,

[0027] amide group,

[0028] phenyl,

[0029] halophenyl,

[0030] A 5- to 12-membered monocyclic or fused bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or optionally substituted with one or more independently selected halogens, C 1-6 alkyl, C 1-6 alkoxy, or

[0031] -NR 7g R 7h ;

[0032] R 2 is selected from:

[0033] - hydrogen,

[0034] C 1-6 alkyl or optionally substituted with one or more independently selected R 3 groups,

[0035] C 3-7 monocyclic cycloalkyl or optionally substituted with one or more independently selected R 3 groups,

[0036] A 4- to 7-membered monocyclic heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S, or the monocyclic heterocycloalkyl optionally substituted with one or more independently selected C 1-6 alkyl, -C(=O)C 1-6 alkyl or -C(=O)OC 1-6 alkyl,

[0037] phenyl or optionally substituted with one or more independently selected R 4 groups,

[0038] phenyl fused to a 5- to 6-membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl optionally substituted with one or more =O, or

[0039] A 5- to 6-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, or the monocyclic heteroaryl optionally substituted with one or more independently selected R 4 groups;

[0040] R 3 is selected from:

[0041] halogen,

[0042] hydroxyl,

[0043] cyano,

[0044] C 1-6 alkyl,

[0045] C1-6 an alkoxy group or an optionally C 1-6 substituted alkoxy group or phenyl group,

[0046] C 1-6 thioalkoxy group,

[0047] a 4- to 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 with one or more halogens or -C(=O)OC 1-6 alkyl group,

[0048] phenyl group,

[0049] -S(=O) 2 C 1-6 alkyl group,

[0050] -C(=O)OR 5a ,

[0051] -C(=O)NR 5b R 5c ,

[0052] -NHC(=O)OR 5d ,

[0053] -NHC(=O)R 5e , or

[0054] -NR 6a R 6b ;

[0055] R 4 is selected from:

[0056] halogen,

[0057] hydroxyl group,

[0058] cyano group,

[0059] C 1-6 alkyl group or an optionally substituted alkyl group with one or more independently selected halogens, -NR 7a R 7b or -C(=O)NR 7c R 7d substituted,

[0060] C 1-6 alkoxy group or an optionally substituted alkoxy group with -NR 7e R 7f substituted, or

[0061] -S(=O) 2 C 1-6 alkyl group;

[0062] R 5a , R5b , R 5c , R 5d or R 5e are independently selected from:

[0063] - hydrogen, or

[0064] - C 1-6 alkyl or optionally substituted by OH or C 1-6 alkoxy;

[0065] R 6a or R 6b are independently selected from:

[0066] - hydrogen, or

[0067] - C 1-6 alkyl or optionally substituted by OH, C 1-6 alkoxy or phenyl;

[0068] R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g or R 7h are independently selected from H or C 1-6 alkyl;

[0069] n = 0 - 2 natural numbers;

[0070] m = 0 - 4 natural numbers.

[0071] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives of formula (Ia), (IIa), (IIIa), (VIa) or their stereoisomers, tautomers, pharmaceutically acceptable salts,

[0072]

[0073] wherein, Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, n are as defined above.

[0074] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives of formula (Ib), (IIb), (IIIb), (VIb) or their stereoisomers, tautomers, pharmaceutically acceptable salts,

[0075]

[0076] Among them, Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, n are defined as above.

[0077] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (IIc), (IId), (IIIc) or their stereoisomers, tautomers, pharmaceutically acceptable salts,

[0078]

[0079] Among them, R 1 , m are defined as above, and R 8 is independently selected from H or C 1-6 alkyl.

[0080] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives of formula (Ij), (Ik) or their stereoisomers, tautomers, pharmaceutically acceptable salts,

[0081]

[0082] R 1 , m are defined as above.

[0083] As a preferred technical solution of the present invention, the halogen is fluorine, chlorine, bromine, iodine;

[0084] The C 1-6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl;

[0085] The C 1-6 alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, neohexyloxy, sec-hexyloxy, tert-hexyloxy;

[0086] The C 3-7 monocyclic cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;

[0087] The 5- to 12-membered monocyclic or fused bicyclic heteroaryl group is selected from pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl; pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl; imidazothiazolyl, imidazoimidazolyl; benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuryl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl and pyrazolopyridyl; quinolinyl, isoquinolinyl, pyridinopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl; and groups, pyrrolyl, benzothienyl, benzofuryl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0088] As a preferred technical solution of the present invention, R 1 is selected from fluorine, chlorine, bromine, methoxy trifluoromethyl, cyano; R 2 is selected from cyclopropyl, n is a natural number from 0 to 2; m is a natural number from 0 to 4. Among them, represents the connection site.

[0089] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives of formula (Ia), (IIa), (IIIa), (VIa), (Ib), (IIb), (IIIb), (VIb) or their stereoisomers, tautomers, pharmaceutically acceptable salts, wherein Y is selected from carbon; Z is selected from carbon, nitrogen, oxygen; T 1 , T 2 , T 3 , T 4 are each independently selected from carbon, sulfur; represents a single bond or a double bond; R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy trifluoromethyl, cyano; n is a natural number from 0 to 2; m is a natural number from 0 to 4

[0090] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (IIc), (IId), (IIIc) or their stereoisomers, tautomers, pharmaceutically acceptable salts, wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy trifluoromethyl, cyano; m is a natural number from 0 to 4; R8 is selected from H, methyl.

[0091] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives of formula (Ij) or (Ik), or their stereoisomers, tautomers, pharmaceutically acceptable salts, wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy trifluoromethyl, cyano; m = 0 to 4 natural numbers.

[0092] As a preferred technical solution of the present invention, the derivative is selected from the tricyclic derivatives shown in the following table, or their stereoisomers, tautomers, pharmaceutically acceptable salts,

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] As a preferred technical solution of the present invention, the pharmaceutically acceptable salts are selected from salts formed with inorganic acids or organic acids.

[0099] The present invention further provides a pharmaceutical composition, characterized in that it comprises the aforementioned tricyclic derivative and one or more pharmaceutically acceptable carriers.

[0100] On the one hand, the present invention provides a pharmaceutical composition comprising the tricyclic derivative of the present invention, and the pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

[0101] 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 drug, wherein the drug is used for the preparation of a drug for treating and / or preventing diseases related to protein glycanase 2 inhibition.

[0102] Furthermore, the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a drug, wherein the drug is for preventing and / or treating inflammatory conditions and / or cartilage degeneration and / or disruption of cartilage homeostasis.

[0103] Further, the use of the compound or the pharmaceutical composition of the present invention in the preparation of a drug, wherein the drug refers to a drug for preventing and / or treating osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete bone formation, metastatic bone disease, malignant hypercalcemia or multiple myeloma and other diseases.

[0104] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals, without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0105] The "pharmaceutically acceptable salts" used herein are derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a base.

[0106] The prodrugs of the compounds described herein are readily chemically transformed under physiological conditions to convert into the compounds of the present invention. In addition, the prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0107] Certain compounds of the present invention may exist in non-solvated form or solvated form, including hydrate form. Generally, the solvated form is equivalent to the non-solvated form and is included within the scope of the present invention.

[0108] The atoms of the compound molecules of the present invention are isotopes. By isotope derivatization, effects such as usually prolonging the half-life, reducing the clearance rate, metabolic stability and enhancing the in vivo activity can be achieved. And, there is included an embodiment in which at least one atom is replaced by an atom having the same number of atoms (proton number) and a different mass number (sum of protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P,35 S, 18 F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for pharmaceutical preparations or local anatomical examinations of in vivo compounds. Stable isotopes neither decay or change in quantity nor are radioactive, and thus can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be transformed according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0109] For example, the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compounds can be labeled with radioactive isotopes such as deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0110] Furthermore, one or more hydrogen atoms of the compounds of the present invention are replaced by the isotope deuterium ( 2 H). After the compounds of the present invention are deuterated, they have effects such as extended half-life, reduced clearance rate, metabolic stability and enhanced in vivo activity.

[0111] The preparation methods of the isotopic derivatives generally include: phase transfer catalysis methods. For example, the preferred deuteration method uses a phase transfer catalyst (e.g., tetraalkylammonium salts, NBu 4 HSO 4 ). Using a phase transfer catalyst to exchange the methylene protons of a diphenylmethane compound results in a higher level of deuterium introduced than by reduction with deuterosilane (e.g., triethyl deuterosilane) in the presence of an acid (e.g., methanesulfonic acid) or with sodium borohydride in the presence of a Lewis acid such as aluminum trichloride.

[0112] 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 is non-toxic and side-effect-free to the host or patient. Representative carriers include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, transdermal promoters, etc. Their preparations are well known to those skilled in the fields of cosmetics or topical pharmaceuticals.

[0113] The term "excipient" generally refers to the carriers, diluents and / or media required for formulating an effective pharmaceutical composition.

[0114] For a drug or a pharmacological active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art according to conventional tests.

[0115] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or condition.

[0116] The terms "tautomer" or "tautomeric form" refer to structural isomers that have different energies and can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion between pyridin-4-ol and pyridin-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.

[0117] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0118] The optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography with a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of a carbamate from an amine).

[0119] "Optional" or "optionally" means that the subsequent described event or condition may but does not necessarily occur, and this description includes both the case where the event or condition occurs and the case where the event or condition does not occur.

[0120] The term "C 1-6 alkyl" means an alkane composed of 1 to 6 carbons. Such examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, cyclopentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, cyclohexyl;

[0121] The term "halo C 1-6 alkyl" means the case where the hydrogen on the alkyl can be replaced by one or more identical or different halogen atoms. Wherein 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-difluoroethyl, 3,3,3-trifluoropropyl, 2-fluoro-2-methylpropyl, etc.

[0122] The term "C 1-6 alkoxy" means the case where the hydrogen on the alkyl can be replaced by one or more oxygen atoms. Wherein the alkyl group has the meaning as described in the present invention. Such examples include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.;

[0123] The term "halo C 1-6 alkoxy" means the case where the hydrogen on the alkoxy can be replaced by one or more identical or different halogen atoms. Wherein 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.;

[0124] The term "nitro" means -NO 2 ;

[0125] The term "amido" means -CO-NH-;

[0126] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0127] The term "halogenated phenyl" means a situation where the hydrogen on the phenyl can be substituted by one or more identical or different halogen atoms. Such examples include, but are not limited to, dichlorophenyl, 3,4-dichlorophenyl.

[0128] "Cycloalkyl" means a monocyclic or polycyclic non-aromatic hydrocarbon ring structure having a specified number of ring atoms. The cycloalkyl may have 3 to 10 carbon atoms, particularly 3 to 7 carbon atoms. The cycloalkyl includes, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0129] "Heteroaryl" means a monocyclic or fused polycyclic aromatic ring structure containing one or more (preferably 1, 2, or 3) 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 a 5- or 6-membered monocyclic heteroaryl. The heteroaryl may be, for example, a five- or six-membered monocyclic ring or a fused bicyclic structure formed by fused five- and six-membered rings or two fused six-membered rings or, as another example, two fused five-membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur, and oxygen. The heteroaryl ring generally contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2 heteroatoms, 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. Generally, the number of basic nitrogen atoms present in the heteroaryl (including any amino substituents on the ring) will be less than five.

[0130] Examples of five-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl. Examples of six-membered monocyclic heteroaryls include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. Specific examples of bicyclic heteroaryls having a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazimidazolyl. Specific examples of bicyclic heteroaryls having a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g., adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridyl. Specific examples of bicyclic heteroaryls having two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridinopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl. Specific heteroaryls are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl, and pyrazinyl.

[0131] Examples of representative heteroaryls include the following:

[0132]

[0133] where each W is independently selected from NH, O, >C(=O), >SO 2 and S.

[0134] Phenyl fused to a 5-6 membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S means that two adjacent carbon atoms of the heterocycle are fused to two adjacent carbon atoms of the benzene ring.

[0135] 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, particularly 4 to 7 ring members. A fused heterocyclic system may include a carbocyclic ring and only needs to include one heterocyclic ring. Examples of heterocycles include (but are not limited to) morpholine, piperidine (e.g., 1-piperidyl, 2-piperidyl, 3-piperidyl, and 4-piperidyl), pyrrolidine (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), pyrrolidone, pyran, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Other examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Other examples include azetidine, piperidone, piperazinone, and N-alkylpiperidines such as N-methylpiperidine. Specific examples of heterocycloalkyl and heterocycloalkyl-fused phenyl are shown in the following illustrative examples:

[0136]

[0137] where each U is independently selected from CH 2 、NH, O, and S; and each W is independently selected from NH, O, >C(=O), >SO 2 and S.

[0138] As used herein, the term "azaheterocycle" means that more than one carbon atom in a cycloalkyl is replaced by a nitrogen atom.

[0139] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0140] Figure 1 , schematic diagram of the single crystal structure of tert-butyl (S)-2-amino-3-(2-bromo-4,5-difluorophenyl)propionate tartrate. DETAILED DESCRIPTION OF THE INVENTION

[0141] The present invention will be further described in detail below in conjunction with examples, but the embodiments of the invention are not limited thereto.

[0142] The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is in 10 -6Given in units of (ppm). The NMR measurement was performed using a Bruker AVANCE-III nuclear magnetic resonance spectrometer, and the solvent for the measurement was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

[0143] The MS measurement was performed using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).

[0144] High performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD high performance liquid chromatograph and an Agilent 1260 high performance liquid chromatograph.

[0145] The CombiFlash rapid preparator used CombiFlash Rf+LUMEN (TELEDYNE ISCO).

[0146] The thin layer chromatography silica gel plate used Yantai Yinlong HSGF 254 or GF 254 silica gel plate. The specifications of the silica gel plate used for thin layer chromatography (TLC) were 0.17 mm - 0.23 mm, and the specifications of the silica gel plate used for thin layer chromatography separation and purification of products were 0.4 mm - 0.5 mm.

[0147] Silica gel column chromatography generally used Rushan Shangbang silica gel with 100 - 200 mesh as the carrier.

[0148] Reagents: LDA - lithium diisopropylamide, THF - tetrahydrofuran, TEA - triethylamine, Dioxane - 1,4 - dioxane, BH 3 - borane, EDCl - 1 - ethyl - (3 - dimethylaminopropyl) carbodiimide hydrochloride, HOBT - 1 - hydroxybenzotriazole, DIPEA - N,N - diisopropylethylamine, DMF - N,N - dimethylformamide, K 2 CO 3 - potassium carbonate, DMSO - dimethyl sulfoxide, EtOH - ethanol, NaH - sodium hydride, toluene - toluene, r.t. - room temperature, PdCl 2 (dppf) - [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, Pd(OAc)2 - palladium acetate, PhMe - toluene, HCl - dioxane - hydrochloric acid in dioxane, NaCO 3- Sodium carbonate, MeOH - Methanol, DCE - Dichloroethane, NCS - N - Chlorosuccinimide, TfOH - Trifluoromethanesulfonic acid, TFA - Trifluoroacetic acid, AcOH - Acetic acid, (CH2O)n - Paraformaldehyde, CDI - N,N'-Carbonyldiimidazole, LAH - Lithium aluminum hydride, PPA - Polyphosphoric acid, TsOH - p - Toluenesulfonic acid, NBS - N - Bromosuccinimide, BPO - Benzoyl peroxide.

[0149] Example 1

[0150] Synthesis of (5S)-5 - Cyclopropyl - 5-(3-(2,3,5,5a,6,7 - hexahydro - [1,4]diazaindolo[1,2 - a]quinolin - 4(1H)-yl)-3 - oxopropyl)imidazolidine - 2,4 - dione

[0151]

[0152] The specific synthesis route is as follows:

[0153] Step A: Synthesis of ethyl 4-(2 - fluorophenyl)-4 - hydroxybut - 2 - ynoate

[0154]

[0155] At - 78 °C, dropwise add lithium diisopropylamide (2.7 mL) to tetrahydrofuran (12.0 mL) containing 2 - fluorobenzaldehyde (500.0 mg, 5.1 mmol), continue the reaction at this temperature for 0.5 h, then add ethyl propiolate (664.0 mg, 5.4 mmol), and slowly warm up to 0 °C.

[0156] After the reaction is completed, quench with saturated ammonium chloride solution, extract with ethyl acetate (30 mL × 3 times), combine the organic phases, wash with saturated brine (2 mL × 3 times), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: ethyl acetate / n - hexane = 1 / 8). 510.0 mg of pale yellow solid ethyl 4-(2 - fluorophenyl)-4 - hydroxybut - 2 - ynoate is obtained (yield: 45.0%). LCMS: RT = 1.65 min, [M + H] + = 223.14.

[0157] Step B: Synthesis of ethyl (E)-4-(2 - fluorophenyl)-4 - oxobut - 2 - enoate

[0158]

[0159] At room temperature, triethylamine (464.6 mg, 4.6 mmol) was added to 1,4-dioxane (15.0 mL) containing ethyl 4-(2-fluorophenyl)-4-hydroxybut-2-ynoate (510.0 mg, 2.3 mmol), and N 2 Under protection, the reaction was carried out at 60 °C for 12 hours.

[0160] After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 20). 362.0 mg of pale yellow solid ethyl (E)-4-(2-fluorophenyl)-4-oxobut-2-enoate was obtained (yield: 71.0%). LCMS: RT = 2.23 min.

[0161] Step C: Synthesis of 1,2,3,4,5a,6-hexahydro-[1,4]diazaindeno[[1,2-a]quinoline-5,7-dione

[0162]

[0163] At room temperature, propylenediamine (85.4 mg, 1.2 mmol) and triethylamine (85.4 mg, 1.2 mmol) were added to N,N-dimethylformamide (5.0 mL) containing ethyl (E)-4-(2-fluorophenyl)-4-oxobut-2-enoate (244.0 mg, 1.1 mmol), and N 2 Under protection, the reaction was carried out at 60 °C overnight.

[0164] After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 100.0 mg of white solid 1,2,3,4,5a,6-hexahydro-[1,4]diazaindeno[[1,2-a]quinoline-5,7-dione was obtained (yield: 40.0%). LCMS: RT = 1.77 min, [M+H] + = 231.42.

[0165] Step D: Synthesis of 1,2,3,4,5,5a,6,7-octahydro-[1,4]diazaindeno[1,2-a]quinoline

[0166]

[0167] At 0 °C, borane tetrahydrofuran solution (1.0 mL, 1.0 mol / L) was added dropwise to tetrahydrofuran (2.5 mL) containing 1,2,3,4,5a,6-hexahydro-[1,4]diazaindeno[[1,2-a]quinoline-5,7-dione (100.0 mg, 0.5 mmol), and N 2 Under protection, the temperature was raised to 60 °C and stirred for 3 hours.

[0168] After the reaction was completed, water was slowly added dropwise to the reaction solution at 0 °C until no bubbles were generated. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was first 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: methanol / dichloromethane = 1 / 20). 48.5 mg of white solid 1,2,3,4,5,5a,6,7-octahydro-[1,4]diazaindeno[1,2-a]quinoline was obtained (yield: 48.0%). LCMS: RT = 1.45 min, [M+H] + = 203.22.

[0169] Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-(2,3,5,5a,6,7-hexahydro-[1,4]diazaindeno[1,2-a]quinolin-4(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0170]

[0171] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 1,2,3,4,5,5a,6,7-octahydro-[1,4]diazaindeno[1,2-a]quinoline (48.5 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0172] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first 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). 35.5 mg of white solid (5S)-5-cyclopropyl-5-(3-(2,3,5,5a,6,7-hexahydro-[1,4]diazaindeno[1,2-a]quinolin-4(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione was obtained (yield: 37.4%). LCMS: RT = 1.82 min, [M+H] + = 397.15.

[0173] Example 2

[0174] Synthesis of (5S)-5-cyclopropyl-5-(3-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinolin-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0175]

[0176] The specific synthesis route is as follows:

[0177] Step A: Synthesis of 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione

[0178]

[0179] At room temperature, ethyl (E)-4-(2-fluorophenyl)-4-oxobut-2-enoate (222.0 mg, 1.0 mmol) was added to N,N-dimethylformamide (10.0 mL), and ethylenediamine (146.0 mg, 1.1 mmol) and triethylamine (22.0 mg, 2.2 mmol) were added. Under N 2 protection, the reaction was carried out at 60 °C overnight.

[0180] After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 89.0 mg of white solid 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione was obtained (yield: 41.0%). LCMS: RT = 1.80 min, [M+H] + = 217.11.

[0181] Step B: Synthesis of 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline

[0182]

[0183] At 0 °C, borane tetrahydrofuran solution (0.8 mL, 1.0 mol / L) was added dropwise to tetrahydrofuran (2.5 mL) containing 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione (89.0 mg, 0.41 mmol). Under N 2 protection, the temperature was raised to 60 °C and stirred for 3 hours.

[0184] The reaction was completed. At 0 °C, water was slowly added dropwise to the reaction solution until no bubbles were generated. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 2 times), 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). 45.4 mg of white solid 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline was obtained (yield: 58.5%). LCMS: RT = 1.46 min, [M+H] + = 189.21.

[0185] Step C: Synthesis of (5S)-5-cyclopropyl-5-(3-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinolin-3-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0186]

[0187] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline (45.4 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 mL). N,N-Diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0188] The reaction was completed, quenched with water, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 25.1 mg of white solid (5S)-5-cyclopropyl-5-(3-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinolin-3-yl)-3-oxopropyl)imidazolidine-2,4-dione was obtained (yield: 27.3%). LCMS: RT = 1.84 min, [M+H] + = 383.15.

[0189] Example 3

[0190] Synthesis of (5S)-5-(3-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0191]

[0192] The specific synthesis route is as follows:

[0193] Step A: Synthesis of tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate

[0194]

[0195] At room temperature, N-tert-butoxycarbonylpiperazine (2.53 g, 13.60 mmol) and potassium carbonate (2.03 g, 14.73 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2-fluorobenzaldehyde (1.40 g, 11.33 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0196] After the reaction was completed, the reaction 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 first washed with saturated brine (50 mL × 2 times), then dried over 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 / 30). 1.66 g of pale yellow solid tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 50.5%). LCMS: RT = 2.16 min, [M+H] + = 291.42.

[0197] Step B: Synthesis of (E)-tert-butyl 4-(2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0198]

[0199] At room temperature, tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate (1.66 g, 5.70 mmol) and 4-methylbenzenesulfonylhydrazide (1.11 g, 5.99 mmol) were added to anhydrous ethanol (20.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0200] After the reaction was completed, the solvent was evaporated to obtain 2.62 g of off-white solid (E)-tert-butyl 4-(2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was directly used in the next step without purification. LCMS: RT = 2.20 min, [M+H] + = 459.12.

[0201] Step C: Synthesis of tert-butyl 3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0202]

[0203] At room temperature, sodium hydride (273.6 mg, 6.84 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (30.0 mL) containing (E)-tert-butyl 4-(2-(((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate (2.62 g, 5.70 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0204] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed successively with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.10 g of pale yellow solid tert-butyl 3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 70.2%). LCMS: RT = 2.27 min, [M+H] + = 275.21.

[0205] Step D: Synthesis of 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0206]

[0207] At room temperature, tert-butyl 3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.10 g, 4.0 mmol) was added to methanol (10.0 mL), and a dioxane solution of hydrochloric acid (5.0 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0208] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.20 g of off-white solid 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.59 min, [M+H] + = 175.18.

[0209] Step E: Synthesis of (5S)-5-(3-(3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0210]

[0211] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (45.6 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL). N,N-Diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out overnight at room temperature.

[0212] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 35.0 mg of white solid (5S)-5-(3-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 39.5%). LCMS: RT = 1.90 min, [M+H] + = 369.23.

[0213] Example 4

[0214] Synthesis of (5S)-5-(3-(7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0215]

[0216] The specific synthesis route is as follows:

[0217] Step A: Synthesis of tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate

[0218]

[0219] At room temperature, N-tert-butoxycarbonylpiperazine (2.82 g, 15.13 mmol) and potassium carbonate (2.26 g, 16.39 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2-fluoro-4-chlorobenzaldehyde (2.00 g, 12.61 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0220] The reaction was completed, quenched with water, and the mixture was extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 1.87 g of pale yellow solid tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 45.7%). LCMS: RT = 2.16 min, [M+H] + = 325.20.

[0221] Step B: Synthesis of (E)-tert-butyl 4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0222]

[0223] At room temperature, tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate (1.87 g, 5.76 mmol) and 4-methylbenzenesulfonylhydrazide (1.13 g, 6.05 mmol) were added to anhydrous ethanol (20.0 mL), and the reaction was carried out at room temperature for 1 hour under N 2 protection.

[0224] After the reaction was completed, the solvent was evaporated to dryness to obtain 3.10 g of off-white solid (E)-tert-butyl 4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.21 min, [M+H] + = 493.22.

[0225] Step C: Synthesis of tert-butyl 7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0226]

[0227] At room temperature, sodium hydride (138.2 mg, 3.45 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (20.0 mL) containing (E)-tert-butyl 4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (1.55 g, 3.14 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0228] The reaction was completed, and the reaction mixture was cooled to room temperature. It was dissolved in ethyl acetate (50 mL), washed successively with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 500.00 mg of pale yellow solid tert-butyl 7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 51.6%). LCMS: RT = 2.23 min, [M+H] + = 309.21.

[0229] Step D: Synthesis of 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0230]

[0231] At room temperature, tert-butyl 7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (500.0 mg, 1.62 mmol) was added to methanol (8.0 mL), and a dioxane solution of hydrochloric acid (2.02 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0232] After the reaction was completed, the solvent was evaporated to dryness to obtain 400.00 mg of off-white solid 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.57 min, [M+H] + = 209.15.

[0233] Step E: Synthesis of (5S)-5-(3-(7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0234]

[0235] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (63.5 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. N2 Under protection, the reaction was carried out at room temperature overnight.

[0236] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 30.0 mg of white solid (5S)-5-(3-(7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 31.0%). LCMS: RT = 1.86 min, [M+H] + = 403.22. 1 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.70 (s, 0.5H), 7.69 (s, 0.5H), 7.04 (d, J = 7.7 Hz, 1H), 6.67–6.54 (m, 2H), 4.41 (dd, J = 36.0, 11.7 Hz, 1H), 3.87–3.64 (m, 2H), 3.57–3.34 (m, 1H), 3.18–3.07 (m, 1H), 3.07–2.91 (m, 1H), 2.88–2.70 (m, 1H), 2.69–2.56 (m, 2H), 2.46–2.35 (m, 1H), 2.35–2.20 (m, 1H), 2.03–1.89 (m, 2H), 1.18–0.99 (m, 1H), 0.54–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.17–0.05 (m, 1H).

[0237] Example 5

[0238] Synthesis of (5S)-5-(3-(9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0239]

[0240] The specific synthetic route is as follows:

[0241] Step A: Synthesis of tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate

[0242]

[0243] At room temperature, N-tert-butoxycarbonylpiperazine (2.24 g, 12.0 mmol) and potassium carbonate (1.79 g, 13.0 mmol) were added to dimethyl sulfoxide (10.0 mL) containing 2-chloro-6-fluorobenzaldehyde (1.59 g, 10.0 mmol), and the reaction was carried out at 95 °C for 12 hours under N 2 protection.

[0244] After the reaction was completed, the reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate (50 mL × 3 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 2.0 g of pale yellow solid tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 61.7%). LCMS: RT = 2.13 min, [M+H] + = 325.19.

[0245] Step B: Synthesis of (E)-tert-butyl 4-(3-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0246]

[0247] At room temperature, tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate (2.00 g, 6.16 mmol) and 4-methylbenzenesulfonylhydrazide (1.13 g, 6.47 mmol) were added to anhydrous ethanol (30.8 mL), and the reaction was carried out at room temperature for 1 hour under N 2 protection.

[0248] After the reaction was completed, the solvent was evaporated to obtain 3.04 g of white solid (E)-tert-butyl 4-(3-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.14 min, [M+H] + = 493.25.

[0249] Step C: Synthesis of tert-butyl 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0250]

[0251] At room temperature, sodium hydride (246 mg, 6.16 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (25.0 mL) containing tert-butyl (E)-4-(3-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (3.04 g, 6.16 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0252] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (80 mL), washed successively with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 924 mg of tert-butyl 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate as a white solid was obtained (yield: 48.7%). LCMS: RT = 2.25 min, [M+H] + = 309.23.

[0253] Step D: Synthesis of 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0254]

[0255] At room temperature, tert-butyl 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (924 mg, 3.00 mmol) was added to methanol (15.0 mL), and a dioxane solution of hydrochloric acid (3.75 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0256] After the reaction was completed, the solvent was evaporated to dryness to obtain 740 mg of 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride as a white solid. It was used directly in the next step without purification. LCMS: RT = 1.61 min, [M+H] + = 209.14. 1 HNMR (500 MHz, DMSO-d6) δ 9.46 (s, 2H), 7.08 (t, J = 7.9 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 7.8 Hz, 1H), 3.92–3.84 (m, 1H), 3.84–3.77 (m, 1H), 3.32–3.29 (m, 1H), 3.29–3.18 (m, 2H), 3.08 (dd, J = 15.9, 8.3 Hz, 1H), 2.95–2.81 (m, 2H), 2.67 (dd, J = 15.9, 7.2 Hz, 1H).

[0257] Step E: Synthesis of (5S)-5-(3-(9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0258]

[0259] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (99 mg, 0.40 mmol) were added to anhydrous dichloromethane (7.0 mL). N,N-Diisopropylethylamine (233 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (102 mg, 0.53 mmol) and 1-hydroxybenzotriazole (7.0 mg, 0.053 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0260] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 25 mg of white solid (5S)-5-(3-(9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 26.4%). LCMS: RT = 1.87 min, [M-H] - = 401.19. 11H NMR (400 MHz, DMSO-d6) δ 10.66–10.54 (m, 1H), 7.69 (s, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 4.42 (dd, J = 46.5, 11.9 Hz, 1H), 3.80 (dd, J = 32.7, 12.2 Hz, 1H), 3.72–3.49 (m, 2H), 3.19–2.98 (m, 2H), 2.93–2.74 (m, 1H), 2.69–2.52 (m, 2H), 2.45–2.17 (m, 2H), 2.04–1.83 (m, 2H), 1.15–0.98 (m, 1H), 0.44 (dd, J = 8.4, 4.8 Hz, 1H), 0.40–0.25 (m, 2H), 0.19–0.03 (m, 1H).

[0261] Example 6

[0262] Synthesis of (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0263]

[0264] The specific synthesis route is as follows:

[0265] Step A: Synthesis of tert-butyl 4-(4-chloro-2-formylphenyl)piperazine-1-carboxylate

[0266]

[0267] At room temperature, N-tert-butoxycarbonylpiperazine (2.82 g, 15.13 mmol) and potassium carbonate (2.26 g, 16.39 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2-fluoro-5-chlorobenzaldehyde (2.00 g, 12.61 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0268] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 2 times), then dried over 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 / 30). 1.26 g of pale yellow solid tert-butyl 4-(4-chloro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 30.8%). LCMS: RT = 2.16 min, [M+H] += 325.23.

[0269] Step B: Synthesis of tert-butyl (E)-4-(4-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0270]

[0271] At room temperature, tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate (1.26 g, 3.88 mmol) and 4-methylbenzenesulfonylhydrazide (758.0 mg, 4.07 mmol) were added to anhydrous ethanol (15.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0272] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.90 g of a white solid, tert-butyl (E)-4-(4-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was directly used in the next step without purification. LCMS: RT = 2.21 min, [M+H] + = 493.23.

[0273] Step C: Synthesis of tert-butyl 8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0274]

[0275] At room temperature, sodium hydride (185.0 mg, 4.62 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (20.0 mL) containing tert-butyl (E)-4-(4-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (1.90 g, 3.85 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0276] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed successively with saturated brine (50 mL × 2 times), dried over 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 / 10). 600.0 mg of a pale yellow solid, tert-butyl 8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (yield: 51.6%) was obtained. LCMS: RT = 2.21 min, [M+H] + = 309.22.

[0277] Step D: Synthesis of 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0278]

[0279] At room temperature, tert-butyl 8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (600.0 mg, 1.94 mmol) was added to methanol (8.0 mL), and a dioxane solution of hydrochloric acid (2.40 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0280] After the reaction was completed, the solvent was evaporated to dryness to obtain 500.0 mg of off-white solid 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. Without purification, it was directly used for the next reaction. LCMS: RT = 1.58 min, [M+H] + = 209.17.

[0281] Step E: Synthesis of (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0282]

[0283] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (63.5 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0284] After the reaction was completed, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, the organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 27.5 mg of white solid (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 28.4%). LCMS: RT = 1.86 min, [M+H] + = 403.25.1 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.70 (s, 0.5H), 7.69 (s, 0.5H), 7.10 (s, 1H), 7.04 (dd, J = 8.3, 1.5 Hz, 1H), 6.55 (dd, J = 8.2, 4.4 Hz, 1H), 4.41 (dd, J = 34.5, 12.1 Hz, 1H), 3.90–3.58 (m, 2H), 3.57–3.37 (m, 1H), 3.23–3.07 (m, 1H), 3.07–2.92 (m, 1H), 2.91–2.70 (m, 1H), 2.67–2.53 (m, 2H), 2.46–2.35 (m, 1H), 2.35–2.19 (m, 1H), 2.06–1.86 (m, 2H), 1.20–1.02 (m, 1H), 0.54–0.41 (m, 1H), 0.41–0.27 (m, 2H), 0.23–0.03 (m, 1H).

[0285] Example 7

[0286] Synthesis of (5S)-5-(3-(7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0287]

[0288] The specific synthetic route is as follows:

[0289] Step A: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate

[0290]

[0291] At room temperature, N-tert-butoxycarbonylpiperazine (2.53 g, 13.60 mmol) and potassium carbonate (2.03 g, 14.73 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 4-chloro-2,6-difluorobenzaldehyde (2.00 g, 11.33 mmol). 2 Under N protection, the reaction was carried out at 95 °C for 12 hours.

[0292] 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 first washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 2.66 g of pale yellow solid tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 68.5%). LCMS: RT = 2.16 min, [M+H] + = 343.29.

[0293] Step B: Synthesis of (E)-tert-butyl 4-(5-chloro-3-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0294]

[0295] At room temperature, tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.66 g, 7.76 mmol) and 4-methylbenzenesulfonylhydrazide (1.52 g, 8.15 mmol) were added to anhydrous ethanol (30.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 h.

[0296] After the reaction was completed, the solvent was evaporated to dryness to obtain 3.97 g of off-white solid (E)-tert-butyl 4-(5-chloro-3-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.20 min, [M+H] + = 511.23.

[0297] Step C: Synthesis of tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0298]

[0299] At room temperature, sodium hydride (373.0 mg, 9.32 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (40.0 mL) containing (E)-tert-butyl 4-(5-chloro-3-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (3.97 g, 7.77 mmol). Nitrogen was displaced for 20 min, and the reaction was carried out at 135 °C for 2 h.

[0300] The reaction was completed, and the reaction mixture was cooled to room temperature and dissolved in ethyl acetate (50 mL). It was first washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 2.00 g of pale yellow solid tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 78.8%). LCMS: RT = 2.27 min, [M+H] + = 327.21.

[0301] Step D: Synthesis of 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0302]

[0303] At room temperature, tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (2.00 g, 6.12 mmol) was added to methanol (8.0 mL), and a dioxane solution of hydrochloric acid (7.65 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0304] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.50 g of off-white solid 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.59 min, [M+H] + = 227.18.

[0305] Step E: Synthesis of (5S)-5-(3-(7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0306]

[0307] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (69.17 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL). N,N-Diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0308] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL × 2 times), dried over 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). 31.0 mg of a white solid, (5S)-5-(3-(7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione, was obtained (yield: 30.7%). LCMS: RT = 1.90 min, [M+H] + = 421.23. 1 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.70 (s, 0.5H), 7.69 (s, 0.5H), 6.57–6.49 (m, 2H), 4.41 (dd, J = 42.1, 13.3 Hz, 1H), 3.79–3.67 (m, 2H), 3.62–3.45 (m, 1H), 3.18–3.07 (m, 1H), 3.07–2.99 (m, 1H), 2.99–2.76 (m, 1H), 2.72–2.54 (m, 2H), 2.46–2.35 (m, 1H), 2.35–2.19 (m, 1H), 2.04–1.85 (m, 2H), 1.19–1.04 (m, 1H), 0.52–0.39 (m, 1H), 0.39–0.26 (m, 2H), 0.17–0.05 (m, 1H).

[0309] Examples 8 and 9

[0310] Synthesis of (S)-5-(3-((S)-7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0311]

[0312] Resolution of (5S)-5-(3-(7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione by chiral HPLC (Chiralpak AD-H, hexane:isopropanol = 80:20, the eluate was concentrated and lyophilized) gave optically pure compound 8 and compound 9 successively.

[0313] Compound 8: HPLC: RT = 11.195 min. LCMS: RT = 1.90 min, [M+H] + = 421.22. 1 1H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.69 (s, 0.5H), 7.66 (s, 0.5H), 6.58–6.45 (m, 2H), 4.46–4.44 (m, 0.5H), 4.36–4.34 (m, 0.5H), 3.88–3.47 (m, 3H), 3.16–2.77 (m, 3H), 2.68–2.52 (m, 2H), 2.46–2.16 (m, 2H), 2.05–1.87 (m, 2H), 1.15–1.03 (m, 1H), 0.52–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.05 (m, 1H).

[0314] Compound 9: HPLC: RT = 12.772 min. LCMS: RT = 1.90 min, [M+H] + = 421.21. 11H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.69 (s, 0.5H), 7.67 (s, 0.5H), 6.53 - 6.50 (m, 2H), 4.47–4.44 (m, 0.5H), 4.36–4.33 (m, 0.5H), 3.85–3.46 (m, 3H), 3.16–2.77 (m, 3H), 2.67–2.52 (m, 2H), 2.47–2.20 (m, 2H), 2.03–1.86 (m, 2H), 1.15–1.01 (m, 1H), 0.52–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.17–0.04 (m, 1H).

[0315] Example 10

[0316] Synthesis of (5S)-5-(3-(7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0317]

[0318] The specific synthetic route is as follows:

[0319] Step A: Synthesis of tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate

[0320]

[0321] At room temperature, N-tert-butoxycarbonylpiperazine (4.47 g, 24.0 mmol) and potassium carbonate (3.59 g, 26.0 mmol) were added to dimethyl sulfoxide (20.0 mL) containing 2,4,6-trifluorobenzaldehyde (3.20 g, 20.0 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0322] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 1.50 g of pale yellow solid tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 23.0%). LCMS: RT = 2.09 min, [M + H] + = 327.20.

[0323] Step B: Synthesis of tert-butyl (E)-4-(3,5-difluoro-2-(((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate

[0324]

[0325] At room temperature, tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate (1.50 g, 4.60 mmol) and 4-methylbenzenesulfonylhydrazide (899 mg, 4.80 mmol) were added to anhydrous ethanol (23.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0326] After the reaction was completed, the solvent was evaporated to dryness to obtain 2.27 g of a white solid, tert-butyl (E)-4-(3,5-difluoro-2-(((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate. It was directly used in the next step without purification. LCMS: RT = 2.14 min, [M+H] + = 495.20.

[0327] Step C: Synthesis of tert-butyl 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0328]

[0329] At room temperature, sodium hydride (184 mg, 4.60 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (20.0 mL) containing tert-butyl (E)-4-(3,5-difluoro-2-(((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate (2.27 g, 4.60 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0330] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed successively with saturated brine (50 mL × 2 times), dried over 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 / 10). 1.13 g of a white solid, tert-butyl 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (yield: 79.1%) was obtained. LCMS: RT = 2.20 min, [M+H] + = 311.22.

[0331] Step D: Synthesis of 7,9-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0332]

[0333] At room temperature, tert-butyl 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.13 g, 3.64 mmol) was added to methanol (18.2 mL), and a dioxane solution of hydrochloric acid (4.5 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0334] After the reaction was completed, the solvent was evaporated to dryness to obtain 900 mg of a white solid, 7,9-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT = 1.57 min, [M+H] + = 211.18. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 2H), 6.43 (dd, J = 10.0, 2.0 Hz, 1H), 6.41–6.34 (m, 1H), 4.02–3.93 (m, 1H), 3.88–3.81 (m, 1H), 3.32–3.28 (m, 1H), 3.27–3.20 (m, 2H), 3.07 (dd, J = 15.5, 8.4 Hz, 1H), 2.95–2.81 (m, 2H), 2.64 (dd, J = 15.6, 6.7 Hz, 1H).

[0335] Step E: Synthesis of (5S)-5-(3-(7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0336]

[0337] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50 mg, 0.24 mmol) and 7,9-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (100 mg, 0.35 mmol) were added to anhydrous dichloromethane (4.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0338] After the reaction was completed, the reaction mixture was quenched by adding water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 43.5 mg of white solid (5S)-5-(3-(7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 45.8%). LCMS: RT = 1.85 min, [M-H] - = 403.24. 1 H NMR (400 MHz, DMSO-d6) δ 10.68–10.51 (m, 1H), 7.69 (d, J = 4.6 Hz, 1H), 6.35 (t, J = 8.3 Hz, 1H), 6.32–6.25 (m, 1H), 4.40 (dd, J = 41.1, 11.4 Hz, 1H), 3.78 (dd, J = 30.0, 11.9 Hz, 1H), 3.72–3.45 (m, 2H), 3.16–2.97 (m, 2H), 2.97–2.77 (m, 1H), 2.68–2.53 (m, 2H), 2.46–2.18 (m, 2H), 2.03–1.87 (m, 2H), 1.15–1.04 (m, 1H), 0.50–0.41 (m, 1H), 0.41–0.26 (m, 2H), 0.16–0.04 (m, 1H).

[0339] Example 11

[0340] Synthesis of (5S)-5-(3-(6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0341]

[0342] The specific synthetic route is as follows:

[0343] Step A: Synthesis of tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate

[0344]

[0345] At room temperature, N-tert-butoxycarbonylpiperazine (4.47 g, 24.0 mmol) and potassium carbonate (3.59 g, 26.0 mmol) were added to dimethyl sulfoxide (20.0 mL) containing 3-chloro-2-fluorobenzaldehyde (3.17 g, 20.0 mmol). N 2Under protection, react at 95 °C for 12 hours.

[0346] After the reaction was completed, it was quenched with water. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 1.39 g of tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate as a white solid was obtained (yield: 21.4%). LCMS: RT = 2.16 min, [M+H] + = 325.18.

[0347] Step B: Synthesis of tert-butyl (E)-4-(2-chloro-6-((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate

[0348]

[0349] At room temperature, tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate (1.39 g, 4.28 mmol) and 4-methylbenzenesulfonylhydrazide (836 mg, 4.49 mmol) were added to anhydrous ethanol (21.4 mL), and under N 2 protection, react at room temperature for 1 hour.

[0350] After the reaction was completed, the solvent was evaporated to dryness to obtain 2.12 g of a pale white solid, tert-butyl (E)-4-(2-chloro-6-((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.22 min, [M+H] + = 493.21.

[0351] Step C: Synthesis of tert-butyl 6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0352]

[0353] At room temperature, sodium hydride (157 mg, 4.28 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (21.4 mL) containing tert-butyl (E)-4-(2-chloro-6-((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate (2.12 g, 4.28 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0354] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed successively with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 157 mg of pale yellow solid tert-butyl 6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 11.9%). LCMS: RT = 2.25 min, [M+H] + = 309.24.

[0355] Step D: Synthesis of 6-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0356]

[0357] At room temperature, tert-butyl 6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (157 mg, 0.51 mmol) was added to methanol (2.6 mL), and a dioxane solution of hydrochloric acid (0.51 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 h.

[0358] After the reaction was completed, the solvent was evaporated to dryness to obtain 120 mg of off-white solid 6-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.57 min, [M+H] + = 209.16.

[0359] Step E: Synthesis of (5S)-5-(3-(6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0360]

[0361] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (90.0 mg, 0.42 mmol) and 6-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (120 mg, 0.49 mmol) were added to anhydrous dichloromethane (2.0 mL), N,N-diisopropylethylamine (281 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) and 1-hydroxybenzotriazole (9.0 mg, 0.064 mmol) were added successively. Under N 2Under protection, the reaction was carried out at room temperature overnight.

[0362] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The combined organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 132.7 mg of white solid (5S)-5-(3-(6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 77.7%). LCMS: RT = 1.86 min, [M+H] + = 403.29. 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.68 (s, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.67–6.57 (m, 1H), 4.56–4.32 (m, 2H), 3.95–3.77 (m, 1H), 3.25–2.86 (m, 4H), 2.79–2.53 (m, 2H), 2.42–2.18 (m, 2H), 1.99–1.89 (m, 2H), 1.14–1.04 (m, 1H), 0.51–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.04 (m, 1H).

[0363] Example 12

[0364] Synthesis of (5S)-5-(3-(8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0365]

[0366] The specific synthesis route is as follows:

[0367] Step A: Synthesis of tert-butyl 4-(4-trifluoromethyl-2-formylphenyl)piperazine-1-carboxylate

[0368]

[0369] At room temperature, N-tert-butoxycarbonylpiperazine (2.33 g, 12.50 mmol) and potassium carbonate (1.87 g, 13.55 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2-fluoro-5-trifluoromethyl-benzaldehyde (2.00 g, 10.42 mmol). 2Under protection, react at 95 °C for 12 hours.

[0370] After the reaction is completed, quench with water. Extract the mixture with ethyl acetate (50 mL × 3 times), combine the organic phases. Wash the organic phase first with saturated brine (50 mL × 2 times), then dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure. Purify the obtained residue by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). Obtain 2.83 g of pale yellow solid tert-butyl 4-(4-trifluoromethyl-2-formylphenyl)piperazine-1-carboxylate (yield: 75.8%). LCMS: RT = 2.16 min, [M+H] + = 359.22.

[0371] Step B: Synthesis of (E)-tert-butyl 4-(4-trifluoromethyl-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0372]

[0373] At room temperature, add tert-butyl 4-(4-trifluoromethyl-2-formylphenyl)piperazine-1-carboxylate (2.83 g, 7.90 mmol) and 4-methylbenzenesulfonylhydrazide (1.54 g, 8.30 mmol) to anhydrous ethanol (25.0 mL). Under N 2 protection, react at room temperature for 1 hour.

[0374] After the reaction is completed, evaporate the solvent to obtain 4.20 g of off-white solid (E)-tert-butyl 4-(4-trifluoromethyl-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. Without purification, directly use it for the next reaction. LCMS: RT = 2.16 min, [M+H] + = 527.22.

[0375] Step C: Synthesis of tert-butyl 8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0376]

[0377] At room temperature, add sodium hydride (383.0 mg, 9.58 mmol, 60% dispersed in paraffin oil) portionwise to toluene (40.0 mL) containing (E)-tert-butyl 4-(4-trifluoromethyl-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (4.20 g, 7.98 mmol). Replace nitrogen for 20 minutes and react at 135 °C for 2 hours.

[0378] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed successively with saturated brine (100 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 2.70 g of tert-butyl 8-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate as a pale yellow solid was obtained (yield: 98.8%). LCMS: RT = 2.23 min, [M+H] + = 343.25.

[0379] Step D: Synthesis of 8-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0380]

[0381] At room temperature, tert-butyl 8-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (2.70 g, 7.89 mmol) was added to methanol (30.0 mL), and a dioxane solution of hydrochloric acid (9.80 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 h.

[0382] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.50 g of 8-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride as an off-white solid. It was used directly in the next step without purification. LCMS: RT = 1.61 min, [M+H] + = 243.19.

[0383] Step E: Synthesis of (5S)-5-(3-(8-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0384]

[0385] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-trifluoromethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (81.6 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0386] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 26.0 mg of white solid (5S)-5-(3-(8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 24.8%). LCMS: RT = 1.89 min, [M+H] + = 437.25. 1 1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 7.70 (s, 0.5H), 7.69 (d, J = 2.5 Hz, 0.5H), 7.35 (d, J = 8.0 Hz, 2H), 6.65 (dd, J = 8.2, 4.5 Hz, 1H), 4.44 (dd, J = 34.5, 11.7 Hz, 1H), 3.96–3.69 (m, 2H), 3.66–3.45 (m, 1H), 3.20–3.08 (m, 1H), 3.08–2.94 (m, 1H), 2.94–2.81 (m, 1H), 2.80–2.52 (m, 2H), 2.45–2.34 (m, 1H), 2.34–2.19 (m, 1H), 2.10–1.86 (m, 2H), 1.16–1.02 (m, 1H), 0.53–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.21–0.04 (m, 1H).

[0387] Example 13

[0388] Synthesis of (5S)-5-(3-(8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0389]

[0390] The specific synthesis route is as follows:

[0391] Step A: Synthesis of tert-butyl 4-(4-cyano-2-formylphenyl)piperazine-1-carboxylate

[0392]

[0393] At room temperature, N-tert-butoxycarbonylpiperazine (2.24 g, 12.0 mmol) and potassium carbonate (1.79 g, 13.0 mmol) were added to dimethyl sulfoxide (10.0 mL) containing 4-fluoro-3-formylbenzonitrile (1.49 g, 10.0 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0394] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 2.876 g of pale yellow solid tert-butyl 4-(4-cyano-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 91.3%). LCMS: RT = 2.02 min, [M+H] + = 316.23.

[0395] Step B: Synthesis of (E)-tert-butyl 4-(4-cyano-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0396]

[0397] At room temperature, tert-butyl 4-(4-cyano-2-formylphenyl)piperazine-1-carboxylate (2.876 g, 9.13 mmol) and 4-methylbenzenesulfonylhydrazide (1.79 mg, 9.59 mmol) were added to anhydrous ethanol (46.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0398] The reaction was completed, and the solvent was evaporated to dryness to obtain 4.42 g of off-white solid tert-butyl (E)-4-(4-cyano-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. Without purification, it was directly used in the next reaction. LCMS: RT = 2.09 min, [M+H] + = 484.30.

[0399] Step C: Synthesis of tert-butyl 8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0400]

[0401] At room temperature, sodium hydride (365 mg, 9.13 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (36.5 mL) containing tert-butyl (E)-4-(4-cyano-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (4.42 g, 9.13 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0402] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed successively with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 940 mg of white solid tert-butyl 8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 34.4%). LCMS: RT = 2.04 min, [M+H] + = 300.25.

[0403] Step D: Synthesis of 8-cyano-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0404]

[0405] At room temperature, tert-butyl 8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (940 mg, 3.14 mmol) was added to (31 mL), and a dioxane solution of hydrochloric acid (3.1 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0406] After the reaction was completed, the solvent was evaporated to dryness to obtain 740 mg of off-white solid 8-cyano-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. Without purification, it was directly used in the next reaction. LCMS: RT = 1.29 min, [M+H]+ = 200.19. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 2H), 7.50 (dd, J = 8.2, 1.6 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.05–3.96 (m, 1H), 3.96–3.89 (m, 1H), 3.34–3.23 (m, 3H), 3.12 (dd, J = 16.2, 8.7 Hz, 1H), 2.97–2.80 (m, 2H), 2.69 (dd, J = 16.2, 7.1 Hz, 1H).

[0407] Step E: Synthesis of (5S)-5-(3-(8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0408]

[0409] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-cyano-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (96.0 mg, 0.41 mmol) were added to anhydrous dichloromethane (2.0 mL). N,N-Diisopropylethylamine (156 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.035 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0410] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 4 / 1). 55.5 mg of white solid (5S)-5-(3-(8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 59.8%). LCMS: RT = 1.74 min, [M-H] - = 392.26. 11H NMR (400 MHz, DMSO-d6) δ 10.63–10.55 (m, 1H), 7.69 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 6.63 (dd, J = 8.1, 5.3 Hz, 1H), 4.44 (dd, J = 37.8, 11.9 Hz, 1H), 3.90–3.51 (m, 3H), 3.14–2.83 (m, 3H), 2.70–2.57 (m, 2H), 2.46–2.19 (m, 2H), 2.01–1.88 (m, 2H), 1.14–1.05 (m, 1H), 0.50–0.41 (m, 1H), 0.41–0.27 (m, 2H), 0.10 (d, J = 5.3 Hz, 1H).

[0411] Example 14

[0412] Synthesis of (5S)-5-cyclopropyl-5-(3-(6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0413]

[0414] The specific synthesis route is as follows:

[0415] Step A: Synthesis of tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate

[0416]

[0417] At room temperature, N-tert-butoxycarbonylpiperazine (2.62 g, 14.07 mmol) and potassium carbonate (2.33 g, 16.89 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2,3-difluorobenzaldehyde (2.00 g, 14.07 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0418] After the reaction was completed, the reaction mixture was diluted with 50 mL of water and 50 mL of ethyl acetate, and then separated. The organic phase was collected, washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 350.0 mg of off-white solid tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate was obtained (yield: 8.1%). LCMS: RT = 2.11 min, [M+H] + = 309.22.

[0419] Step B: Synthesis of tert-Butyl (E)-4-(2-Fluoro-6-((2-Toluenesulfonylhydrazonomethyl)phenyl)Piperazine-1-Carboxylate

[0420]

[0421] At room temperature, tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate (350.0 mg, 1.14 mmol) and 4-methylbenzenesulfonylhydrazide (222.0 mg, 1.19 mmol) were added to anhydrous ethanol (10.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 2 hours.

[0422] After the reaction was completed, the solvent was evaporated to dryness to obtain 540.9 mg of a beige solid, tert-butyl (E)-4-(2-fluoro-6-((2-toluenesulfonylhydrazonomethyl)phenyl)piperazine-1-carboxylate. It was directly used in the next step without purification. LCMS: RT = 2.18 min, [M+H] + = 477.28.

[0423] Step C: Synthesis of tert-Butyl 6-Fluoro-3,4,10,10a-Tetrahydropyrazino[1,2-a]Indole-2(1H)-Carboxylate

[0424]

[0425] At room temperature, sodium hydride (49.0 mg, 1.23 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (10.0 mL) containing tert-butyl (E)-4-(2-fluoro-6-((2-toluenesulfonylhydrazonomethyl)phenyl)piperazine-1-carboxylate (540.9 mg, 1.13 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0426] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 110.2 mg of a beige solid, tert-butyl 6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (yield: 33.2%) was obtained. LCMS: RT = 2.20 min, [M+H] + = 293.23.

[0427] Step D: Synthesis of 6-Fluoro-1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]Indole Hydrochloride

[0428]

[0429] At room temperature, tert-butyl 6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (110.2 mg, 0.38 mmol) was added to methanol (5 mL), and a dioxane solution of hydrochloric acid (1 mL, 4.0 mol / L) was added dropwise. The reaction was carried out at room temperature for 1 hour.

[0430] After the reaction was completed, the solvent was evaporated to dryness to obtain 85.0 mg of white solid 6-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used for the next reaction without purification. LCMS: RT = 1.50 min, [M+H] + = 193.16.

[0431] Step E: (5S)-5-cyclopropyl-5-(3-(6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazoline-2,4-dione

[0432]

[0433] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (94.7 mg, 0.45 mmol) and 6-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (85.0 mg, 0.37 mmol) were added to N,N-dimethylformamide (5.0 mL), N,N-diisopropylethylamine (144.1 mg) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (85.5 mg, 0.45 mmol) and 1-hydroxybenzotriazole (7.5 mg, 0.06 mmol) were added in sequence. The reaction was carried out at room temperature overnight.

[0434] After the reaction was completed, the mixture was diluted with water (50 mL) and ethyl acetate (50 mL), separated, the organic phase was collected, washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 55.0 mg of off-white solid (5S)-5-cyclopropyl-5-(3-(6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazoline-2,4-dione was obtained (yield: 38.3%). LCMS: RT = 1.81 min, [M+H] + = 387.24. 1 H NMR (400 MHz, DMSO-d 6)δ (ppm): 10.59 (s, 1H), 7.68 (s, 1H), 6.92 (d, J = 6.8 Hz, 1H), 6.88 (dd, J = 12.4, 8.4 Hz, 1H), 6.67–6.57 (m, 1H), 4.55–4.34 (m, 1H), 3.95–3.75 (m, 2H), 3.25–2.86 (m, 3H), 2.79–2.57 (m, 2H), 2.45–2.18 (m, 2H), 2.02–1.90 (m, 2H), 1.31–1.21 (m, 1H), 1.15–1.04 (m, 1H), 0.50–0.41 (m, 1H), 0.40–0.28 (m, 2H), 0.17–0.06 (m, 1H).

[0435] Example 15

[0436] Synthesis of (5S)-5-cyclopropyl-5-(3-(7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0437]

[0438] The specific synthesis route is as follows:

[0439] Step A: Synthesis of tert-butyl 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylate

[0440]

[0441] At room temperature, N-tert-butoxycarbonylpiperazine (2.62 g, 14.07 mmol) and potassium carbonate (2.33 g, 16.89 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2,4-difluorobenzaldehyde (2.00 g, 14.07 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0442] After the reaction was completed, it was diluted with 50 mL of water and 50 mL of ethyl acetate, and separated. The organic phase was collected, washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 550.0 mg of off-white solid tert-butyl 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 12.7%). LCMS: RT = 2.09 min, [M+H] + = 309.22. 1 1H NMR (400 MHz, CDCl 3) δ (ppm): 10.20 (s, 1H), 7.84 (dd, J = 8.4, 6.8 Hz, 1H), 6.86–6.79 (m, 1H), 6.75 (dd, J = 10.8, 2.4 Hz, 1H), 3.69–3.60 (m, 4H), 3.10–3.00 (m, 4H), 1.49 (s, 9H).

[0443] Step B: Synthesis of tert-butyl (E)-4-(5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0444]

[0445] At room temperature, 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (550.0 mg, 1.78 mmol) and 4-methylbenzenesulfonylhydrazide (348.8 mg, 1.87 mmol) were added to anhydrous ethanol (10.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 2 hours.

[0446] After the reaction was completed, the solvent was evaporated to dryness to obtain 850.0 mg of a beige solid, tert-butyl (E)-4-(5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. Without purification, it was directly used for the next reaction. LCMS: RT = 2.14 min, [M+H] + = 477.25.

[0447] Step C: Synthesis of tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0448]

[0449] At room temperature, sodium hydride (77.0 mg, 1.93 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (10.0 mL) containing tert-butyl (E)-4-(5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (850.0 mg, 1.78 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0450] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 340.5 mg of a beige solid, tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (yield: 65.3%) was obtained. LCMS: RT = 2.16 min, [M+H]+ = 293.26.

[0451] Step D: Synthesis of 7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0452]

[0453] At room temperature, tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (340.5 mg, 1.16 mmol) was added to methanol (5.0 mL), and a dioxane solution of hydrochloric acid (1 mL, 4.0 mol / L) was added dropwise. The reaction was carried out at room temperature for 1 hour.

[0454] After the reaction was completed, the solvent was evaporated to dryness to obtain 260.0 mg of white solid 7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.49 min, [M+H] + = 193.18.

[0455] Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-(7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)imidazoline-2,4-dione

[0456]

[0457] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (289.5 mg, 1.36 mmol) and 7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (260.0 mg, 1.14 mmol) were added to N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (440.8 mg) was added dropwise. Then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (261.5 mg, 1.36 mmol) and 1-hydroxybenzotriazole (23.0 mg, 0.17 mmol) were added successively. The reaction was carried out at room temperature overnight.

[0458] The reaction was completed, diluted with water (50 mL) and ethyl acetate (50 mL), separated by liquid-liquid extraction, the organic phase was collected, washed with saturated brine (3 mL×2), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 90.0 mg of a pale yellow solid, (5S)-5-cyclopropyl-5-(3-(7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione, was obtained (yield: 20.5%). LCMS: RT = 1.81 min, [M+H] + = 387.27. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.59 (s, 1H), 7.68 (d, J = 4.8 Hz, 1H), 7.01 (s, 1H), 6.46–6.38 (m, 1H), 6.35–6.27 (m, 1H), 4.49–4.32 (m, 1H), 3.85–3.71 (m, 1H), 3.70–3.60 (m, 1H), 3.21–2.81 (m, 4H), 2.78–2.61 (m, 1H), 2.41–2.17 (m, 2H), 2.01–1.89 (m, 2H), 1.35–1.25 (m, 1H), 1.13–1.05 (m, 1H), 0.51–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.05 (m, 1H).

[0459] Example 16

[0460] Synthesis of (5S)-5-(3-(8-Fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0461]

[0462] The specific synthetic route is as follows:

[0463] Step A: Synthesis of tert-Butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate

[0464]

[0465] At room temperature, N-tert-butoxycarbonylpiperazine (3.15 g, 16.90 mmol) and potassium carbonate (2.53 g, 18.30 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2,5-difluorobenzaldehyde (2.00 g, 14.08 mmol). N 2Under protection, react at 95 °C for 12 hours.

[0466] After the reaction is completed, quench with water. Extract the mixture with ethyl acetate (50 mL × 3 times), combine the organic phases, wash the organic phase with saturated brine (50 mL × 2 times), then dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 700.0 mg of pale yellow solid tert-butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate is obtained (yield: 16.1%). LCMS: RT = 2.16 min, [M+H] + = 309.27.

[0467] Step B: Synthesis of (E)-tert-butyl 4-(4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0468]

[0469] At room temperature, add tert-butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate (700.0 mg, 2.27 mmol) and 4-methylbenzenesulfonylhydrazide (443.9 mg, 2.38 mmol) to anhydrous ethanol (10.0 mL), under N 2 protection, react at room temperature for 1 hour.

[0470] After the reaction is completed, evaporate the solvent to obtain 1.08 g of off-white solid (E)-tert-butyl 4-(4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It is used directly in the next step without purification. LCMS: RT = 2.16 min, [M+H] + = 477.30.

[0471] Step C: Synthesis of tert-butyl 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0472]

[0473] At room temperature, add sodium hydride (109.0 mg, 2.72 mmol, 60% dispersed in paraffin oil) portionwise to toluene (10.0 mL) containing (E)-tert-butyl 4-(4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (1.08 g, 2.27 mmol), displace nitrogen for 20 minutes, and react at 135 °C for 2 hours.

[0474] The reaction was completed, and the reaction mixture was cooled to room temperature. It was dissolved in ethyl acetate (50 mL), washed successively with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 192.0 mg of pale yellow solid tert-butyl 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 28.93%). LCMS: RT = 2.05 min, [M+H] + = 293.27.

[0475] Step D: Synthesis of 8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0476]

[0477] At room temperature, tert-butyl 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (192.0 mg, 0.66 mmol) was added to methanol (2.0 mL), and a dioxane solution of hydrochloric acid (821.0 μL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0478] After the reaction was completed, the solvent was evaporated to dryness to obtain 59.0 mg of off-white solid 8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.43 min, [M+H] + = 193.17.

[0479] Step E: Synthesis of (5S)-5-(3-(8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0480]

[0481] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (59.0 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (156.0 μL) was added dropwise. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N2 Under protection, the reaction was carried out at room temperature overnight.

[0482] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times). The organic layers were combined, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 22.0 mg of white solid (5S)-5-(3-(8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 23.7%). LCMS: RT = 1.79 min, [M+H] + = 387.28. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.70 (s, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.83 (td, J = 9.6, 1.8 Hz, 1H), 6.57–6.45 (m, 1H), 4.42 (dd, J = 38.9, 11.8 Hz, 1H), 3.80 (dd, J = 27.3, 11.3 Hz, 1H), 3.67–3.53 (m, 1H), 3.49–3.36 (m, 1H), 3.20–2.90 (m, 2H), 2.90–2.73 (m, 1H), 2.72–2.63 (m, 1H), 2.63–2.53 (m, 1H), 2.42 (ddd, J = 36.3, 12.6, 10.1 Hz, 1H), 2.33–2.16 (m, 1H), 2.07–1.85 (m, 2H), 1.17–1.00 (m, 1H), 0.57–0.41 (m, 1H), 0.41–0.20 (m, 2H), 0.19–0.02 (m, 1H).

[0483] Example 17

[0484] Synthesis of (5S)-5-(3-(7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0485]

[0486] The specific synthesis route is as follows:

[0487] Step A: Synthesis of (4,5-dichloro-2-fluorophenyl)methanol

[0488]

[0489] At zero degrees Celsius, a solution of borane in tetrahydrofuran (38.0 mL, 1.0 mol / L) was added dropwise to a solution of 4,5-dichloro-2-fluorobenzoic acid (4.0 g, 19.14 mmol) in tetrahydrofuran (20.0 mL) under N 2 protection. The reaction mixture was heated to 65 degrees Celsius and stirred for 1 hour.

[0490] After completion of the reaction, water was slowly added dropwise to the reaction mixture at zero degrees Celsius until no more bubbles were produced. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the combined organic phases were washed successively with saturated brine (30 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3.46 g of white solid (4,5-dichloro-2-fluorophenyl)methanol (yield: 92.7%). LCMS: RT = 1.91 min.

[0491] Step B: Synthesis of 4,5-dichloro-2-fluorobenzaldehyde

[0492]

[0493] At zero degrees Celsius, sodium bicarbonate (7.53 g, 88.70 mmol) and Dess-Martin periodinane (11.29 g, 26.61 mmol) were added to a solution of (4,5-dichloro-2-fluorophenyl)methanol (3.46 g, 17.74 mmol) in dichloromethane (177.0 mL) under N 2 protection. The reaction mixture was stirred at room temperature for 1 hour.

[0494] After completion of the reaction, the reaction was quenched with water, and sodium sulfite was added until the reaction mixture was separated and clear. The aqueous phase was extracted with dichloromethane (50.0 mL × 3 times), and the combined organic phases were washed successively with saturated brine (30 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1) to give 1.80 g of white solid 4,5-dichloro-2-fluorobenzaldehyde (yield: 52.6%). LCMS: RT = 2.04 min.

[0495] Step C: Synthesis of tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate

[0496]

[0497] At room temperature, N-tert-butoxycarbonylpiperazine (2.08 g, 11.20 mmol) and potassium carbonate (1.67 g, 12.13 mmol) were added to a solution of 4,5-dichloro-2-fluorobenzaldehyde (1.80 g, 9.33 mmol) in dimethyl sulfoxide (11.0 mL) under N 2 protection. The reaction mixture was heated to 95 degrees Celsius and stirred for 12 hours.

[0498] The reaction was terminated, quenched with water, and the mixture was extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 1.16 g of pale yellow solid tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 34.7%). LCMS: RT = 2.25 min, [M+H] + = 359.17.

[0499] Step D: Synthesis of (E)-tert-butyl 4-(4,5-dichloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0500]

[0501] At room temperature, tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate (1.16 g, 3.23 mmol) and 4-methylbenzenesulfonyl hydrazide (632.0 mg, 3.39 mmol) were added to anhydrous ethanol (12.0 mL), and the reaction was carried out at room temperature for 1 hour under N 2 protection.

[0502] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.10 g of off-white solid (E)-tert-butyl 4-(4,5-dichloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.16 min, [M+H] + = 527.22.

[0503] Step E: Synthesis of tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0504]

[0505] At room temperature, sodium hydride (100.3 mg, 2.51 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (10.0 mL) containing (E)-tert-butyl 4-(4,5-dichloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (1.10 g, 2.09 mmol). The nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0506] The reaction was completed, and the reaction mixture was cooled to room temperature and dissolved in ethyl acetate (50 mL). It was first washed with saturated brine (100 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 568.0 mg of pale yellow solid tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 79.2%). LCMS: RT = 2.30 min, [M+H] + = 343.15.

[0507] Step F: Synthesis of 7,8-dichloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0508]

[0509] At room temperature, tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (568.0 mg, 1.65 mmol) was added to methanol (4.0 mL), and a dioxane solution of hydrochloric acid (2.1 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0510] The reaction was completed, and the solvent was evaporated to dryness to obtain 450.0 mg of off-white solid 7,8-dichloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.67 min, [M+H] + = 243.12.

[0511] Step G: Synthesis of (5S)-5-(3-(7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0512]

[0513] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7,8-dichloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (98.0 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL). N,N-Diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0514] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed successively with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 35.0 mg of white solid (5S)-5-(3-(7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 33.4%). LCMS: RT = 1.93 min, [M+H] + = 437.15. 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.70 (s, 0.5H), 7.68 (s, 0.5H), 7.25 (s, 0.5H), 7.25 (s, 0.5H), 6.81 (s, 0.5H), 6.79 (s, 0.5H), 4.40 (dd, J = 37.0, 12.7 Hz, 1H), 3.87–3.74 (m, 1H), 3.73–3.65 (m, 1H), 3.64–3.45 (m, 1H), 3.26–3.08 (m, 1H), 3.05–2.93 (m, 1H), 2.92–2.74 (m, 1H), 2.73–2.53 (m, 2H), 2.48–2.33 (m, 1H), 2.35–2.19 (m, 1H), 2.10–1.87 (m, 2H), 1.16–1.00 (m, 1H), 0.56–0.41 (m, 1H), 0.41–0.26 (m, 2H), 0.23–0.04 (m, 1H).

[0515] Examples 18 and 19

[0516] Synthesis of (S)-5-(3-((S)-7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0517]

[0518] Resolution of (5S)-5-(3-(7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione by chiral HPLC (Chiralpak AD-H, hexane:isopropanol = 80:20, eluate concentrated and lyophilized) gave optically pure compound 18 and compound 19 successively.

[0519] Compound 18: HPLC: RT = 18.225 min. LCMS: RT = 1.93 min, [M+H] + = 437.15. 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (s, 1H), 7.12 (s, 0.5H), 7.11 (s, 0.5H), 6.50 (s, 0.5H), 6.48 (s, 0.5H), 5.90 (s, 0.5H), 5.79 (s, 0.5H), 4.68–4.58 (m, 1H), 3.77 (d, J = 13.3 Hz, 1H), 3.57–3.19 (m, 3H), 3.15–2.72 (m, 3H), 2.69–2.18 (m, 5H), 1.23–1.12 (m, 1H), 0.64–0.53 (m, 1H), 0.53–0.36 (m, 2H), 0.36–0.25 (m, 1H).

[0520] Compound 19: HPLC: RT = 22.461 min. LCMS: RT = 1.93 min, [M+H] + = 437.18. 1 H NMR (400 MHz, CDCl 3)δ 7.57 (s, 1H), 7.12 (s, 1H), 6.50 (s, 0.5H), 6.47 (s, 0.5H), 5.84 (s, 0.5H), 5.75 (s, 0.5H), 4.69–4.56 (m, 1H), 3.77 (d, J = 13.5 Hz, 1H), 3.55–3.43 (m, 2H), 3.28–2.72 (m, 4H), 2.67–2.46 (m, 2H), 2.46–2.17 (m, 3H), 1.23–1.14 (m, 1H), 0.65–0.54 (m, 1H), 0.52–0.36 (m, 2H), 0.36–0.25 (m, 1H).

[0521] Example 20

[0522] Synthesis of (5S)-5-cyclopropyl-5-(3-(9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0523]

[0524] The specific synthesis route is as follows:

[0525] Step A: Synthesis of tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate

[0526]

[0527] At room temperature, N-tert-butoxycarbonylpiperazine (2.62 g, 14.07 mmol) and potassium carbonate (2.33 g, 16.89 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2,6-difluorobenzaldehyde (2.00 g, 14.07 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0528] After the reaction was completed, the reaction mixture was diluted with 50 mL of water and 50 mL of ethyl acetate, and the layers were separated. The organic layer was washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 2.5 g of a light yellow solid, tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate, was obtained (yield: 57.6%). LCMS: RT = 2.07 min, [M+H] + = 309.20.

[0529] Step B: Synthesis of (E)-tert-butyl 4-(3-fluoro-2-((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate

[0530]

[0531] At room temperature, tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.50 g, 8.11 mmol) and 4-methylbenzenesulfonyl hydrazide (1.59 g, 8.51 mmol) were added to anhydrous ethanol (15.0 mL), and under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0532] After the reaction was completed, the solvent was evaporated to dryness to obtain 3.80 g of a beige solid, tert-butyl (E)-4-(3-fluoro-2-((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. Without purification, it was directly used for the next reaction. LCMS: RT = 2.13 min, [M+H] + = 477.22.

[0533] Step C: Synthesis of tert-butyl 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0534]

[0535] At room temperature, sodium hydride (344.4 mg, 8.61 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (12 mL) containing tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate (3.8 g, 7.97 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0536] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (100 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.50 g of a beige solid, tert-butyl 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (yield: 64.4%) was obtained. LCMS: RT = 2.18 min, [M+H] + = 293.23.

[0537] Step D: Synthesis of 9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0538]

[0539] At room temperature, tert-butyl 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.50 g, 5.13 mmol) was added to methanol (10 mL), and a dioxane solution of hydrochloric acid (4 mL, 4.0 mol / L) was added dropwise. The reaction was carried out at room temperature for 1 hour.

[0540] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.1 g of a beige solid, 9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next reaction without purification. LCMS: RT = 147 min, [M+H] + = 193.18. 1 HNMR (400 MHz, DMSO) δ (ppm): 9.90–9.61 (m, 2H), 7.13–7.03 (m, 1H), 6.49–6.41 (m, 2H), 3.97–3.86 (m, 1H), 3.84–3.76 (m, 1H), 3.34–3.18 (m, 3H), 3.12–3.03 (m, 1H), 2.93–2.76 (m, 2H), 2.69–2.60 (m, 1H).

[0541] Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-(9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazoline-2,4-dione

[0542]

[0543] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (55.7 mg, 0.26 mmol) and 9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (60.0 mg, 0.26 mmol) were added to N,N-dimethylformamide (5.0 mL), and N,N-diisopropylethylamine (101.7 mg) was added dropwise. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (60.4 mg, 0.31 mmol) and 1-hydroxybenzotriazole (5.3 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0544] After the reaction was completed, it was diluted with water (50 mL) and ethyl acetate (50 mL), separated by liquid-liquid extraction, and the organic phase was collected. The organic phase was washed with saturated brine (3 mL×2), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 30.2 mg of a beige solid, (5S)-5-cyclopropyl-5-(3-(9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazoline-2,4-dione, was obtained (yield: 29.8%). LCMS: RT = 1.81 min, [M+H] + = 387.21. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.59 (s, 1H), 7.69 (s, 1H), 7.09–7.00 (m, 1H), 6.43–6.35 (m, 2H), 4.51–4.32 (m, 1H), 3.86–3.71 (m, 2H), 3.70–3.62 (m, 1H), 3.60–3.35 (m, 1H), 3.06–2.99 (m, 1H), 2.94–2.73 (m, 1H), 2.68–2.52 (m, 2H), 2.45–2.17 (m, 2H), 2.01–1.87 (m, 2H), 1.14–1.04 (m, 1H), 0.49–0.40 (m, 1H), 0.39–0.27 (m, 2H), 0.15–0.04 (m, 1H).

[0545] Example 21

[0546] Synthesis of (5S)-5-(3-(7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0547]

[0548] The specific synthetic route is as follows:

[0549] Step A: Synthesis of tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate

[0550]

[0551] At room temperature, N-tert-butoxycarbonylpiperazine (6.15 g, 33.0 mmol) and potassium carbonate (5.17 g, 37.5 mmol) were added to dimethyl sulfoxide (30.0 mL) containing 4-chloro-2,5-difluorobenzaldehyde (5.30 g, 30.0 mmol). N 2Under protection, react at 95 °C for 12 hours.

[0552] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The combined organic phase was first washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 2.40 g of white solid tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 23.4%). LCMS: RT = 2.18 min, [M+H] + = 343.18.

[0553] Step B: Synthesis of tert-butyl (E)-4-(5-chloro-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0554]

[0555] At room temperature, tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.40 g, 7.02 mmol) and 4-methylbenzenesulfonyl hydrazide (1.37 g, 7.37 mmol) were added to anhydrous ethanol (35.0 mL). Under N 2 protection, react at room temperature for 1 hour.

[0556] After the reaction was completed, the solvent was evaporated to dryness to obtain 3.59 g of off-white solid tert-butyl (E)-4-(5-chloro-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.23 min, [M+H] + = 511.25.

[0557] Step C: Synthesis of tert-butyl 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0558]

[0559] At room temperature, sodium hydride (281 mg, 7.02 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (28.0 mL) containing tert-butyl (E)-4-(5-chloro-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (3.59 g, 7.02 mmol). The nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0560] The reaction was completed, and the reaction mixture was cooled to room temperature. It was dissolved in ethyl acetate (100 mL), washed successively with saturated brine (100 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 260 mg of pale yellow solid tert-butyl 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 11.4%). LCMS: RT = 2.23 min, [M+H] + = 327.21.

[0561] Step D: Synthesis of 7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0562]

[0563] At room temperature, tert-butyl 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (260 mg, 0.80 mmol) was added to methanol (4.0 mL), and a dioxane solution of hydrochloric acid (0.80 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0564] After the reaction was completed, the solvent was evaporated to dryness to obtain 210 mg of off-white solid 7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.57 min, [M+H] + = 227.13. 1 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 2H), 7.19 (dd, J = 9.0 Hz, 1H), 6.81 (d, J = 6.1 Hz, 1H), 3.86–3.74 (m, 2H), 3.29–3.11 (m, 3H), 3.03 (dd, J = 16.0, 8.0 Hz, 1H), 2.98–2.80 (m, 2H), 2.62 (dd, J = 16.0, 7.2 Hz, 1H).

[0565] Step E: Synthesis of (5S)-5-(3-(7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0566]

[0567] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (60.0 mg, 0.28 mmol) and 7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (89 mg, 0.34 mmol) were added to anhydrous dichloromethane (4.0 mL). N,N-Diisopropylethylamine (187 μL, 1.13 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg, 0.42 mmol) and 1-hydroxybenzotriazole (6.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0568] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 33.5 mg of white solid (5S)-5-(3-(7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 28.1%). LCMS: RT = 1.88 min, [M + H] + = 421.15. 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 6.71 (t, J = 6.9 Hz, 1H), 4.39 (dd, J = 38.9, 11.0 Hz, 1H), 3.77 (dd, J = 28.4, 12.3 Hz, 1H), 3.66 (t, J = 11.5 Hz, 1H), 3.54–3.34 (m, 1H), 3.18–2.92 (m, 2H), 2.90–2.69 (m, 1H), 2.69–2.52 (m, 2H), 2.46–2.17 (m, 2H), 2.02–1.86 (m, 2H), 1.14–1.04 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.26 (m, 2H), 0.16–0.05 (m, 1H).

[0569] Example 22 and Example 23

[0570] Synthesis of (5S)-5-(3-((S)-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (5S)-5-(3-((R)-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0571]

[0572] Resolution of ((5S)-5-(3-(7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione by chiral HPLC (Chiralpak AD-H, hexane:isopropanol = 80:20, the eluate was concentrated and lyophilized), and optically pure compound 22 and compound 23 were obtained successively.

[0573] Compound 22: HPLC: RT = 17.479 min. LCMS: RT = 1.88 min, [M + H] + = 421.15. 1 1H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.70 (s, 0.5H), 7.68 (s, 0.5H), 7.16 (d, J = 4.4 Hz, 0.5H), 7.14 (d, J = 4.4 Hz, 0.5H), 6.73 (d, J = 6.1 Hz, 0.5H), 6.71 (d, J = 6.1 Hz, 0.5H), 4.46–4.44 (m, 0.5H), 4.37–4.34 (m, 0.5H), 3.83–3.81 (m, 0.5H), 3.76–3.73 (m, 0.5H), 3.66 (t, J = 12.2 Hz, 1H), 3.53–3.34 (m, 1H), 3.16–2.93 (m, 2H), 2.88–2.69 (m, 1H), 2.68–2.52 (m, 2H), 2.48–2.17 (m, 2H), 2.01–1.88 (m, 2H), 1.14–1.05 (m, 1H), 0.49–0.41 (m, 1H), 0.39–0.27 (m, 2H), 0.14–0.05 (m, 1H).

[0574] Compound 23: HPLC: RT = 20.353 min. LCMS: RT = 1.88 min, [M + H] + = 421.15. 11H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 0.5H), 10.60 (s, 0.5H), 7.70 (s, 0.5H), 7.68 (s, 0.5H), 7.16 (d, J = 4.0 Hz, 0.5H), 7.15 (d, J = 4.0 Hz, 0.5H), 6.73 (d, J = 6.1 Hz, 0.5H), 6.71 (d, J = 6.1 Hz, 0.5H), 4.46–4.44 (m, 0.5H), 4.37 - 4.34 (m, 0.5H), 3.83–3.81 (m, 0.5H), 3.76–3.74 (m, 0.5H), 3.66 (t, J = 13.7 Hz, 1H), 3.54–3.34 (m, 1H), 3.17–2.93 (m, 2H), 2.87–2.69 (m, 1H), 2.68–2.52 (m, 2H), 2.48–2.20 (m, 2H), 2.01–1.88 (m, 2H), 1.14–1.05 (m, 1H), 0.49–0.41 (m, 1H), 0.40–0.28 (m, 2H), 0.10 (dt, J = 9.7, 4.7 Hz, 1H).

[0575] Example 24

[0576] Synthesis of (5S)-5-(3-(8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0577]

[0578] The specific synthesis route is as follows:

[0579] Step A: Synthesis of tert-butyl 4-(4-chloro-5-fluoro-2-formylphenyl)piperazine-1-carboxylate

[0580]

[0581] At room temperature, N-tert-butoxycarbonylpiperazine (3.91 g, 21.0 mmol) and potassium carbonate (3.31 g, 24.0 mmol) were added to dimethyl sulfoxide (20.0 mL) containing 5-chloro-2,4-difluorobenzaldehyde (3.53 g, 20.0 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0582] The reaction was terminated, and the mixture was quenched with water. The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The combined organic phase was washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 4.27 g of tert-butyl 4-(4-chloro-5-fluoro-2-formylphenyl)piperazine-1-carboxylate as a white solid was obtained (yield: 62.5%). LCMS: RT = 2.18 min, [M+H] + = 343.19.

[0583] Step B: Synthesis of tert-butyl (E)-4-(4-chloro-5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0584]

[0585] At room temperature, tert-butyl 4-(4-chloro-5-fluoro-2-formylphenyl)piperazine-1-carboxylate (4.27 g, 12.5 mmol) and 4-methylbenzenesulfonylhydrazide (2.44 g, 13.1 mmol) were added to anhydrous ethanol (62.5 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 h.

[0586] After the reaction was completed, the solvent was evaporated to dryness to obtain 6.39 g of tert-butyl (E)-4-(4-chloro-5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate as an off-white solid. It was used directly in the next step without purification. LCMS: RT = 2.21 min, [M+H] + = 511.23.

[0587] Step C: Synthesis of tert-butyl 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0588]

[0589] At room temperature, sodium hydride (500 mg, 12.5 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (28.0 mL) containing tert-butyl (E)-4-(4-chloro-5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (6.39 g, 12.5 mmol). Nitrogen was displaced for 20 min, and the reaction was carried out at 135 °C for 2 h.

[0590] The reaction was completed, and the reaction mixture was cooled to room temperature. It was dissolved in ethyl acetate (100 mL), washed successively with saturated brine (100 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 369 mg of pale yellow solid tert-butyl 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 9.0%). LCMS: RT = 2.23 min, [M+H] + = 327.22.

[0591] Step D: Synthesis of 8-chloro-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0592]

[0593] At room temperature, tert-butyl 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (369 mg, 1.13 mmol) was added to methanol (5.7 mL), and a dioxane solution of hydrochloric acid (1.4 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0594] After the reaction was completed, the solvent was evaporated to dryness to obtain 300 mg of off-white solid 8-chloro-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.59 min, [M+H] + = 227.12. 1 1H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 2H), 7.19 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 6.1 Hz, 1H), 3.86–3.76 (m, 2H), 3.28–3.18 (m, 3H), 3.03 (dd, J = 16.0, 7.9 Hz, 1H), 2.97–2.80 (m, 2H), 2.62 (dd, J = 16.0, 7.2 Hz, 1H).

[0595] Step E: Synthesis of (5S)-5-(3-(8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0596]

[0597] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (60.0 mg, 0.28 mmol) and 8-chloro-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (89 mg, 0.34 mmol) were added to anhydrous dichloromethane (4.0 mL). N,N-Diisopropylethylamine (187 μL, 1.13 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg, 0.42 mmol) and 1-hydroxybenzotriazole (6.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0598] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 41.4 mg of white solid (5S)-5-(3-(8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 34.7%). LCMS: RT = 1.89 min, [M-H] - = 419.20. 1 1H NMR (400 MHz, DMSO-d6) δ 10.67–10.52 (m, 1H), 7.68 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 6.71–6.58 (m, 1H), 4.39 (dd, J = 33.3, 12.9 Hz, 1H), 3.87–3.73 (m, 2H), 3.44 (s, 1H), 3.17–2.54 (m, 5H), 2.45–2.17 (m, 2H), 2.03–1.86 (m, 2H), 1.15–1.03 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.15–0.04 (m, 1H).

[0599] Examples 25 and 26

[0600] Synthesis of (5S)-5-(3-((S)-8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (5S)-5-(3-((R)-8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0601]

[0602] (5S)-5-(3-(8-Chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was resolved by chiral HPLC (Chiralpak AD-H, n-hexane:isopropanol = 80:20, the eluate was concentrated and lyophilized), and optically pure Compound 25 and Compound 26 were obtained successively.

[0603] Compound 25: HPLC: RT = 18.760 min. LCMS: RT = 1.89 min, [M-H] - = 419.20. 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.11–7.01 (m, 1H), 6.25 (d, J = 3.8 Hz, 0.5H), 6.23 (d, J = 3.8 Hz, 0.5H), 5.90 (s, 0.5H), 5.80 (s, 0.5H), 4.68–4.65 (m, 0.5H), 4.62–4.58 (m, 0.5H), 3.80–3.74 (m, 1H), 3.55–3.40 (m, 2H), 3.30–3.07 (m, 1H), 3.06–2.86 (m, 2H), 2.83–2.18 (m, 6H), 1.24–1.13 (m, 1H), 0.59 (d, J = 5.0 Hz, 1H), 0.51–0.36 (m, 2H), 0.36–0.25 (m, 1H).

[0604] Compound 26: HPLC: RT = 22.109 min. LCMS: RT = 1.89 min, [M-H] - = 419.20. 1 H NMR (400 MHz, CDCl 3)δ 7.67–7.54 (m, 1H), 7.06 (s, 0.5H), 7.04 (s, 0.5H), 6.25 (d, J = 9.5 Hz, 0.5H), 6.22 (d, J = 9.5 Hz, 0.5H), 5.86 (s, 0.5H), 5.78 (s, 0.5H), 4.71–4.56 (m, 1H), 3.80–3.74 (m, 1H), 3.51–3.45 (m, 2H), 3.30–3.08 (m, 1H), 3.05–2.85 (m, 2H), 2.83–2.18 (m, 6H), 1.23–1.13 (m, 1H), 0.65–0.52 (m, 1H), 0.52–0.36 (m, 2H), 0.36–0.24 (m, 1H).

[0605] Example 27

[0606] Synthesis of (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydro-1H-[1,4]diazaindolo[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0607]

[0608] The specific synthesis route is as follows:

[0609] Step A: Synthesis of tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepane-1-carboxylate

[0610]

[0611] At room temperature, tert-butyl 1,4-diazepane-1-carboxylate (6.06 g, 30.28 mmol) and potassium carbonate (4.53 g, 32.80 mmol) were added to dimethyl sulfoxide (24.0 mL) containing 2-fluoro-4-chlorobenzaldehyde (4.00 g, 25.23 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0612] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (100 mL × 3 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 6.20 g of pale yellow solid tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepane-1-carboxylate was obtained (yield: 72.5%). LCMS: RT = 2.16 min, [M + H] + = 339.19.

[0613] Step B: Synthesis of tert-butyl (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-1,4-diazepane-1-carboxylate

[0614]

[0615] At room temperature, tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepane-1-carboxylate (6.20 g, 18.30 mmol) and 4-methylbenzenesulfonylhydrazide (3.58 mg, 19.22 mmol) were added to anhydrous ethanol (60.0 mL), and the reaction was carried out at room temperature for 1 hour under N 2 protection.

[0616] After the reaction was completed, the solvent was evaporated to dryness to obtain 9.28 g of a pale white solid, tert-butyl (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-1,4-diazepane-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.25 min, [M+H] + = 507.23.

[0617] Step C: Synthesis of tert-butyl 8-chloro-4,5,11,11a-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-2(1H)-carboxylate

[0618]

[0619] At room temperature, sodium hydride (878.0 mg, 21.96 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (100.0 mL) containing tert-butyl (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-1,4-diazepane-1-carboxylate (9.28 g, 18.30 mmol). The nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0620] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed successively with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 2.12 g of a pale yellow solid, tert-butyl 8-chloro-4,5,11,11a-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-2(1H)-carboxylate (yield: 35.9%) was obtained. LCMS: RT = 2.27 min, [M+H] + = 323.26.

[0621] Step D: Synthesis of 8-chloro-1,2,3,4,10,10a-hexahydro-1H-[1,4]diazepino[1,2-a]indole hydrochloride

[0622]

[0623] At room temperature, tert-butyl 8-chloro-4,5,11,11a-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-2(1H)-carboxylate (2.12 g, 6.57 mmol) was added to methanol (20.0 mL), and a dioxane solution of hydrochloric acid (8.2 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0624] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.35 g of off-white solid 8-chloro-1,2,3,4,10,10a-hexahydro-1H-[1,4]diazepino[1,2-a]indole hydrochloride. Without purification, it was directly used for the next reaction. LCMS: RT = 1.59 min, [M+H] + = 223.18. 1 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 2H), 6.97 (d, J = 7.7 Hz, 1H), 6.57 (dd, J = 7.7, 1.7 Hz, 1H), 6.45 (d, J = 1.5 Hz, 1H), 4.32–4.18 (m, 1H), 3.52–3.43 (m, 1H), 3.41–3.29 (m, 2H), 3.26–3.15 (m, 1H), 3.11–2.96 (m, 3H), 2.66 (dd, J = 16.6, 7.9 Hz, 1H), 2.24–1.98 (m, 2H).

[0625] Step E: Synthesis of (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0626]

[0627] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-chloro-1,2,3,4,10,10a-hexahydro-1H-[1,4]diazepino[1,2-a]indole hydrochloride (67.1 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0628] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 35.5 mg of white solid (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 35.6%). LCMS: RT = 1.84 min, [M+H] + = 416.91. 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.77–7.65 (m, 1H), 6.96 (dd, J = 13.6, 7.5 Hz, 1H), 6.55–6.47 (m, 2H), 4.15–3.86 (m, 1H), 3.85–3.59 (m, 3H), 3.23–3.01 (m, 2H), 3.00–2.77 (m, 2H), 2.66–2.53 (m, 1H), 2.46–2.17 (m, 2H), 2.02–1.76 (m, 4H), 1.14–1.02 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.25 (m, 2H), 0.15–0.02 (m, 1H).

[0629] Example 28

[0630] Synthesis of (5S)-5-(3-(8-chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0631]

[0632] The specific synthesis route is as follows:

[0633] Step A: Synthesis of tert-butyl 8-chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate

[0634]

[0635] At room temperature, sodium hydride (878.0 mg, 21.96 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (100.0 mL) containing (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (9.28 g, 18.30 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0636] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed successively with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.28 g of pale yellow solid tert-butyl 8-chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate was obtained (yield: 21.7%). LCMS: RT = 2.25 min, [M+H] + = 323.37.

[0637] Step B: Synthesis of 8-chloro-2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indole hydrochloride

[0638]

[0639] At room temperature, tert-butyl 8-chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate (1.28 g, 4.00 mmol) was added to methanol (20.0 mL), and a dioxane solution of hydrochloric acid (5.0 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0640] After the reaction was completed, the solvent was evaporated to dryness to obtain 750.0 mg of off-white solid 8-chloro-2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.59 min, [M+H] += 223.18. 1 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.07 (s, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.57 (dd, J = 7.7, 1.6 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 4.04–3.89 (m, 1H), 3.84–3.63 (m, 1H), 3.37–3.29 (m, 1H), 3.29–3.23 (m, 2H), 3.23–3.08 (m, 3H), 2.61 (dd, J = 16.4, 8.0 Hz, 1H), 2.15–2.04 (m, 1H), 2.00–1.81 (m, 1H).

[0641] Step C: Synthesis of (5S)-5-(3-(8-chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0642]

[0643] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-chloro-2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indole hydrochloride (67.1 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0644] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 31.5 mg of white solid (5S)-5-(3-(8-chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 31.5%). LCMS: RT = 1.88 min, [M+H] + = 416.23. 11H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.69 (dd, J = 10.6, 6.8 Hz, 1H), 7.00–6.88 (m, 1H), 6.58–6.38 (m, 2H), 3.93–3.79 (m, 1H), 3.79–3.49 (m, 4H), 3.42–3.08 (m, 2H), 3.04–2.76 (m, 1H), 2.61–2.52 (m, 1H), 2.46–2.14 (m, 2H), 2.05–1.85 (m, 3H), 1.84–1.57 (m, 1H), 1.14–1.02 (m, 1H), 0.49–0.39 (m, 1H), 0.39–0.25 (m, 2H), 0.14–0.04 (m, 1H).

[0645] Example 29

[0646] Synthesis of (5S)-5-(3-(8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0647]

[0648] The specific synthetic route is as follows:

[0649] Step A: Synthesis of tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate

[0650]

[0651] At room temperature, N-tert-butoxycarbonylpiperazine (9.17 g, 49.26 mmol) and potassium carbonate (8.17 g, 59.11 mmol) were added to dimethyl sulfoxide (35.0 mL) containing 5-bromo-2-fluorobenzaldehyde (10.00 g, 49.26 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0652] After the reaction was completed, it was diluted with ethyl acetate (200 mL) and water (200 mL), separated, and the organic phase was collected. The organic phase was first washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 3.76 g of a beige solid, tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate, was obtained (yield: 20.7%). LCMS: RT = 2.20 min, [M+H] + = 369.13.

[0653] Step B: Synthesis of tert-butyl (E)-4-(4-bromo-2-((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate

[0654]

[0655] At room temperature, tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate (3.76 g, 10.18 mmol) and 4-methylbenzenesulfonylhydrazide (1.90 mg, 10.18 mmol) were added to anhydrous ethanol (20.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 2 hours.

[0656] After the reaction was completed, the solvent was evaporated to dryness to obtain 5.47 g of a beige solid, tert-butyl (E)-4-(4-bromo-2-((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate. It was directly used in the next step without purification. LCMS: RT = 2.21 min, [M+H] + = 539.19.

[0657] Step C: Synthesis of tert-butyl 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0658]

[0659] At room temperature, sodium hydride (439.6 mg, 10.99 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (25.0 mL) containing tert-butyl (E)-4-(4-bromo-2-((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate (5.47 g, 10.18 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0660] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (100 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.5 g of a beige solid, tert-butyl 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (yield: 41.7%) was obtained. LCMS: RT = 2.25 min, [M+H] + = 353.16.

[0661] Step D: Synthesis of 8-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0662]

[0663] At room temperature, tert-butyl 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (100.0 mg, 0.28 mmol) was added to methanol (3.0 mL), and a dioxane solution of hydrochloric acid (1 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 12 hours.

[0664] After the reaction was completed, the solvent was evaporated to dryness to obtain 75.0 mg of off-white solid 8-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next reaction without purification. LCMS: RT = 1.59 min, [M+H] + = 253.09. 1 1H NMR (400 MHz, DMSO) δ (ppm): 9.72–9.52 (m, 2H), 7.25 (s, 1H), 7.19 (dd, J = 8.4, 1.6 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 3.86–3.73 (m, 2H), 3.33–3.17 (m, 3H), 3.09–2.98 (m, 1H), 2.98–2.76 (m, 2H), 2.67–2.57 (m, 1H).

[0665] Step E: Synthesis of (5S)-5-(3-(8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione

[0666]

[0667] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (66.0 mg, 0.31 mmol) and 8-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (75.0 mg, 0.26 mmol) were added to N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (100.4 mg) was added dropwise. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (59.6 mg, 0.31 mmol) and 1-hydroxybenzotriazole (5.3 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0668] After the reaction was completed, it was diluted with water (50 mL) and ethyl acetate (50 mL), and then liquid-liquid separated. The organic phase was collected, washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 60.0 mg of a beige solid, (5S)-5-(3-(8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione, was obtained (yield: 51.8%). LCMS: RT = 1.88 min, [M+H] + = 447.20. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.69 (d, J = 3.6 Hz, 1H), 7.21 (s, 1H), 7.15 (dd, J = 8.4, 1.6 Hz, 1H), 6.51 (dd, J = 8.4, 4.4 Hz, 1H), 4.49–4.31 (m, 1H), 3.86–3.71 (m, 1H), 3.68–3.58 (m, 1H), 3.54–3.42 (m, 1H), 3.19–2.93 (m, 2H), 2.91–2.69 (m, 1H), 2.68–2.52 (m, 2H), 2.47–2.15 (m, 2H), 1.98–1.87 (m, 2H), 1.14–1.05 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.05 (m, 1H).

[0669] Example 30

[0670] Synthesis of (5S)-5-(3-(7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0671]

[0672] The specific synthetic route is as follows:

[0673] Step A: Synthesis of tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate

[0674]

[0675] At room temperature, N-tert-butoxycarbonylpiperazine (10.24 g, 55.0 mmol) and potassium carbonate (8.97 g, 65.0 mmol) were added to dimethyl sulfoxide (50.0 mL) containing 4-bromo-2-fluorobenzaldehyde (10.15 g, 50.0 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0676] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined. The combined organic phase was first washed with saturated brine (100 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 9.68 g of white solid tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 52.4%). LCMS: RT = 2.19 min, [M+H] + = 369.15.

[0677] Step B: Synthesis of (E)-tert-butyl 4-(5-bromo-2-((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate

[0678]

[0679] At room temperature, tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate (9.68 g, 26.2 mmol) and 4-methylbenzenesulfonylhydrazide (5.13 g, 27.5 mmol) were added to anhydrous ethanol (131 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0680] After the reaction was completed, the solvent was evaporated to dryness to obtain 14.2 g of off-white solid (E)-tert-butyl 4-(5-bromo-2-((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.23 min, [M+H] + = 539.17.

[0681] Step C: Synthesis of tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0682]

[0683] At room temperature, sodium hydride (1.15 g, 26.2 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (144 mL) containing tert-butyl (E)-4-(5-bromo-2-((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate (14.2 g, 26.2 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0684] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (500 mL), washed successively with saturated brine (150 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 5.40 g of tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate as a pale yellow solid was obtained (yield: 58.4%). LCMS: RT = 2.27 min, [M+H] + = 353.10.

[0685] Step D: Synthesis of 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0686]

[0687] At room temperature, tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (900 mg, 2.55 mmol) was added to methanol (12.7 mL), and a dioxane solution of hydrochloric acid (2.5 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0688] After the reaction was completed, the solvent was evaporated to obtain 740 mg of 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride as an off-white solid. It was used directly in the next step without purification. LCMS: RT = 1.59 min, [M+H] + = 253.13.

[0689] Step E: Synthesis of (5S)-5-(3-(7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0690]

[0691] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (300 mg, 1.41 mmol) and 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (492 mg, 1.70 mmol) were added to anhydrous dichloromethane (14.0 mL). N,N-Diisopropylethylamine (934 μL, 5.65 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (406 mg, 2.12 mmol) and 1-hydroxybenzotriazole (29 mg, 0.21 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0692] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (40 mL × 3 times). The organic phases were combined, washed successively with saturated brine (30 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 495 mg of white solid (5S)-5-(3-(7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 77.4%). LCMS: RT = 1.89 min, [M-H] - = 445.17. 1 1H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.78–6.66 (m, 2H), 4.40 (dd, J = 45.3, 12.8 Hz, 1H), 3.86–3.64 (m, 2H), 3.54–3.35 (m, 1H), 3.17–2.80 (m, 4H), 2.80–2.60 (m, 1H), 2.46–2.18 (m, 2H), 2.05–1.85 (m, 2H), 1.14–1.04 (m, 1H), 0.52–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.16–0.04 (m, 1H).

[0693] Example 31

[0694] Synthesis of (5S)-5-(3-(8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0695]

[0696] The specific synthesis route is as follows:

[0697] Step A: Synthesis of tert-butyl 4-(4-fluoro-2-formyl-5-methoxyphenyl)piperazine-1-carboxylate

[0698]

[0699] At room temperature, N-tert-butoxycarbonylpiperazine (2.60 g, 13.94 mmol) and potassium carbonate (2.09 g, 15.11 mmol) were added to dimethyl sulfoxide (12.0 mL) containing 2,5-difluoro-4-methoxybenzaldehyde (2.0 g, 11.62 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0700] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 2 times), then dried over 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 / 30). 2.03 g of pale yellow solid tert-butyl 4-(4-fluoro-2-formyl-5-methoxyphenyl)piperazine-1-carboxylate was obtained (yield: 51.6%). LCMS: RT = 2.09 min, [M+H] + = 339.24.

[0701] Step B: Synthesis of (E)-tert-butyl 4-(4-fluoro-5-methoxy-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0702]

[0703] At room temperature, tert-butyl 4-(4-fluoro-2-formyl-5-methoxyphenyl)piperazine-1-carboxylate (2.03 g, 6.00 mmol) and 4-methylbenzenesulfonylhydrazide (1.17 g, 6.30 mmol) were added to anhydrous ethanol (20.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0704] After the reaction was completed, the solvent was evaporated to obtain 3.04 g of off-white solid (E)-tert-butyl 4-(4-fluoro-5-methoxy-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was directly used in the next step without purification. LCMS: RT = 2.13 min, [M+H] + = 507.28.

[0705] Step C: Synthesis of tert-butyl 8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0706]

[0707] At room temperature, sodium hydride (288.0 mg, 7.20 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (30.0 mL) containing tert-butyl (E)-4-(4-fluoro-5-methoxy-2-(((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate (3.04 g, 6.00 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0708] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed successively with saturated brine (100 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.01 g of pale yellow solid tert-butyl 8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 52.17%). LCMS: RT = 2.13 min, [M+H] + = 323.24.

[0709] Step D: Synthesis of 8-fluoro-7-methoxy-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0710]

[0711] At room temperature, tert-butyl 8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.01 g, 3.13 mmol) was added to methanol (10.0 mL), and a dioxane solution of hydrochloric acid (3.9 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0712] After the reaction was completed, the solvent was evaporated to dryness to obtain 809.1 mg of off-white solid 8-fluoro-7-methoxy-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.47 min, [M+H] + = 223.22.

[0713] Step E: Synthesis of (5S)-5-(3-(8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0714]

[0715] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-fluoro-7-methoxy-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (67.0 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0716] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 29.0 mg of white solid (5S)-5-(3-(8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 29.0%). LCMS: RT = 1.79 min, [M+H] + = 417.25. 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.69 (d, J = 6.1 Hz, 1H), 6.94 (d, J = 10.9 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 4.40 (dd, J = 25.8, 11.4 Hz, 1H), 3.89–3.61 (m, 5H), 3.46–3.20 (m, 1H), 3.08 (dt, J = 44.0, 11.9 Hz, 1H), 2.97–2.54 (m, 3H), 2.57–2.16 (m, 3H), 2.01–1.85 (m, 2H), 1.14–1.02 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.25 (m, 2H), 0.16–0.04 (m, 1H).

[0717] Example 32

[0718] Synthesis of (5S)-5-(3-(7-(1H-pyrazol-4-yl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0719]

[0720] The specific synthesis route is as follows:

[0721] At room temperature, to a solution of (5S)-5-(3-(7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (50.0 mg, 0.11 mmol) in ethylene glycol dimethyl ether / ethanol / water (1.6 mL / 0.2 mL / 0.2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (43 mg, 0.22 mmol), sodium carbonate (24 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (8.0 mg, 0.011 mmol), under N 2 protection, and the reaction was carried out at 110 °C for 4 hours.

[0722] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL), washed successively with water (20 mL), the organic phase was first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 4 mg of white solid (5S)-5-(3-(7-(1H-pyrazol-4-yl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 8.4%). LCMS: RT = 1.68 min, [M+H] + = 435.30.

[0723] Example 33

[0724] Synthesis of (5S)-5-(3-(7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0725]

[0726] The specific synthesis route is as follows:

[0727] Step A: Synthesis of tert-Butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate

[0728]

[0729] At room temperature, to toluene (54.0 mL) containing 4,5-difluoro-2-fluorobenzaldehyde (3.0 g, 13.6 mmol) was added N-Boc piperazine (3.03 g, 16.3 mmol), cesium carbonate (6.20 g, 19.04 mmol), palladium acetate (61 mg, 0.27 mmol) and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) BINAP (423 mg, 0.68 mmol). Under N 2 protection, the reaction was carried out at 110 °C for 4 h.

[0730] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (200 mL), washed successively with water (100 mL), and the organic phase was first washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 500 mg of pale yellow solid tert-butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 11.3%). LCMS: RT = 2.13 min, [M+H] + = 327.20.

[0731] Step D: Synthesis of (E)-tert-Butyl 4-(4,5-difluoro-2-(((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate

[0732]

[0733] At room temperature, tert-butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate (500 mg, 1.53 mmol) and 4-methylbenzenesulfonylhydrazide (300 mg, 1.61 mmol) were added to anhydrous ethanol (7.6 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 h.

[0734] After the reaction was completed, the solvent was evaporated to obtain 760 mg of off-white solid (E)-tert-butyl 4-(4,5-difluoro-2-(((2-toluenesulfonylhydrazono)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.19 min, [M+H] + = 495.21.

[0735] Step E: Synthesis of tert-Butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0736]

[0737] At room temperature, sodium hydride (61 mg, 1.53 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (7.6 mL) containing tert-butyl (E)-4-(4,5-difluoro-2-(((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate (760 mg, 1.53 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0738] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed successively with saturated brine (100 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 280 mg of pale yellow solid tert-butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 59.0%). LCMS: RT = 2.18 min, [M+H] + = 311.25.

[0739] Step F: Synthesis of 7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0740]

[0741] At room temperature, tert-butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (280 mg, 0.90 mmol) was added to methanol (4.5 mL), and a dioxane solution of hydrochloric acid (0.90 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0742] After the reaction was completed, the solvent was evaporated to dryness to obtain 250 mg of off-white solid 7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.56 min, [M+H] + = 211.16.

[0743] Step G: Synthesis of (5S)-5-(3-(7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0744]

[0745] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (72 mg, 0.26 mmol) were added to anhydrous dichloromethane (2.0 mL). N,N-Diisopropylethylamine (156.0 μL, 0.94 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0746] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed successively with saturated brine (20 mL × 2 times), dried over 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). 27.2 mg of white solid (5S)-5-(3-(7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 28.6%). LCMS: RT = 1.82 min, [M+H] + = 405.29.

[0747] Examples 34 and 35

[0748] Synthesis of (5S)-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (5S)-5-(3-((R)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0749]

[0750] (5S)-5-(3-(7,8-Difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was resolved by chiral HPLC (Chiralpak AD-H, n-hexane: isopropanol = 80:20, the eluate was concentrated and lyophilized) to obtain optically pure compound 34 and compound 35 successively.

[0751] Compound 34: HPLC: RT = 16.898 min. LCMS: RT = 1.82 min, [M+H] + = 405.29. 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (s, 1H), 6.95–6.89 (m, 1H), 6.28 (d, J = 6.4 Hz, 0.5H), 6.25 (d, J = 6.4 Hz, 0.5H), 5.94 (m, 0.5H), 5.83 (m, 0.5H), 4.69–4.63 (m, 0.5H), 4.62–4.57 (m, 0.5H), 3.81–3.74 (m, 1H), 3.52–3.34 (m, 2H), 3.32–3.09 (m, 1H), 3.04–2.84 (m, 2H), 2.84–2.64 (m, 1H), 2.64–2.46 (m, 2H), 2.46–2.17 (m, 3H), 1.24–1.13 (m, 1H), 0.65–0.53 (m, 1H), 0.53–0.35 (m, 2H), 0.35–0.28 (m, 1H).

[0752] Compound 35: HPLC: RT = 19.139 min. LCMS: RT = 1.82 min, [M+H] + = 405.29. 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 0.5H), 7.70 (s, 0.5H), 6.96–6.89 (m, 1H), 6.31–6.21 (m, 1H), 5.92 (s, 0.5H), 5.85 (s, 0.5H), 4.66–4.63 (m, 0.5H), 4.61–4.58 (m, 0.5H), 3.79 (d, J = 12.7 Hz, 1H), 3.48–3.41 (m, 2H), 3.31–3.09 (m, 1H), 3.03–2.62 (m, 3H), 2.63–2.47 (m, 2H), 2.46–2.17 (m, 3H), 1.24–1.13 (m, 1H), 0.64–0.53 (m, 1H), 0.52–0.36 (m, 2H), 0.34–0.28 (m, 1H).

[0753] Another synthetic route of Compound 34

[0754] Synthesis of (S)-5-cyclopropyl-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0755]

[0756] The specific synthetic route is as follows:

[0757] Step A: Synthesis of (2-bromo-4,5-difluorophenyl)methanol

[0758]

[0759] At 0 degrees Celsius, add borane tetrahydrofuran solution (3.8 liters, 1.0 mol per liter) dropwise to tetrahydrofuran (4 liters) containing 2-bromo-4,5-difluorobenzoic acid (600 g, 2.53 mol). The reaction is exothermic and the dropping rate maintains the internal temperature between 50 and 80 degrees Celsius. After the addition is completed, continue stirring the reaction for 1 hour.

[0760] After the reaction was completed, the reaction solution was slowly poured into ice water and stirred until no bubbles were generated. The mixed solution was concentrated under reduced pressure to remove most of the solvent tetrahydrofuran, and the residue was filtered. The filtrate was extracted with ethyl acetate (1.2 L × 3 times), and the combined organic phases were first washed with saturated brine (1.5 L × 2 times), then dried over anhydrous sodium sulfate, and concentrated to obtain 585 g of white solid (2-bromo-4,5-difluorophenyl) methanol (yield: 98.4%). LCMS: RT = 1.88 min.

[0761] Step B: Synthesis of 1-bromo-2-(bromomethyl)-4,5-difluorobenzene

[0762]

[0763] Phosphorus tribromide (397 g / 137 ml, 1.46 mol) was slowly added dropwise in portions to a solution of (2-bromo-4,5-difluorophenyl)methanol (545 g, 2.44 mol) in dichloromethane (4 L) at 0°C. After the addition, the mixture was stirred at room temperature for 2 hours.

[0764] After the reaction was completed, the reaction solution was slowly poured into ice water, and the mixed solution was extracted with dichloromethane (1.5 liters x 2 times). The organic phases were combined and washed twice with sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 50) to obtain 596 grams of colorless transparent liquid 1-bromo-2-(bromomethyl)-4,5-difluorobenzene (yield: 85.4%). LCMS: RT = 2.13 min.

[0765] Step C: (S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((diphenylmethylene)amino)propanoate

[0766]

[0767] At zero degrees Celsius, (1S,2R,4S,5R)-2-((S)-(allyloxy)(quinolin-5-yl)methyl)-1-(anthracen-9-ylmethyl)-5-vinyl quinuclidinium bromide (76 g, 126 mmol) and 50% aqueous potassium hydroxide solution (3.4 kg, 50.4 mol) were successively added to dichloromethane (2 L) containing 1-bromo-2-(bromomethyl)-4,5-difluorobenzene (720 g, 2.51 mol) and tert-butyl 2-((diphenylmethylene)amino)acetate (705 g, 2.39 mol), and the reaction was continued with stirring at room temperature for 4 hours.

[0768] After the reaction was completed, the reaction mixture was allowed to stand for liquid separation. The organic phase was washed with water twice, separated, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1198 g of tert-butyl (S)-3-(2-bromo-4,5-difluorophenyl)-2-((diphenylmethylene)amino)propionate (yield: 95.5%, ee = 84%) was obtained as a pale yellow oil. LCMS: RT = 2.45 min, [M+H] + = 500.17.

[0769] Step D: Synthesis of tert-butyl (S)-2-amino-3-(2-bromo-4,5-difluorophenyl)propionate

[0770]

[0771] At room temperature, tert-butyl (S)-3-(2-bromo-4,5-difluorophenyl)-2-((diphenylmethylene)amino)propionate (1190 g, 2.38 mol) was dissolved in tetrahydrofuran (3 L), and a 3 L aqueous solution of citric acid (1143 g, 5.95 mol) was added, and the reaction was carried out at room temperature for 16 hours.

[0772] After the reaction was completed, most of the solvent tetrahydrofuran was concentrated under reduced pressure from the reaction mixture. The resulting residue was adjusted to a pH of about 2 with 5 M hydrochloric acid. Extraction was carried out 6 times with (1 L extraction solution: ethyl acetate / n-hexane = 1 / 10) until there was no upper point in the aqueous phase. The resulting aqueous phase was adjusted to a pH of about 10 with 50% sodium hydroxide, and then extracted with ethyl acetate (1.5 L × 3 times). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain 714 g of transparent oil of tert-butyl (S)-2-amino-3-(2-bromo-4,5-difluorophenyl)propionate (yield: 89.5%). LCMS: RT = 1.65 min, [M- t Bu+H] + = 280.07.

[0773] Step E: Resolution of tert-butyl (S)-2-amino-3-(2-bromo-4,5-difluorophenyl)propionate

[0774]

[0775] At room temperature, L-tartaric acid (347.0 g, 2.31 mol) was added to methanol (3.24 L) containing tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propionate (324.0 g, 964.3 mmol, ee = 84%). The mixture was stirred at room temperature for 12 h.

[0776] After the reaction was completed, filtration was carried out by suction. The filter cake was washed with a small amount of cold methanol and dried to obtain 282.3 g of white solid (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propionate tartrate (yield: 60.2%, ee = 100%). 1 1H NMR (400 MHz, DMSO) δ 7.86 (dd, J = 10.3, 7.8 Hz, 1H), 7.54 (dd, J = 11.7, 8.6 Hz, 1H), 3.78–3.73 (m, 1H), 3.06 (dd, J = 13.8, 7.4 Hz, 1H), 2.91 (dd, J = 13.9, 7.9 Hz, 1H), 1.32 (s, 9H).

[0777] Among them, the schematic diagram of the single crystal structure of (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propionate tartrate is as Figure 1 shown, and the specific crystal parameters are as follows:

[0778]

[0779] Step F: Synthesis of (S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((2-(tert-butoxy)-2-oxoethyl)amino)propionate

[0780]

[0781] Water was added to (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propionate tartrate (282.3 g, 582.1 mol). Under an ice bath, the pH was adjusted to 12 with saturated sodium hydroxide. Extraction was carried out with ethyl acetate (500 mL × 3 times). First, it was washed with saturated brine (200 mL × 2 times), then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product of (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propionate was dissolved in acetonitrile (2.0 L). Potassium carbonate (120.1 g, 870.6 mmol) and tert-butyl bromoacetate (118.9 g, 609.4 mol) were added in sequence. Nitrogen was displaced, and the reaction was carried out at 70 °C overnight.

[0782] The reaction was completed, and the reaction mixture was cooled to room temperature, followed by suction filtration. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 233.8 g of a pale yellow oil, (S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((2-(tert-butoxy)-2-oxoethyl)amino)propionate, was obtained (yield: 89.5%). LCMS: RT = 2.24 min, [M+H] + = 450.19.

[0783] Step G: Synthesis of (S)-tert-butyl 1-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoroindole-2-carboxylate

[0784]

[0785] At room temperature, cesium carbonate (220.0 g, 675.4 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (32.4 g, 52.0 mmol), and palladium(II) acetate (5.8 g, 26.0 mmol) were successively added to 1,4-dioxane (1.5 L) containing (S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((2-(tert-butoxy)-2-oxoethyl)amino)propionate (233.8 g, 519.5 mmol). The reaction system was purged with nitrogen, and the reaction was carried out at 110 °C overnight.

[0786] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (300 mL × 3 times), and the combined organic phases were washed with saturated brine (300 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 175.6 g of a pale yellow solid, (S)-tert-butyl 1-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoroindole-2-carboxylate, was obtained (yield: 91.5%). LCMS: RT = 2.23 min. 1 1H NMR (500 MHz, CDCl 3 ) δ 6.87–6.79 (m, 1H), 6.14 (dd, J = 11.1, 6.4 Hz, 1H), 4.47 (dd, J = 10.6, 8.7 Hz, 1H), 3.90 (q, J = 18.1 Hz, 2H), 3.32 (dd, J = 16.0, 10.6 Hz, 1H), 3.10 (dd, J = 16.0, 8.7 Hz, 1H), 1.49 (s, 9H), 1.42 (s, 9H).

[0787] Step H: Synthesis of (S)-2-(5,6-difluoro-2-(hydroxymethyl)indol-1-yl)ethan-1-ol

[0788]

[0789] N 2 Under protection and an ice-water bath, a toluene solution (365.6 mL, 1.5 mol / L) of diisobutylaluminum hydride was slowly added dropwise to toluene (100 mL) containing tert-butyl (S)-1-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoroindole-2-carboxylate (44.9 g, 121.5 mmol). After the addition was complete, the ice-water bath was removed, and the mixture was heated to 80 °C and reacted for 0.5 h.

[0790] After the reaction was completed, the reaction solution was slowly poured into ice. After the reaction was quenched, 30% NaOH solution (300 mL) was added to break the emulsion. The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (300 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was directly used for the next reaction. LCMS: RT = 1.74 min, [M+H] + = 230.15. 1 1H NMR (500 MHz, CDCl 3 ) δ 6.90–6.83 (m, 1H), 6.29–6.17 (m, 1H), 3.93–3.85 (m, 2H), 3.85–3.75 (m, 2H), 3.67 (dd, J = 12.0, 4.2 Hz, 1H), 3.34–3.25 (m, 2H), 3.07–2.96 (m, 1H), 2.95–2.85 (m, 1H).

[0791] Step I: Synthesis of (S)-7,8-difluoro-2-((trifluoromethyl)sulfonyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

[0792]

[0793] The above crude product was dissolved in tetrahydrofuran (486 mL), and triphenylphosphine (95.6 g, 364.5 mmol) and trifluoromethanesulfonamide (19.0 g, 127.6 mmol) were added successively. The mixture was cooled in an ice-water bath, and diisopropyl azodicarboxylate (73.7 g, 364.5 mmol) was slowly added. After the addition was complete, the cold bath was removed, and the mixture was reacted at room temperature for 1 h.

[0794] After the reaction was completed, the solvent was evaporated to dryness. The resulting viscous mixture was dissolved in ethyl acetate (200 mL), 2 L of n-hexane was added, and the mixture was filtered by suction. The filter cake was washed with a mixed solvent of n-hexane / ethyl acetate (10 / 1) until no product remained. The filtrate was evaporated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 20 - 1 / 10) to obtain 13.5 g of a pale yellow solid, (S)-7,8-difluoro-2-((trifluoromethyl)sulfonyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (yield: 32.5%). LCMS: RT = 2.13 min. 1 H NMR(500MHz,CDCl 3 )δ6.92–6.85(m,1H),6.21(dd,J=11.0,6.4Hz,1H),3.84(dd,J=11.2,3.4Hz,2H),3.70–3.60(m,1H),3.57(td,J=11.6,2.8Hz,1H),3.45(t,J=10.8Hz,1H),3.31(dd,J=12.9,2.6Hz,1H),3.13(ddd,J=12.8,11.8,3.5Hz,1H),2.90(dd,J=15.1,7.9Hz,1H),2.45(dd,J=15.1,7.9Hz,1H).

[0795] Step J: Synthesis of (S)-7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

[0796]

[0797] Under ice-water bath cooling, bis(2-methoxyethoxy)aluminum sodium dihydride (25.7 mL, 90.1 mmol, 70% toluene solution) was slowly added to toluene (64.3 mL) containing ((S)-7,8-difluoro-2-((trifluoromethyl)sulfonyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (7.7 g, 22.5 mmol)). After the addition was complete, the ice-water bath was removed, and the reaction was carried out at room temperature overnight.

[0798] After the reaction was completed, the reaction solution was slowly poured into ice. After sufficient quenching, 30% NaOH solution (100 mL) was added. The mixture was extracted with ethyl acetate (150 mL × 3 times). The organic phases were combined, washed first with saturated brine (200 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was directly used for the next reaction. LCMS: RT = 1.56 min, [M+H] + = 211.16.

[0799] Step K: Synthesis of (S)-5-cyclopropyl-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0800]

[0801] At room temperature, the above-mentioned crude product was dissolved in anhydrous dichloromethane (75 mL), (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (4.78 g, 22.5 mmol) was added, N,N-diisopropylethylamine (5.6 mL, 33.8 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.47 g, 33.8 mmol) and 1-hydroxybenzotriazole (304 mg, 2.254 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0802] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 2 times), then dried over 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). 6.4 g of white solid (S)-5-cyclopropyl-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione was obtained (yield: 70.3%). LCMS: RT = 1.82 min, [M+H] + = 405.29.

[0803] Example 36

[0804] Synthesis of (5S)-5-(3-(7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0805]

[0806] The specific synthesis route is as follows:

[0807] Step A: Synthesis of tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate

[0808]

[0809] At room temperature, N-Boc-piperazine (2.60 g, 32.58 mmol) and potassium carbonate (4.87 g, 35.30 mmol) were added to dimethyl sulfoxide (36.0 mL) containing 4-bromo-2,5-difluorobenzaldehyde (6.00 g, 27.15 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0810] After the reaction was completed, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the combined organic phases were washed with saturated brine (100 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 30). 2.60 g of pale yellow solid tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained (yield: 17.2%). LCMS: RT = 2.20 min, [M+H] + = 387.12.

[0811] Step B: Synthesis of (E)-tert-butyl 4-(5-bromo-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate

[0812]

[0813] At room temperature, tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.60 g, 6.71 mmol) and 4-methylbenzenesulfonyl hydrazide (1.31 g, 7.04 mmol) were added to anhydrous ethanol (25.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0814] After the reaction was completed, the solvent was evaporated to obtain 3.73 g of off-white solid (E)-tert-butyl 4-(5-bromo-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.25 min, [M+H] + = 555.19.

[0815] Step C: Synthesis of tert-butyl 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0816]

[0817] At room temperature, sodium hydride (322.0 mg, 7.20 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (40.0 mL) containing tert-butyl (E)-4-(5-bromo-4-fluoro-2-(((2-toluenesulfonylhydrazinyl)methyl)phenyl)piperazine-1-carboxylate (3.73 g, 6.72 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0818] After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed successively with saturated brine (100 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.77 g of pale yellow solid tert-butyl 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 71.1%). LCMS: RT = 2.25 min, [M+H] + = 371.21.

[0819] Step D: Synthesis of 7-bromo-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0820]

[0821] At room temperature, tert-butyl 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (200.0 mg, 0.54 mmol) was added to methanol (2.0 mL), and a dioxane solution of hydrochloric acid (674 μL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0822] After the reaction was completed, the solvent was evaporated to dryness to obtain 150.0 mg of off-white solid 7-bromo-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.59 min, [M+H] + = 271.08.

[0823] Step E: Synthesis of (5S)-5-(3-(7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0824]

[0825] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7-bromo-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (79.7 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL). N,N-Diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0826] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 25.3 mg of white solid (5S)-5-(3-(7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 22.6%). LCMS: RT = 1.88 min, [M+H] + = 465.18. 1 1H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.68 (d, J = 9.3 Hz, 1H), 7.12 (dd, J = 8.4, 3.1 Hz, 1H), 6.81 (dd, J = 9.4, 5.6 Hz, 1H), 4.39 (dd, J = 49.1, 11.5 Hz, 1H), 3.77 (dd, J = 37.1, 12.2 Hz, 1H), 3.66 (t, J = 13.1 Hz, 1H), 3.54–3.33 (m, 1H), 3.18–2.89 (m, 2H), 2.86–2.51 (m, 3H), 2.47–2.16 (m, 2H), 2.03–1.85 (m, 2H), 1.16–1.03 (m, 1H), 0.52–0.39 (m, 1H), 0.39–0.24 (m, 2H), 0.17–0.03 (m, 1H).

[0827] Examples 37 and 38

[0828] Synthesis of (S)-5-(3-((S)-7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0829]

[0830] Resolution of (5S)-5-(3-(7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione by chiral HPLC (Chiralpak AD-H, hexane:isopropanol = 80:20, eluate concentrated and lyophilized) gave optically pure compound 37 and compound 38 successively.

[0831] Compound 37: HPLC: RT = 17.451 min. LCMS: RT = 1.88 min, [M+H] + = 465.19. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 6.94–6.85 (m, 1H), 6.57 (d, J = 2.7 Hz, 0.5H), 6.56 (d, J = 2.7 Hz, 0.5H), 5.92 (s, 0.5H), 5.81 (s, 0.5H), 4.69–4.64 (m, 0.5H), 4.62–4.56 (m, 0.5H), 3.81–3.74 (m, 1H), 3.54–3.43 (m, 1H), 3.43–3.20 (m, 1H), 3.17–2.63 (m, 4H), 2.63–2.18 (m, 5H), 1.24–1.12 (m, 1H), 0.64–0.54 (m, 1H), 0.52–0.36 (m, 2H), 0.36–0.25 (m, 1H).

[0832] Compound 38: HPLC: RT = 21.053 min. LCMS: RT = 1.88 min, [M+H] + = 465.18. 1 1H NMR (400 MHz, CDCl 3)δ 7.82 (s, 0.5H), 7.80 (s, 0.5H), 6.91 (s, 0.5H), 6.89 (s, 0.5H), 6.57 (d, J = 5.4 Hz, 0.5H), 6.55 (d, J = 5.4 Hz, 0.5H), 5.96 (s, 0.5H), 5.88 (s, 0.5H), 4.68–4.63 (m, 0.5H), 4.62–4.57 (m, 0.5H), 3.81–3.74 (m, 1H), 3.50–3.39 (m, 2H), 3.19–2.61 (m, 4H), 2.62–2.17 (m, 5H), 1.24–1.13 (m, 1H), 0.65–0.53 (m, 1H), 0.53–0.35 (m, 2H), 0.35–0.25 (m, 1H).

[0833] Example 39

[0834] Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)propyl)imidazolidine-2,4-dione

[0835]

[0836] The specific synthesis route is as follows:

[0837] Step A: Synthesis of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0838]

[0839] At room temperature, N-tert-butoxycarbonylpiperazine (1.94 g, 10.41 mmol) and potassium carbonate (1.73 g, 12.49 mmol) were added to dimethyl sulfoxide (10.0 mL) containing 2-fluoro-4-trifluoromethyl-benzaldehyde (2.00 g, 10.41 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0840] After the reaction was completed, it was diluted with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic layer was collected, washed successively with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.30 g of a beige solid, tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate, was obtained (yield: 34.9%). LCMS: RT = 2.18 min, [M+H] + = 359.24.

[0841] Step B: Synthesis of tert-butyl (E)-4-(2-((2-toluenesulfonylhydrazinyl)methyl)-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0842]

[0843] At room temperature, tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate (1.30 g, 3.63 mmol) and 4-methylbenzenesulfonylhydrazide (709.4 mg, 3.81 mmol) were added to anhydrous ethanol (12 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0844] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.91 g of a beige solid, tert-butyl (E)-4-(2-((2-toluenesulfonylhydrazinyl)methyl)-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate. It was directly used in the next step without purification. LCMS: RT = 2.21 min, [M+H] + = 527.25.

[0845] Step C: Synthesis of tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[0846]

[0847] At room temperature, sodium hydride (145.1 mg, 3.63 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (15 mL) containing tert-butyl (E)-4-(2-((2-toluenesulfonylhydrazinyl)methyl)-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate (1.91 g, 3.63 mmol). Nitrogen was displaced for 20 minutes, and the reaction was carried out at 135 °C for 2 hours.

[0848] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 710.2 mg of a beige solid, tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (yield: 57.2%) was obtained. LCMS: RT = 2.25 min, [M+H] + = 343.19.

[0849] Step D: Synthesis of 7-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[0850]

[0851] At room temperature, tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (710.2 mg, 2.07 mmol) was added to methanol (8 mL), and a dioxane solution of hydrochloric acid (2.1 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 1 hour.

[0852] After the reaction was completed, the solvent was evaporated to dryness to obtain 410.0 mg of off-white solid 7-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used for the next reaction without purification. LCMS: RT = 1.59 min, [M+H] + = 243.17.

[0853] Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)propyl)imidazoline-2,4-dione

[0854]

[0855] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (167.5 mg, 0.79 mmol) and 7-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (200.0 mg, 0.72 mmol) were added to N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (278.3 mg) was added dropwise. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (165.1 mg, 0.86 mmol) and 1-hydroxybenzotriazole (14.6 mg, 0.11 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0856] After the reaction was completed, the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL), separated, the organic phase was collected, washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 150.0 mg of white solid (5S)-5-cyclopropyl-5-(3-oxo-3-(7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-yl)propyl)imidazoline-2,4-dione was obtained (yield: 47.9%). LCMS: RT = 1.89 min, [M+H] + = 437.23. 11H NMR (500 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 7.0, 4.0 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.0 Hz, 1H), 4.52–4.34 (m, 1H), 3.92–3.85 (m, 1H), 3.76–3.72 (m, 1H), 3.65–3.52 (m, 1H), 3.49–3.36 (m, 1H), 3.18–3.00 (m, 2H), 2.95–2.75 (m, 1H), 2.71–2.59 (m, 2H), 2.48–2.20 (m, 2H), 2.03–1.88 (m, 2H), 1.14–1.06 (m, 1H), 0.49–0.41 (m, 1H), 0.40–0.28 (m, 2H), 0.15–0.06 (m, 1H).

[0857] Example 40

[0858] Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propyl)imidazolidine-2,4-dione

[0859]

[0860] The specific synthesis route is as follows:

[0861] Step A: Synthesis of tert-butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate

[0862]

[0863] At room temperature, N-tert-butoxycarbonylpiperazine (4.34 g, 24.0 mmol) and potassium carbonate (4.96 g, 36.0 mmol) were added to dimethyl sulfoxide (30 mL) containing 2-fluoronicotinic acid (3.00 g, 24.0 mmol). Under N 2 protection, the reaction was carried out at 95 °C for 12 hours.

[0864] The reaction was terminated, quenched with water, and the mixture was extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, washed successively with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 5.50 g of pale yellow solid tert-butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate (yield: 78.8%). LCMS: RT = 2.16 min, [M+H] + = 292.27.

[0865] Step B: Synthesis of (E)-tert-butyl 4-(3-((2-toluenesulfonylbenzylidene)methyl)pyridin-2-yl)piperazine-1-carboxylate

[0866]

[0867] At room temperature, tert-butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate (1.00 g, 3.43 mmol) and 4-methylbenzenesulfonyl hydrazide (706 mg, 3.78 mmol) were added to anhydrous ethanol (20.0 mL). Under N 2 protection, the reaction was carried out at room temperature for 1 h.

[0868] After the reaction was completed, the solvent was evaporated to dryness to obtain 1.36 g of off-white solid (E)-tert-butyl 4-(3-((2-toluenesulfonylbenzylidene)methyl)pyridin-2-yl)piperazine-1-carboxylate. It was used directly in the next step without purification. LCMS: RT = 2.21 min, [M+H] + = 460.23.

[0869] Step C: Synthesis of tert-butyl 5a,6,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylate

[0870]

[0871] At room temperature, sodium hydride (142.1 mg, 3.45 mmol, 60% dispersed in paraffin oil) was added portionwise to toluene (15.0 mL) containing (E)-tert-butyl 4-(3-((2-toluenesulfonylbenzylidene)methyl)pyridin-2-yl)piperazine-1-carboxylate (1.36 g, 2.96 mmol). The nitrogen was displaced for 20 min, and the reaction was carried out at 135 °C for 2 h.

[0872] The reaction was completed, and the reaction mixture was cooled to room temperature and dissolved in ethyl acetate (50 mL). It was first washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 600.0 mg of pale yellow solid tert-butyl 5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylate was obtained (yield: 73.2%). LCMS: RT = 2.23 min, [M+H] + = 276.35.

[0873] Step D: Synthesis of 5,5a,6,7,8,9-hexahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine hydrochloride

[0874]

[0875] At room temperature, tert-butyl 5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylate (600.0 mg, 2.17 mmol) was added to methanol (6.0 mL), and a dioxane solution of hydrochloric acid (2.71 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0876] After the reaction was completed, the solvent was evaporated to dryness to obtain 430.0 mg of off-white solid 5,5a,6,7,8,9-hexahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine hydrochloride. It was used directly in the next step without purification. LCMS: RT = 1.49 min, [M+H] + = 176.23.

[0877] Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine-7(5H)-yl)propyl)imidazolidine-2,4-dione

[0878]

[0879] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 5,5a,6,7,8,9-hexahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine hydrochloride (45.7 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (156.0 μL) was added dropwise. Then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0880] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 28.0 mg of white solid (5S)-5-cyclopropyl-5-(3-oxo-3-(5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propyl)imidazolidine-2,4-dione was obtained (yield: 31.5%). LCMS: RT = 1.83 min, [M+H] + = 370.10. 1 1H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.77 (d, J = 4.8 Hz, 1H), 7.68 (s, 1H), 7.29 (d, J = 6.8 Hz, 1H), 6.47 (dd, J = 6.9, 5.3 Hz, 1H), 4.50–4.33 (m, 1H), 4.01–3.92 (m, 1H), 3.86–3.74 (m, 1H), 3.74–3.50 (m, 1H), 3.09–2.77 (m, 3H), 2.66–2.20 (m, 4H), 1.98–1.88 (m, 2H), 1.14–1.06 (m, 1H), 0.49–0.41 (m, 1H), 0.40–0.28 (m, 2H), 0.14–0.06 (m, 1H).

[0881] Example 41

[0882] Synthesis of (5S)-5-(3-(6,7-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0883]

[0884] The specific synthesis route is as follows:

[0885] Step A: Synthesize 6,7-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate

[0886]

[0887] At room temperature, add 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (241.7 mg, 0.92 mmol) and N-chlorosuccinimide (122.85 mg, 0.92 mmol) to dichloroethane (3.0 mL), and dropwise add trifluoromethanesulfonic acid (161.7 μL). Under N 2 protection, react at 75 °C overnight.

[0888] After the reaction is completed, 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, wash the organic phase first with saturated brine (20 mL × 2 times), then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The crude product is 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: eluted with 30% acetonitrile in 14.50 minutes; detection wavelength: 254 nm. After purification, lyophilize to obtain 40.0 mg of white solid 6,7-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (yield: 11.6%). LCMS: RT = 1.66 min, [M+H] + = 261.11. 1 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.83 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.82 (dd, J = 14.1, 3.6 Hz, 1H), 3.88 (qd, J = 8.8, 2.9 Hz, 1H), 3.34–3.22 (m, 3H), 3.13 (ddd, J = 15.0, 11.9, 4.7 Hz, 2H), 3.03 (ddd, J = 15.9, 8.0, 4.7 Hz, 1H), 2.66 (dd, J = 15.8, 8.7 Hz, 1H).

[0889] Step B: Synthesis of (5S)-5-(3-(6,7-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0890]

[0891] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (22.6 mg, 0.11 mmol) and 6,7-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (40.0 mg, 0.11 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (72.7 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) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0892] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 10.5 mg of white solid (5S)-5-(3-(6,7-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 21.0%). LCMS: RT = 1.97 min, [M+H] + = 455.21.

[0893] Example 42

[0894] Synthesis of (5S)-5-(3-(7,8-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0895]

[0896] The specific synthesis route is as follows:

[0897] Step A: Synthesis of 7,8-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate

[0898]

[0899] At room temperature, 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (241.7 mg, 0.92 mmol) and N-chlorosuccinimide (122.85 mg, 0.92 mmol) were added to dichloroethane (3.0 mL), and trifluoromethanesulfonic acid (161.7 μL) was added dropwise. Under N 2 protection, the reaction was carried out at 75 °C overnight.

[0900] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, quenched with water, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL × 2 times), 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 were as follows: chromatographic column: Agilent 5Prep-C18 100 mm × 30 mm 5 μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 mL / min; gradient: eluted with 30% acetonitrile in 15.50 minutes; detection wavelength: 254 nm. After purification, it was freeze-dried to obtain 40.0 mg of white solid 7,8-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (yield: 11.6%). LCMS: RT = 1.66 min, [M+H] + = 261.12. 1 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 2H), 6.83 (s, 1H), 3.93 (ddd, J = 16.6, 9.9, 3.3 Hz, 1H), 3.30–3.20 (m, 2H), 3.20–3.12 (m, 2H), 2.93 (dt, J = 17.5, 8.0 Hz, 2H), 2.75 (dd, J = 16.0, 6.0 Hz, 1H).

[0901] Step B: Synthesis of (5S)-5-(3-(7,8-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0902]

[0903] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (22.6 mg, 0.11 mmol) and 6,7-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (40.0 mg, 0.11 mmol) were added to N,N-dimethylformamide (2.0 mL). N,N-Diisopropylethylamine (72.7 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) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0904] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed successively with saturated brine (20 mL × 2 times), dried over 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). 8.5 mg of white solid (5S)-5-(3-(7,8-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 17.0%). LCMS: RT = 1.97 min, [M+H] + = 455.21. 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.68 (d, J = 5.5 Hz, 1H), 6.75 (d, J = 7.0 Hz, 1H), 4.39 (dd, J = 43.6, 11.3 Hz, 1H), 3.87–3.51 (m, 3H), 3.16–2.77 (m, 3H), 2.74–2.54 (m, 2H), 2.48–2.15 (m, 2H), 2.04–1.81 (m, 2H), 1.17–1.03 (m, 1H), 0.53–0.41 (m, 1H), 0.41–0.26 (m, 2H), 0.19–0.05 (m, 1H).

[0905] Example 43

[0906] Synthesis of (5S)-5-(3-(6,7,8-trichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0907]

[0908] The specific synthesis route is as follows:

[0909] Step A: Synthesis of 6,7,8-trichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate

[0910]

[0911] At room temperature, 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (241.7 mg, 0.92 mmol) and N-chlorosuccinimide (122.85 mg, 0.92 mmol) were added to dichloroethane (3.0 mL), and trifluoromethanesulfonic acid (161.7 μL) was added dropwise. Under N 2 protection, the reaction was carried out at 75 °C overnight.

[0912] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, quenched with water, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed first 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 were as follows: column: Agilent 5Prep-C18 100 mm × 30 mm 5 μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 mL / min; gradient: eluted with 30% acetonitrile in 17.50 minutes; detection wavelength: 254 nm. After purification, it was lyophilized to obtain 40.0 mg of white solid 6,7,8-trichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (yield: 14.7%). LCMS: RT = 1.66 min, [M+H] + = 295.09.

[0913] Step B: Synthesis of (5S)-5-(3-(6,7,8-trichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0914]

[0915] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (20.8 mg, 0.10 mmol) and 6,7,8-trichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (40.0 mg, 0.10 mmol) were 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 (21.1 mg, 0.11 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0916] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 5.6 mg of white solid (5S)-5-(3-(6,7,8-trichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 11.4%). LCMS: RT = 2.02 min, [M+H] + = 489.13. 1 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.68 (s, 1H), 4.61 (d, J = 12.1 Hz, 1H), 4.41 (dd, J = 62.5, 12.1 Hz, 1H), 3.96–3.55 (m, 2H), 3.23–2.62 (m, 5H), 2.47–2.17 (m, 2H), 2.03–1.86 (m, 2H), 1.14–1.04 (m, 1H), 0.52–0.41 (m, 1H), 0.41–0.25 (m, 2H), 0.18–0.04 (m, 1H).

[0917] Example 44

[0918] Synthesis of (S)-5-cyclopropyl-5-(3-oxo-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propyl)imidazolidine-2,4-dione

[0919]

[0920] The specific synthesis route is as follows:

[0921] Step A: Synthesis of (S)-5-cyclopropyl-5-(3-oxo-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propyl)imidazolidine-2,4-dione

[0922]

[0923] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (45.0 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (111.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0924] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 40.0 mg of white solid (S)-5-cyclopropyl-5-(3-oxo-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propyl)imidazolidine-2,4-dione was obtained (yield: 45.5%). LCMS: RT = 1.77 min, [M+H] + = 367.23. 1 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.61 (s, 1H), 7.72 (d, J = 19.3 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.07–6.99 (m, 1H), 6.99–6.91 (m, 1H), 4.66 (d, J = 8.9 Hz, 2H), 3.85–3.67 (m, 2H), 2.79–2.60 (m, 2H), 2.57–2.30 (m, 2H), 2.04–1.91 (m, 2H), 1.17–1.04 (m, 1H), 0.50–0.41 (m, 1H), 0.41–0.26 (m, 2H), 0.14–0.05 (m, 1H).

[0925] Example 45

[0926] Synthesis of (S)-5-(3-(6-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0927]

[0928] The specific synthesis route is as follows:

[0929] Step A: Synthesis of 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate

[0930]

[0931] At room temperature, paraformaldehyde (156.0 mg, 5.20 mmol) was added to a mixed solution of acetic acid (10.0 mL) and methanol (1.0 mL) containing 2-(5-chloro-1H-indol-3-yl)ethan-1-amine (1.00 g, 4.33 mmol). Under N 2 protection, the reaction was carried out at 80 °C for 3.5 hours.

[0932] After the reaction was completed, it was cooled to room temperature, filtered by suction, the filter cake was washed with a small amount of acetic acid, and dried to obtain 500.0 mg of white solid 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate (yield: 43.3%). LCMS: RT = 1.58 min, [M+H] + = 207.13.

[0933] Step B: Synthesis of (S)-5-(3-(6-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0934]

[0935] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate (69.1 mg, 0.26 mmol) were added to N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (156.0 μL) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[0936] After the reaction was completed, the reaction mixture was quenched by adding water. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined. The combined organic phase was washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 53.4 mg of white solid (S)-5-(3-(6-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 55.5%). LCMS: RT = 1.86 min, [M+H] + = 401.17. 1 H NMR (500 MHz, DMSO-d6) δ 11.11–11.03 (m, 1H), 10.62 (s, 1H), 7.72 (d, J = 23.0 Hz, 1H), 7.47–7.40 (m, 1H), 7.32 (dd, J = 8.5, 3.0 Hz, 1H), 7.07–7.00 (m, 1H), 4.66 (d, J = 7.1 Hz, 2H), 3.76 (dt, J = 39.6, 5.6 Hz, 2H), 2.70 (d, J = 51.9 Hz, 2H), 2.57–2.46 (m, 1H), 2.43–2.31 (m, 1H), 2.04–1.91 (m, 2H), 1.15–1.06 (m, 1H), 0.50–0.41 (m, 1H), 0.41–0.27 (m, 2H), 0.15–0.07 (m, 1H).

[0937] Example 46

[0938] Synthesis of (S)-5-(3-(7-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0939]

[0940] The specific synthesis route is as follows:

[0941] Step A: Synthesis of 2-(6-chloro-1H-indol-3-yl)acetamide

[0942]

[0943] At room temperature, N,N'-carbonyldiimidazole (426.5 mg, 2.63 mmol) was added to a solution of 2-(6-chloro-1H-indol-3-yl)acetic acid (500.0 mg, 2.39 mmol) in tetrahydrofuran (7.0 mL). 2Under protection, after stirring for 1.5 hours, ammonia water (10.0 mL) was added, and the reaction was carried out overnight at room temperature.

[0944] After the reaction was completed, it was cooled to room temperature, quenched with water, and the mixture was extracted with ethyl acetate (30 mL × 3 times). The organic phases were combined, washed successively with saturated brine (30 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 400.0 mg of yellow solid 2-(6-chloro-1H-indol-3-yl)acetamide was obtained (yield: 80.2%). LCMS: RT = 1.70 min, [M+H] + = 209.15.

[0945] Step B: Synthesis of 2-(6-chloro-1H-indol-3-yl)ethan-1-amine hydrochloride

[0946]

[0947] At room temperature, lithium aluminum hydride in THF solution (7.7 mL, 1.0 mol / L) was added dropwise to a solution of 2-(6-chloro-1H-indol-3-yl)acetamide (400.0 mg, 1.92 mmol) in THF (2.0 mL) under N 2 protection, and the reaction was carried out at 40 °C for 1 hour.

[0948] After the reaction was completed, it was cooled to room temperature, quenched slowly with saturated sodium hydroxide solution, diluted with ethyl acetate, filtered by suction, and the filtrate was washed successively with water (30 mL × 2 times) and saturated brine (30 mL × 2 times), then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The residue obtained was dissolved in ethyl acetate (10 mL), and the pH was adjusted to 3 with hydrochloric acid in ethyl acetate solution (1.0 mol / L), then filtered by suction. The filter cake was washed with ethyl acetate and dried to obtain 150.0 mg of yellow solid 2-(6-chloro-1H-indol-3-yl)ethan-1-amine hydrochloride (yield: 33.7%). LCMS: RT = 1.56 min, [M+H] + = 195.15.

[0949] Step C: Synthesis of 7-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate

[0950]

[0951] At room temperature, paraformaldehyde (23.3 mg, 0.78 mmol) was added to a mixed solution of acetic acid (1.0 mL) and methanol (0.1 mL) containing 2-(6-chloro-1H-indol-3-yl)ethan-1-amine hydrochloride (150.0 mg, 0.65 mmol) under N2 Under protection, react at 80 °C for 3.5 hours.

[0952] After the reaction is completed, cool to room temperature, filter by suction, wash the filter cake with a small amount of acetic acid, and dry to obtain 35.0 mg of white solid 7-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate (yield: 20.2%). LCMS: RT = 1.58 min, [M+H] + = 207.20.

[0953] Step D: Synthesis of (S)-5-(3-(7-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0954]

[0955] At room temperature, add (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (25.3 mg, 0.12 mmol) and 7-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate (35.0 mg, 0.13 mmol) to N,N-dimethylformamide (2.0 mL), dropwise add N,N-diisopropylethylamine (78.8 μL), then successively add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (25.2 mg, 0.13 mmol) and 1-hydroxybenzotriazole (2.5 mg, 0.01 mmol), under N 2 protection, react at room temperature overnight.

[0956] After the reaction is completed, quench with water, extract the mixture with ethyl acetate (20 mL × 3 times), combine the organic phases, wash the organic phase first with saturated brine (20 mL × 2 times), then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). Obtain 23.0 mg of white solid (S)-5-(3-(7-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 47.8%). LCMS: RT = 1.86 min, [M+H] + = 401.20. 11H NMR (500 MHz, DMSO) δ 11.03 (s, 1H), 10.62 (s, 1H), 7.72 (d, J = 19.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.38–7.33 (m, 1H), 6.98 (dd, J = 8.4, 1.9 Hz, 1H), 4.65 (d, J = 7.7 Hz, 2H), 3.77 (dt, J = 40.4, 5.6 Hz, 2H), 2.80–2.61 (m, 2H), 2.58–2.43 (m, 1H), 2.43–2.30 (m, 1H), 2.03–1.91 (m, 2H), 1.17–1.05 (m, 1H), 0.50–0.41 (m, 1H), 0.41–0.25 (m, 2H), 0.16–0.05 (m, 1H).

[0957] Example 47

[0958] Synthesis of (S)-5-(3-(7-chloro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[0959]

[0960] The specific synthesis route is as follows:

[0961] Step A: Synthesis of ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1H-indole-2-carboxylate

[0962]

[0963] At 0 °C, sodium hydride (536.5 mg, 13.41 mmol, 60% dispersed in paraffin oil) was added portionwise to DMF (15.0 mL) containing ethyl 6-chloro-1H-indole-2-carboxylate (2.00 g, 8.94 mmol). The temperature was raised to room temperature and the reaction was stirred for 0.5 h. (2-Bromoethyl)carbamic acid tert-butyl ester (2.61 g, 11.62 mmol) was added, and the temperature was raised to 70 °C and stirred for 12 h.

[0964] After completion of the reaction, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.60 g of a beige solid, ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1H-indole-2-carboxylate, was obtained (yield: 57.2%). LCMS: RT = 2.21 min, [M - Boc + H] + = 267.19.

[0965] Step B: Synthesis of ethyl 1-(2-aminoethyl)-6-chloro-1H-indole-2-carboxylate trifluoroacetate

[0966]

[0967] At room temperature, ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1H-indole-2-carboxylate (1.60 g, 4.36 mmol) was added to dichloromethane (15 mL), and trifluoroacetic acid (3 mL, 40.39 mmol) was added dropwise. The reaction was carried out at room temperature for 1 hour.

[0968] After the reaction was completed, the solvent was evaporated to dryness to obtain 2.00 g of a beige solid, ethyl 1-(2-aminoethyl)-6-chloro-1H-indole-2-carboxylate trifluoroacetate. It was directly used in the next step without purification. LCMS: RT = 1.66 min, [M+H] + = 267.18.

[0969] Step C: Synthesis of 7-chloro-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one

[0970]

[0971] At room temperature, water (15 mL) and sodium bicarbonate (3.49 g, 41.59 mmol) were added to tetrahydrofuran (30 mL) containing ethyl 1-(2-aminoethyl)-6-chloro-1H-indole-2-carboxylate trifluoroacetate (2.00 g, 4.16 mmol). Under N 2 protection, the reaction was carried out at 60 °C for 12 hours.

[0972] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 900 mg of a yellow solid, 7-chloro-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (yield: 77.7%) was obtained. LCMS: RT = 1.81 min, [M+H] + = 221.15.

[0973] Step D: Synthesis of 7-chloro-1,2,3,4-tetrahydropyrazino[1,2-a]indole

[0974]

[0975] At 0 °C, lithium aluminum hydride (464.4 mg, 12.24 mmol) was added portionwise to a solution of 7-chloro-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (900.0 mg, 4.08 mmol) in tetrahydrofuran (23 mL). After the addition, the temperature was raised to 60 °C, and the reaction was stirred for 3 h under N 2 protection.

[0976] After completion of the reaction, the reaction system was cooled to 0 °C, and water (0.9 mL), 15% NaOH(aq) (2.7 mL), and water (0.9 mL) were added. The mixture was stirred for 0.5 h, filtered through diatomaceous earth, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 800.0 mg of yellow solid 7-chloro-1,2,3,4-tetrahydropyrazino[1,2-a]indole was obtained (yield: 94.9%). LCMS: RT = 1.59 min, [M+H] + = 207.15. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.47–7.43 (m, 2H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 6.17–6.13 (m, 1H), 5.75 (s, 1H), 4.02 (d, J = 0.4 Hz, 2H), 3.94 (t, J = 5.6 Hz, 2H), 3.15 (t, J = 5.6 Hz, 2H).

[0977] Step E: Synthesis of (S)-5-(3-(7-chloro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione

[0978]

[0979] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (102.7 mg, 0.48 mmol) and 7-chloro-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100.0 mg, 0.48 mmol) were added to dichloromethane (12.0 mL). N,N-Diisopropylethylamine (93.8 mg) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (111.3 mg, 0.58 mmol) and 1-hydroxybenzotriazole (9.8 mg, 0.07 mmol) were added successively. The reaction was carried out overnight at room temperature under N 2 protection.

[0980] After the reaction was completed, it was diluted with water (50 mL) and dichloromethane (50 mL), separated by liquid-liquid extraction, and the organic phase was collected. The organic phase was washed with saturated brine (3 mL×2), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 45.0 mg of white solid (S)-5-(3-(7-chloro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione was obtained (yield: 23.2%). LCMS: RT = 1.88 min, [M+H] + = 401.22. 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.71 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.35 (d, J = 10.5 Hz, 1H), 4.88 (s, 1H), 4.83 (s, 1H), 4.21–4.15 (m, 1H), 4.11–4.06 (m, 1H), 3.99–3.91 (m, 2H), 3.00–2.86 (m, 1H), 2.44–2.31 (m, 1H), 2.05–1.92 (m, 2H), 1.15–1.05 (m, 1H), 0.48–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.14–0.06 (m, 1H).

[0981] Example 48

[0982] Synthesis of (S)-5-cyclopropyl-5-(3-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0983]

[0984] The specific synthetic route is as follows:

[0985] Step A: Synthesis of tert-butyl 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate

[0986]

[0987] At zero degrees Celsius, under nitrogen protection, triethylamine (323.0 μL) and di-tert-butyl dicarbonate (294.0 μL) were successively added dropwise to dichloromethane containing 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200.0 mg, 1.16 mmol), and the reaction was carried out at room temperature for 2 hours.

[0988] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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 / 30). 240.0 mg of tert-butyl 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate as a white solid was obtained (yield: 75.97%). LCMS: RT = 2.11 min, [M+H] + = 273.20.

[0989] Step B: Synthesis of tert-butyl 9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate

[0990]

[0991] At zero degrees Celsius, sodium hydride (44.0 mg, 1.84 mmol, 60% dispersed in paraffin oil) was added to tetrahydrofuran containing tert-butyl 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (240.0 mg, 2.32 mmol). Under nitrogen protection, after stirring at room temperature for 30 minutes, iodomethane (109.8 μL) was added, and the reaction was carried out at [temperature not specified] for 2 hours.

[0992] After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (40 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 2 times), then dried over 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 / 30). 140.0 mg of tert-butyl 9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate as a white solid was obtained (yield: 21.1%). LCMS: RT = 2.21 min, [M+H] + = 287.22.

[0993] Step C: Synthesis of 9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride

[0994]

[0995] At room temperature, tert-butyl 9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (140.0 mg, 0.49 mmol) was added to methanol (2.0 mL), and a dioxane solution of hydrochloric acid (610 μL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[0996] After the reaction was completed, the solvent was evaporated to dryness to obtain 110.0 mg of off-white solid 9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT = 1.52 min, [M+H] + = 187.21.

[0997] Step D: Synthesis of (S)-5-cyclopropyl-5-(3-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)imidazolidine-2,4-dione

[0998]

[0999] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (104.0 mg, 0.49 mmol) and 9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride (110.0 mg, 0.49 mmol) were added to N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (328.0 μL) was added dropwise. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (105.0 mg, 0.54 mmol) and 1-hydroxybenzotriazole (10.0 mg, 0.07 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[1000] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 39.5 mg of white solid (S)-5-cyclopropyl-5-(3-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl)imidazolidine-2,4-dione was obtained (yield: 21.2%). LCMS: RT = 1.84 min, [M+H] + = 381.24. 11H NMR (500 MHz, DMSO) δ 10.62 (s, 1H), 7.73 (d, J = 22.5 Hz, 1H), 7.51–7.34 (m, 2H), 7.17–7.06 (m, 1H), 7.01 (t, J = 7.4 Hz, 1H), 4.73 (s, 2H), 3.88–3.75 (m, 1H), 3.72 (t, J = 5.6 Hz, 1H), 3.66 (d, J = 10.9 Hz, 3H), 2.72 (d, J = 54.0 Hz, 2H), 2.60–2.49 (m, 1H), 2.45–2.33 (m, 1H), 2.11–1.90 (m, 2H), 1.17–1.05 (m, 1H), 0.51–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.17–0.06 (m, 1H).

[1001] Example 49

[1002] Synthesis of (5S)-5-(3-(3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[1003]

[1004] The specific synthesis route is as follows:

[1005] Step A: Synthesis of N-(2-(benzofuran-3-yl)ethyl)formamide

[1006]

[1007] At room temperature, a solution of ethyl formate (3.0 mL) containing 2-(benzofuran-3-yl)ethylamine (1.00 g, 6.20 mmol) was heated to 60 °C and reacted for 3 hours.

[1008] After the reaction was completed, it was diluted with ethyl acetate (100), and the organic phase was washed successively with saturated ammonium chloride and saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 1.22 g of pale yellow solid N-(2-(benzofuran-3-yl)ethyl)formamide was obtained, and the crude product was directly used for the next reaction. LCMS: RT = 1.75 min, [M+H] + = 190.19.

[1009] Step B: Synthesis of 3,4-dihydrobenzofuro[2,3-c]pyridine

[1010]

[1011] At room temperature, polyphosphoric acid (750 mg) was added to a solution of N-(2-(benzofuran-3-yl)ethyl)formamide (1.22 g, 6.45 mmol) in methanesulfonic acid (6.2 mL), and the mixture was heated to 90 °C and reacted for 3 hours.

[1012] After the reaction was completed, the reaction solution was slowly added dropwise to ice water, extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phase was washed successively with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 1.01 g of pale yellow solid 3,4-dihydrobenzofuro[2,3-c]pyridine. The crude product was used directly in the next step without purification. LCMS: RT = 1.40 min, [M+H] + = 172.12.

[1013] Step C: Synthesis of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine

[1014]

[1015] At room temperature, ammonium formate solution (1.86 g, 29.6 mmol, dissolved in 14.5 mL of water) and 10% palladium on carbon (59 mg) were successively added to a solution of 3,4-dihydrobenzofuro[2,3-c]pyridine (1.01 g, 5.91 mmol) in methanol (58.8 mL), nitrogen was displaced, and the mixture was reacted at 70 °C for 3 hours.

[1016] After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phase was washed successively with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 900 mg of pale yellow solid 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine. The crude product was used directly in the next step without purification. LCMS: RT = 1.49 min, [M+H] + = 174.17.

[1017] Step D: Synthesis of (5S)-5-(3-(3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[1018]

[1019] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 1,2,3,4-tetrahydrobenzofuran[2,3-c] (49 mg, 0.28 mmol) were added to anhydrous dichloromethane (2.0 mL), and N,N-diisopropylethylamine (156.0 μL, 0.94 mmol) was added dropwise. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[1020] After the reaction was completed, the reaction was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2 times), then dried over 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). 19.2 mg of white solid (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 22.1%). LCMS: RT = 1.83 min, [M-H] - = 366.23.

[1021] Example 50

[1022] Synthesis of (5S)-5-(3-(5,6-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-7(8H)-yl)-5-cyclopropylimidazolidine-2,4-dione

[1023]

[1024] The specific synthesis route is as follows:

[1025] Step A: Synthesis of ethyl 4-(2-(((tert-butoxycarbonyl)amino)ethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate

[1026]

[1027] Under an ice bath, sodium hydride (451 mg, 11.3 mmol, 60% dispersed in paraffin oil) was added portionwise to N,N-dimethylformamide (10.2 mL) containing ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (2.00 g, 10.2 mmol), and the mixture was stirred at room temperature for 15 minutes. Then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.62 g, 11.7 mmol) was added, and the reaction was carried out at room temperature for 12 hours.

[1028] After the reaction was completed, the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate (80 mL × 3 times). The organic phases were combined, washed successively with saturated sodium bicarbonate (80 mL) and brine (80 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.00 g of brown solid ethyl 4-(2-(((tert-butoxycarbonyl)amino)ethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate, which was directly used in the next step of the reaction. LCMS: RT = 1.73 min, [M - Boc + H] + = 239.17.

[1029] Step B: Synthesis of 6,7-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-8(5H)-one

[1030]

[1031] At room temperature, trifluoroacetic acid (10.0 mL) was added to a solution of ethyl 4-(2-(((tert-butoxycarbonyl)amino)ethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (4.00 g, 11.82 mmol) in dichloromethane (35.0 mL), and the reaction was carried out at room temperature for two hours. The solvent was evaporated under reduced pressure, and the resulting crude product was directly used in the next step of the reaction. LCMS: RT = 1.58 min, [M + H] + = 239.19.

[1032] The above crude product was dissolved in a mixed solvent of tetrahydrofuran (51.0 mL) and methanol (51.0 mL), potassium carbonate (8.4 g, 61.2 mmol) was added, and the reaction was carried out for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL × 3 times). The organic phases were combined, washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.90 g of yellow solid. The resulting crude product was used directly in the next step of the reaction without purification. LCMS: RT = 1.65 min, [M + H] + = 193.11.

[1033] Step C: Synthesis of 5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine

[1034]

[1035] At room temperature, borane tetrahydrofuran solution (51.0 mL, 51.0 mmol, 1 mol / L) was added to 6,7-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-8(5H)-one (1.90 g, 9.90 mmol), and the mixture was heated to 60 °C and reacted for 3 hours.

[1036] After the reaction was completed, the reaction mixture was cooled to room temperature, and slowly added to ice water. The mixture was extracted with ethyl acetate (80 mL × 2 times), and the organic phases were combined, washed successively with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 165 mg of white solid 5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine was obtained (yield: 9.4%). LCMS: RT = 1.72 min, [M+H] + = 179.02.

[1037] Step D: Synthesis of (5S)-5-(3-(5,6-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-7(8H)-yl)-5-cyclopropylimidazolidine-2,4-dione

[1038]

[1039] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine (50.3 mg, 0.28 mmol) were added to anhydrous dichloromethane (2.0 mL), and N,N-diisopropylethylamine (156.0 μL, 0.94 mmol) was added dropwise. Then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68.0 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[1040] The reaction was terminated, and the mixture was quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The combined organic phase was first washed with saturated brine (20 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 8.0 mg of white solid (5S)-5-(3-(5,6-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-7(8H)-yl)-5-cyclopropylimidazolidine-2,4-dione was obtained (yield: 9.1%). LCMS: RT = 1.78 min, [M-H] - = 371.23.

[1041] Example 51

[1042] Synthesis of (S)-5-(3-(7-chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione

[1043]

[1044] The specific synthetic route is as follows:

[1045] Step A: Synthesis of ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate

[1046]

[1047] At room temperature, ethyl 2-oxopropionate (1.41 g, 12.18 mmol) was added to ethanol (15 mL) containing (3-chloro-4-fluorophenyl)hydrazine hydrochloride (2.00 g, 10.15 mmol), and the temperature was raised to 78 °C. The mixture was stirred and reacted for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in toluene (25 mL). p-Toluenesulfonic acid (5.24 g) was added, and under N 2 protection, the reaction was carried out at 110 °C for 12 hours.

[1048] After the reaction was completed, the mixture was diluted with water (100 mL), extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The combined organic phase was first washed with saturated brine (5 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 260.0 mg of off-white solid ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate was obtained (yield: 10.6%). LCMS: RT = 2.05 min, [M + MeCN + H] + = 283.11.

[1049] Step B: Synthesis of Ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate

[1050]

[1051] At zero degrees Celsius, sodium hydride (64.5 mg, 1.61 mmol, 60% dispersed in paraffin oil) was added portionwise to DMF (13.0 mL) containing ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate (260.0 mg, 1.08 mmol). The temperature was raised to room temperature and the reaction was stirred for 0.5 h. (2-Bromoethyl) tert-butylcarbamate (313.5 mg, 1.40 mmol) was added, and the temperature was raised to 70 degrees Celsius and stirred for 12 h.

[1052] After the reaction was completed, it was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, washed with saturated brine (5 mL × 2 times), then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 240.0 mg of a beige solid, ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate, was obtained (yield: 58.0%). LCMS: RT = 2.23 min, [M - Boc + H] + = 285.16.

[1053] Step B: Synthesis of Ethyl 1-(2-aminoethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate Trifluoroacetate

[1054]

[1055] At room temperature, ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate (240.0 mg, 0.62 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (1 mL, 13.46 mmol) was added dropwise. The reaction was carried out at room temperature for 1 h.

[1056] After the reaction was completed, the solvent was evaporated to obtain 248.6 mg of a yellow solid, ethyl 1-(2-aminoethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate trifluoroacetate. It was used directly in the next step without purification. LCMS: RT = 1.70 min, [M + H] + = 285.16.

[1057] Step C: Synthesis of 7-Chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one

[1058]

[1059] At room temperature, water (3 mL) and sodium bicarbonate (523.8 mg, 6.23 mmol) were added to a solution of ethyl 1-(2-aminoethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate trifluoroacetate (248.6 mg, 0.62 mmol) in tetrahydrofuran (6 mL). Under N 2 protection, the reaction was carried out at 80 °C for 3 h.

[1060] After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic layer was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 145.0 mg of yellow solid 7-chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one was obtained (yield: 97.5%). LCMS: RT = 1.81 min, [M+H] + = 239.10.

[1061] Step D: Synthesis of 7-chloro-8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]indole

[1062]

[1063] At 0 °C, lithium aluminum hydride (76.3 mg, 2.01 mmol) was added portionwise to a solution of 7-chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (145 mg, 0.61 mmol) in tetrahydrofuran (10 mL). After the addition, the temperature was raised to 60 °C. Under N 2 protection, the reaction mixture was stirred for 3 h.

[1064] After the reaction was completed, the reaction system was cooled to 0 °C, and Na 2 SO 4 ·10H 2 O was added and the mixture was stirred for 0.5 h. The mixture was filtered through diatomaceous earth, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 102.0 mg of yellow solid 7-chloro-8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]indole was obtained (yield: 74.7%). LCMS: RT = 1.59 min, [M+H] + = 225.12.

[1065] Step E: Synthesis of (S)-5-(3-(7-chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione

[1066]

[1067] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (106.0 mg, 0.50 mmol) and 7-chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (102.0 mg, 0.45 mmol) were added to DMF (10 mL), N,N-diisopropylethylamine (176.0 mg, 1.36 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (104.4 mg, 0.54 mmol) and 1-hydroxybenzotriazole (9.2 mg, 0.07 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[1068] After the reaction was completed, the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL), separated, the organic phase was collected, washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 103.1 mg of a beige solid, (S)-5-(3-(7-chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione, was obtained (yield: 54.2%). LCMS: RT = 1.88 min, [M+H] + = 419.22. 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.71 (s, 1H), 7.47–7.40 (m, 1H), 7.13 (dd, J = 10.0, 9.0 Hz, 1H), 6.42 (d, J = 4.0 Hz, 1H), 4.92 (s, 1H), 4.87 (s, 1H), 4.22 (t, J = 5.0 Hz, 1H), 4.12 (t, J = 5.0 Hz, 1H), 4.01–3.92 (m, 2H), 3.17 (s, 1H), 2.44–2.31 (m, 1H), 2.06–1.93 (m, 2H), 1.16–1.06 (m, 1H), 0.49–0.41 (m, 1H), 0.40–0.28 (m, 2H), 0.14–0.07 (m, 1H).

[1069] Example 52

[1070] Synthesis of (5S)-5-(3-(6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[1071]

[1072] The specific synthesis route is as follows:

[1073] Step A: Synthesis of tert-butyl 6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate

[1074]

[1075] At room temperature, N-bromosuccinimide (301 mg, 1.69 mmol) and benzoyl peroxide (4.0 mg, 0.015 mmol) were added to carbon tetrachloride (15.0 mL) containing tert-butyl 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (500 mg, 1.54 mmol). Under N 2 protection, the reaction was carried out at 80 °C for 1 hour.

[1076] After the reaction was completed, the reaction solution was diluted with dichloromethane (80 mL). The organic phase was washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), then dried over 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 / 20). 420 mg of yellow solid tert-butyl 6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained (yield: 67.2%). LCMS: RT = 2.34 min, [M+H] + = 407.15.

[1077] Step D: Synthesis of 6-bromo-7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride

[1078]

[1079] At room temperature, tert-butyl 6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (92 mg, 0.23 mmol) was added to methanol (2.0 mL), and a dioxane solution of hydrochloric acid (0.28 mL, 4.0 mol / L) was added dropwise. Under N 2 protection, the reaction was carried out at room temperature for 3 hours.

[1080] The reaction was completed, and the solvent was evaporated to dryness to obtain 78 mg of a white solid, 6-bromo-7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT = 1.65 min, [M+H] + = 307.04.

[1081] Step E: Synthesis of (5S)-5-(3-(6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione

[1082]

[1083] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (50 mg, 0.24 mmol) and 6-bromo-7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (78 mg, 0.23 mmol) were added to anhydrous dichloromethane (4.0 mL). N,N-Diisopropylethylamine (156 μL, 0.94 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[1084] The reaction was completed, quenched with water, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 38.5 mg of a white solid, (5S)-5-(3-(6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 33.9%) was obtained. LCMS: RT = 1.95 min, [M+H] + = 499.12. 11H NMR (500 MHz, DMSO-d6) δ 10.62–10.56 (m, 1H), 7.68 (s, 1H), 7.27–7.22 (m, 1H), 4.72–4.65 (m, 1H), 4.37 (dd, J = 68.9, 12.3 Hz, 1H), 3.86 (dd, J = 45.5, 12.6 Hz, 1H), 3.60–3.50 (m, 1H), 3.26–3.11 (m, 1H), 3.10–2.75 (m, 3H), 2.75–2.57 (m, 1H), 2.47–2.17 (m, 2H), 2.00–1.90 (m, 2H), 1.10 (d, J = 7.7 Hz, 1H), 0.49–0.40 (m, 1H), 0.40–0.28 (m, 2H), 0.14–0.06 (m, 1H).

[1085] Example 53

[1086] Synthesis of (S)-5-cyclopropyl-5-(3-(3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione

[1087]

[1088] The specific synthesis route is as follows:

[1089] Step A: Synthesis of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-benzo[d]imidazole-2-carboxylate

[1090]

[1091] At 0 °C, sodium hydride (340.5 mg, 8.51 mmol, 60% dispersed in paraffin oil) was added portionwise to DMF (12 mL) containing ethyl 1H-benzo[d]imidazole-2-carboxylate (1.00 g, 5.68 mmol). The temperature was raised to room temperature and stirred for 0.5 h. (2-Bromoethyl) tert-butylcarbamate (1.65 g, 7.38 mmol) was added, and the temperature was raised to 70 °C and stirred for 12 h.

[1092] After the reaction was completed, it was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, washed with saturated brine (2 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 20). 1.20 g of a beige solid, ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-benzo[d]imidazole-2-carboxylate, was obtained (yield: 68.3%). LCMS: RT = 2.21 min, [M+H]+ = 320.28.

[1093] Step B: Synthesis of ethyl 1-(2-aminoethyl)-1H-benzo[d]imidazole-2-carboxylate hydrochloride

[1094]

[1095] At room temperature, ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-benzo[d]imidazole-2-carboxylate (1.00 g, 3.13 mmol) was added to dichloromethane (15 mL), and hydrochloric acid / dioxane (2 mL, 8 mmol) was added dropwise. The reaction was carried out at room temperature for 1 hour.

[1096] After the reaction was completed, the solvent was evaporated to dryness to obtain 800.7 mg of yellow solid ethyl 1-(2-aminoethyl)-1H-benzo[d]imidazole-2-carboxylate hydrochloride. It was used directly in the next step without purification. LCMS: RT = 0.86 min, [M+H] + = 220.20.

[1097] Step C: Synthesis of 3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-1(2H)-one

[1098]

[1099] At room temperature, water (10 mL) and sodium bicarbonate (2.63 g, 31.31 mmol) were added to tetrahydrofuran (20 mL) containing ethyl 1-(2-aminoethyl)-1H-benzo[d]imidazole-2-carboxylate hydrochloride (800.7 mg, 3.13 mmol). Under N 2 protection, the reaction was carried out at 60 °C for 12 hours.

[1100] After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (100 mL), separated, and the organic phase was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 112.4 mg of yellow oil 3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-1(2H)-one was obtained (yield: 19.2%). LCMS: RT = 1.29 min, [M+H] + = 188.16.

[1101] Step D: Synthesis of 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine

[1102]

[1103] At 0 °C, lithium aluminum hydride (68.4 mg, 1.80 mmol) was added portionwise to a solution of 3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-1(2H)-one (112.4 mg, 0.60 mmol) in tetrahydrofuran (10 mL). After addition, the temperature was raised to 66 °C, and under N 2 protection, the reaction mixture was stirred for 3 h.

[1104] After the reaction was completed, the reaction system was cooled to 0 °C, and Na 2 SO 4 ·10H 2 O was added, and the mixture was stirred for 0.5 h. The mixture was filtered through diatomaceous earth, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 75.2 mg of yellow oil, 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine was obtained (yield: 72.3%). LCMS: RT = 0.28 min, [M+H] + = 174.20.

[1105] Step E: Synthesis of (S)-5-cyclopropyl-5-(3-(3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-3-oxopropyl)imidazoline-2,4-dione

[1106]

[1107] At room temperature, (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid (101.3 mg, 0.48 mmol) and 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (75.2 mg, 0.43 mmol) were added to DMF (5 mL). N,N-Diisopropylethylamine (168.3 mg, 1.30 mmol) was added dropwise, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (108.2 mg, 0.56 mmol) and 1-hydroxybenzotriazole (11.7 mg, 0.09 mmol) were added successively. Under N 2 protection, the reaction was carried out at room temperature overnight.

[1108] After the reaction was completed, it was diluted with water (100 mL), extracted with a mixed solvent of MeOH:DCM = 1:10 (30 mL × 3 times), the organic phases were combined, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 61.1 mg of yellow solid (S)-5-cyclopropyl-5-(3-(3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-3-oxopropyl)imidazoline-2,4-dione was obtained (yield: 38.3%). LCMS: RT = 1.47 min, [M+H] + = 368.26. 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm): 10.62 (s, 1H), 7.86–7.75 (m, 2H), 7.72 (s, 1H), 7.54–7.46 (m, 2H), 5.09 (s, 1H), 5.06 (d, J = 7.5 Hz, 1H), 4.41–4.38 (m, 1H), 4.27–4.24 (m, 1H), 4.08–4.06 (m, 2H), 2.86–2.71 (m, 1H), 2.46–2.34 (m, 1H), 2.03–1.96 (m, 2H), 1.16–1.08 (m, 1H), 0.50–0.42 (m, 1H), 0.40–0.26 (m, 2H), 0.15–0.07 (m, 1H).

[1109] Example 54

[1110] Inhibitory Activity of Compound 54.1 against Human ADAMTS5

[1111] (1) Main Experimental Materials

[1112] Enzyme: Human ADAMTS5 (R&D systems, catalog number: 2198-AD);

[1113] Substrate: WAAG-3R (Anaspec, catalog number: 60431-1);

[1114] Detection buffer: 50 mM Tris, 100 mM NaCl, 5 mM CaCl2, 0.05% Brij35, pH 7.5

[1115] (2) Experimental Procedure

[1116] Dissolve the compound in DMSO to prepare 30 or 100 mM stock solutions. When detecting, set 8 concentration gradients. First, adjust the concentration of the stock solution to 3 or 3.33 mM with DMSO to obtain the highest concentration, and then dilute the highest concentration with DMSO in a 1 / 3 gradient to obtain the remaining 7 concentrations. Then, take 2 μl from a series of DMSO dilutions and add them to 198 μl of buffer to obtain serial dilutions of the compound with the highest concentration of 30 or 33.3 μM.

[1117] Add 5 μl of human ADAMTS5 enzyme solution (30 μg / ml) and 5 μl of the serial dilutions of the compound to a 384-well plate (CISBIO, catalog number: 6008280), incubate at 37 °C for 30 min, then add 5 μl of substrate diluted with buffer (75 μM) to initiate the reaction, and read the fluorescence at 37 °C for 30 min (excitation wavelength 355 nm, emission wavelength 460 nm) using FLUOstar Omega (BMG LABTECH).

[1118] (3) Data processing

[1119] Use the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, and calculate the IC 50 value after fitting with GraphPad 6.

[1120] Table 1 Potency of the compounds of the present invention against human ADAMTS5

[1121]

[1122] 54.2 Inhibitory activity of the compound against human MMP-9

[1123] (1) Experimental materials

[1124] Enzyme: human MMP-9 (R&D systems, catalog number: 911-MP);

[1125] Substrate: MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH2 (R&D systems, catalog number: ES001);

[1126] Detection buffer: 50 mM Tris, 10 mM CaCl2, 150 mM NaCl, 0.05% (w / v) Brij-35, pH 7.5 (TCNB).

[1127] (2) Experimental procedures

[1128] The compound was dissolved in DMSO to prepare 30 or 100 mM stock solutions. When detecting, 8 concentration gradients were set. First, the stock solution concentration was adjusted to 30 or 33.3 mM with DMSO to obtain the highest concentration, and the remaining 7 concentrations were obtained by diluting the stock solution from the highest concentration with a 1 / 3 gradient using DMSO. Then, 2 μl was taken from a series of DMSO dilutions and added to 198 μl of buffer to obtain a serial dilution of the compound with the highest concentration of 300 or 333.3 μM.

[1129] 5 μl of human MMP-9 enzyme solution (0.2 μg / ml, pre-activated by incubating with 1 mM APMA at 37 °C for 24 h) and 5 μl of the serial dilution of the compound were added to a 384-well plate (CISBIO, catalog number: 6008280), and incubated at 37 °C for 20 min. Then, 5 μl of the substrate diluted with buffer (30 μM) was added to initiate the reaction. Under the condition of 37 °C, fluorescence was read for 20 min using FLUOstar Omega (BMGLABTECH) (excitation wavelength 340 nm, emission wavelength 420 nm).

[1130] (3) Data processing

[1131] With the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, the IC50 value was calculated after fitting with GraphPad 6.

[1132] Table 8 Potency of the compounds of the present invention against human MMP-9

[1133]

[1134] As can be seen from the above results, the compounds of the present invention exhibited excellent ADAMTS5 inhibitory activity. At the same time, they had better selectivity relative to MMP-9.

[1135] Example 55: Investigation of the pharmacokinetic characteristics of the compounds of the present invention in rats

[1136] (1) Experimental materials

[1137] SD rats: male, 180 - 250 g, purchased from the Guangdong Provincial Medical Experimental Animal Center.

[1138] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, propranolol (internal standard) were all commercially available.

[1139] Instruments: Thermo Fisher LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[1140] (2) Experimental methods

[1141] Weigh the compound and dissolve it in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After intravenous or intragastric administration to rats, collect 200 μL of venous blood at 5 min, 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h into heparinized EP tubes, centrifuge at 12,000 rpm for 2 min, and store the plasma at -80 °C for future measurement. Weigh a certain amount of the test sample precisely and dissolve it in DMSO to 1 mg / mL to prepare a stock solution. Accurately pipette an appropriate amount of the compound stock solution and dilute it with acetonitrile to prepare a standard series of solutions. Accurately pipette 20 μL of each of the above standard series of solutions, add 180 μL of blank plasma, vortex and mix well to prepare plasma samples with plasma concentrations equivalent to 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng / mL. Analyze each concentration in duplicate to establish a standard curve. Take 20 μL of plasma (dilute the plasma at 5 min, 15 min, 30 min, and 1 h after intravenous administration by 10 times), add 200 μL of an acetonitrile solution of the internal standard propranolol (5 ng / mL), vortex and mix well, then centrifuge at 4000 rpm for 5 min, and take the supernatant for LC-MS analysis. The LC-MS detection conditions are as follows:

[1142] Chromatographic column: Thermo Fisher HYPERSIL GOLD C-18 UPLC column, 100 * 2.1 mm, 1.9 μm.

[1143] Mobile phase: Water (0.1% formic acid)-acetonitrile for gradient elution according to the following table

[1144] 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％

[1145] (3). Data processing

[1146] After LC-MS detection of the blood drug concentration, use WinNonlin 6.1 software and the non-compartmental model method to calculate the pharmacokinetic parameters. The results are shown in Table 11.

[1147] Table 11 Pharmacokinetic parameters of the compound of the present invention in rats (IV and PO administration)

[1148]

[1149] Conclusion: The compound of the present invention has good absorption after oral administration to rats, a slower clearance rate than the control compound, a larger apparent volume of distribution than the control compound, and good oral bioavailability.

[1150] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. Tricyclic fused derivatives, characterized in that, the derivatives are selected from tricyclic fused derivatives of formula (I), (III) or their stereoisomers, tautomers, pharmaceutically acceptable salts: wherein: X is selected from nitrogen; Z is selected from carbon, nitrogen, oxygen; T 1 、T 2 、T 3 、T 4 are respectively selected from carbon and nitrogen; represents a single bond or a double bond; wherein, there are no substituents on ring A and ring B; The C ring is substituted by more than one R 1 , where R 1 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, or -NR 7g R 7 h; R 2 Selected from: hydrogen, C 1-6 alkyl or optionally substituted by one or more independently selected R 3 groups, C 3-7 a monocyclic cycloalkyl group or an optionally substituted one or more independently selected R 3 groups; R 3 Selected from: halogen, hydroxyl, cyano, or -NR 6a R 6b ; R 6a or R 6b are independently selected from: -hydrogen, or -C 1-6 alkyl; R 7g or R 7h is independently selected from H or C 1-6 alkyl; n＝1； m = 0 to 4 natural numbers.

2. The tricyclic fused derivative according to claim 1, characterized in that, the derivatives are selected from tricyclic fused derivatives of formula (Ia), (IIIa) or their stereoisomers, tautomers, pharmaceutically acceptable salts, Among them, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, n are defined as above.

3. The tricyclic fused derivative according to claim 1, characterized in that, the derivatives are selected from tricyclic fused derivatives of formula (Ib), (IIIb) or their stereoisomers, tautomers, pharmaceutically acceptable salts, Among them, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, n are defined as above.

4. The tricyclic fused derivative according to claim 1, characterized in that, the derivatives are selected from tricyclic fused derivatives of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (IIc), (IId), (IIIc) or their stereoisomers, tautomers, pharmaceutically acceptable salts, wherein, R 1 , m are defined as above, and R 8 is selected from H.

5. The tricyclic fused derivative according to claim 1, characterized in that, the derivatives are selected from tricyclic fused derivatives of formula (Ij), (Ik) or their stereoisomers, tautomers, pharmaceutically acceptable salts, R 1 , m is defined as above.

6. The tricyclic fused derivative according to claim 1, characterized in that, the halogen is fluorine, chlorine, bromine, iodine; The C 1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl; The C 1-6 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, neohexyloxy, sec-hexyloxy, tert-hexyloxy; The said C 3-7 The monocyclic cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

7. The tricyclic fused derivative according to claim 1, characterized in that, R 1 selected from fluorine, chlorine, bromine, methoxy, trifluoromethyl, cyano; R 2 selected from cyclopropyl, n = 1; m is a natural number from 0 to 4.

8. The tricyclic fused derivative according to claim 2 or 3, characterized in that, Z is selected from carbon, nitrogen, oxygen; T 1 , T 2 , T 3 , T 4 are each independently selected from carbon; represents a single bond or a double bond; R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy, trifluoromethyl, cyano; n = 1; m is a natural number from 0 to 4.

9. The tricyclic fused derivative according to claim 4, characterized in that, R 1 selected from hydrogen, fluorine, chlorine, bromine, methoxy, trifluoromethyl, cyano; m = 0 to 4 natural numbers; R 8 is selected from H.

10. The tricyclic fused derivative according to claim 5, characterized in that, R 1 selected from hydrogen, fluorine, chlorine, bromine, methoxy, trifluoromethyl, cyano; m is a natural number from 0 to 4.

11. The tricyclic fused derivative according to claim 1, characterized in that, the derivatives are selected from the tricyclic fused derivatives shown in the following table or their stereoisomers, tautomers, pharmaceutically acceptable salts, 12. The tricyclic fused derivative according to any one of claims 1-7, 9-11, characterized in that, the pharmaceutically acceptable salts are selected from salts formed with inorganic acids or organic acids.

13. The tricyclic fused derivative according to any one of claims 1-7, 9-11, characterized in that, one or more hydrogen atoms of the tricyclic fused derivative are replaced by the isotope deuterium.

14. A pharmaceutical composition, characterized in that, it comprises the tricyclic fused derivative according to any one of claims 1-13 and one or more pharmaceutically acceptable carriers.

15. Use of the tricyclic fused derivative according to any one of claims 1-13 in the preparation of a drug for treating and / or preventing diseases related to the inhibition of proteoglycanase 2.

16. Use of the pharmaceutical composition according to claim 14 in the preparation of a drug for treating and / or preventing diseases related to the inhibition of proteoglycanase 2.

17. The use according to claim 15 or 16, wherein the disease involves an inflammatory condition and / or cartilage degeneration and / or disruption of cartilage homeostasis.

18. The use according to claim 15 or 16, wherein the disease is osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete bone formation, metastatic bone disease, malignant hypercalcemia or multiple myeloma.

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