Compounds that modulate the activity of NMDA receptors, pharmaceutical compositions and uses thereof

Abstract

The present invention provides compounds that modulate NMDA receptor activity, pharmaceutical compositions thereof, and uses thereof. Specifically, the present invention provides a compound represented by Formula I, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof. The compound has the effect of enhancing NMDA receptor activity and can be used in the manufacture of drugs for the prevention and treatment of disorders such as depression, anxiety, stress, learning and cognitive disorders, and neuropathic pain. [Formula 1] JPEG2023525860000311.jpg18170

Description

[Technical field]

[0001] The present invention is in the field of medicinal chemistry and relates to compounds that modulate the activity of NMDA receptors, pharmaceutical compositions and uses thereof. Specifically, the present invention relates to compounds that modulate the activity of NMDA receptors and the use of such compounds in the manufacture of medicaments for the prevention and treatment of depression, anxiety, stress, learning and cognitive dysfunction, neuropathic pain and other disorders. [Background technology]

[0002] N-methyl-d-aspartate (NMDA) receptors are ionotropic receptors for the excitatory neurotransmitter glutamate and are involved in a variety of complex physiological and pathological mechanisms. 2+ It mediates the influx of Ca, enhancing synaptic plasticity and contributing to learning, memory, and nervous system development; it activates NMDA receptors and induces Ca 2+ This causes a massive influx of NMDA receptors, ultimately resulting in cell death. Dysregulation of NMDA receptor function is thought to be an important cause of central nervous system diseases such as neurodegenerative diseases, depression, epilepsy, and ischemic brain injury.

[0003] The NMDA receptor is deeply involved in excitotoxicity. Excitotoxicity causes excessive release of extracellular glutamate, which leads to overactivation of the NMDA receptor, which then leads to Ca 2+ and Na + inflow and K + This leads to the release of intracellular Ca, which activates intracellular signaling pathways. 2+ This causes cellular dysfunction due to overload, and then induces apoptosis or initiates cell death signaling pathways, ultimately leading to neuronal cell death, neurodegenerative diseases, depression, and other disorders. NMDA receptor antagonists inhibit its activation, thereby reducing cellular excitotoxicity. Furthermore, NMDA receptors act by upregulating Ca 2+By mediating the influx of NMDA receptors, it enhances synaptic plasticity and neuronal excitability, induces long-term promotion (LTP), and improves neuronal development, thereby playing an important role in the treatment of neurodegenerative diseases, depression, schizophrenia, and the cognitive impairment caused by these diseases. Therefore, it is believed that appropriate regulation of the activity of NMDA receptors will be an effective solution in the treatment of neurological diseases.

[0004] Research has shown that NMDA receptor antagonists have a rapid antidepressant effect, whereas NMDA receptor agonists exert their antidepressant effect by increasing neurotransmitter release through the NMDA receptor and modulating postsynaptic AMPA sensitivity.NMDA receptor partial agonists are thought to exert a dual (antagonist / agonist) effect on the NMDA receptor via an allosteric site.

[0005] In the field of antidepressant research, designing and producing NMDA receptor modulators that exert partial agonistic and / or antagonistic effects on NMDA receptors, such as NMDA partial agonists / antagonists, is of great importance for the treatment of depression.

[0006] Detailed Description of the Invention Through thorough research and creative work, the inventors of the present invention have obtained a compound represented by formula I. The inventors have surprisingly found that the compound represented by formula I or a pharma- ceutically acceptable salt, solvate or mixture thereof is an agonist, particularly a partial agonist, of the NMDA receptor and has high affinity for the NMDA receptor; in an animal model, it is shown to be capable of rapidly, effectively and persistently preventing and treating depression and anxiety in the model animal.

[0007] Compounds of the Invention According to one aspect of the present invention, there is provided a compound of formula I, a pharma- ceutically acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof,

[0008] [ka]

[0009] During the ceremony, Ring A is a 3-8 membered aliphatic heterocycle; R1 is H, C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, -CONRR' and natural amino acid fragments; R2 is H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl, -CONRR' and natural amino acid fragments; R3 is H, cyano, 3-8 membered nitrogen-containing aliphatic heterocycle -C1-C4 acyl, C1-C6 alkoxycarbonyl and -CONHR4; R and R' are each independently H and C1-C6 alkyl; R4 is H, C1-C6 alkyl, natural amino acid fragments and carboxylic acid derivatives of said natural amino acid fragments;

[0010] In the present specification, the C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, 3-8 membered nitrogen-containing aliphatic heterocycle-C1-C4 acyl, C1-C6 alkoxycarbonyl, -CONRR', -CONHR4 and natural amino acid fragments may each independently be substituted with one or more of the following groups: halogen, amino, hydroxyl, cyano, carboxyl, nitro, C1-C6 alkyl and C1-C6 alkoxy; And R1, R2 and R3 satisfy the following conditions: (1) R1, R2 and R3 are not simultaneously H; (2) when R1 and R3 are H, R2 is not Boc; (3) Formula I [ka] and R1 is [ka] and when R3 is H, R2 is H; [ka] rather than; (4) Formula I [ka] and R1 is [ka] and when R3 is H, R2 is C2-C6 acyl and not -CONRR'; (5) Formula I [ka] When R1 and R3 are both H, R2 is C1-C4 alkyl, acetyl, [ka] rather than; (6) The compound represented by formula I [ka] isn't it.

[0011] In some embodiments, ring A is a 4-7 membered aliphatic heterocycle, preferably a 4-6 membered aliphatic heterocycle.

[0012] In some embodiments, ring A is a 4-7 membered nitrogen-containing aliphatic heterocycle, preferably a 4-6 membered nitrogen-containing aliphatic heterocycle.

[0013] In some embodiments, ring A is [ka] It is.

[0014] In some embodiments, ring A is [ka] It is.

[0015] In some embodiments, R1 is H, C1-C6 alkyl, phenyl-C1-C4 alkyl, C2-C6 acyl, and a natural amino acid fragment.

[0016] In some embodiments, R1 is H, C1-C6 alkyl, and C2-C6 acyl.

[0017] In some embodiments, R 1 is H.

[0018] In some embodiments, R1 is a carboxyl residue of a natural amino acid.

[0019] In some embodiments, R1 is H, acetyl, methyl, [ka] It is.

[0020] In some embodiments, R1 is H, acetyl, methyl, [ka] It is.

[0021] In some embodiments, R1 is H, acetyl, methyl, [ka] It is.

[0022] In some embodiments, R2 is H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl, and natural amino acid fragments; as used herein, the C1-C6 alkyl, phenyl-C1-C4 alkyl, C2-C6 acyl, and natural amino acid fragments may each be independently substituted with one or more of the following groups: halogen, amino, hydroxyl, cyano, carboxyl, nitro, C1-C6 alkyl, and C1-C6 alkoxy.

[0023] In some embodiments, R2 is H, C1-C4 alkoxycarbonyl, C2-C6 acyl, and a carboxyl residue of a natural amino acid.

[0024] In some embodiments, R2 is H, C1-C6 alkyl, and C2-C6 acyl, and a carboxyl residue of a natural amino acid.

[0025] In some embodiments, R2 is H, C1-C6 alkyl, and C2-C6 acyl.

[0026] In some embodiments, R2 is a carboxyl residue of a natural amino acid.

[0027] In some embodiments, R2 is H, methyl, ethyl, propyl, butyl, tert-butoxycarbonyl, acetyl, [ka] It is.

[0028] In some embodiments, R2 is H, methyl, ethyl, tert-butoxycarbonyl, acetyl, [ka] It is.

[0029] In some embodiments, R2 is H, methyl, tert-butoxycarbonyl, acetyl, [ka] It is.

[0030] In some embodiments, R3 is H, cyano, 5-7 membered (e.g., 6 membered) nitrogen-containing aliphatic heterocycle-C1-C3 acyl (e.g., methyl acyl), C1-C4 alkoxycarbonyl, and -CONHR4; and R4 is H, a natural amino acid fragment, an amide derivative of the natural amino acid fragment, and a cyano derivative of the natural amino acid fragment.

[0031] In some embodiments, R3 is H, cyano, 5-7 membered nitrogen-containing aliphatic heterocycle-C1-C3 acyl, C1-C4 alkoxycarbonyl, and -CONHR4; R4 is H, a natural amino acid fragment, and an amide derivative of said natural amino acid fragment.

[0032] In some embodiments, R3 is H, cyano, 5-7 membered nitrogen-containing aliphatic heterocycle-C1-C3 acyl, C1-C4 alkoxycarbonyl, and -CONHR4; R4 is H and a natural amino acid fragment.

[0033] In some embodiments, R3 is H, cyano, 5-7 membered nitrogen-containing aliphatic heterocycle-C1-C3 acyl, C1-C4 alkoxycarbonyl, and -CONHR4; R4 is H and an amide derivative of a natural amino acid fragment.

[0034] In some embodiments, R3 is H.

[0035] In some embodiments, R3 is -CONHR4; R4 is a natural amino acid residue, and an amide derivative of said natural amino acid residue.

[0036] In some embodiments, R3 is H, cyano, [ka] It is.

[0037] In some embodiments, R3 is H, cyano, [ka] It is.

[0038] In some embodiments, R3 is H, cyano, C1-C4 alkoxycarbonyl, and -CONHR4; and R4 is H, a natural amino acid fragment, an amide derivative of said natural amino acid fragment, and a cyano derivative of said natural amino acid fragment.

[0039] In some embodiments, R3 is H, cyano, C1-C4 alkoxycarbonyl, and -CONHR4; and R4 is H, a natural amino acid fragment, and an amide derivative of said natural amino acid fragment.

[0040] In some embodiments, R3 is H, cyano, C1-C4 alkoxycarbonyl, and -CONHR4; and R4 is H and a natural amino acid fragment.

[0041] In some embodiments, R3 is H, cyano, C1-C4 alkoxycarbonyl, and -CONHR4; R4 is H and an amide derivative of a natural amino acid fragment.

[0042] In some embodiments, ring A is [ka] and; R1 is independently -H, C1-C6 alkyl, and C2-C6 acyl; R2 is H, Boc, C2-C6 acyl and natural amino acid fragments; R3 is H.

[0043] In some embodiments, ring A is [ka] and; R1 is a natural amino acid fragment; R2 is H, C1-C6 alkyl, C2-C6 acyl, and natural amino acid fragments; R3 is H.

[0044] In some embodiments, ring A is [ka] and; R1 is H; R2 is a natural amino acid fragment; R3 is methyl ester, ethyl ester, propyl ester, isopropyl ester, methylamide, cyano, and CONHR4; R4 is a natural amino acid fragment or a carboxylic acid derivative of said natural amino acid fragment.

[0045] In some embodiments, ring A is [ka] and; R1 is H; R2 is H, C1-C6 alkyl, C2-C6 acyl; R3 is CONHR4; R4 is a natural amino acid fragment or a carboxylic acid derivative of said natural amino acid fragment.

[0046] In some embodiments, the natural amino acid fragments are carboxyl residues of the following amino acids: Thr, Ser, Val, Gly, Ala, He, Phe, Gln, and Tyr.

[0047] In some embodiments, the natural amino acid fragments are amino acid residues of the following amino acids: Thr, Ser, Val, Gly, Ala, He, Phe, Gln, and Tyr.

[0048] In some embodiments, the natural amino acid fragment is [ka] It is.

[0049] In some embodiments, the natural amino acid fragment is [ka] It is.

[0050] In some embodiments, the natural amino acid fragment is [ka] It is.

[0051] In some embodiments, the natural amino acid fragment is [ka] It is.

[0052] In one embodiment of the present invention, the carboxylic acid derivative of the natural amino acid fragment refers to a structure in which a part of the carboxyl group of the natural amino acid fragment is replaced with another atom, and a carboxylic acid is obtained by hydrolysis. The carboxylic acid derivative of the natural amino acid fragment includes an amide derivative, a cyano derivative, and a carboxylate derivative. In some embodiments, the carboxylic acid derivative of the natural amino acid fragment includes, but is not limited to, an amide derivative, a cyano derivative, and a carboxylate derivative of the following amino acid fragments, such as Thr, Ser, Val, Gly, Ala, Ile, Phe, Gln, and Tyr ... [ka] may be also possible.

[0053] In some embodiments, ring A is a 3-8 membered aliphatic heterocycle; R1 is H, C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, -CONRR' and natural amino acid fragments; R2 is H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl, -CONRR' and natural amino acid fragments; R3 is H, cyano, C1-C6 alkoxycarbonyl, and -CONHR4; Each R and R' is independently H and C1-C6 alkyl; R4 is H, C1-C6 alkyl, natural amino acid fragments and carboxylic acid derivatives of said natural amino acid fragments; As used herein, the C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, C1-C6 alkoxycarbonyl, -CONRR', -CONHR4 and natural amino acid fragments may each independently be substituted with one or more of the following groups: halogen, amino, hydroxyl, cyano, carboxyl, nitro, C1-C6 alkyl and C1-C6 alkoxy.

[0054] In some embodiments, R1, R2, and R3 satisfy all of the following conditions: (1) R1, R2 and R3 are not simultaneously H; (2) when R1 and R3 are H, R2 is not Boc; (3) Formula I [ka] and R1 is [ka] and when R3 is H, R2 is H; [ka] rather than; (4) Formula I [ka] and R1 is [ka] and when R3 is H, R2 is C2-C6 acyl and not -CONRR'; (5) Formula I [ka] and when R1 and R3 are both H, R2 is C1-C4 alkyl, acetyl, [ka] rather than; (6) The compound represented by formula I [ka] isn't it.

[0055] In some embodiments, R3 is H, cyano, C1-C4 alkoxycarbonyl, and -CONHR4; and R4 is H, a natural amino acid fragment, an amide derivative of said natural amino acid fragment, and a cyano derivative of said natural amino acid fragment.

[0056] In some embodiments, the present invention provides the following compound or a salt thereof:

[0057] [Table 1-1]

[0058] [Table 1-2]

[0059] [Table 1-3]

[0060] [Table 1-4]

[0061]

Table 1-5

[0062]

Table 1-6

[0063]

Table 1-7

[0064]

Table 1-8

[0065]

Table 1-9

[0066]

Table 1-10

[0067]

Table 1-11

[0068]

Table 1-12

[0069]

Table 1-13

[0070]

Table 1-14

[0071]

Table 1-15

[0072]

Table 1-16

[0073]

Table 1-17

[0074]

Table 1-18

[0075]

Table 1-19

[0076]

Table 1-20

[0077]

Table 1-21

[0078]

Table 1-22

[0079]

Table 1-23

[0080]

Table 1-24

[0081] [Table 1-25]

[0082] [Table 1-26]

[0083] [Table 1-27]

[0084] Compound Production The compounds of the present invention can be prepared by a variety of methods known in the art.

[0085] In some embodiments, when R1, R2, and R3 in formula I are all H, the compound of formula I can be prepared by the following method:

[0086] [ka]

[0087] In some embodiments, formula I-1 can further provide the following series of compounds represented by formula I:

[0088] [ka]

[0089] In some embodiments, starting from L-cysteine ​​methyl ester hydrochloride, the following series of compounds represented by formula I can be obtained:

[0090] [ka]

[0091] In some embodiments, compounds of Formula I-7, I-8, and I-9 can be further deprotected and reacted with R2-LG or R3H to produce the corresponding compounds of Formula I, respectively.

[0092] In said embodiment, LG represents a leaving group for a nucleophilic substitution reaction, such as, for example, a halogen; Pg represents an amino protecting group, such as, for example, Boc, Fmoc, and the like.

[0093] In some embodiments, the sequence of the experiments can be adjusted depending on the structure of the product of interest.

[0094] Therapeutic Methods and Pharmaceutical Compositions In another embodiment, the present invention provides a pharmaceutical composition, comprising a compound of the present invention, a pharma- ceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof; herein, optionally further comprising one or more pharma- ceutically acceptable excipients.

[0095] In some embodiments, a pharmaceutical composition of the invention may contain a compound of the invention and a pharma- ceutically acceptable excipient.

[0096] In some embodiments, the pharmaceutical compositions of the present invention may contain 0.1-90% by weight of the compound of formula I and / or a physiologically acceptable salt thereof.

[0097] The compound in the pharmaceutical composition of the present invention, a pharma- ceutical acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof may be administered to a subject, (a) modulating the activity of NMDA receptors (e.g., upregulating or downregulating); (b) enhancing NMDA receptor activity; (c) prevent depression; (d) Treating depression; (e) preventing anxiety disorders; (f) Treating anxiety disorders; (g) prevent stroke; (h) Treating stroke; (i) Preventing Huntington's disease; (j) Treating Huntington's disease; (k) Preventing Alzheimer's disease; (l) Treating Alzheimer's disease; (m) Prevents neuralgia; (n) Treating neuralgia; (o) Preventing schizophrenia; (p) Treating schizophrenia; (q) Any combination of (a)-(p).

[0098] In another aspect, the present invention provides the use of the compound, a pharma- ceutically acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof in the manufacture of a medicament, the medicament being used for: (a) modulating the activity of NMDA receptors (e.g., upregulating or downregulating); (b) enhancing NMDA receptor activity; (c) prevent depression; (d) Treating depression; (e) preventing anxiety disorders; (f) Treating anxiety disorders; (g) prevent stroke; (h) Treating stroke; (i) Preventing Huntington's disease; (j) Treating Huntington's disease; (k) Preventing Alzheimer's disease; (l) Treating Alzheimer's disease; (m) Prevents neuralgia; (n) Treating neuralgia; (o) Preventing schizophrenia; (p) Treating schizophrenia; (q) Any combination of (a)-(p).

[0099] In another aspect, the present invention provides a method for preventing and / or treating depression, anxiety, stroke, Huntington's disease, Alzheimer's disease, neuralgia or schizophrenia in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a pharma- ceutically acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof, a pharmaceutical composition thereof.

[0100] In another aspect, the present invention provides a method of modulating (e.g., upregulating or downregulating) the activity of an NMDA receptor (e.g., a human NMDA receptor) in vivo or in vitro, the method comprising administering to a subject, a mammalian cell, or an NMDA receptor an effective amount of a compound of Formula I, a pharma- ceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as defined in any one of the present invention.

[0101] In another aspect, the compounds of formula I provided by the present invention, their pharma- ceutically acceptable salts or esters, their stereoisomers or their solvates are used for the treatment and / or prevention of depression, anxiety, stroke, Huntington's disease, Alzheimer's disease, neuralgia or schizophrenia.

[0102] In another aspect, the compounds of formula I provided herein, their pharma- ceutically acceptable salts or esters, their stereoisomers, or their solvates, are used to modulate (e.g., upregulate or downregulate) the activity of an NMDA receptor, e.g., a human NMDA receptor, in vivo or in vitro.

[0103] The compound of the present invention, its pharma- ceutically acceptable salt or ester, its stereoisomer or solvate, or the pharmaceutical composition of the present invention can be prepared into a dosage form known in the medical field, for example, tablets, pills, suspensions, emulsions, solutions, gels, capsules, powders, granules, elixirs, troches, suppositories, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), inhalants, sprays, etc. The preferred dosage form is determined according to the administration method and the purpose of treatment. The pharmaceutical composition of the present invention should be sterile and stable under the manufacturing and storage conditions. The preferred dosage form is an injection. The injection may be a sterile injection solution. For example, a sterile injection solution can be prepared by the following method: doping a necessary amount of the compound of the present invention, its pharma- ceutically acceptable salt or ester, its stereoisomer or solvate into a suitable solvent, and doping other desired components (including but not limited to pH adjusters, surfactants, ionic strength adjusters, isotonicity agents, preservatives, diluents, or any combination thereof) at the same time, followed by filtration sterilization. Moreover, for ease of storage and use, the sterile injectable solutions can be manufactured into sterile lyophilized (e.g., vacuum-dried or freeze-dried) powders, which can be dispersed in a suitable carrier prior to use, e.g., sterile pyrogen-free water.

[0104] Also, for ease of administration, the compounds of the present invention, their pharma- ceutically acceptable salts or esters, their stereoisomers or their solvates may be present in pharmaceutical compositions in the form of unit doses.

[0105] The compound of the present invention, its pharma- ceutically acceptable salt or ester, its stereoisomer or solvate, pharmaceutical composition can be administered by any suitable method known in the art, including, but not limited to, oral, buccal, sublingual, ocular, topical, parenteral, rectal, intrathecal, intracytoplasmic reticulum, inguinal, intravesical, topical (e.g., powder, ointment or drops), or nasal administration routes. However, for many therapeutic applications, the preferred route / method of administration is parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). Those skilled in the art should understand that the route and / or method of administration will vary depending on the anticipated purpose. In a preferred embodiment, the compound of the present invention, its pharma- ceutically acceptable salt or ester, its stereoisomer or solvate, pharmaceutical composition is administered by intravenous infusion or injection.

[0106] The pharmaceutical composition of the present invention may contain a "therapeutically effective amount" or a "prophylactically effective amount" of the compound of the present invention, its pharma- ceutically acceptable salt or ester, its stereoisomer, or its solvate. A "prophylactically effective amount" refers to an amount sufficient to prevent, inhibit, or delay the onset of a disease. A "therapeutically effective amount" refers to an amount sufficient to cure or at least partially inhibit the disease and its complications in a patient already suffering from the disease. The therapeutically effective amount of the compound of the present invention, its pharma- ceutical acceptable salt or ester, its stereoisomer, or its solvate varies depending on the following factors: the severity of the disease to be treated, the general state of the patient's own immune system, the patient's overall condition, such as age, weight, and sex, the method of administration of the drug, and other therapies used simultaneously.

[0107] In the present invention, administration schedules can be adjusted to obtain an optimal response (e.g., a therapeutic or prophylactic response), including, for example, a single administration, repeated administration over a period of time, or rate-dependent reduction or increase depending on the exigencies of the therapeutic situation.

[0108] A typical non-limiting range of therapeutically or prophylactically effective amount of the compound of the present invention, its pharma- ceutically acceptable salt or ester, its stereoisomer, or its solvate is 0.02-100 mg / kg, for example, 0.1-100 mg / kg, 0.1-50 mg / kg, or 1-50 mg / kg. It should be noted that the dosage varies depending on the type and severity of the condition to be treated. In addition, one skilled in the art should understand that for any particular patient, the particular dosing schedule needs to be adjusted over time according to the needs of the patient and the professional evaluation of the physician; the dosage ranges herein are for illustrative purposes only and are not intended to limit the use or scope of the pharmaceutical composition of the present invention.

[0109] In the present invention, the subject may be a mammal, for example a human.

[0110] In the present invention, unless otherwise specified, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. In addition, the operation procedures of cell culture, biochemistry, nucleic acid chemistry, immunology laboratory, etc. used herein are all common procedures widely used in the corresponding fields. At the same time, in order to better understand the present invention, the following definitions and interpretations of related terms are provided.

[0111] As used herein, the term "natural amino acid" YesIt refers to the following 20 types of amino acids: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamic acid (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), leucine (Leu), isoleucine (Ile), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val). It is known that amino acid molecules contain two functional groups, amino and carboxyl, and the "amino acid fragment" described herein refers to the remaining portion of an amino acid molecule obtained by removing one hydrogen atom from the amino group or removing a hydroxyl group from the carboxyl group. Therefore, the "carboxyl residue" refers to the remaining structure obtained by removing a hydroxyl from the carboxyl group of an amino acid molecule.

[0112] The term "alkyl" as used herein refers to a linear or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl contains 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, the term "C1-C6 alkyl" as used herein refers to a linear or branched alkyl containing 1 to 6 carbon atoms (e.g., methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, isopentyl, neopentyl, or normal hexyl, etc.).

[0113] The term "C1-C6 alkoxy" as used herein refers to C1-C6 alkyl-O-, where C1-C6 alkyl is as defined above. Non-limiting examples of suitable C1-C6 alkoxy include methoxy, ethoxy and isopropoxy.

[0114] As used herein, the term "C2-C6 acyl" refers to a monovalent group having the general formula RC(O)- containing 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms, where R may have the structure of alkyl, alkenyl, etc. Non-limiting examples of suitable C2-C6 acyls include acetyl, propionyl, isopropionyl, normal butyryl, sec-butyryl, tert-butyryl, normal valeryl, isovaleryl, and pivaloyl.

[0115] The term "C1-C6 alkoxycarbonyl" as used herein refers to C1-C6 alkyl-OC(O)-, where C1-C6 alkyl is as defined above. Non-limiting examples of suitable C1-C6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and the like.

[0116] The term "aryl" as used herein refers to a monocyclic or fused ring group having aromatic character, e.g., phenyl, naphthyl, and the like.

[0117] The term "aliphatic heterocycle" as used herein refers to a cyclic aliphatic hydrocarbon having at least one ring-forming heteroatom selected from N, O, and S. In some embodiments, the term "3-8 membered aliphatic heterocycle" refers to the aliphatic heterocycle containing 3 to 8 ring members (e.g., 3, 4, 5, 6, 7, or 8), such as a 3-8 membered N-containing alicyclic heterocycle, a 4-6 membered N-containing aliphatic heterocycle. Specific examples include, but are not limited to, the following:

[0118] [ka] etc.

[0119] The term "nitrogen-containing aliphatic heterocycle" as used herein refers to an aliphatic heterocycle containing at least one N atom, where the aliphatic heterocycle is defined as above; the term "3- to 8-membered nitrogen-containing aliphatic heterocycle" refers to the nitrogen-containing aliphatic heterocycle containing 3 to 8 ring members (e.g., 3, 4, 5, 6, 7, or 8).

[0120] The term "3-8 membered nitrogen-containing aliphatic heterocycle-C1-C4 acyl" as used herein refers to a monovalent group having a 3-8 membered nitrogen-containing aliphatic heterocycle-RC(O)- structure, where the definition of 3-8 membered nitrogen-containing aliphatic heterocycle is as described above, and R is absent or has a structure such as alkyl, alkenyl, etc. Specific examples include, but are not limited to, the following examples.

[0121] [ka]

[0122] As used herein, the term "substituted" refers to the selective replacement of one or more (e.g., 1, 2, 3, or 4) hydrogen atoms bonded to the designated atom with the designated group, where the designated atom does not exceed its normal valence and where said substitution results in the formation of a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in the formation of stable compounds.

[0123] When substituents are described as "independently," it means that each substituent is independent of the other. Thus, each substituent can be the same or different from the other substituents.

[0124] As used herein, the term "one or more" refers to one or more than one, under reasonable conditions, including, for example, two, three, four, five or ten.

[0125] Unless otherwise stated, the site of attachment of a substituent as used herein may be any suitable position of the substituent.

[0126] The term "stereoisomer" as used herein refers to an isomer that has the same bond order of atoms but differs due to the spatial arrangement of the atoms, such as enantiomers, geometric isomers, etc. "Enantiomer" refers to an isomer formed due to at least one asymmetric center. In a compound having one or more (e.g., 1, 2, 3 or 4) asymmetric centers, enantiomers, diastereomers, etc. may exist. When the molecule has a double bond, e.g., C=C, C=N or N=N double bond, the two atoms bonded to the double bond cannot rotate freely, so geometric isomers (cis / trans) may exist.

[0127] In this specification, solid lines [ka] , solid wedge bond [ka] or dashed wedge bond [ka] The bonds in the compounds of the present invention are represented by: When a bond to an asymmetric carbon atom is represented by a solid line, all possible stereoisomers formed by that carbon atom are included. When a bond to an asymmetric carbon atom is represented by a solid or dashed wedge bond, the depicted stereoisomer exists.

[0128] The compounds of the present invention may exist in the form of solvates (preferably hydrates), where the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, particularly water, methanol or ethanol. The amount of polar solvent, including water, is present in stoichiometric or non-stoichiometric ratios. Any solvates of the compounds of formula I used to treat the diseases or conditions described herein may provide different properties (including pharmacokinetic properties), but once absorbed by a subject, the compounds of formula I are obtained, and therefore it should be understood that the use of the compounds of formula I encompasses the use of any solvates of the compounds of formula I, respectively.

[0129] It should also be understood that certain compounds of the present invention may exist in free form and be used in therapy, or, where appropriate, may exist in the form of a pharma- ceutically acceptable derivative thereof, which in the context of the present invention includes, but is not limited to, a pharma- ceutically acceptable salt or ester, a compound or a metabolite or residue thereof that is capable of providing the present invention directly or indirectly upon administration thereof to a patient in need thereof.

[0130] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and alkali addition salts thereof.

[0131] For reviews of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002), or SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19. Methods for preparing pharma- ceutically acceptable salts of the compounds of the present invention are generally known to those skilled in the art.

[0132] Suitable acid addition salts are formed with acids that form pharma- ceutically acceptable salts. Suitable alkali addition salts are formed with alkalis that form pharma-ceutically acceptable salts. In some embodiments, suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid; organic acids include formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, niacin, palmoic acid, pectic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2- Examples of suitable acids include hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, etc. For example, a pharma- ceutically acceptable salt is formed with a compound of formula I using HCl (or hydrochloric acid), HBr (or hydrobromic acid solution), methanesulfonic acid, sulfuric acid, tartaric acid, or fumaric acid.

[0133] As used herein, the term "pharmaceutical acceptable ester" refers to an ester derived from a compound of the invention, and includes physiologically hydrolyzable esters (compounds of the invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol). The compounds of the invention themselves may be esters.

[0134] The term "metabolic stability" as used herein refers to the ability of a compound to enter the body in an unchanged form and exist stably there, without being metabolized to other structural forms.

[0135] The term "subject" as used herein refers to a patient or other animal that receives the composition of the present invention to treat, prevent, alleviate and / or ameliorate said disease or condition of the present invention, particularly mammals, such as humans, dogs, monkeys, cows, horses, etc.

[0136] The term "additive" as used herein refers to an excipient or carrier used to administer a compound, including, but not limited to, diluents, disintegrants, anti-settling agents, surfactants, flow agents, binders, lubricants, coating agents, etc. Examples of additives include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethylcellulose, hydroxymethylcellulose, hydroxydioctyl hydroxystearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, etc. EXAMPLES

[0137] The following examples are provided to explain the embodiments of the present invention in detail, but those skilled in the art should understand that the following examples are used only to explain the present invention and do not limit the scope of the present invention. If no specific conditions are specified in the examples, the examples are carried out under normal conditions or conditions suggested by the manufacturer. Reagents and instruments without manufacturer's names may be ordinary products available on the market.

[0138] [Table A]

[0139] Exemplary Synthetic Routes Synthesis of Examples A-001 and A-002

[0140] [ka]

[0141] At -15℃, 1.14g (10mmol, 1.0eq) of raw material mercaptoethylamine hydrochloride was dissolved in 100ml of methanol, and 1.75ml (15mmol, 1.5eq) of triethylamine was added to fully release the mixture. Then, 1.8g (10mmol, 1.0eq) of 1-Boc-3-azetidinone was added, and the mixture was reacted at low temperature for 15min, and then returned to room temperature. The mixture was monitored by TLC. After the raw material was completely reacted, the mixture was concentrated under reduced pressure, and the concentrate was dissolved in 100ml of ethyl acetate, washed with a small amount of water several times (15ml×4), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column (PE:EtOAc=2:1) ​​to obtain 2.25g of white solid A-002, with a yield of 92.6%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.37(s,9H,-CH3), 3.12(t,2H,J=8.2Hz), 3.34(t,2H,J=6.1Hz), 4.1-4.20(d,2H,J=9.2Hz), 4.59-4.62(d,2H,J=9.5Hz), 9.3(s,1H). M+1:231.11

[0142] Dissolve 1g (6mmol) of intermediate A-002 in 10mL of anhydrous ethyl acetate, add 10mL of 4mol / L HCl / EtOAc, and stir at room temperature overnight. A white solid appeared in the system; TLC was monitored and the reaction was terminated after the raw material was completely reacted. Filter and wash with anhydrous ether to obtain 0.54g of white solid A-001, with a yield of 76%. 1 H-NMR (400MHz,DMSO-d6), δppm:3.10(t,2H,J=6.8Hz), 3.37(t,2H,J=6.4Hz), 4.1-4.15(d,2H,J=11.2Hz), 4.55-4.6(d,2H,J=10.5Hz), 9.5(s,1H), 9.8(s,1H). M+1:131.06.

[0143] The preparation method of A-002 can prepare products A-016, A-030, A-044 corresponding to five-membered rings and six-membered rings, which are the same as A-002 and only require replacing the corresponding cyclic ketones; similarly, the preparation method of A-001 can prepare products A-015, A-029, A-043 corresponding to five-membered rings and six-membered rings.

[0144] A-016: The raw material 1-Boc-3-azetidinone in the synthesis of A-002 was replaced with N-Boc-3-pyrrolidone, and the other operations were the same as those in the synthesis of A-002. M+1: 245.12. A-030: The raw material 1-Boc-3-azetidinone in the synthesis of A-002 was replaced with N-Boc-4-piperidone, and the other operations were the same as those in the synthesis of A-002. M+1: 259.14. A-044: The raw material 1-Boc-3-azetidinone in the synthesis of A-002 was replaced with N-Boc-3-piperidone, and the other operations were the same as those in the synthesis of A-002. M+1: 259.14. A-015: The intermediate A-002 in the synthesis of A-001 is replaced with A-016, and the other operations are the same as those in the synthesis of A-001. M+1: 145.07. A-029: The intermediate A-002 in the synthesis of A-001 is replaced with A-030, and the other operations are the same as those in the synthesis of A-001. M+1: 159.09. A-043: The intermediate A-002 in the synthesis of A-001 is replaced with A-044, and the other operations are the same as those in the synthesis of A-001. M+1: 159.09.

[0145] Example A-003

[0146] [ka]

[0147] Compound A-001 0.4g (2.4mmol) was dissolved in anhydrous DCM 20ml, and TEA 665μL (4.8mmol) was added to release; acetyl chloride 155μL (2.2mmol) was added to DCM 5ml, and slowly dripped into the reaction system through a dropping funnel under ice bath, and then reacted at low temperature for half an hour and then returned to room temperature; reacted at room temperature for 4h, monitored by TLC, and the reaction was terminated after the raw material was completely reacted. Washed with a small amount of water (5ml x 3), separated the organic phase, dried, filtered, concentrated, and separated by silica gel column chromatography to obtain a brown oily product, added hydrochloric acid and stirred to generate salt, and a solid appeared; product A-003 0.31g was obtained, with a yield of 61.9%. 1 H-NMR (400MHz,DMSO-d6), δppm:2.03(s,3H), 3.15(t,2H,J=6.8Hz), 3.29(t,2H,J=7.4Hz), 4.11-4.21(d,2H,J=7.1Hz), 4.51-4.63(d,2H,J=8.1Hz), 9.53(s,1H). M+1:173.07.

[0148] Preparation of Examples A-004 and A-005: A-004: The acetyl chloride in the synthesis of A-003 was replaced with isobutyryl chloride, and the other operations were the same as those in the synthesis of A-003. M+1: 201.10. A-005: The acetyl chloride in the synthesis of A-003 was replaced with pivaloyl chloride, and the other procedures were the same as those in the synthesis of A-003. M+1: 215.11.

[0149] Preparation of Examples A-017 to A-019: A-017: A-001 in the synthesis of A-003 is replaced with A-015, and the other operations are the same as A-003. M+1: 187.08. A-018: In the synthesis of A-003, A-001 is replaced with A-015, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-003. M+1: 215.11. A-019: In the synthesis of A-003, A-001 is replaced with A-015, and acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as those of A-003. M+1: 229.13.

[0150] Preparation of Examples A-031 to A-033: A-031: A-001 in the synthesis of A-003 is replaced with A-029, and the other operations are the same as A-003. M+1: 201.10. A-032: In the synthesis of A-003, A-001 is replaced with A-029, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-003. M+1: 229.13. A-033: In the synthesis of A-003, A-001 is replaced with A-029, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-003. M+1: 243.15.

[0151] Preparation of Examples A-045 to A-047: A-045: A-001 in the synthesis of A-003 is replaced with A-043, and other operations are the same as A-003. M+1: 201.10. A-046: In the synthesis of A-003, A-001 is replaced with A-043, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-003. M+1: 229.13. A-047: In the synthesis of A-003, A-001 is replaced with A-043, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-003. M+1: 243.15.

[0152] Example A-006 This example illustrates a method for synthesizing compound A-006.

[0153] [ka]

[0154] 0.4g (2.4mmol) of intermediate A-001 was dissolved in 20ml of anhydrous DCM, and 665μL (4.8mmol) of TEA was added to release the product. After stirring for 5min, 0.63g (2.3mmol) of Boc-tBu-Thr, 0.49g (3.6mmol) of HOBt and 0.62g (3.6mmol) of EDCI were added and reacted at room temperature overnight. The reaction was monitored by TLC, and the reaction was terminated after the raw materials had completely reacted. The organic phase was washed with saturated aqueous citric acid (10mL x 2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 0.61g of colorless oily intermediate 1a, with a yield of 68.8%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.14-1.20(m,12H), 1.37(s,9H), 3.24(t,2H,J=7.2Hz), 3.38-3.65(m,2H), 3.72-3.95(m,3H), 4.10-4.30(m,1H), 4.65-4.94(m,3H), 7.34(s,1H), 8.23(s,1H). M+1:388.22

[0155] Dissolve 0.5g (1.3mmol) of intermediate 1a in 5ml of anhydrous ethyl acetate, add 10mL of 4mol / L HCl / EtOAc, react overnight at room temperature, a white solid appeared in the system, and monitor by TLC. After the raw material reacted completely, the reaction was terminated. Filter under reduced pressure and wash with anhydrous ether to obtain 0.25g of white solid A-006, the yield is 73%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.21(m,3H), 3.21(t,2H,J=6.4Hz), 3.36-3.65(m,2H), 3.7-3.97(m,3H), 4.10-4.30(m,1H), 4.60-4.71(m,2H), 4.86-5.01(m,1H), 5.65(s,1H), 8.23-8.28(d,2H,J=21Hz). M+1:232.10

[0156] Preparation of Examples A-007 to A-014: A-007: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:218.09. A-007-1: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:218.09. A-008: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:230.12. A-008-1: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:230.12. A-009: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:188.08. A-010: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:202.09. A-011: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:244.14. A-012: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:278.12. A-013: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:245.10. A-014: In the synthesis of A-006 [ka] and other operations are the same as A-006. M+1:294.12.

[0157] Preparation of Examples A-020 to A-028: A-020: A-001 in the synthesis of A-006 is replaced with A-015, and other operations are the same as A006. M+1: 246.12. A-021: A-001 in the synthesis of A-006 to A-015, [ka] and other operations are the same as A-006. M+1:232.10. A-022: A-001 in the synthesis of A-006 to A-015, [ka] and other operations are the same as A-006. M+1:244.14. A-023: A-001 in the synthesis of A-006 to A-015, [ka] and other operations are the same as A-006. M+1:202.09. A-024: A-001 in the synthesis of A-006 to A-015, [ka] and other operations are the same as A-006. M+1:216.11. A-025: A-001 in the synthesis of A-006 to A-015, [ka] and other operations are the same as A-006. M+1:258.16. A-026: A-001 in the synthesis of A-006 was replaced with A-015. [ka] and other operations are the same as A-006. M+1:292.14. A-027: A-001 in the synthesis of A-006 to A-015, [ka] and other operations are the same as A-006. M+1:259.12. A-028: A-001 in the synthesis of A-006 to A-015, [ka] and other operations are the same as A-006. M+1:308.14.

[0158] Preparation of Examples A-034 to A-042: A-034: A-001 in the synthesis of A-006 is replaced with A-029, and the other operations are the same as A-006. M+1: 260.14. A-035: A-001 in the synthesis of A-006 to A-029, [ka] and other operations are the same as A-006. M+1:246.12. A-036: A-001 in the synthesis of A-006 was replaced with A-029. [ka] and other operations are the same as A-006. M+1:258.16. A-037: A-001 in the synthesis of A-006 to A-029, [ka] and other operations are the same as A-006. M+1:216.11. A-038: A-001 in the synthesis of A-006 to A-029, [ka] and other operations are the same as A-006. M+1:230.12. A-039: A-001 in the synthesis of A-006 was replaced with A-029. [ka] and other operations are the same as A-006. M+1:272.17. A-040: A-001 in the synthesis of A-006 to A-029, [ka] and other operations are the same as A-006. M+1:306.16. A-041: A-001 in the synthesis of A-006 to A-029, [ka] and other operations are the same as A-006. M+1:273.13. A-042: A-001 in the synthesis of A-006 to A-029, [ka] and other operations are the same as A-006. M+1:322.15.

[0159] Preparation of Examples A-048 to A-056: A-048: A-001 in the synthesis of A-006 is replaced with A-043, and other operations are the same as A-006. M+1: 260.14. A-049: A-001 in the synthesis of A-006 was replaced with A-043. [ka] and other operations are the same as A-006. M+1:246.12. A-050: A-001 in the synthesis of A-006 to A-043, [ka] and other operations are the same as A-006. M+1:258.16. A-051: A-001 in the synthesis of A-006 to A-043, [ka] and other operations are the same as A-006. M+1:216.11. A-052: A-001 in the synthesis of A-006 to A-043, [ka] and other operations are the same as A-006. M+1:230.12. A-053: A-001 in the synthesis of A-006 was replaced with A-043. [ka] and other operations are the same as A-006. M+1:272.17. A-054: A-001 in the synthesis of A-006 was replaced with A-043. [ka] and other operations are the same as A-006. M+1:306.16. A-055: A-001 in the synthesis of A-006 was replaced with A-043. [ka] and other operations are the same as A-006. M+1:273.13. A-056: A-001 in the synthesis of A-006 was replaced with A-043. [ka] and other operations are the same as A-006. M+1:322.15.

[0160] Example A-059 This example illustrates a method for the synthesis of compound A-059.

[0161] [ka]

[0162] 1. Synthesis of intermediate A-058 Compound A-002 0.6g (2.6mmol) was dissolved in anhydrous DCM 20ml, TEA 1.4mL (10mmol) was added, and then acetyl chloride 350μL (5mmol) was added to DCM 5mL. The reaction system was slowly dripped through a dropping funnel under ice bath, reacted at low temperature for half an hour, then returned to room temperature and reacted for 4h, monitored by TLC, and the reaction was terminated after the raw material was completely reacted. Washed with water (10mL x 3), the organic phase was separated, dried, filtered, concentrated, and separated by silica gel column chromatography to obtain brown oil A-058 0.57g, with a yield of 81.4%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.38(s,9H), 2.05(s,3H), 3.14(t,2H,J=7.8Hz), 3.35(t,2H,J=5.8Hz), 4.13-4.22(d,2H,J=8.7Hz), 4.60-4.63(d,2H,J=10.2Hz). M+1:273.12

[0163] 2. Synthesis of intermediate A-057 A-057 is obtained by deprotection of A-058, and the synthetic method is the same as that of A-001. 1 H-NMR (400MHz,DMSO-d6), δppm:2.06(s,3H), 3.17(t,2H,J=6.3Hz), 3.34(t,2H,J=5.8Hz), 4.09-4.17(d,2H,J=6.9Hz), 4.49-4.61(d,2H,J=7.9Hz), 9.21(s,1H). M+1:173.07

[0164] 3. Synthesis of the final product A-059 The synthesis method is the same as A-058. 1 H-NMR (400MHz,DMSO-d6), δppm:1.73(s,3H), 2.06(s,3H), 3.01(t,2H,J=6Hz), 3.74-3.82(m,3H), 4.05-4.07(d,1H,J=10Hz), 4.64-4.66(d,1H,J=9.6Hz), 4.90-4.92(d,1H,J=8.8Hz). M+1:215.08

[0165] The synthesis method of A-058 produces the following products:

[0166] Preparation of Examples A-070, A-078, A-086: A-070: Replace A-002 with A-016, other operations are the same as A-058. M+1: 287.14. A-078: Replace A-002 with A-030, other operations are the same as A-058. M+1: 301.15. A-086: Replace A-002 with A-044, and other operations are the same as A-058. M+1: 301.15.

[0167] Preparation of Examples A-094, A-102, A-110, A-118: A-094: Acetyl chloride is replaced with isobutyryl chloride, and the other procedures are the same as A-058. M+1: 301.15. A-102: Replace A-002 with A-016, replace acetyl chloride with isobutyryl chloride, and other operations are the same as A-058. M+1: 315.17. A-110: Replace A-002 with A-030, replace acetyl chloride with isobutyryl chloride, and other operations are the same as A-058. M+1: 329.18. A-118: Replace A-002 with A-044, replace acetyl chloride with isobutyryl chloride, and other operations are the same as A-058. M+1: 329.18.

[0168] Preparation of Examples A-126, A-134, A-142, A-150: A-126: Acetyl chloride was replaced with pivaloyl, and the other procedures were the same as A-058. M+1: 315.17. A-134: Replace A-002 with A-016, acetyl chloride with pivaloyl chloride, and other operations are the same as A-058. M+1: 329.18. A-142: A-002 is replaced with A-030, acetyl chloride is replaced with pivaloyl chloride, and other operations are the same as A-058. M+1: 343.20. A-150: Replace A-002 with A-044, acetyl chloride with pivaloyl chloride, and other operations are the same as A-058. M+1: 343.20.

[0169] Preparation of Examples A-158, A-166, A-174, A-182: A-158: The solvent was replaced with DMF, acetyl chloride with iodoisobutane, and TEA with potassium carbonate, and the other operations were the same as A-058. M+1: 287.17. A-166: A-002 was replaced with A-016, the solvent was replaced with DMF, acetyl chloride with iodoisobutane, and TEA with potassium carbonate, and the other operations were the same as A-058. M+1: 301.19. A-174: A-002 was replaced with A-030, the solvent was replaced with DMF, acetyl chloride was replaced with iodoisobutane, and TEA was replaced with potassium carbonate, and the other operations were the same as A-058. M+1: 315.20. A-182: A-002 was replaced with A-044, the solvent was replaced with DMF, acetyl chloride was replaced with iodoisobutane, and TEA was replaced with potassium carbonate, and the other operations were the same as A-058. M+1: 315.20.

[0170] Preparation of Examples A-190, A-198, A-206, A-214: A-190: Iodoisobutane is replaced with benzyl bromide, and the other procedures are the same as A-158. M+1: 321.16. A-198: Iodoisobutane is replaced with benzyl bromide, and the other procedures are the same as A-158. M+1: 335.17. A-206: Iodoisobutane is replaced with benzyl bromide, and the other procedures are the same as A-158. M+1: 349.19. A-214: Iodoisobutane is replaced with benzyl bromide, and the other procedures are the same as A-158. M+1: 349.19.

[0171] Preparation of Examples A-222, A-230, A-238, A-246: A-222: The solvent was replaced with DMF, acetyl chloride with iodomethane, and TEA with potassium carbonate, and the other operations were the same as A-058. M+1: 245.12. A-230: A-002 was replaced with A-016, the solvent was replaced with DMF, acetyl chloride with iodomethane, and TEA with potassium carbonate, and the other operations were the same as A-058. M+1: 259.14. A-238: A-002 was replaced with A-030, the solvent was replaced with DMF, acetyl chloride with iodomethane, and TEA with potassium carbonate, and the other operations were the same as A-058. M+1: 273.16. A-246: A-002 was replaced with A-044, the solvent was replaced with DMF, acetyl chloride with iodomethane, and TEA with potassium carbonate, and the other operations were the same as A-058. M+1: 273.16. The synthesis method for A-057 produces the following products:

[0172] Preparation of Examples A-069, A-077, A-085: A-069: Replace A-058 with A-070, and other operations are the same as A-057. M+1: 187.08. A-077: Replace A-058 with A-078, other operations are the same as A-057. M+1: 201.10. A-085: Replace A-058 with A-086, other operations are the same as A-057. M+1: 201.10.

[0173] Preparation of Examples A-093, A-101, A-109, A-117: A-093: Replace A-058 with A-094, other operations are the same as A-057. M+1: 201.10. A-101: Replace A-058 with A-102, other operations are the same as A-057. M+1: 215.11. A-109: Replace A-058 with A-110, other operations are the same as A-057. M+1: 229.13. A-117: Replace A-058 with A-118, other operations are the same as A-057. M+1: 229.13.

[0174] Preparation of Examples A-125, A-133, A-141, A-149: A-125: Replace A-058 with A-126, other operations are the same as A-057. M+1: 215.11. A-133: Replace A-058 with A-134, and other operations are the same as A-057. M+1: 229.13. A-141: Replace A-058 with A-142, and other operations are the same as A-057. M+1: 243.15. A-149: Replace A-058 with A-150, and other operations are the same as A-057. M+1: 243.15.

[0175] Preparation of Examples A-157, A-165, A-173, A-181: A-157: Replace A-058 with A-158, and other operations are the same as A-057. M+1: 187.12. A-165: Replace A-058 with A-166, other operations are the same as A-057. M+1: 201.13. A-173: Replace A-058 with A-174, and other operations are the same as A-057. M+1: 215.15. A-181: Replace A-058 with A-182, and other operations are the same as A-057. M+1: 215.15.

[0176] Preparation of Examples A-189, A-197, A-205, A-213: A-189: Replace A-058 with A-190, other operations are the same as A-057. M+1: 221.10. A-197: Replace A-058 with A-198, and other operations are the same as A-057. M+1: 235.12. A-205: Replace A-058 with A-206, and other operations are the same as A-057. M+1: 249.13. A-213: Replace A-058 with A-214, and other operations are the same as A-057. M+1: 249.13.

[0177] Preparation of Examples A-221, A-229, A-237, A-245: A-221: Replace A-058 with A-222, and other operations are the same as A-057. M+1: 145.07. A-229: Replace A-058 with A-230, other operations are the same as A-057. M+1: 159.09. A-237: Replace A-058 with A-238, other operations are the same as A-057. M+1: 173.10. A-245: Replace A-058 with A-246, other operations are the same as A-057. M+1: 173.10. The synthesis method for A-059 produces the following products:

[0178] Preparation of Examples A-060 and A-061: A-060: Starting from A-057, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 243.11. A-061: Starting from A-057, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 257.12.

[0179] Preparation of Examples A-062 to A-064: A-062: Using A-057 as the raw material, the solvent was replaced with DMF, acetyl chloride with iodomethane, and TEA with potassium carbonate, and the other operations were the same as A-059. M+1: 187.08. A-063: Using A-057 as the raw material, the solvent was replaced with DMF, acetyl chloride with iodoethane, and TEA with potassium carbonate, and the other operations were the same as A-062. M+1: 201.10. A-064: A-057 is used as the raw material, the solvent is DMF, and acetyl chloride is added. [ka] The procedure is the same as A-062, except that TEA is replaced with potassium carbonate. M+1: 230.09.

[0180] Preparation of Examples A-071 to A-073: A-071: A-069 is used as raw material, and other operations are the same as A-059. M+1: 229.09. A-072: Starting from A-069, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 257.12. A-073: Starting from A-069, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 271.14.

[0181] Preparation of Examples A-079 to A-081: A-079: A-077 is used as raw material, and other operations are the same as A-059. M+1: 243.11. A-080: Starting from A-077, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 271.14. A-081: Starting from A-077, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 285.16.

[0182] Preparation of Examples A-087 to A-089: A-087: A-085 is used as raw material, and other operations are the same as A-059. M+1: 243.11. A-088: Starting from A-085, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 271.14. A-089: Starting from A-085, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 285.16.

[0183] Preparation of Examples A-095 to A-097: A-095: Acetyl chloride is obtained from A-093. [ka] and other operations are the same as A-059. M+1:258.12. A-096: Starting from A-093, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 271.14. A-097: Starting from A-093, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 285.16.

[0184] Preparation of Examples A-103 to A-105: A-103: A-101 is used as raw material, and other operations are the same as A-059. M+1: 257.12. A-104: Starting from A-101, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 285.16. A-105: Starting from A-101, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 299.17.

[0185] Preparation of Examples A-111 to A-113: A-111: A-109 is used as the starting material, and other operations are homologous to A-059; A-112: Starting from A-109, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 299.17. A-113: Starting from A-109, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 313.19.

[0186] Preparation of Examples A-119 to A-121: A-119: A-117 is used as raw material, and other operations are the same as A-059. M+1: 271.14. A-120: Starting from A-117, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 299.17. A-121: Starting from A-117, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 313.19.

[0187] Preparation of Examples A-127 to A-129: A-127: A-125 is used as raw material, and other operations are the same as A-059. M+1: 257.12. A-128: Starting from A-125, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 285.16. A-129: Starting from A-125, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 299.17.

[0188] Preparation of Examples A-135 to A-137: A-135: A-133 is used as raw material, and other operations are the same as A-059. M+1: 271.14. A-136: Starting from A-133, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 299.17. A-137: Starting from A-133, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 313.19.

[0189] Preparation of Examples A-143 to A-145: A-143: A-141 is used as raw material, and other operations are the same as A-059. M+1: 285.16. A-144: Starting from A-141, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 313.19. A-145: Starting from A-141, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 327.20.

[0190] Preparation of Examples A-151 to A-153: A-151: A-149 is used as raw material, and other operations are the same as A-059. M+1: 285.16. A-152: Starting from A-149, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 313.19. A-153: Starting from A-149, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 327.20.

[0191] Preparation of Examples A-159 to A-161: A-159: A-157 is used as raw material, and other operations are the same as A-059. M+1: 229.13. A-160: Starting from A-157, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 257.16. A-161: Starting from A-157, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 271.18.

[0192] Preparation of Examples A-167 to A-169: A-167: A-165 is used as raw material, and other operations are the same as A-059. M+1: 243.15. A-168: Starting from A-165, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 271.18. A-169: Starting from A-165, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 285.19.

[0193] Preparation of Examples A-175 to A-177: A-175: A-173 is used as raw material, and other operations are the same as A-059. M+1: 257.16. A-176: Starting from A-173, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 285.19. A-177: Starting from A-173, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 299.21.

[0194] Preparation of Examples A-183 to A-185: A-183: A-181 is used as raw material, and other operations are the same as A-059. M+1: 257.16. A-184: Starting from A-181, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 285.19. A-185: Starting from A-181, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 299.21.

[0195] Preparation of Examples A-191 to A-193: A-191: A-189 is used as raw material, and other operations are the same as A-059. M+1: 263.11. A-192: Starting from A-189, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 291.15. A-193: Starting from A-189, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 305.16.

[0196] Preparation of Examples A-199 to A-201: A-199: A-197 is used as raw material, and other operations are the same as A-059. M+1: 277.13. A-200: Starting from A-197, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 305.16. A-201: Starting from A-197, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 319.18.

[0197] Preparation of Examples A-207 to A-209: A-207: A-205 is used as raw material, and other operations are the same as A-059. M+1: 291.15. A-208: Starting from A-205, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 319.18. A-209: Starting from A-205, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 333.19.

[0198] Preparation of Examples A-215 to A-217: A-215: A-213 is used as raw material, and other operations are the same as A-059. M+1: 291.15. A-216: Starting from A-213, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 319.18. A-217: Starting from A-213, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 333.19.

[0199] Preparation of Examples A-223 to A-225: A-223: A-221 is used as raw material, and other operations are the same as A-059. M+1: 187.08. A-224: Starting from A-221, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 215.11. A-225: Starting from A-221, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 229.13.

[0200] Preparation of Examples A-231 to A-233: A-231: A-229 is used as raw material, and other operations are the same as A-059. M+1: 201.10. A-232: Starting from A-229, acetyl chloride is replaced with isobutyryl chloride, and the other operations are the same as A-059. M+1: 229.13. A-233: Starting from A-229, acetyl chloride is replaced with pivaloyl chloride, and the other operations are the same as A-059. M+1: 243.15.

[0201] Preparation of Examples A-239 to A-241: A-239: A-237 is used as raw material, and other operations are the same as A-059. M+1: 215.11. A-240: Starting from A-237, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 243.15. A-241: Starting from A-237, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 257.16.

[0202] Preparation of Examples A-247 to A-249: A-247: A-245 is used as raw material, and other operations are the same as A-059. M+1: 215.11. A-248: Starting from A-245, acetyl chloride is replaced with isobutyryl chloride, and other operations are the same as A-059. M+1: 243.15. A-249: Starting from A-245, acetyl chloride was replaced with pivaloyl chloride, and the other operations were the same as A-059. M+1: 257.16.

[0203] Example A-066 This Example illustrates a method for synthesizing compound A-066.

[0204] [ka]

[0205] 1. Method for synthesizing intermediate 2a Dissolve 0.3g (1.74mmol) of compound A-057 in 20ml of anhydrous DCM under ice bath, add 490μL (3.5mmol) of TEA and stir for 5min, then add 0.49g (1.74mmol) of Boc-tBu-Thr, 0.35g (2.6mmol) of HOBt and 0.5g (2.6mmol) of EDCI, slowly return to room temperature, react for 6h, monitor by TLC, and terminate the reaction after the raw material is completely reacted. Wash with saturated citric acid solution (10mL x 3), separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate, and separate by silica gel column chromatography to obtain 0.59g of colorless oily intermediate 2a, with a yield of 78%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13-1.22(m,12H), 1.37(s,9H), 2.34(s,3H), 3.25(t,2H,J=5.9Hz), 3.37-3.98(m,4H), 4.09-4.28(m,1H), 4.58-4.89(m,3H), 7.89(s,1H). M+1:430.23

[0206] 2. Method for synthesizing the final product A-066 Dissolve 0.5g (1.17mmol) of intermediate 2a in 5mL of anhydrous ethyl acetate, add 10mL of 4mol / L HCl / EtOAc, react overnight at room temperature, white solid appears in the system, monitor by TLC, after the raw material is completely reacted, the reaction is terminated, filter under reduced pressure, wash with anhydrous ether to obtain 0.26g of white solid A-066, the yield is 72.6%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.17-1.22(m,3H), 2.36(s,3H), 3.23(t,2H,J=6.7Hz), 3.35-3.95(m,4H), 4.12-4.32(m,1H), 4.58-4.92(m,3H), 5.65(s,1H), 8.21-8.29(d,2H,J=19Hz). M+1:274.11

[0207] Preparation of Examples A-065, A-067 to A-068: A-065: Raw materials [ka] and other operations are the same as A-066. M+1:230.09. A-067: Raw materials [ka] and other operations are the same as A-066. M+1:260.10. A-068: Raw materials [ka] and other operations are the same as A-066. M+1:272.14.

[0208] Preparation of Examples A-074 to A-076: A-074: Replace A-057 with A-069, other operations are the same as A-066. M+1: 288.13. A-075: A-057 to A-069, raw material [ka] and other operations are the same as A-066. M+1:274.11. A-076: A-057 to A-069, raw material [ka] and other operations are the same as A-066. M+1:286.15.

[0209] Preparation of Examples A-082 to A-084: A-082: Replace A-057 with A-077, and other operations are the same as A-066. A-083: A-057 to A-077, raw material [ka] and other operations are the same as A-066. M+1:288.13. A-084: A-057 to A-077, raw material [ka] and other operations are the same as A-066. M+1:300.17.

[0210] Preparation of Examples A-090 to A-092: A-090: Replace A-057 with A-085, other operations are the same as A-066. M+1: 302.15. A-091: A-057 to A-085, raw material [ka] and other operations are the same as A-066. M+1:288.13. A-092: A-057 to A-085, raw material [ka] and other operations are the same as A-066. M+1:300.17.

[0211] Preparation of Examples A-098 to A-100: A-098: Replace A-057 with A-093, other operations are the same as A-066. M+1: 302.15. A-099: A-057 to A-093, raw material [ka] and other operations are the same as A-066. M+1:288.13. A-100: A-057 to A-093, raw material [ka] and other operations are the same as A-066. M+1:300.17.

[0212] Preparation of Examples A-106 to A-108: A-106: Replace A-057 with A-101, other operations are the same as A-066. M+1: 316.16. A-107: A-057 to A-101, raw material [ka] and other operations are the same as A-066. M+1:302.15. A-108: A-057 to A-101, raw material [ka] and other operations are the same as A-066. M+1:314.18.

[0213] Preparation of Examples A-114 to A-116: A-114: Replace A-057 with A-109, other operations are the same as A-066. M+1: 330.18. A-115: A-057 to A-109, raw material [ka] and other operations are the same as A-066. M+1:316.16. A-116: A-057 to A-109, raw material [ka] and other operations are the same as A-066. M+1:328.20.

[0214] Preparation of Examples A-122 to A-124: A-122: Replace A-057 with A-117, other operations are the same as A-066. M+1: 330.18. A-123: A-057 to A-117, raw material [ka] and other operations are the same as A-066. M+1:316.16. A-124: A-057 to A-117, raw material [ka] and other operations are the same as A-066. M+1:328.20.

[0215] Preparation of Examples A-130 to A-132: A-130: Replace A-057 with A-125, other operations are the same as A-066. M+1: 316.16. A-131: A-057 to A-125, raw material [ka] and other operations are the same as A-066. M+1:302.15. A-132: A-057 to A-125, raw material [ka] and other operations are the same as A-066. M+1:314.18.

[0216] Preparation of Examples A-138 to A-140: A-138: Replace A-057 with A-133, other operations are the same as A-066. M+1: 330.18. A-139: A-057 to A-133, raw material [ka] and other operations are the same as A-066. M+1:316.16. A-140: A-057 to A-133, raw material

[0217] [ka] and other operations are the same as A-066. M+1:328.20.

[0218] Preparation of Examples A-146 to A-148: A-146: Replace A-057 with A-141, other operations are the same as A-066. M+1: 344.19. A-147: A-057 to A-141, raw material [ka] and other operations are the same as A-066. M+1:330.18. A-148: A-057 to A-141, raw material [ka] and other operations are the same as A-066. M+1:342.21.

[0219] Preparation of Examples A-154 to A-156: A-154: Replace A-057 with A-149, other operations are the same as A-066. M+1: 344.19. A-155: A-057 to A-149, raw material [ka] and other operations are the same as A-066. M+1:330.18. A-156: A-057 to A-149, raw materials [ka] and other operations are the same as A-066. M+1:342.21.

[0220] Preparation of Examples A-162 to A-164: A-162: Replace A-057 with A-157, other operations are the same as A-066. M+1: 288.17. A-163: A-057 to A-157, raw material [ka] and other operations are the same as A-066. M+1:274.15. A-164: A-057 to A-157, raw material [ka] and other operations are the same as A-066. M+1:286.19.

[0221] Preparation of Examples A-170 to A-172: A-170: Replace A-057 with A-165, other operations are the same as A-066. M+1: 302.18. A-171: A-057 to A-165, raw material [ka] and other operations are the same as A-066. M+1:288.17. A-172: A-057 to A-165, raw material [ka] and other operations are the same as A-066. M+1:300.20.

[0222] Preparation of Examples A-178 to A-180: A-178: Replace A-057 with A-173, other operations are the same as A-066. M+1: 316.20. A-179: A-057 to A-173, raw material [ka] and other operations are the same as A-066. M+1:302.18. A-180: A-057 to A-173, raw material [ka] and other operations are the same as A-066. M+1:314.22.

[0223] Preparation of Examples A-186 to A-188: A-186: Replace A-057 with A-181, other operations are the same as A-066. M+1: 315.20. A-187: A-057 to A-181, raw material [ka] and other operations are the same as A-066. M+1:302.18. A-188: A-057 to A-181, raw material [ka] and other operations are the same as A-066. M+1:314.22.

[0224] Preparation of Examples A-194 to A-196: A-194: Replace A-057 with A-189, other operations are the same as A-066. M+1: 322.15. A-195: A-057 to A-189, raw material [ka] and other operations are the same as A-066. M+1:308.14. A-196: A-057 to A-189, raw material [ka] and other operations are the same as A-066. M+1:320.17.

[0225] Preparation of Examples A-202 to A-204: A-202: Replace A-057 with A-197, other operations are the same as A-066. M+1: 336.17. A-203: A-057 to A-197, raw material [ka] and other operations are the same as A-066. M+1:322.15. A-204: A-057 to A-197, raw material [ka] and other operations are the same as A-066. M+1:334.19.

[0226] Preparation of Examples A-210 to A-212: A-210: Replace A-057 with A-205, other operations are the same as A-066. M+1: 350.18. A-211: A-057 to A-205, raw material [ka] and other operations are the same as A-066. M+1:336.17. A-212: A-057 to A-205, raw material [ka] and other operations are the same as A-066. M+1:348.20.

[0227] Preparation of Examples A-218 to A-220: A-218: Replace A-057 with A-213, other operations are the same as A-066. M+1: 350.18. A-219: A-057 to A-213, raw material [ka] and other operations are the same as A-066. M+1:336.17. A-220: A-057 to A-213, raw material [ka] and other operations are the same as A-066. M+1:348.20.

[0228] Preparation of Examples A-226 to A-228: A-226: Replace A-057 with A-221, other operations are the same as A-066. M+1: 246.12. A-227: A-057 to A-221, raw material [ka] and other operations are the same as A-066. M+1:232.10. A-228: A-057 to A-221, raw material [ka] and other operations are the same as A-066. M+1:244.14.

[0229] Preparation of Examples A-234 to A-236: A-234: Replace A-057 with A-229, other operations are the same as A-066. M+1: 260.14. A-235: A-057 to A-229, raw material [ka] and other operations are the same as A-066. M+1:246.12. A-236: A-057 to A-229, raw material [ka] and other operations are the same as A-066. M+1:258.16.

[0230] Preparation of Examples A-242 to A-244: A-242: Replace A-057 with A-237, other operations are the same as A-066. M+1: 274.15. A-243: A-057 to A-237, raw material [ka] and other operations are the same as A-066. M+1:260.14. A-244: A-057 to A-237, raw material [ka] and other operations are the same as A-066. M+1:272.17.

[0231] Preparation of Examples A-250 to A-252: A-250: Replace A-057 with A-245, other operations are the same as A-066. M+1: 274.15. A-251: A-057 to A-245, raw material [ka] and other operations are the same as A-066. M+1:260.14. A-252: A-057 to A-245, raw material [ka] and other operations are the same as A-066. M+1:272.17.

[0232] Example A-253 This example illustrates a method for the synthesis of compound A-253.

[0233] [ka]

[0234] 1. Method for synthesizing intermediate 3a At -15℃, 1.8g (10mmol) of raw material L-cysteine ​​methyl ester hydrochloride was dissolved in 100mL of methanol, and the mixture was stirred until completely dissolved. 1.75mL (15mmol) of TEA was added. After the raw material was completely released, 1.8g (10mmol, 1.0eq) of raw material 1-Boc-3-azetidinone was added, and the mixture was reacted at low temperature for 15min and then returned to room temperature. After reacting at room temperature for 4h, the mixture was monitored by TLC. After the raw material was completely reacted, the reaction solution was dried by spin drying, the concentrate was dissolved in 100mL of ethyl acetate, washed several times with a small amount of water (15ml x 4), dried with anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel chromatography (PE: EtOAc = 2: 1) to obtain 2.4g of intermediate 3a as a yellow transparent oil, with a yield of 83%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.37(s,9H), 3.06-3.55(m,6H), 3.91-4.19(m,4H), 8.69(s,1H). M+1:289.11

[0235] 2. Method for synthesizing intermediate A-254 Dissolve 0.8g (2.8mmol) of intermediate 3a in 5mL of anhydrous methanol, add 5mL of 7mol / L NH3 / CH3OH solution, stir overnight at room temperature, monitor by TLC, and terminate the reaction after the raw materials are completely reacted. Concentrate under reduced pressure to obtain a white solid, add petroleum ether and stir to improve the properties, filter, and obtain 0.68g of white solid A-254, with a yield of 90.7%. 1H-NMR (400MHz, DMSO-d6), δppm:1.37(s,9H), 3.02-3.27(m,2H), 3.36-3.45(m,1H), 3.94-4.23 (m,4H), 8.14(s,2H), 8.78(s,1H). M+1:274.11

[0236] 3. Method for synthesizing product A-253 Dissolve 0.4g of A-254 in 3mL of anhydrous ethyl acetate, add 5mL of 4mol / L HCl / EtOAc, stir at room temperature for 4h, monitor by TLC, after the raw materials are completely reacted, a white solid appears in the system, filter and wash with anhydrous ether to obtain 0.21g of the final product A-253, the yield is 70%. 1 H-NMR (400MHz,DMSO-d6), δppm:3.04-3.28(m,2H), 3.37-3.42(m,1H), 3.91-4.22(m,4H), 8.15(s,2H), 8.54(s,1H). M+1:174.06

[0237] Similarly, in the synthesis of intermediate 3a, the raw material 1-Boc-3-azetidinone is replaced with N-Boc-3-pyrrolidone, N-Boc-4-piperidone, or N-Boc-3-piperidone, and the other operations are the same as those for the synthesis of intermediate 3a, to obtain intermediates 3b, 3c, and 3d, respectively.

[0238] [ka]

[0239] Preparation of Examples A-262, A-270, A-278: A-262: Intermediate 3a is replaced with intermediate 3b, and the other procedures are the same as A-254. M+1: 288.13. A-270: Intermediate 3a is replaced with intermediate 3c, and the other procedures are the same as A-254. M+1: 302.15. A-278: Intermediate 3a is replaced with intermediate 3d, and the other procedures are the same as A-254. M+1: 302.15.

[0240] Preparation of Examples A-261, A-269, A-277: A-261: Replace A-254 with A-262, and other operations are the same as A-253. M+1: 188.08. A-269: Replace A-254 with A-270, and other operations are the same as A-253. M+1: 202.09. A-277: Replace A-254 with A-278, and other operations are the same as A-253. M+1: 202.09.

[0241] Example A-255 This example illustrates a method for the synthesis of compound A-255.

[0242] [ka]

[0243] 1. Method for synthesizing intermediate 4a 2.4 g (8.3 mmol) of intermediate 3a was dissolved in 10 mL of anhydrous ethyl acetate, and 20 mL of 4 mol / L hydrochloric acid / ethyl acetate solution was added under ice bath, and the mixture was reacted overnight. An off-white solid appeared, and the reaction was monitored by TLC. After the raw material was completely reacted, the solid was filtered, washed with anhydrous ether, and dried to obtain 1.8 g of intermediate 4a. 1 H-NMR (400MHz, DMSO-d6), δppm:3.05-3.55(m,6H), 3.91-4.19(m,4H), 8.26(s,1H), 8.69(s,1H). M+1:189.06

[0244] 2. Method for synthesizing intermediate 5a Dissolve 1.6g (7.15mmol) of intermediate 4a in 20mL of DCM under ice bath, add 4mL (28mmol) of TEA to release, then slowly add 1mL (14mmol) of acetyl chloride, gradually return to room temperature, and react overnight. Monitor by TLC. After the raw materials have completely reacted, the reaction is terminated, washed with saturated aqueous citric acid (10mL x 3), the organic phase is separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 1.53g of pale yellow oily intermediate 5a, with a yield of 76.5%. 1 H-NMR (400MHz,DMSO-d6), δppm:2.05(s,3H), 3.07-3.53(m,6H), 3.95-4.21(m,4H), 8.48(s,1H). M+1:231.07

[0245] 3. Method for synthesizing product A-255 Intermediate 5a was hydrolyzed, and the synthesis method was the same as that of A-254. 1 H-NMR (400MHz,DMSO-d6), δppm:2.04(s,3H), 3.02-3.25(m,2H), 3.38-3.47(m,1H), 3.97-4.22(m,4H), 8.23(s,2H), 9.01(s,1H). M+1:216.07

[0246] In the synthesis process of intermediate 4a, the raw material intermediate 3a is replaced with intermediate 3b, intermediate 3c, intermediate 3d, respectively, and the other operations are the same as the synthesis of intermediate 4a, to obtain intermediate 4b, intermediate 4c, intermediate 4d, respectively; Similarly, in the synthesis process of intermediate 5a, the raw material intermediate 4a is replaced with intermediate 4b, intermediate 4c, and intermediate 4d, respectively, and the other operations are the same as the synthesis of intermediate 5a, to obtain intermediate 5b, intermediate 5c, and intermediate 5d, respectively; Similarly, in the synthesis of intermediate 5a, acetyl chloride can be replaced with isobutyryl chloride or pivaloyl chloride to give intermediates 6a, 6b, 6c, and 6d, and intermediates 7a, 7b, 7c, and 7d, respectively.

[0247] [ka]

[0248] Production of A-256 to A-257: A-256: Intermediate 5a is replaced with intermediate 6a, and the other procedures are the same as A-255. M+1: 244.10. A-257: Intermediate 5a is replaced with intermediate 7a, and the other procedures are the same as A-255. M+1: 258.12. Manufacturing of A-263 to A-265: A-263: Intermediate 5a is replaced with intermediate 5b, and the other procedures are the same as A-255. M+1: 230.09. A-264: Intermediate 5a is replaced with intermediate 6b, and the other procedures are the same as A-255. M+1: 258.12. A-265: Intermediate 5a was converted to intermediate 7b, and the other procedures were the same as those for A-255. M+1: 272.14. Manufacturing of A-271 to A-273: A-271: Intermediate 5a is replaced with intermediate 5c, and the other procedures are the same as A-255. M+1: 244.10. A-272: Intermediate 5a is replaced with intermediate 6c, and the other procedures are the same as A-255. M+1: 272.14. A-273: Intermediate 5a is replaced with intermediate 7c, and the other procedures are the same as A-255. M+1: 286.15. Production of A-279~A-281: A-279: Intermediate 5a is replaced with intermediate 5d, and the other procedures are the same as A-255. M+1: 244.10. A-280: Intermediate 5a is replaced with intermediate 6d, and the other procedures are the same as A-255. M+1: 272.14. A-281: Intermediate 5a is replaced with intermediate 7d, and the other procedures are the same as A-255. M+1: 286.15.

[0249] Example A-258 This example illustrates the synthesis of compound A-258.

[0250] [ka]

[0251] 1. Method for synthesizing intermediate 8a Dissolve 1.8g (8mmol) of intermediate 4a in 50mL of dichloromethane, add 0.89g (8.8mmol) of triethylamine under ice bath, and after sufficient liberation, add 2.2g (8mmol) of Boc-tBu-Thr, 1.18g (8.8mmol) of HOBt, and 1.68g (8.8mmol) of EDCI, and return to room temperature to react and monitor by TLC. After complete reaction, wash with aqueous citric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence, dry with anhydrous sodium sulfate, filter, and concentrate. The concentrate is purified by silica gel chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 1.9g of intermediate 8a, with a yield of 53%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.12-1.20(m,12H), 1.37(s,9H), 3.14-3.41(m,2H), 3.59-3.87(m,5H), 4.04-4.84(m,5H), 7.84(s,1H), 8.52(s,1H). M+1:446.22

[0252] 2. Method for synthesizing intermediate 9a 1.5 g (3.37 mmol) of intermediate 8a was dissolved in a small amount of methanol, and 10 mL of 7 mol / L NH3 / CH3OH solution was added under ice bath, and the mixture was reacted overnight. After the raw materials were completely reacted, the reaction solution was spun dry to give 1.45 g of intermediate 9a as an off-white solid, with a yield of 99.4%. 1H-NMR (400MHz,DMSO-d6), δppm:1.12-1.22(m,12H), 1.37(s,9H), 3.15-3.43(m,2H), 3.59-3.89(m,2H), 4.07-4.81(m,5H), 7.84(s,1H), 8.24(s,2H), 8.57(s,1H). M+1:431.22

[0253] 3. Method for synthesizing product A-258 Dissolve 1.3g (3mmol) of intermediate 9a in 10mL of anhydrous ethyl acetate, add 10mL of 4mol / L HCl / EtOAc solution under ice bath, gradually return to room temperature, react for 6h, monitor by TLC, the raw material is completely reacted, and white solid is precipitated in the reaction system, filtered and washed with anhydrous ether to obtain 0.81g of final product A-258, the yield is 86.1%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.12-1.17(m,3H), 3.05-3.17(m,1H), 3.39-3.43(m,1H), 3.72-3.92(m,2H), 4.06-4.81(m,5H), 5.65(s,1H), 7.55(s,1H), 7.93(s,2H), 8.24(s,2H). M+1:275.11

[0254] By replacing intermediate 4a with intermediate 4b, intermediate 4c, and intermediate 4d, intermediates 8b, 8c, and 8d, respectively, could be prepared, and intermediates 9b, 9c, and 9d were correspondingly prepared. Intermediate 4a was replaced with intermediate 4b, intermediate 4c, and intermediate 4d, respectively. [ka] By replacing the above, intermediates 10a, 10b, 10c, and 10d could be produced, respectively, and the corresponding intermediates 11a, 11b, 11c, and 11d were further produced. Intermediate 4a was replaced with intermediate 4b, intermediate 4c, and intermediate 4d, respectively. [ka] By replacing the above, intermediates 12a, 12b, 12c, and 12d could be produced, respectively, and the corresponding intermediates 13a, 13b, 13c, and 13d were further produced.

[0255] [ka]

[0256] Preparation of Examples A-259 to A-260 A-259: Raw materials [ka] and other operations are the same as A-258. M+1:261.09. A-260: Raw materials [ka] and other operations are the same as A-258. M+1:273.13.

[0257] Manufacturing method of Examples A-266 to A-268 A-266: The raw material intermediate 4a was replaced with intermediate 4b, and the other operations were the same as those of A-258. M+1: 289.13. A-267: The raw material intermediate 4a is replaced with intermediate 4b. [ka] and other operations are the same as A-258. M+1:275.11. A-268: The raw material intermediate 4a is replaced with intermediate 4b. [ka] and other operations are the same as A-258. M+1:287.15.

[0258] Manufacturing method of Examples A-274 to A-276 A-274: The raw material intermediate 4a was replaced with intermediate 4c, and the other operations were the same as those of A-258. M+1: 303.14. A-275: The raw material intermediate 4a is replaced with intermediate 4c. [ka] and other operations are the same as A-258. M+1:289.13. A-276: The raw material intermediate 4a is replaced with intermediate 4c. [ka] and other operations are the same as A-258. M+1:301.16.

[0259] Preparation of Examples A-282 to A-284 A-282: The raw material intermediate 4a is replaced with intermediate 4d, and the other operations are the same as A-258. M+1: 303.14. A-283: The raw material intermediate 4a is replaced with intermediate 4d. [ka] and other operations are the same as A-258. M+1:289.13. A-284: The raw material intermediate 4a is replaced with intermediate 4d. [ka] and other operations are the same as A-258. M+1:301.16.

[0260] Example A-285 This example illustrates the synthesis of compound A-285.

[0261] [ka]

[0262] In an ice bath, 0.8g (1.74mmol) of intermediate 8a was dissolved in 10mL of anhydrous ethyl acetate, 5mL of 4mol / L HCl / EtOAc was added, and the mixture was gradually cooled to room temperature. After reacting for 4h, it was monitored by TLC that the raw materials were completely reacted, and a white solid was precipitated in the reaction system. The reaction was stopped, filtered under reduced pressure, and the filter cake was added to 15mL of anhydrous ethyl acetate and stirred for 10min, then filtered to obtain 0.51g of white solid A-285, with a yield of 90.1%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.12-1.17(m,3H), 3.07-3.19(m,1H), 3.38-3.42(m,1H), 3.68-3.91(m,5H), 4.07-4.83(m,5H), 5.63(s,1H), 7.53(s,1H), 7.88(s,2H). M+1:290.11

[0263] Preparation of Examples A-286 to A-287 A-286: Intermediate 8a is replaced with intermediate 10a, and the other procedures are the same as A-285. M+1: 276.09. A-287: Intermediate 8a is replaced with intermediate 12a, and the other procedures are the same as A-285. M+1: 288.13.

[0264] Preparation of Examples A-288 to A-290 A-288: Intermediate 8a is replaced with intermediate 8b, and the other procedures are the same as A-285. M+1: 304.13. A-289: Intermediate 8a is replaced with intermediate 10b, and the other procedures are the same as A-285. M+1: 290.11. A-290: Intermediate 8a is replaced with intermediate 12b, and the other procedures are the same as A-285. M+1: 302.15.

[0265] Preparation of Examples A-291 to A-293 A-291: Intermediate 8a is replaced with intermediate 8c, and the other procedures are the same as A-285. M+1: 318.14. A-292: Intermediate 8a is replaced with intermediate 10c, and the other procedures are the same as A-285. M+1: 304.13. A-293: Intermediate 8a is replaced with intermediate 12c, and the other procedures are the same as A-285. M+1: 316.16.

[0266] Preparation of Examples A-294 to A-296 A-294: Intermediate 8a is replaced with intermediate 8d, and the other procedures are the same as A-285. M+1: 318.14. A-295: Intermediate 8a is replaced with intermediate 10d, and the other procedures are the same as A-285. M+1: 304.13. A-296: Intermediate 8a is replaced with intermediate 12d, and the other procedures are the same as A-285. M+1: 316.16.

[0267] Example A-302 This example illustrates a method for synthesizing compound A-302.

[0268] [ka]

[0269] 1. Method for synthesizing intermediate 14a Dissolve 0.7g (1.6mmol) of intermediate 9a in 10mL of anhydrous DCM, add 832μL (6mmol) of TEA, add 0.7g of trifluoroacetic anhydride (TFAA, 3.2mmol) under ice bath, gradually return to room temperature, stir at room temperature for 12h, monitor by TLC, the raw material reacts completely, stop the reaction, wash the organic phase with 10mL of water, 10mL of saturated aqueous sodium chloride solution, and dry with anhydrous sodium sulfate. Filtration, concentration, and separation by silica gel chromatography column (PE: EtOAc = 2: 1) to obtain 0.62g of the final product intermediate 14a, the yield is 92%. 1H-NMR(400MHz,DMSO-d6), δppm:1.13-1.21(m,12H), 1.37(s,9H), 3.03-3.14(m,1H), 3.39-3.42(m,1H), 3.69-3.86(m,2H), 4.03-4.75(m,5H), 7.81(s,1H), 8.34(s,1H). M+1:413.21

[0270] 2. Preparation of Example A-302 Dissolve 0.5g of intermediate 14a in 10mL of anhydrous ethyl acetate under ice bath, stir thoroughly to dissolve, add 5mL of 4mol / L HCl / EtOAc, and gradually return to room temperature. After reacting at room temperature for 5h, a yellow solid precipitated in the reaction system, which was monitored by TLC. After the raw material was completely reacted, the reaction was stopped. Filter, add the filter cake to anhydrous ethyl acetate, stir for 15min, and then filter to obtain 0.26g of A-302, with a yield of 83%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13-1.18(m,3H), 3.06-3.18(m,1H), 3.39-3.42(m,1H), 3.74-3.91(m,2H), 4.05-4.79(m,5H), 5.68 (s,1H), 8.29(s,2H), 8.52(s,1H). M+1:257.10

[0271] Preparation of Examples A-297 to A-301, A-303, and A-304 A-297: Intermediate 9a is replaced with A-254, and the other procedures are the same as A-302. M+1: 156.05. A-298: Intermediate 9a is replaced with A-254, and the other procedures are the same as for intermediate 14a. M+1: 256.10. A-299: Intermediate 9a is replaced with A-255, and the other procedures are the same as for intermediate 14a. M+1: 198.06. A-300: Intermediate 9a is replaced with A-256, and the other procedures are the same as for intermediate 14a. M+1: 226.09. A-301: Intermediate 9a is replaced with A-257, and the other procedures are the same as for intermediate 14a. M+1: 240.11. A-303: Intermediate 9a is replaced with intermediate 11a, and the other procedures are the same as A-302. M+1: 243.08. A-304: Intermediate 9a is replaced with intermediate 13a, and the other procedures are the same as A-302. M+1: 255.12.

[0272] Preparation of Examples A-305 to A-312 A-305: Intermediate 9a is replaced with A-262, and the other procedures are the same as A-302. M+1: 170.07. A-306: Intermediate 9a is replaced with A-262, and the other procedures are the same as for intermediate 14a. M+1: 270.12. A-307: Intermediate 9a is replaced with A-263, and the other procedures are the same as for intermediate 14a. M+1: 212.08. A-308: Intermediate 9a is replaced with A-264, and the other procedures are the same as for intermediate 14a. M+1: 240.11. A-309: Intermediate 9a is replaced with A-265, and the other procedures are the same as for intermediate 14a. M+1: 254.12. A-310: Intermediate 9a is replaced with intermediate 9b, and the other procedures are the same as A-302. M+1: 271.12. A-311: Intermediate 9a is replaced with intermediate 11b, and the other procedures are the same as A-302. M+1: 257.10. A-312: Intermediate 9a is replaced with intermediate 13b, and the other procedures are the same as A-302. M+1: 269.14.

[0273] Preparation of Examples A-313 to A-320 A-313: Intermediate 9a is replaced with A-270, and other procedures are the same as A-302. A-314: Intermediate 9a is replaced with A-270, and the other procedures are the same as for intermediate 14a. M+1: 284.14. A-315: Intermediate 9a is replaced with A-271, and the other procedures are the same as for intermediate 14a. M+1: 226.09. A-316: Intermediate 9a is replaced with A-272, and the other procedures are the same as for intermediate 14a. M+1: 254.12. A-317: Intermediate 9a is replaced with A-273, and the other procedures are the same as for intermediate 14a. M+1: 268.14. A-318: Intermediate 9a is replaced with intermediate 9c, and the other procedures are the same as A-302. M+1: 285.13. A-319: Intermediate 9a is replaced with intermediate 11c, and the other procedures are the same as A-302. M+1: 271.12. A-320: Intermediate 9a is replaced with intermediate 13c, and the other procedures are the same as A-302. M+1: 283.15.

[0274] Preparation of Examples A-321 to A-328 A-321: Intermediate 9a is replaced with A-278, and the other procedures are the same as A-302. M+1: 184.08. A-322: Intermediate 9a is replaced with A-278, and the other procedures are the same as for intermediate 14a. M+1: 284.14. A-323: Intermediate 9a is replaced with A-279, and the other procedures are the same as for intermediate 14a. M+1: 226.09. A-324: Intermediate 9a is replaced with A-280, and the other procedures are the same as for intermediate 14a. M+1: 254.12. A-325: Intermediate 9a is replaced with A-281, and the other procedures are the same as for intermediate 14a. M+1: 268.14. A-326: Intermediate 9a is replaced with intermediate 9d, and the other procedures are the same as A-302. M+1: 285.13. A-327: Intermediate 9a is replaced with intermediate 11d, and the other procedures are the same as A-302. M+1: 271.12. A-328: Intermediate 9a is replaced with intermediate 13d, and the other procedures are the same as A-302. M+1: 283.15.

[0275] Synthesis of Example A-329

[0276] [ka]

[0277] 1. Synthesis of intermediate 15a In an ice bath, dissolve 0.5g (1.5mmol) of Fmoc-Val in 10mL of anhydrous DCM, add 2 drops of DMF to carry out the catalytic reaction, then add 230μL (1.65mmol) of TEA, drop by drop 133μL (1.58mmol) of oxalyl chloride, return to room temperature, react overnight, monitor by TLC, after the raw materials are completely reacted, add 0.35g (1.5mmol) of compound A-002 to the reaction system, continue to stir at room temperature for 4h, monitor by TLC, after the raw materials are completely reacted, stop the reaction, wash twice with saturated citric acid, wash once with saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and separate by silica gel chromatography column (PE:EtOAC=3:1), obtain 0.69g of colorless oil, yield 83.3%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.12-1.23(m,6H), 1.37(9H), 2.15-2.25(m,1H), 3.16-3.73(m,5H), 4.16-4.79(m,8H), 7.21-8.29(m,9H). M+1:552.25

[0278] 2. Synthesis of intermediate 16a Dissolve 0.48g of intermediate 15a in 5mL of anhydrous acetonitrile, add 5mL of diethylamine, react for 4h at internal temperature of 50℃, monitor by TLC, after the raw material is completely reacted, stop the reaction, swirl dry under reduced pressure, add 10mL of DCM, continue swirl dry, repeat twice, and separate by silica gel chromatography column to obtain 0.25g of oil, yield 87.2%. 1H-NMR (400MHz,DMSO-d6), δppm:1.12-1.20(m,6H), 1.37(s,9H), 2.14-2.27(m,1H), 3.13-3.77(m,5H), 4.13-4.57(m,4H), 8.23(s,2H). M+1:330.18

[0279] 3.Synthesis of A-329 Dissolve 0.25g of intermediate 16 in 4mL of ethyl acetate, add 3mL of 4mol / L HCl / EtOAc, stir at room temperature for 3h, monitor by TLC, after the raw materials are completely reacted, white solid precipitates in the reaction system, filter and dry to obtain 0.16g of white solid, the yield is 79%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.12-1.19(m,6H), 2.14-2.25(m,1H), 3.13-3.75(m,5H), 4.16-4.61(m,4H), 8.29(s,2H), 9.01(s,1H). M+1:230.12

[0280] Synthesis of Example A-330

[0281] [ka]

[0282] Synthesis of intermediate 17a The synthesis method is the same as that of A-329, and 0.65 g of a pale yellow solid is obtained, with a yield of 89.3%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.14-1.27(m,6H), 2.15-2.25(m,1H), 3.16-3.73(m,5H), 4.16-4.79(m,8H), 7.21-8.29(m,9H). M+1:452.19

[0283] Synthesis of intermediate 18a: In an ice bath, dissolve 0.62g of intermediate 17 in 10mL of anhydrous DCM, add 300μL of TEA to release, slowly add 185μL of acetic anhydride, gradually return to room temperature, continue to react for 6h, monitor by TLC, after the raw material reacts completely, stop the reaction, wash with saturated aqueous citric acid solution and saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and separate by silica gel chromatography column to obtain 0.52g of oil, the yield is 83%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.13-1.27(m,6H), 2.05-2.27(m,4H), 3.15-3.70(m,5H), 4.12-4.75(m,8H), 7.21-8.28(m,9H). M+1:494.2

[0284] Synthesis of Example A-330 The synthesis method is the same as intermediate 16a, 0.38g of oil is obtained, after adding HCl / EtOAc and stirring, white solid is precipitated in the reaction system, filtered and dried to obtain 0.34g of product A-330. 1 H-NMR (400MHz,DMSO-d6), δppm:1.12-1.18(m,6H), 2.05-2.24(m,4H), 3.11-3.78(m,5H), 4.12-4.65(m,4H), 8.60(s,2H). M+1:272.14

[0285] Synthesis of Example A-331

[0286] [ka]

[0287] Synthesis of intermediate 19a The synthesis method was the same as that of intermediate 8a, and 1.52 g of a colorless oil was obtained, with a yield of 81.3%. 1H-NMR (400MHz,DMSO-d6), δppm:1.03-1.37 (m,27H), 2.32-2.38(m,1H), 3.02-3.73(m,4H), 4.14-4.68(m,10H), 7.12-8.32(m,10H). M+1:709.36.

[0288] Synthesis of intermediate 20a The synthesis method was the same as that of intermediate 16a, and 0.84 g of an oily product was obtained, with a yield of 86.9%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.01-1.38 (m,27H), 2.32-2.38(m,1H), 3.05-3.77(m,4H), 4.12-4.71(m,7H), 7.76(s,1H), 8.35(s,2H). M+1:487.29.

[0289] Synthesis of Example A-331: The synthesis method was the same as that of A-329, and 0.49 g of a white solid was obtained, with a yield of 87.5%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.07-1.22 (m,9H), 2.18-2.27(m,1H), 3.07-3.78(m,7H), 4.14-4.59(m,4H), 5.72(s,1H), 8.21-8.32(m,4H). M+1:331.17.

[0290] Synthesis of Examples A-347 and A-348 A-347: In the synthesis of A-331 [ka] and other operations are the same as A-331. M+1:317.16. A-348: In the synthesis of A-331 [ka] and other operations are the same as A-331. M+1:329.20.

[0291] Synthesis of Example A-332 [ka]

[0292] Synthesis of intermediate 21a Dissolve 5.2g (18mmol) of intermediate 3a in 20mL of methanol, add NaOH aqueous solution (10mL, 9.0M) slowly in an ice-water bath, and after the color of the reaction solution becomes dark, return to room temperature. React for 3 hours, check the reaction by TLC, and after intermediate 3a has completely disappeared, stop the reaction, distill off the solvent under reduced pressure, add dilute hydrochloric acid to make the pH value weakly acidic, and precipitate a white solid. After filtering and drying, obtain 4.3g of white solid, yield 86.9%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.37(s,9H), 3.06-3.56(m,3H), 3.94-4.23(m,4H), 8.54(s,1H). M-1:273.1

[0293] Synthesis of intermediate 22a In an ice bath, 0.8g (2.9mmol) of intermediate 21a was dissolved in 20mL of acetonitrile, and 0.8mL (5.8mmol) of TEA and 1.1g (3.5mmol) of TBTU were added, followed by 0.53g (3.1mmol) of O-TERT-butyl-L-serine methyl ester hydrochloride. The mixture was gradually brought back to room temperature and reacted for 4h. The reaction was monitored by TLC. After the raw materials were completely reacted, the reaction was stopped. The mixture was washed with saturated citric acid and saturated sodium chloride in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel chromatography column to obtain 0.86g of oil, with a yield of 76.1%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13(s,9H), 1.42(s,9H), 2.67-4.38(m,13H), 7.43(s,1H), 8.21(s,1H). M+1:432.21

[0294] Synthesis of intermediate 23a The synthesis method was the same as that of intermediate 9a, and 0.76 g of an oily product was obtained, with a yield of 93.5%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13(s,9H), 1.42(s,9H), 2.67-4.38(m,10H), 7.06-7.21(m,3H), 8.21(s,1H). M+1:417.21

[0295] Synthesis of Example A-332 The synthesis method was the same as that of A-329, and 0.53 g of a white solid was obtained, with a yield of 81.3%. 1 H-NMR (400MHz, DMSO-d6), δppm:2.67-4.54(m,10H), 4.94(s,1H), 7.21-8.11(m,5H). M+1:261.10.

[0296] Synthesis of Example A-370 A-370: The synthesis method is the same as A-332. [ka] and other operations are the same as A-332. M+1:275.11

[0297] Synthesis of Examples A-383, A-390, and A-397 A-383: Intermediate 5a in the synthesis of A-332 is converted to 5b, [ka] and other operations are the same as A-332. M+1:289.13 A-390: Intermediate 5a in the synthesis of A-332 is converted to 5c, [ka] and other operations are the same as A-332. M+1:303.14 A-397: Intermediate 5a in the synthesis of A-332 is converted to 5d, [ka] and other operations are the same as A-332. M+1:303.14

[0298] Synthesis of Example A-371 [ka]

[0299] Synthesis of intermediate 24a The synthesis method was the same as that of Intermediate 21a, and 0.68 g of an oily product was obtained, with a yield of 76.7%. 1 H-NMR (400MHz,DMSO-d6), δppm:2.10(s,3H), 2.67-2.92(m,2H), 3.67(m,1H), 4.12-4.38(m,4H), 7.06(s,1H), 12.39(s,1H). M+1:217.06

[0300] Synthesis of intermediate 25a The synthesis method was the same as that of intermediate 22a, and 0.93 g of an oily product was obtained, with a yield of 79.1%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13(s,12H), 2.10(s,3H), 2.67-2.92(m,2H), 3.67(s,3H), 3.69-4.38(m,7H), 7.06(s,1H), 8.32(s,1H). M+1:374.17

[0301] Synthesis of intermediate 26a The synthesis method was the same as that of intermediate 23a, and 0.67 g was obtained, with a yield of 75.2%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13(s,12H), 2.10(s,3H), 2.67-2.92(m,2H), 3.33-4.38(m,7H), 7.06(s,1H), 7.21(s,2H), 8.32(s,1H). M+1:359.17

[0302] Synthesis of A-371 The synthesis method is the same as that of A-332. 0.48 g of colorless oil is obtained, which is dried by suction with an oil pump to obtain a white solid, with a yield of 85.7%. 1 H-NMR (400MHz,DMSO-d6), δppm:2.10(s,6H), 2.33-2.85(m,2H), 4.12-4.54(m,7H), 4.94(s,1H), 7.21(s,2H), 8.26(s,2H). M+1:303.11

[0303] Synthesis of Example A-333 A-333: In the synthesis of A-371 [ka] and other operations are the same as A-371. M+1:317.12

[0304] Examples A-372 and A-373 A-372: 5a in the synthesis of A-371 is replaced with 6a, and the other procedures are the same as A-371. M+1: 345.16 A-373: 5a in the synthesis of A-371 is replaced with 7a, and the other procedures are the same as A-371. M+1: 359.17

[0305] Synthesis of Examples A-384, A-391, and A-398 A-384: Intermediate 5a in the synthesis of A-371 is replaced with 5b, and the other procedures are the same as A-371. M+1: 331.14 A-391: Intermediate 5a in the synthesis of A-371 is replaced with 5c, and the other procedures are the same as A-371. M+1: 345.16 A-398: Intermediate 5a in the synthesis of A-371 is replaced with 5d, and the other procedures are the same as A-371. M+1: 345.16

[0306] Synthesis of Examples A-385 and A-386 A-385: Intermediate 5a in the synthesis of A-371 is replaced with 6b, and the other procedures are the same as A-371. M+1: 359.17 A-386: Intermediate 5a in the synthesis of A-371 is replaced with 7b, and the other procedures are the same as A-371. M+1: 373.19

[0307] Synthesis of Examples A-392 and A-393 A-392: Intermediate 5a in the synthesis of A-371 is replaced with 6c, and the other procedures are the same as A-371. M+1: 373.18 A-393: Intermediate 5a in the synthesis of A-371 is replaced with 7c, and the other procedures are the same as A-371. M+1: 387.2

[0308] Synthesis of Examples A-399 and A-400 A-399: Intermediate 5a in the synthesis of A-371 is replaced with 6d, and the other procedures are the same as A-371. M+1: 373.19 A-400: Intermediate 5a in the synthesis of A-371 is replaced with 7d, and the other procedures are the same as A-371. M+1: 387.21

[0309] Synthesis of Example A-334 [ka]

[0310] Synthesis of intermediate 27a The synthesis method was the same as that of intermediate 19a, and 0.56 g of a colorless oil was obtained, with a yield of 75.4%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.19(s,9H), 1.42(s,9H), 2.32-2.67(m,2H), 3.33-4.54(m,11H), 4.94(s,1H), 7.06(s,1H), 7.21(s,2H), 7.31(s,1H), 8.06(s,1H). M+1:504.24

[0311] Synthesis of Example A-334 The synthesis method was the same as that of A-371, and 0.31 g of a white solid was obtained, with a yield of 87.9%. 1 H-NMR (400MHz,DMSO-d6), δppm:2.67-2.92(m,2H), 3.54-4.52(m,11H), 5.08(s,2H), 7.06-7.21(m,3H), 8.32(s,1H), 8.92(s,2H). M+1:348.13

[0312] Synthesis of Example A-335 [ka]

[0313] Synthesis of intermediate 28a In an ice bath, dissolve 0.7g of intermediate 8a in 20mL of DCM, add 0.4g of K2CO3, dissolve 170μL of acetyl chloride in 5mL of DCM, dropwise add to the reaction system, gradually return to room temperature, react for 4h, monitor by TLC, after the raw material is completely reacted, stop the reaction, wash with saturated citric acid solution and saturated sodium chloride solution in sequence, dry with anhydrous sodium sulfate, filter, concentrate, and separate by silica gel chromatography column to obtain 0.53g of colorless oily intermediate 27a, the yield is 69%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13-1.23(m,12H), 1.37(s,9H), 2.05(s,3H), 3.15-3.43(m,2H), 3.61-3.87(m,5H), 4.05-4.87(m,5H), 7.84(s,1H). M+1:488.24

[0314] Synthesis of intermediate 29a The synthesis method was the same as that of intermediate 23a, and 0.46 g of an oily product was obtained, with a yield of 92.6%. 1H-NMR (400MHz,DMSO-d6), δppm:1.13-1.25(m,12H), 1.37(s,9H), 2.04(s,3H), 3.16-3.44(m,2H), 3.62-3.87(m,2H), 4.06-4.85(m,5H), 7.84(s,1H), 8.35(s,2H). M+1:473.24

[0315] A-335 synthesis: The synthesis method was the same as that of A-329, and 0.25 g of a white solid was obtained, with a yield of 87.5%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13-1.17(m,3H), 2.03(s,3H), 3.07-3.18(m,1H), 3.39-3.43(m,1H), 3.73-3.92(m,2H), 4.07-4.83(m,5H), 5.63(s,1H), 7.57(s,1H), 7.95(s,1H), 8.25(s,2H). M+1:317.12.

[0316] Synthesis of Example A-336 [ka]

[0317] Synthesis of intermediate 30a The synthesis method is the same as that of intermediate 15a, and 0.89 g of a yellow powdery solid is obtained, with a yield of 78.6%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13-1.42(m,21H), 2.7-3.57(m,4H), 4.26-4.51(m,9H), 7.28-7.91(m,9H). M+1:610.29

[0318] Synthesis of intermediate 31a The synthesis method is the same as that of intermediate 16a, and 0.45 g of a yellow solid is obtained, with a yield of 80.3%. 1H-NMR (400MHz,DMSO-d6), δppm:1.13-1.42(m,21H), 2.7-3.57(m,4H), 4.26-4.51(m,9H), 8.96(s,1H). M+1:388.22

[0319] Synthesis of A-336 The synthesis method was the same as that of A-329, and 0.22 g of white powder was obtained, with a yield of 70.9%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.16(d,3H), 2.70(t,2H), 3.47-4.21(m,8H), 5.37(s,1H), 8.96(s,3H). M+1:232.11

[0320] Synthesis of Examples A-349, A-356, and A-363 A-349: A-002 in the synthesis of A-336 is replaced with A-016, and the other operations are the same as A-336. M+1: 246.12 A-356: A-002 in the synthesis of A-336 is replaced with A-030, and the other operations are the same as A-336. M+1: 260.14 A-363: A-002 in the synthesis of A-336 is replaced with A-044, and the other operations are the same as A-336. M+1: 260.11

[0321] Synthesis of Example A-337 [ka]

[0322] Synthesis of intermediate 32a The synthesis method was the same as that of intermediate 17a, and 0.42 g of white powder was obtained, with a yield of 102.4%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.43(s,3H), 2.7-3.57(m,4H), 4.26-4.51(m,9H), 5.44(s,1H), 7.28-7.91(m,10H). M+1:454.18

[0323] Synthesis of intermediate 33a The synthesis method was the same as that of 18a, and 0.33 g of solid was obtained, with a yield of 77.6%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.43(s,3H), 2.10(s,3H), 2.7-3.57(m,4H), 4.26-4.51(m,9H), 5.44(s,1H), 7.28-7.91(m,9H). M+1:496.19

[0324] Synthesis of A-337 The synthesis method is the same as A-330, and 0.14 g is obtained, with a yield of 70%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.43(s,3H), 2.10(s,3H), 2.7-3.57(m,4H), 4.26-4.51(m,9H), 5.44(s,1H), 7.8(s,2H). M+1:274.12

[0325] In the synthesis of intermediate 30a, the raw material intermediate A-002 was replaced with A-016, A-030, and A-044, and the other operations were the same as those in the synthesis of intermediate 30a, and intermediates 30b, 30c, and 30d were produced, respectively. Similarly, in the synthesis of intermediate 32a, the raw material intermediate 30a was replaced with intermediate 30b, intermediate 30c, and intermediate 30d, and the other operations were the same as in the synthesis of intermediate 32a, and intermediates 32b, 32c, and 32d, respectively, could be produced. Similarly, in the synthesis of intermediate 33a, the raw material intermediate 30a was replaced with intermediate 30b, intermediate 30c, or intermediate 30d, and the other operations were the same as in the synthesis of intermediate 33a, and intermediates 33b, 33c, and 33d, respectively, could be produced. Similarly, in the synthesis of intermediate 33a, acetyl chloride was replaced with isobutyryl chloride or pivaloyl chloride to produce intermediates 34a, 34b, 34c, 34d, 35a, 35b, 35c, and 35d, respectively.

[0326] [ka]

[0327] Synthesis of Examples A-338 to A-343 A-338: In the synthesis of A-337 [ka] and other operations are the same as A-337. M+1:230.09 A-339: In the synthesis of A-337 [ka] and other operations are the same as A-337. M+1:244.11 A-340: In the synthesis of A-337 [ka] and other operations are the same as A-337. M+1:286.15 A-341: In the synthesis of A-337 [ka] and other operations are the same as A-337. M+1:320.14 A-342: In the synthesis of A-337 [ka] and other operations are the same as A-337. M+1:287.11 A-343: In the synthesis of A-337 [ka] and other operations are the same as A-337. M+1:336.13

[0328] Synthesis of Examples A-344 and A-345 A-344: 33a in the synthesis of A-337 is replaced with 34a, and the other procedures are the same as A-337. M+1: 302.15 A-345: 33a in the synthesis of A-337 is replaced with 35a, and the other procedures are the same as A-337. M+1: 316.17

[0329] Synthesis of Examples A-350, A-357, and A-364 A-350: 33a in the synthesis of A-337 is replaced with 33b, and the other procedures are the same as A-337. M+1: 288.13 A-357: 33a in the synthesis of A-337 is replaced with 33c, and the other procedures are the same as A-337. M+1: 302.15 A-364: 33a in the synthesis of A-337 is replaced with 33d, and the other procedures are the same as A-337. M+1: 302.1

[0330] Synthesis of Examples A-351, A-352, A-358, A-359, A-365, and A-366 A-351: 33a in the synthesis of A-337 is replaced with 34b, and the other procedures are the same as A-337. M+1: 316.17 A-352: 33a in the synthesis of A-337 is replaced with 35b, and the other procedures are the same as A-337. M+1: 330.18 A-358: 33a in the synthesis of A-337 is replaced with 34c, and the other procedures are the same as A-337. M+1: 330.18 A-359: 33a in the synthesis of A-337 is replaced with 35c, and the other procedures are the same as A-337. M+1: 344.20 A-365: 33a in the synthesis of A-337 is replaced with 34d, and the other procedures are the same as A-337. M+1: 330.16 A-366: 33a in the synthesis of A-337 is replaced with 35d, and the other procedures are the same as A-337. M+1: 344.15

[0331] Synthesis of Example A-346 [ka]

[0332] Synthesis of intermediate 36a The synthesis method was the same as that of 1a, and 0.22 g of yellow powder was obtained, with a yield of 37%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13-1.42(m,24H), 2.7-3.57(m,4H), 4.26-4.70(m,11H), 5.37(s,1H), 7.28-7.90(m,10H). M+1:711.34

[0333] Synthesis of intermediate 37a The synthesis method was the same as that of intermediate 16a, and 0.13 g of solid was obtained, with a yield of 41%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13-1.42(m,24H), 2.7(t,2H), 3.47-4.64(m,10H), 5.37(s,1H), 7.28-7.90(m,3H). M+1:489.27

[0334] Synthesis of A-346: The synthesis method was the same as that of A-331, and 59 mg was obtained, with a yield of 22.3%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.16(s,6H), 2.7(t,2H), 3.47-4.64(m,10H), 5.37(s,2H), 8.95(s,4H). M+1:333.16

[0335] In the synthesis of intermediate 36a, the raw material intermediate 32a was replaced with 32b, 32c, and 32d, and the other operations were the same as in the synthesis of intermediate 36a, and intermediates 36b-1, 36c-1, and 36d-1 could be produced, respectively. Similarly, in the synthesis of intermediate 36a, the raw material intermediates 32b, 32c, and 32d are [ka] By replacing the above, 36b-2 and 36b-3, 36c-2 and 36c-3, and 36d-2 and 36d-3 could be obtained, respectively.

[0336] [ka]

[0337] Synthesis of Examples A-353, A-360, and A-367 A-353: 36a in the synthesis of A-346 is replaced with 36b-1, and the other procedures are the same as A-346. M+1: 347.17 A-360: 36a in the synthesis of A-346 is replaced with 36c-1, and the other procedures are the same as A-346. M+1: 361.19 A-367: 36a in the synthesis of A-346 is replaced with 36d-1, and the other procedures are the same as A-346. M+1: 361.2

[0338] Synthesis of Examples A-354, A-355, A-361, A-362, A-368, and A-369 A-354: 36a in the synthesis of A-346 is replaced with 36b-2, and the other procedures are the same as A-346. M+1: 333.16 A-355: 36a in the synthesis of A-346 is replaced with 36b-3, and the other procedures are the same as A-346. M+1: 345.19 A-361: 36a in the synthesis of A-346 is replaced with 36c-2, and the other procedures are the same as A-346. M+1: 347.17 A-362: 36a in the synthesis of A-346 is replaced with 36c-3, and the other procedures are the same as A-346. M+1: 359.21 A-368: 36a in the synthesis of A-346 is replaced with 36d-2, and the other procedures are the same as A-346. M+1: 347.3 A-369: 36a in the synthesis of A-346 is replaced with 36d-3, and the other procedures are the same as A-346. M+1: 359.25

[0339] Synthesis of Example A-374 [ka]

[0340] Synthesis of intermediate 38a Dissolve 8.0g (18mmol) of intermediate 8a in 30mL of methanol, and further dissolve 3.6g (90mmol) of NaOH in 10mL of water. Under ice bath, slowly add NaOH aqueous solution to the reaction system of intermediate 8a, the color of the reaction solution darkens, and gradually return to room temperature. After reacting for 3h, monitor by TLC, after the raw materials react completely, stop the reaction, concentrate under reduced pressure, remove methanol in the reaction system, adjust the pH value with dilute hydrochloric acid until it becomes weakly acidic, precipitate a white solid in the reaction system, filter, dry by infrared, obtain 4.3g of white solid, yield 58.1%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13(s,12H), 1.37(s,9H), 2.67-3.77(m,3H), 4.12-4.64(m,6H), 7.39-7.06(m,2H), 12.01(s,1H). M-1:432.1

[0341] Synthesis of intermediate 39a In an ice bath, 4.3g (10mmol) of intermediate 38a was dissolved in 20mL of acetonitrile, 2.7mL (20mmol) of TEA and 3.78g (12mmol) of TBTU were added, and then 1.83g (10.7mmol) of O-TERT-butyl-L-serine methyl ester hydrochloride was added. The mixture was gradually brought back to room temperature and reacted for 4h. The reaction was monitored by TLC. After the raw materials were completely reacted, the reaction was stopped. The mixture was washed with saturated citric acid and saturated sodium chloride in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel chromatography column to obtain 4.58g of oil, with a yield of 76.1%. 1H-NMR (400MHz,DMSO-d6), δppm:1.13(s,24H), 1.37(s,9H), 2.67-3.84(m,3H), 3.67(s,3H), 4.12-4.64(m,8H), 7.39-8.06(m,3H). M+1:603.34

[0342] Synthesis of intermediate 40a 4.58g (7.60mmol) of intermediate 39a was dissolved in a small amount of methanol, and 10mL of 7mol / L NH3 / CH3OH solution was added under ice bath, and the mixture was allowed to react overnight. After the raw materials were completely reacted, the reaction solution was spun dry to give 4.04g of intermediate 40a as an off-white solid, with a yield of 90.4%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.13(s,24H), 1.37(s,9H), 2.67-3.84(m,3H), 4.12-4.64(m,8H), 7.39-8.06(m,5H). M+1:588.34

[0343] Synthesis of A-374 Dissolve 1g of intermediate 40a in 4mL of ethyl acetate, add 3mL of 4mol / L HCl / EtOAc, stir at room temperature for 3h, monitor by TLC, after the raw materials are completely reacted, white solid precipitates in the reaction system, filter and dry to obtain 0.51g of white solid, the yield is 79%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.16(m,6H), 2.67-4.62(m,11H), 5.32(s,2H), 7.3(s,2H), 8.96(s,4H). M+1:376.16

[0344] In the synthesis of intermediate 38a, [ka] and the other procedures were the same as in the synthesis of intermediate 38a, whereby intermediates 38b and 38c could be produced, respectively.

[0345] [ka]

[0346] Similarly, in the synthesis of intermediate 39a, [ka] could be substituted to give 39b, 39c, and 39d, respectively.

[0347] [ka]

[0348] Synthesis of Examples A-375 and A-376 A-375: Intermediate 38a in the synthesis of A-374 is replaced with 38b, and the other procedures are the same as A-374. M+1: 362.15 A-376: Intermediate 38a in the synthesis of A-374 is replaced with 38c, and the other procedures are the same as A-374. M+1: 374.18

[0349] Synthesis of Examples A-377, A-378, A-379, A-380, A-381, and A-382 A-377: Intermediate 39a in the synthesis of A-374 is replaced with 39b, and the other procedures are the same as A-374. M+1: 332.13 A-378: In the synthesis of intermediate 39a, 39a is replaced with 39c, and the other procedures are the same as A-374. M+1: 346.15 A-379: Intermediate 39a in the synthesis of A-374 is replaced with 39d, and the other procedures are the same as A-374. M+1: 388.20 A-380: In the synthesis of A-374, intermediate 38a was replaced with 38c, and intermediate 39a was synthesized. [ka] and other operations are the same as A-374. M+1:422.18 A-381: In the synthesis of A-374, intermediate 38a was replaced with 38b, and intermediate 39a was synthesized. [ka] and other operations are the same as A-374. M+1:389.16 A-382: In the synthesis of A-374, intermediate 38a was replaced with 38c, and intermediate 39a was synthesized. [ka] and other operations are the same as A-374. M+1:438.18

[0350] Synthesis of Examples A-387, A-388, and A-389 A-387: Intermediate 3a in the synthesis of A-374 is replaced with 3b, and the other procedures are the same as A-374. M+1: 390.18 A-388: In the synthesis of A-374, intermediate 3a was replaced with 3b, and intermediate 38a was synthesized. [ka] and other operations are the same as A-374. M+1:376.16 A-389: In the synthesis of A-374, intermediate 3a is replaced with 3b, and intermediate 38a is synthesized. [ka] and other operations are the same as A-374. M+1:388.2

[0351] Synthesis of Examples A-394, A-395, and A-396 A-394: Intermediate 3a in the synthesis of A-374 is replaced with 3c, and the other procedures are the same as A-374. M+1: 404.19 A-395: In the synthesis of A-374, intermediate 3a is replaced with 3c, and intermediate 38a is synthesized. [ka] The rest is the same as A-374. M+1:390.18 A-396: In the synthesis of A-374, intermediate 3a was replaced with 3c, and intermediate 38a was synthesized. [ka] The rest is the same as A-374. M+1:402.21

[0352] Synthesis of Examples A-401, A-402, and A-403 A-401: Intermediate 3a in the synthesis of A-374 is replaced with 3d, and the other procedures are the same as A-374. M+1: 404.19 A-402: In the synthesis of A-374, intermediate 3a is replaced with 3d, and intermediate 38a is synthesized. [ka] and other operations are the same as A-374. M+1:390.18 A-403: In the synthesis of A-374, intermediate 3a is replaced with 3d, and intermediate 38a is synthesized. [ka] and other operations are the same as A-374. M+1:402.21

[0353] Synthesis of Example A-405

[0354] [ka]

[0355] Synthesis of intermediate 41a 21a (4.32g, 15.7mmol) was added to 100ml of DCM under ice bath (not dissolved), and after adding 2.5eq of TEA, the solid in the solution gradually dissolved, and then piperidine 1.1eq, HOBt 1.2eq and EDCI 1.2eq were added, and the reaction was carried out for 10min while maintaining the temperature, and the reaction was carried out overnight at room temperature, and the reaction was monitored by TLC (PE:EA=1:1). After the reaction was completed, the mixture was washed with water, saturated citric acid solution and saturated saline solution in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. 4.9g was obtained by separation by column chromatography, with a yield of 90%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.42(s,9H), 1.55-2.92(m,8H), 3.54-4.38(m,9H), 7.28(s,1H). M+1:342.18

[0356] Synthesis of Example A-404 Intermediate 41a (4.9 g, 14.4 mmol) was added to ethyl acetate to completely dissolve, then 28 ml of HCl-EtOAc solution was added, stirred at room temperature for 6 h, and monitored by TLC (PE:EA=1:2). After the reaction was complete, it was filtered, and the filter cake was washed with ethyl acetate and dried to obtain 4.69 g of white solid, with a yield of 93%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.55-2.92(m,8H), 3.54-4.38(m,9H), 7.28(s,2H). M+1:242.13

[0357] Synthesis of intermediate 42a Add A-404 (0.5g, 1.8mmol) to DCM 20ml under ice bath, solid does not dissolve, add TEA 2.5eq, solid gradually dissolves, add Boc-tBu-Thr 1.1eq, HOBt 1.2eq and EDCI 1.2eq, react for 10min while maintaining temperature, react at room temperature for 5h, monitor by TLC (DCM:MeOH=10:1), after complete reaction, wash with water, saturated citric acid solution, saturated saline solution in sequence, dry with anhydrous sodium sulfate, filter, concentrate filtrate. Separate by column chromatography to obtain 0.85g, yield 94%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.16(s,21H), 1.55-2.92(m,8H), 3.54-4.64(m,11H), 7.28(s,2H). M+1:499.29

[0358] Synthesis of Example A-405 Intermediate 42a was added to 8ml ethyl acetate to completely dissolve, then 8ml HCl-EtOAc solution was added, stirred at room temperature for 6h, and monitored by TLC (PE:EA=1:2). After the reaction was complete, it was filtered, and the filter cake was washed with ethyl acetate and dried to obtain 0.45g of white solid, with a yield of 69.6%. 1 H-NMR (400MHz,DMSO-d6), δppm:1.16(s,3H), 1.55-2.92(m,8H), 3.54-4.38(m,11H), 5.37(s,1H), 7.28(s,1H), 8.93(s,2H). M+1:343.18

[0359] Synthesis of Examples A-408, A-412, and A-416 A-408: In the synthesis of A-404 [ka] and other operations are the same as A-404. M+1:244.11 A-412: In the synthesis of A-404 [ka] and other operations are the same as A-404. M+1:257.14 A-416: In the synthesis of A-404 [ka] and other operations are the same as A-404. M+1:260.08

[0360] Synthesis of Examples A-406 and A-407 A-406: In the synthesis of A-405 [ka] and other operations are the same as A-405. M+1:341.20 A-407: In the synthesis of A-405 [ka] and other operations are the same as A-405. M+1:329.16

[0361] Synthesis of Examples A-409, A-410, and A-411 A-409: A-404 in the synthesis of A-405 is replaced with A-408, and the other operations are the same as A-405. M+1: 345.16 A-410: A-404 was replaced with A-408 in the synthesis of A-405. [ka] and other operations are the same as A-405. M+1:343.18 A-411: A-404 was replaced with A-408 in the synthesis of A-405. [ka] and other operations are the same as A-405. M+1:331.14

[0362] Synthesis of Examples A-413, A-414, and A-415 A-413: A-404 in the synthesis of A-405 is replaced with A-412, and the other operations are the same as A-405. M+1: 358.19 A-414: A-404 was replaced with A-412 in the synthesis of A-405; [ka] and other operations are the same as A-405. M+1:356.21 A-415: A-404 in the synthesis of A-405 was replaced with A-412, [ka] and other operations are the same as A-405. M+1:344.17

[0363] Synthesis of Examples A-417, A-418, and A-419 A-417: A-404 in the synthesis of A-405 is replaced with A-416, and the other operations are the same as A-405. M+1: 361.13 A-418: A-404 in the synthesis of A-405 was replaced with A-416, [ka] and other operations are the same as A-405. M+1:359.15 A-419: A-404 in the synthesis of A-405 was replaced with A-416, [ka] and other operations are the same as A-405. M+1:347.12

[0364] Synthesis of Examples A-420, A-436, and A-452 A-420: Intermediate 3a in the synthesis of A-404 is replaced with 3b, and the other procedures are the same as A-404. M+1: 256.14 A-436: Intermediate 3a in the synthesis of A-404 is replaced with 3c, and the other procedures are the same as A-404. M+1: 270.16 A-452: Intermediate 3a in the synthesis of A-404 is replaced with 3d, and the other procedures are the same as A-404. M+1: 270.16

[0365] Synthesis of Examples A-421, A-422, and A-423 A-421: A-404 in the synthesis of A-405 is replaced with A-420, and the other operations are the same as A-405. M+1: 357.19 A-422: A-404 in the synthesis of A-405 was replaced with A-420, [ka] and other operations are the same as A-405. M+1:355.21 A-423: A-404 in the synthesis of A-405 was replaced with A-420; [ka] and other operations are the same as A-405. M+1:343.18

[0366] Synthesis of Examples A-424, A-428, and A-432 A-424: Synthesis of A-404 by replacing 3a with 3b, [ka] and other operations are the same as A-404. M+1:258.12 A-428: Synthesis of A-404 by replacing 3a with 3b, [ka] and other operations are the same as A-404. M+1:271.15 A-432: Synthesis of A-404 by replacing 3a with 3b, [ka] and other operations are the same as A-404. M+1:274.10

[0367] Synthesis of Examples A-425, A-426, and A-427 A-425: A-404 in the synthesis of A-405 is replaced with A-424, and the other operations are the same as A-405. M+1: 359.17 A-426: A-404 in the synthesis of A-405 was replaced with A-424. [ka] and other operations are the same as A-405. M+1:357.19 A-427: A-404 in the synthesis of A-405 was replaced with A-424. [ka] and other operations are the same as A-405. M+1:345.16

[0368] Synthesis of Examples A-429, A-430, and A-431 A-429: A-404 in the synthesis of A-405 was replaced with A-428, and the other operations were the same as A-405. M+1: 372.20 A-430: A-404 in the synthesis of A-405 to A-428; [ka] and other operations are the same as A-405. M+1:370.22 A-431: A-404 in the synthesis of A-405 to A-428, [ka] and other operations are the same as A-405. M+1:358.19

[0369] Synthesis of Examples A-433, A-434, and A-435 A-433: A-404 in the synthesis of A-405 is replaced with A-432, and the other operations are the same as A-405. M+1: 375.15 A-434: A-404 in the synthesis of A-405 to A-432; [ka] and other operations are the same as A-405. M+1:373.17 A-435: A-404 in the synthesis of A-405 was replaced with A-432; [ka] and other operations are the same as A-405. M+1:361.13

[0370] Synthesis of Examples A-437, A-438, and A-439 A-437: A-404 in the synthesis of A-405 is replaced with A-436, and the other operations are the same as A-405. M+1: 371.21 A-438: A-404 in the synthesis of A-405 was replaced with A-436. [ka] and other operations are the same as A-405. M+1:369.23 A-439: A-404 in the synthesis of A-405 was replaced with A-436. [ka] and other operations are the same as A-405. M+1:357.19

[0371] Synthesis of Examples A-440, A-444, and A-448 A-440: Synthesis of A-404 by replacing 3a with 3c, [ka] and other operations are the same as A-404. M+1:272.14 A-444: Synthesis of A-404 by replacing 3a with 3c, [ka] and other operations are the same as A-404. M+1:285.17 A-448: Synthesis of A-404 by replacing 3a with 3c, [ka] and other operations are the same as A-404. M+1:288.12

[0372] Synthesis of Examples A-441, A-442, and A-443 A-441: A-404 in the synthesis of A-405 is replaced with A-440, and the other operations are the same as A-405. M+1: 373.19 A-442: A-404 in the synthesis of A-405 to A-440; [ka] and other operations are the same as A-405. M+1:371.21 A-443: A-404 in the synthesis of A-405 to A-440; [ka] and other operations are the same as A-405. M+1:359.17

[0373] Synthesis of Examples A-445, A-446, and A-447 A-445: A-404 in the synthesis of A-405 is replaced with A-444, and the other operations are the same as A-405. M+1: 386.22 A-446: A-404 in the synthesis of A-405 was replaced with A-444. [ka] and other operations are the same as A-405. M+1:384.24 A-447: A-404 in the synthesis of A-405 was replaced with A-444. [ka] and other operations are the same as A-405. M+1:372.20

[0374] Synthesis of Examples A-449, A-450, and A-451 A-449: A-404 in the synthesis of A-405 is replaced with A-448, and the other operations are the same as A-405. M+1: 389.16 A-450: A-404 in the synthesis of A-405 to A-448; [ka] and other operations are the same as A-405. M+1:387.18 A-451: A-404 in the synthesis of A-405 to A-448; [ka] and other operations are the same as A-405. M+1:375.15

[0375] Synthesis of Examples A-456, A-460, and A-464 A-456: Synthesis of A-404 by replacing 3a with 3d, [ka] and other operations are the same as A-404. M+1:272.14 A-460: Synthesis of A-404 by replacing 3a with 3d, [ka] and other operations are the same as A-404. M+1:285.17 A-464: Synthesis of A-404 by replacing 3a with 3d, [ka] and other operations are the same as A-404. M+1:288.12

[0376] Synthesis of Examples A-453, A-454, and A-455 A-453: A-404 in the synthesis of A-405 is replaced with A-452, and the other operations are the same as A-405. M+1: 371.21 A-454: A-404 in the synthesis of A-405 to A-452; [ka] and other operations are the same as A-405. M+1:369.23 A-455: A-404 in the synthesis of A-405 was replaced with A-452; [ka] and other operations are the same as A-405. M+1:357.19

[0377] Synthesis of Examples A-457, A-458, and A-459 A-457: A-404 in the synthesis of A-405 is replaced with A-456, and the other operations are the same as A-405. M+1: 373.19 A-458: A-404 in the synthesis of A-405 was replaced with A-456. [ka] and other operations are the same as A-405. M+1:371.21 A-459: A-404 in the synthesis of A-405 to A-456, [ka] and other operations are the same as A-405. M+1:359.17

[0378] Synthesis of Examples A-461, A-462, and A-463 A-461: A-404 in the synthesis of A-405 is replaced with A-460, and the other operations are the same as A-405. M+1: 386.22 A-462: A-404 in the synthesis of A-405 to A-460; [ka] and other operations are the same as A-405. M+1:384.24 A-463: A-404 in the synthesis of A-405 was replaced with A-460; [ka] and other operations are the same as A-405. M+1:372.20

[0379] Synthesis of Examples A-465, A-466, and A-467 A-465: A-404 in the synthesis of A-405 is replaced with A-464, and the other operations are the same as A-405. M+1: 389.16 A-466: A-404 in the synthesis of A-405 was replaced with A-464; [ka] and other operations are the same as A-405. M+1:387.18 A-467: A-404 in the synthesis of A-405 was replaced with A-464. [ka] and other operations are the same as A-405. M+1:375.15

[0380] Synthesis of Example 468

[0381] [ka]

[0382] Synthesis of intermediate 43a In an ice bath, intermediate 38a (1.1g, 2.55mmol) was added to 50ml of DCM, the solid did not dissolve, and after adding 2.5eq of TEA, the solid gradually dissolved, then 1.1eq of N-Boc piperazine, 1.2eq of HOBt and 1.2eq of EDCI were added, and the reaction was carried out for 10min while maintaining the temperature, and the reaction was carried out overnight at room temperature, and the reaction was monitored by TLC (DCM:MeOH=5:1). After the reaction was complete, the mixture was washed with water, saturated citric acid solution, and saturated saline solution in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After separation by column chromatography, 0.87g was obtained, with a yield of 57.2%. 1 H-NMR (400MHz, DMSO-d6), δppm: 1.16 (s, 12H), 1.42 (s, 18H), 2.67-4.64 (m, 17H), 7.38 (s, 2H). M+1:600.34

[0383] Synthesis of A-468 Intermediate 43a (0.87 g, 1.45 mmol) was added to 10 ml ethyl acetate, and 10 ml HCl-EtOAc solution was added, stirred at room temperature for 6 h, and monitored by TLC (PE:EA=1:2). After complete reaction, it was filtered, and the filter cake was washed with ethyl acetate and dried to give 0.74 mg of white solid, the yield is 95%. 1 H-NMR (400MHz, DMSO-d6), δppm:1.16(s,3H), 2.81-4.38(m,17H), 5.37(s,1H), 7.28(s,4H). M+1:344.17

[0384] Synthesis of Examples A-469 and A-470 A-469: In the synthesis of A-468 [ka] and other operations are the same as A-468. M+1:342.19 A-470: In the synthesis of A-468 [ka] and other operations are the same as A-468. M+1:330.16

[0385] Synthesis of Examples A-471, A-472, and A-473 A-471: Intermediate 3a in the synthesis of A-468 is replaced with 3b, and the other procedures are the same as A-468. M+1: 358.19 A-472: Replacing intermediate 3a with 3b in the synthesis of A-468; [ka] and other operations are the same as A-468. M+1:356.21 A-473: Replacing intermediate 3a with 3b in the synthesis of A-468; [ka] and other operations are the same as A-468. M+1:344.17

[0386] Synthesis of Examples A-474, A-475, and A-476 A-474: Intermediate 3a in the synthesis of A-468 is replaced with 3c, and the other procedures are the same as A-468. M+1: 372.20 A-475: Intermediate 3a in the synthesis of A-468 to 3c, [ka] and other operations are the same as A-468. M+1:370.22 A-476: Intermediate 3a in the synthesis of A-468 to 3c, [ka] and other operations are the same as A-468. M+1:358.19

[0387] Synthesis of Examples A-477, A-478, and A-479 A-477: Intermediate 3a in the synthesis of A-468 was converted to 3c, and the other procedures were the same as those for A-468. M+1: 372.1 A-478: Intermediate 3a in the synthesis of A-468 to 3c, [ka] and other operations are the same as A-468. M+1:370.2 A-479: Intermediate 3a in the synthesis of A-468 to 3c, [ka] and other operations are the same as A-468. M+1:358.19

[0388] Example 1: In vitro receptor binding assay 1. Purpose of the experiment The affinity of test compounds for the NMDA receptor is studied by receptor ligand binding experiments. 2. Experimental Method Ten SPF grade SD male rats are purchased and bred for 7 days before being used for the study. (1) Preparation of crude synaptosomes from the prefrontal cortex and hippocampus After the rats were killed by decapitation, the prefrontal cortex and hippocampus were quickly separated on ice, weighed, and then 10-fold volume of Tris-HCl buffer (50 mM Tris-HCl, 5 mM MgCl2·6H2O, 1 mM EDTA, 0.5% (w / v) BSA, 1 mM PMSF, 0.32 M sucrose, pH 7.4) 50 mM was added and homogenized 5 times at 1500 rpm for 30 s each time. The homogenate was centrifuged at 1000×g for 10 min, and the supernatant was centrifuged at 40000×g for 10 min. The precipitate was collected, resuspended in 10-fold volume of Tris-HCl buffer, incubated at 37°C for 10 min, and centrifuged at 40000×g for 10 min. Finally, the precipitate obtained was resuspended in the above buffer, aliquoted, and stored at -80°C for study. (2) Crude rat synaptosomes and [ 3Measurement of inhibitory activity of test drugs against the binding of [H]-MK-801 50 μg of crude rat synaptosomal protein was added to all tubes in sequence. MK-801 (dizocilpine) was added to the non-specific binding tube in a volume of 50 μl to a final concentration of 100 μM and pre-reacted for 15 min. 20 μL of a control drug of the corresponding concentration was added to the test tube and reacted for 15 min. All test tubes were added with a volume of 30 μl of labeled ligand [ 3 [H]-MK-801 was added sequentially to the tubes to a final concentration of 10 nM. The tubes were supplemented with 50 mM Tris-HCl buffer (Tris-HCl 50 mM, MgCl2·6H2O 5 mM, EDTA 1 mM, 0.5% (W / V) BSA, 0.1% NaN3, pH 7.4) until the volume of all reaction tubes reached 200 μl. The reaction was carried out at 37 °C for 10 min. A 49-type glass fiber filter was prepared and spotted simultaneously. The filter was placed in a multi-head cell harvester, and the reaction system was suction filtered under negative pressure, and then washed five times with 10 ml of ice-cold Tris-HCl buffer 50 mM each time. After suction and drying, the filter was added to 1 ml of scintillation fluid and shaken on a shaker for 1.5 h, and the radioactivity was measured the next day by placing it in a liquid scintillation counter. (3) Measurement of agonistic activity of test drugs against NMDA receptors in crude synaptosomal proteins from rats All tubes were sequentially added with 100 μg of crude rat synaptosomal protein. 50 μl of 5,7-dichlorokynurenic acid was added to the non-specific binding tube for a final concentration of 10 μM. 50 μM glutamic acid was added to all test tubes in advance and pre-reacted for 15 min. 20 μL of control drug of the corresponding concentration was added to the test tube and reacted for 15 min. 1 mM glycine was added to the largest reaction tube. All test tubes were added with a volume of 30 μl of labeled ligand [ 3[H]-MK-801 was added sequentially to the tubes to a final concentration of 10 nM, and the reaction was allowed to proceed for 15 min. The reaction tubes were supplemented with 50 mM Tris-HCl buffer (Tris-HCl 50 mM, MgCl2·6H2O 5 mM, EDTA, 0.5% (W / V) BSA 1 mM, 0.1% NaN3, pH 7.4) until the volume of all reaction tubes reached 500 μl. The reaction was allowed to proceed for 15 min under reaction conditions at 37 °C. A 49-type glass fiber filter was prepared and spotted at the same time. The filter was placed in a multi-head cell harvester, and the reaction system was suction filtered under negative pressure, and then washed five times with 10 ml of ice-cold Tris-HCl buffer 50 mM each time. After suction and drying, the filter was added to 1 ml of scintillation fluid and shaken on a shaker for 1.5 h, and the radioactivity was measured the next day in a liquid scintillation counter. (4) Data processing and statistical analysis The data was analyzed and processed with GraphPad 5.0 software, and the competitive inhibition percentage was calculated by nonlinear fitting, where: Percentage of inhibition % = ((total binding tube cpm - compound cpm) / (total binding tube cpm - non-specific binding tube cpm)) x 100% Specific binding amount = total binding amount - non-specific binding amount Each binding point was determined by two duplicate tubes. In agonist experiments, the maximum 3 3H]-MK-801 binding%=((cpm of test compound−cpm of 5,7-dichlorokynurenic acid) / (cpm of 1 mM glycine−cpm of 5,7-dichlorokynurenic acid))×100%.

[0389] [Table 2]

[0390] As is clear from the experimental results, all of the compounds in the examples have agonist potency at the NMDA receptor, with maximum agonist potency ranging from 12% to 78%, and belong to the category of NMDA receptor partial agonists.

[0391] Example 2: In vivo metabolic studies in rats Pharmacokinetic parameters such as plasma concentration exposure of the example compounds were evaluated and in vivo metabolic stability was evaluated by oral / tail vein administration studies in rats. In this experiment, SPF grade male SD rats weighing 200±20 g purchased from Siberia were used. Preparation of intravenous solution: Each test drug was accurately weighed out at about 1 mg, and 0.9% sodium chloride solution was added to make exactly 5 mL, and the concentration was adjusted to 0.2 mg / mL. The administration volume was 1 mL / 200 g, and the dose after concentration conversion was 1 mg / kg. Preparation of oral gavage solution: Each test drug was accurately weighed out at about 10 mg, and 0.9% sodium chloride solution was added to make exactly 10 mL, and the concentration was adjusted to 1 mg / mL. The administration volume was 2 mL / 200 g, and the dose after concentration conversion was 10 mg / kg. The rats were randomly assigned to eight groups, six rats per group, and administered the above-mentioned doses by forced oral administration and intravenous administration into the tail vein. Approximately 0.2 mL of blood was collected from the orbit before administration and at 2, 5, 15, 30 min, 1 h, 2 h, 3 h, 4 h, and 6 h after administration, and centrifuged at 3000 rpm for 10 min at 4°C, and the supernatant was measured by LC / MS / MS. The measured data was analyzed using the DAS pharmacokinetic analysis program, and the main pharmacokinetic parameters were calculated. The experimental results are shown in the table below.

[0392] [Table 3]

[0393] As is clear from the results, the Example compounds have good pharmacokinetic properties when administered orally / by injection to rats.

[0394] Example 3: Animal Pharmacodynamics Studies Pharmacodynamic evaluation was performed by a forced swimming experiment in rats. The experimental animals were SPF grade male SD rats weighing 150g to 180g, which were pre-bred for one week after purchase and then subjected to a forced swimming experiment, and the rats were required to be fasted for 12 hours before the experiment. All of the compounds in the examples were dissolved in saline, and a blank control group (saline) and a group administered with the compounds in the examples were set up. Each group contained 8 to 10 rats. On the day before the experiment, the rats were placed in a glass tank with a height of 40 cm, an inner diameter of 18 cm, and a water depth of 23 cm, and allowed to swim for 15 min. The water temperature was 28 °C. After the preliminary swimming was completed, the rats were taken out, wiped dry with a dry cloth, dried with an electric heater, returned to their breeding cages, and administered. On the second day, a full-scale forced swimming experiment was conducted, and a 5-min experiment was conducted. The cumulative immobility time within 5 min was recorded, and a second forced swimming experiment was conducted on the 7th day. The criterion for immobility was that the animal stopped struggling in the water, remained floating, and kept its head floating on the water surface with only slight limb movements. The results are shown in Table 4, and the experimental data were statistically analyzed using GraphPad Prism 5.0 software.

[0395] [Table 4]

[0396] As is clear from the experimental results, multiple example compounds are effective when administered by forced oral administration, and the efficacy can be maintained for the next day to 7 days later.

[0397] Although specific embodiments of the present invention have been described in detail, it should be understood that those skilled in the art may, based on all the teachings disclosed herein, make various modifications and substitutions to these details, and all such modifications are within the scope of the claims of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. Formula I 【Chemistry 1】 During the ceremony, Ring A is a 3-8 membered alicyclic ring; R １ is selected from H, a C1-C6 alkyl group, an aryl-C1-C4 alkyl group, a C2-C6 acyl group, -CONRR', and a natural amino acid fragment; R ２ is selected from a tert-butoxycarbonyl group, a C2-C6 acyl group, -CONRR', and a natural amino acid fragment; R ３ is H, a cyano group, a 5-7 membered nitrogen-containing alicyclic ring -C1-C3 acyl group, a methoxycarbonyl group and -CONHR ４ is selected from R and R' are each independently selected from H and a C1-C6 alkyl group; R ４ is selected from H, a natural amino acid fragment, an amide derivative of said natural amino acid fragment, and a cyano derivative of said natural amino acid fragment; Optionally, the C1-C6 alkyl group, the aryl-C1-C4 alkyl group, -CONRR' and the natural amino acid fragment are each independently substituted with one or more groups selected from halogen, amino group, hydroxyl group, cyano group, carboxyl group, nitro group, C1-C6 alkyl group and C1-C6 alkoxy group, and the 5-7 membered nitrogen-containing alicyclic ring-C1-C3 acyl group is optionally substituted with one or more groups selected from C1-C6 alkyl group; And R １ , R ２ and R ３ satisfies: (1) R １ and R ３ is H, then R ２ is not Boc, (2) Formula I 【Chemistry 2】 and R １ but 【Chemistry 3】 and R ３ is H, then R ２ but, 【Chemistry 4】 Instead, (3) Formula I 【Chemistry 5】 and R １ but 【Chemistry 6】 and R ３ is H, then R ２ is not a C2-C6 acyl group or -CONRR', (4) Formula I 【Chemistry 7】 and R １ and R ３ are both H, then R ２ acetyl group and 【Chemistry 8】 Instead, (5) The compound represented by formula I is 【Chemistry 9】 isn't it, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is selected from 4-7 membered nitrogen-containing alicyclic rings.

3. Ring A is 【Chemistry 10】 2. The compound of claim 1 selected from:

4. R １ is selected from H, a C1-C6 alkyl group, a phenyl-C1-C4 alkyl group, a C2-C6 acyl group, and a natural amino acid fragment, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

5. R １ is H, acetyl group, methyl group, 【Chemistry 11】 2. The compound of claim 1 selected from:

6. R ２ tert-butoxycarbonyl group, acetyl group, 【Chemistry 12】 2. The compound of claim 1 selected from:

7. R ３ is H, a cyano group, 【Chemistry 13】 2. The compound of claim 1 selected from:

8. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, wherein the natural amino acid fragment is selected from the carboxyl or amino residues of the amino acids Thr, Ser, Val, Gly, Ala, Ile, Phe, Gln and Tyr.

9. 【Chemical 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 【Chemistry 14-7】 【Chemistry 14-8】 【Chemistry 14-9】 【Chemistry 14-10】 【Chemistry 14-11】 【Chemistry 14-12】 【Chemistry 14-13】 【Chemistry 14-14】 【Chemistry 14-15】 【Chemistry 14-16】 【Chemistry 14-17】 【Chemistry 14-18】 【Chemistry 14-19】 or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

10. 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, wherein the solvate is a hydrate.

11. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 10, a pharma- ceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition contains one or more pharma- ceutically acceptable excipients.

13. 13. The pharmaceutical composition according to claim 11 or 12, which is used for treating and / or preventing depression, anxiety disorder, stroke, Huntington's disease, Alzheimer's disease, neuralgia or schizophrenia.

14. 13. The pharmaceutical composition according to claim 11 or 12, which is used to modulate the activity of NMDA receptors in vivo or in vitro.

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