Polyamide compounds, methods for preparing the same, and their pharmaceutical use

Abstract

This invention provides a novel κ-opioid receptor (KOR receptor) agonist compound that exhibits excellent efficacy and action. [Solution] In one embodiment, a compound represented by formula IB, its stereoisomer, or a pharmaceutically acceptable salt thereof is provided. Such novel amide bond-containing compounds not only have excellent KOR receptor agonist activity (high affinity for κ opioid receptors), but also have very good hydrophilicity, and therefore have a lower ability to cross the blood-brain barrier and enter the brain. JPEG2026086406000232.jpg3368

Description

[Technical Field]

[0001] This invention relates to the medical field, and more specifically to synthetic polyamide compounds or pharmaceutically acceptable salts thereof, stereoisomers and compositions containing the same, and their applications in the pharmaceutical field. [Background technology]

[0002] Opioid receptors are an important class of G protein-coupled receptors that are targets to which endogenous opioid peptides and opioid drugs bind. After activation, opioid receptors affect the nervous system. Opioid drugs have regulatory effects on the immune and endocrine systems, and are currently the most potent and commonly used central analgesics. Opioid receptors present in the central nervous system include μ, δ, and κ receptors.

[0003] The κ-opioid receptor (KOR) consists of 380 amino acids and is expressed in the periphery of sensory neurons, dorsal root ganglion cells, and primary afferent neurons. It is involved in important physiological activities such as pain perception, neuroendocrine function, emotional behavior, and cognition.

[0004] KOR agonists have promising future applications in the pharmaceutical industry as drugs. For example, CN108290926A is a phenylpropionamide derivative that can be used as a KOR agonist. Disclosing CN101627049A, a synthetic peptide amide that can be used as a KOR agonist. Of these, the compound D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH (research and development code CR845) is currently undergoing clinical research.

[0005] While several KOR agonists already exist in prior art, improved activity and / or creation There is still a need for novel KOR agonists with drug potential. [Overview of the Initiative]

[0006] This invention relates to a novel κ-opioid receptor (KOR) that exhibits remarkably excellent effects and actions. The present invention provides receptor agonist compounds. Specifically, such novel amide-bond-containing compounds exhibit excellent KOR receptor agonist activity (high affinity for κ-opioid receptors). In addition to possessing hydrophilic properties, they also have very good hydrophilicity, and therefore have a lower ability to penetrate the blood-brain barrier and a lower ability to enter the brain. In some embodiments, the compounds of the present invention also have higher selectivity for κ opioid receptors compared to μ and δ opioid receptors. In some embodiments, the compounds of the present invention have lower addictiveness, better physicochemical properties (e.g., solubility, physical and / or chemical stability), and improved pharmacokinetic properties (e.g., cytochrome P 450 The compounds also possess superior drug potential, such as lower isozyme inhibition, improved bioavailability, appropriate half-life and duration of action, improved safety (lower toxicity and / or fewer side effects (e.g., central nervous system side effects, respiratory depression, sedation, hallucinations, antidiuresis, nausea, constipation, dependence, etc.)), good patient compliance, and / or less likelihood of developing tolerance. In some embodiments, the compounds of the present invention have improved safety, i.e., lower acute toxicity and cardiotoxicity. In some embodiments, the compounds of the present invention have an improved safety window (e.g., a wider safe dose range or a lower likelihood of side effects at the same dose). In some embodiments, the compounds of the present invention have improved pharmacokinetic properties (e.g., improved bioavailability and longer half-life, etc.).

[0007] One aspect of the present invention provides a compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] [ka]

[0009] Among them, R 1A is H or -COOH, preferably H, and R 2A is -NR aA C(=O)OR bA or -NR aA S (=O)2OR bA and is preferably -NR aA C(=O)OR bA wherein R aA is H, or a C 1-6 alkylamino group, C 1-6 alkoxy group, halogen, hydroxy group, nitro group, cyano group, NH2C(=O)-, C 1-6 alkyl group substituted with one or more groups selected from 1-6 alkoxy groups, and is preferably H, or an amino group, C 1-6 alkylamino group , or a C 1-6 alkyl group substituted with a C 1-6 alkoxy group, and more preferably H, or an amino group, C 1-6 alkyl group substituted with a C 1-6 alkylamino group, and R bA is a C 1-6 alkyl group, C 6-14 aryl group, 5- to 14-membered heteroaryl group, C 3-8 cycloalkyl group, 3- to 8-membered heterocyclyl group, and is preferably a C 1-6 alkyl group, 3- to 8-membered heterocycly l group, and more preferably a C 1-6 alkyl group,

[0010]

Chemical formula

[0011] selected from, and more preferably a C 1-6 alkyl group,

[0012] [ka]

[0013] Selected from the above R bA The groups are halogen, hydroxyl, amino, nitro, and cyano groups. , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Selected from alkoxy groups It is optionally substituted with one or more groups, R eA and R fA These are each independently -(CH2) n1A - and -(CH2) n1A' - and n1A and n1A' are each independently selected from 0, 1, 2, and 3, preferably 2, and n1A and n1A' are not 0 at the same time, W A -NH-C(=O)-, -NH-S(=O)2-, -NR 5A -, -O-, -S-, -S(=O)2- are selected, preferably -O-, -S(=O)2- Selected from, R 5A H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A - is selected from, and n3A is selected from 1, 2 and 3, or R 1A and R 2A These, along with the carbon atoms to which they are linked, are optionally substituted with 9 ~10-membered bicyclic portions are formed, preferably the bicyclic portions together with the piperidine rings to which they are connected.

[0014] [ka]

[0015] Form a structure selected from, Q 1A ~Q 4AIf any one of them is N, then the rest is either C or Q 1A ~Q 4A All of them are C, W 1A and W 2A These are independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, and -NR. 6A -, -NR 6A It is -CH2-, -NH2, -OH, halogen, nitro group, cy A group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2A - is either or does not exist, of which R 6A H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A - Selected from, preferably, W 1A and W 2A It is impossible for them to exist simultaneously. W 3A NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2A - And,

[0016] n2A is selected from 0, 1, 2, and 3. More preferably, the bicyclic portion, together with the piperidine ring to which they are connected,

[0017] [ka]

[0018] Forms a structure selected from, comfortable

[0019] [ka]

[0020] Selected from, and more preferably

[0021] [ka]

[0022] Selected from, R 3A is H or -(CH2) mA NR cA R dA Selected from, R cA and R dA H and C are independent of each other. 1-6 Alkyl group, amidino group, C 1-6 Alkoxyca Selected from rubonyl groups, R 4A These are halogen, NO2, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, cyano group, NH2C(=O)-, C 1-6 Selected from alkoxy groups, mA and nA are independently 0, 1, 2, 3, 4, or 5, respectively.

[0023] A further aspect of the present invention provides a method for preparing the compound of the present invention, selected from the following methods: Method 1: Method 1 is,

[0024] [ka]

[0025] This includes the following steps: Method 2: Method 2 is,

[0026] [ka]

[0027] including the step of wherein R 1A ' is R 1A or R in which NH2 is protected by an amino protecting group 1A and R 2A ' is R 2A or R in which NH2 is protected by an amino protecting group 2A and R 3A ' is R 3A or R in which NH2 is protected by an amino protecting group 3A and R 1A , R 2A , R 3A , R 4A and nA are as defined above, and R xA is an amino protecting group, each of the above amino protecting groups is independently selected from a tert-butoxycarbonyl group, 9-fluorenyl methoxycarbonyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoroacetyl group, methoxycarbonyl group, tert-butylsulfinyl group or ethoxycarbonyl group and is preferably selected.

[0028] The present invention further provides a compound represented by the general formula, a stereoisomer thereof or a salt thereof,

[0029]

Chemical formula

[0030] wherein R 1A ' is R 1A or R in which NH2 is protected by an amino protecting group 1A and R 2A ' is R 2A or R in which NH2 is protected by an amino protecting group 2A and R 3A ' is R 3Aor R in which NH2 is protected with an amino protecting group 3A where R 1A R 2A R 3A R 4A and nA are as defined above, and R xA is an amino protecting group, each of the above amino protecting groups is independently a tert-butoxycarbonyl group, 9-fluorenyl methoxycarbonyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoroacetyl group, methoxycarbonyl group, tert-butylsulfinyl group or ethoxycarbonyl group and is preferably selected therefrom.

[0031] One aspect of the present invention provides a compound represented by formula IB, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0032]

Chemical formula

[0033] Among them, R 1B is H, C 1-6 alkyl group (e.g., methyl group), C 1-6 alkylcarbonyl group (e.g., methylcarbonyl group), C 1-6 alkoxycarbonyl group (e.g., methoxycarbonyl group), C 6-14 aryl group, C 6-14 arylcarbonyl group, C 6-14 aryloxycarbonyl group C 3-8 cycloalkyl group, C 3-8 cycloalkylcarbonyl group, C 3-8 cycloalkoxycarbonyl group, 5- to 14-membered heteroaryl group, 5- to 14-membered heteroarylcarbonyl group, 5- to 14-membered he Selected from a teloaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocycloxycarbonyl group, preferably H, C 1-6 Alkyl group (e.g., methyl group), C 1-6 Alkylcarbonyl group (e.g., methylcarbon) nyl group), C 1-6 Selected from alkoxycarbonyl groups (e.g., methoxycarbonyl group), more preferably C 1-6 Alkyl group (e.g., methyl group), C 1-6 Selected from alkylcarbonyl groups (e.g., methylcarbonyl group), the substituents are halogen, hydroxyl group, amino group, nitro group, cyano group, and C, respectively. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Optionally substituted with one or more alkoxy groups, R 2B and R 3B H and C are independent of each other. 1-6 Alkyl groups (e.g., methyl group, isopropyl group) (Lu group), amidino group, C 1-6 Selected from alkoxycarbonyl groups (e.g., methoxycarbonyl groups), R 4B These are halogen, NO2, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, cyano group, NH2C(=O)-, C 1-6 Selected from alkoxy groups, mB and nB are independently 0, 1, 2, 3, 4, or 5, for example, mB is 3, and ☐ or nB is 0.

[0034] A further aspect of the present invention provides a method for preparing the compound of the present invention, comprising the following steps:

[0035] [ka]

[0036] Eventually, R 1B , R 4B mB and nB are as previously defined, and R xB and R yB These are amino protecting groups, preferably independently of a tert-butoxycarbonyl group and a 9-fluorine group. Lenylmethoxycarbonyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoroacetyl A group selected from a hydroxyl group, a methoxycarbonyl group, or an ethoxycarbonyl group.

[0037] Yet another aspect of the present invention provides a compound of formula iB-1, its stereoisomer, or a salt thereof,

[0038] [ka]

[0039] Eventually, R 1B , R 4B mB and nB are as previously defined, and R xB and R yB These are amino protecting groups, preferably independently of a tert-butoxycarbonyl group and a 9-fluorine group. Lenylmethoxycarbonyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoroacetyl A group selected from a hydroxyl group, a methoxycarbonyl group, or an ethoxycarbonyl group.

[0040] One aspect of the present invention provides a compound represented by formula IC, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0041] [ka]

[0042] Eventually, Ring A is C 3-8 Cycloalkyl groups, C 6-14 It is an aryl group or a 5-14 membered heteroaryl group. Preferably a phenyl group, Y is selected from CH or N. G is -S-, -O-, -CR 4C R 5C -, -NR 6C -, -S(=O)2-, -S(=O)(=NR 6C ')-、

[0043] [ka]

[0044] Selected from, preferably -O-, -CR 4C R 5C -, -NR 6C -, -S(=O)2-, -S(=O)(=NR 6C ')-、

[0045] [ka]

[0046] And, R 1C is H or -(CH2) t NR aC R bC Selected from, R 2C H, amino group, hydroxyl group, C 1-6 Alkyl alkyl group, C 1-6 Alkylamino group, C 1-6 Selected from aminoalkyl groups, of which alkyl groups include halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Optionally substituted with one or more alkoxy groups, R 3C In the case where Y is CH, H, hydroxyl group, C 1-6 Alkyl group, 3-8 membered heterocyclyl group, C 1-6 Selected from alkoxy groups, if Y is N, then H, C 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl-(CH2) mC -, 3-8 membered heterocyclyl group, 3-8 membered heterocyclyl-(CH2) mC -,-(CH2) mC NR 10 R 11 Selected from among alkyl groups and cycloalkyl groups. Heterocyclyl groups and alkoxy groups include halogens, hydroxyl groups, amino groups, nitro groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Alkoxy group, C 1-6 Optionally substituted with one or more alkylamino groups, R 4C and R 5C H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-6 Alkyl-O-, hydroxyl group, -C(O)OR7, -NR8R9, -NR cC C(O)NR8R9, C 1-6 Alkylamino group, 3-8 member heterocyclyl-(CH2) mC -, halogen, cyano group, -NR cC S(=O)2NR8R9, -NR cC C(O)OR dC , -NR cC S(=O)2OR dC , -NR cC C(O)R7', -NH(CH2) mC Selected from NR8R9, the alkyl group and heterocyclyl group can be a halogen, hydroxyl group, amino group, nitro group, cyano group, or C 1-6 Alkyl alkyl group, C 1-6Haloalkyl group, NH2C(=O)-, C 1-6 Optionally substituted with one or more alkoxy groups, Or, CR 4C R 5C These form a 3-8 membered heterocycle or a 9-10 membered bicyclic portion, and these 3-8 membered heterocycle or 9-10 membered bicyclic portions, together with the piperidine rings to which they are connected,

[0047] [ka]

[0048] Form a structure selected from, Q 1C ~Q 4C If any one of them is N, then the rest is C or Q 1C ~Q 4C All of them are C, W 1C and W 2C These are independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, and -NR. 12 -, -NR 12 It is -CH2-, -NH2, -OH, halogen, nitro group, cy A group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2C - is either or does not exist, R 12 H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3C - Selected from, preferably, W 1C and W 2C At the same time There is no possibility that it does not exist. W 3C NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups.n2C - It is either present or absent, preferably NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2C -and, W 4C and W 5C NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2C - is either or does not exist, n2C is selected from 0, 1, 2, and 3. More preferably, the 3-8 member heterocyclic ring or 9-10 member bicyclic ring portion is connected to each other. Along with the piperidine ring,

[0049] [ka]

[0050] Forms a structure selected from, comfortable

[0051] [ka]

[0052] Selected from, R aC and R bC H and C are independent of each other. 1-6 Alkyl group, amidino group, C 1-6 Alkoxyca Selected from rubonyl groups, R cC is H, or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxyl group, nitro group, cyano group, NH2C(=O)-, C1-6 C substituted with one or more alkoxy groups selected from 1-6 It is an alkyl group, preferably H, or an amino group, C 1- 6 alkylamino group or C 1-6 C substituted with an alkoxy group 1-6 It is an alkyl group, and Preferably H, or an amino group, C 1-6 C substituted with alkylamino group 1-6 alkyl group And, R dC C 1-6 Alkyl alkyl group, C 6-14 Aryl group, 5-14 member heteroaryl group, C 3-8 Cycloa A lucyl group is selected from a 3- to 8-membered heterocyclyl group, preferably C 1-6 Selected from alkyl groups and 3- to 8-membered heterocyclyl groups, more preferably C 1-6 alkyl group,

[0053] [ka]

[0054] Selected from, more preferably C 1-6 alkyl group,

[0055] [ka]

[0056] Selected from the above R dC The groups are halogen, hydroxyl, amino, nitro, and cyano groups. , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Selected from alkoxy groups It is optionally substituted with one or more groups, R eC and R fC These are each independently -(CH2)n1C - and -(CH2) n1C' - and n1C and n1C' are each independently selected from 0, 1, 2, and 3. Preferably, it is 2, and n1C and n1C' are not 0 at the same time, W C -NH-C(=O)-, -NH-S(=O)2-, -NR 12 -, -O-, -S-, -S(=O)2- are selected, preferably -O-, -S(=O)2-, R 12 H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3C - is selected from, and n3C is selected from 1, 2 and 3, R 6C and R 6C ' is independently H, C 1-6 Alkyl alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkoxycarbonyl group, C 6-14 Aryl group, C 6-14 Arylcarbonyl group, C 6-14 Aryloxycarbonyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl Carbonyl group, C 3-8 Cycloalkoxycarbonyl group, 5-14 member heteroaryl group, 5-14 member heteroarylcarbonyl group, 5-14 member heteroaryloxycarbonyl group, 3-8 member hetero The substituents are selected from a rosykyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocyclyloxycarbonyl group, and the substituents are halogen, hydroxyl group, amino group, nitro group, cyano group, and C, respectively. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Alkoxy It is optionally substituted with one or more groups selected from the group, R7 and R7' are independently H and C 1-6 Alkyl alkyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-14 Selected from aryl groups and 5-14 membered heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Optionally substituted with one or more alkoxy groups, R8 and R9 are each independently H, or halogen, hydroxyl group, amino group, or nitrile. Tro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Alcocy C is optionally substituted with one or more groups selected from the C group. 1-6 It is an alkyl group, R 10 and R 11 These are H or C, respectively, independently. 1-6 It is an alkyl group, or R 10 and R 11 These, together with the nitrogen atom to which they are linked, form a 3- to 8-membered heterocyclyl group, of which alkyl and heterocyclyl groups are halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Selected from alkoxy groups It is optionally replaced by one or more selected elements, p and t are each independently selected from 0, 1, 2, 3, 4, or 5. Each time mC appears, it is independently selected from 1, 2, 3, and 4. R0 is H, halogen, NO2, cyano group, NH2C(=O)-, C 1-6 Selected from alkoxy groups, Halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6Haloalkyl group, NH2C(=O)-, C 1-6 C is optionally substituted with one or more alkoxy groups. 1-6 Selected from alkyl groups.

[0057] A further aspect of the present invention provides a method for preparing the compound of the present invention, selected from the following methods: Method 1: Method 1 is,

[0058] [ka]

[0059] This includes the following steps: Method 2: Method 2 is,

[0060] [ka]

[0061] This includes the following steps: Preferably, the compound of formula iiC-2 is prepared by a method selected from the following: Method 3: Method 3 involves a condensation reaction between the compound represented by formula iiC-4-a and the compound represented by formula iiC-5-a, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, using formula iiC-2 The step includes obtaining the compound shown,

[0062] [ka]

[0063] Method 4: Method 4 involves a condensation reaction between the compound represented by formula iiC-4-b and the compound represented by formula iiC-5-b, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, with formula iiC-2 The step includes obtaining the compound shown,

[0064] [ka]

[0065] Method 5: Method 5 involves a condensation reaction between the compound represented by formula iiC-4-c and the compound represented by formula iiC-5-c, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, with formula iiC-2 The step includes obtaining the compound shown,

[0066] [ka]

[0067] Method 6: Method 6 involves a condensation reaction between the compound represented by formula iiC-4-d and the compound represented by formula iiC-5-d, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, with formula iiC-2 The step includes obtaining the compound shown,

[0068] [ka]

[0069] Preferably, the above formula iC-2 is

[0070] [ka]

[0071] And, Preferably, the above iiC-2 is

[0072] [ka]

[0073] Selected from, Of these, R0' is R0 or R0 in which NH2 is protected with an amino protecting group, and R 1C 'and R 1C ''teeth , R 1C Or R protected by an amino protecting group 1C And R 2C 'and R 2C '' is R 2C Or R protected by an amino protecting group 2C And R 3C 'and R 3C '' is R 3C Alternatively, R is a group protected by an amino protecting group, such as NH2 or a cyclic imino group. 3C G' is a group of G or NH2 and / or a cyclic imino group that holds an amino acid. G is protected by a protective group and / or the carboxyl group is protected by a carboxyl protecting group, and Rw is a carboxyl protecting group, and rings A, Y, R0, R 1C , R 2C , R 3C G and p are as defined above. Rs, Rt, and Ru are each independently selected from H and an amino protecting group. Preferably, the above amino protecting groups are independently a tert-butoxycarbonyl group and a 9- Fluorenyl methoxycarbonyl group, allyloxycarbonyl group, trichlorooxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoro Cetyl group, methoxycarbonyl group, tert-butylsulfinyl group, 1-phenylethyl group, Alternatively, selected from ethoxycarbonyl groups, the above carboxy protecting groups are each independently C 1-6The group is selected from alkyl groups, allyl groups, benzyl groups, 2,4-dimethoxybenzyl groups, p-methoxybenzyl groups, methoxyethoxymethyl groups, pentafluorophenyl groups, and 4-p-methylbenzyloxybenzyl groups.

[0074] Another aspect of the present invention provides a compound represented by a general formula, a stereoisomer thereof, or a salt thereof,

[0075] [ka]

[0076] Preferably, formula iiC-2-X is,

[0077] [ka]

[0078] Selected from, Of these, R0' is R0 or R0 in which NH2 is protected with an amino protecting group, and R 1C ' is R 1C Or R protected by an amino protecting group 1C And R 2C ' is R 2C Alternatively, NH2 is protected by an amino protecting group. R 2C And R 3C ' is R 3C Alternatively, R is a group protected by an amino protecting group, such as NH2 or a cyclic imino group. 3C G' is G or NH2 and / or a cyclic imino group protected with an amino protecting group and / or a carboxyl group protected with a carboxyl protecting group, and ring A, Y, R0, R 1C , R 2C , R 3C , G and p is as previously defined, Rs and Rt are independently selected from H and an amino protecting group, and Rv is selected from H and a carboxy protecting group. Preferably, the above amino protecting groups are independently a tert-butoxycarbonyl group and a 9- Fluorenyl methoxycarbonyl group, allyloxycarbonyl group, trichlorooxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoro Cetyl group, methoxycarbonyl group, tert-butylsulfinyl group, 1-phenylethyl group, Alternatively, selected from ethoxycarbonyl groups, the above carboxy protecting groups are each independently C 1-6 The group is selected from alkyl groups, allyl groups, benzyl groups, 2,4-dimethoxybenzyl groups, p-methoxybenzyl groups, methoxyethoxymethyl groups, pentafluorophenyl groups, and 4-p-methylbenzyloxybenzyl groups.

[0079] Another aspect of the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or excipient, and optionally another therapeutic agent.

[0080] Another aspect of the present invention provides the use of the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions in the preparation of drugs for agonizing κ-opioid receptors.

[0081] Another aspect of the present invention provides a method for preventing and / or treating κ-opioid receptor-mediated related diseases, comprising administering an effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0082] Another aspect of the present invention provides the use of the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions in the preparation of drugs, in particular the drugs used to prevent and / or treat related diseases mediated by κ-opioid receptors.

[0083] In this disclosure, the κ-opioid receptor-mediated related disorders are selected from pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma, and are preferably pain. In this disclosure, pain is selected from neuropathic pain, trunk pain, visceral pain, skin pain, arthritis pain, kidney stone pain, uterine spasms, dysmenorrhea, endometriosis, indigestion, postoperative pain, post-medical procedure pain, eye pain, otitis media pain, cancer explosion pain, and GI disorder-related pain. [Modes for carrying out the invention]

[0084] term Unless otherwise defined, all scientific and technical terms used herein have the same meaning as those generally understood by those skilled in the art to which the claimed subject matter belongs.

[0085] Unless otherwise specified, the present invention relates to mass spectrometry, NMR, HPLC, and protein analysis within the scope of the art. Conventional methods such as chemical chemistry, biochemistry, recombinant DNA technology, and pharmacology are employed. Specific definition Unless otherwise provided, the chemically related nomenclature, laboratory and technique described herein in analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry is known to those skilled in the art. In general, the techniques and steps described herein are well known in the art and can be carried out by conventional methods described in various general and more specific literature, which are cited and discussed herein.

[0086] The term "alkyl group" refers to an aliphatic hydrocarbon group, which may be a branched or linear alkyl group. Depending on the structure, the alkyl group may be monovalent or divalent (i.e., an alkylene group). In the present invention, alkyl groups having 1 to 8 carbon atoms are preferred, "lower alkyl groups" having 1 to 6 carbon atoms are more preferred, and alkyl groups having 1 to 4 carbon atoms are even more preferred. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, and hexyl groups. The "alkyl group" referred to herein includes all possible stereoconfigurations and stereostructures of such alkyl groups. For example, the "propyl group" referred to herein includes n-propyl and isopropyl groups, and the "butyl group" includes n-butyl, isobutyl, and tert-butyl groups. It should be understood that the group includes an n-pentyl group, isopropyl group, neopentyl group, tert-pentyl group, and pentyl-3-yl, etc. In some embodiments, the alkyl group is optionally selected with one or more (e.g., 1 to 3) suitable substituents. It will be replaced.

[0087] The term "aryl group" refers to an all-carbon monocyclic or polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, "C 6-14 The term "aryl group" refers to an aromatic group having 6 to 14 carbon atoms. In some embodiments, C 6-14 The aryl group is C 6-10 Aryl groups are preferred. Examples of aryl groups may include phenyl groups, naphthyl groups, anthracene, etc. In some embodiments, there are one or more aryl groups (for example, 1 to 3). It is optionally substituted with an appropriate substituent.

[0088] The term "heteroaryl group" refers to one or more homologous or heteroaryl groups, such as oxygen, nitrogen, or sulfur. This refers to monocyclic or polycyclic aromatic groups containing heteroatoms of different phases. For example, as used herein, the term "5-14 membered heteroaryl group" refers to a heteroaryl group having 5 to 14 ring atoms. Furthermore, the heteroaryl group has 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and contains oxygen, nitrogen, and nitrogen. Alternatively, a monoring containing at least one heteroatom, which may be homologous or different, such as sulfur. The formula means a bicyclic or tricyclic aromatic group, and the heteroaryl group may also be a benzo-condensed group. In particular, the heteroaryl group may be a thienyl group, a furanyl group, or a pyrrolyl group. The heteroaryl group is selected from oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo derivatives, or from pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives. In some embodiments, the heteroaryl group is placed in one or more (e.g., 1 to 3) appropriate positions. It is arbitrarily substituted by the substitution base.

[0089] The term "cycloalkyl group" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (bicyclic, etc.) hydrocarbon ring groups (e.g., monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl groups, or bicyclic groups including spirocycles, condensed systems, or crosslinked systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, dekalinyl, etc.). Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. In some embodiments, one or more (e.g., 1 to 3) of the above cycloalkyl groups are present. It is optionally substituted with an appropriate substituent.

[0090] The term "heterocyclyl group" means a saturated or unsaturated monocyclic or polycyclic group having 3 to 12 ring atoms or 3 to 8 ring atoms, each containing, for example, one or more heteroatoms (e.g., 1, 2, 3, or 4) selected from carbon atoms and nitrogen, oxygen, or sulfur within the ring, and the heterocyclyl group is connected via any one of the carbon atoms or a nitrogen atom (if present) It can then be linked to the rest of the molecule. The carbon atoms in the heterocyclyl group may be optionally substituted with oxo (=O) groups. The sulfur atoms of the ring can be S-oxidized to SO, SO2, etc. The group may be optionally oxidized to a substance. The nitrogen atom of the ring may be optionally oxidized to an N-oxygen compound. For example, a 3- to 8-membered heterocyclyl group is a group having 3 to 8 ring atoms including carbon atoms and heteroatoms, and includes, but is not limited to, oxylanyl group, azilidinyl group, azetidinyl group, oxetanyl group, thietanyl group, tetrahydrofuranyl group, dioxolyl group, pyrrolidinyl group, pyrrolidonyl group, imidazolidinyl group, pyrazolidinyl group, pyrrolinyl group, tetrahydropyranyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, pyrimidinedione group, 2-oxopyrrolidinyl, 3,5-dioxopiperidinyl, sulfolane group, 1,1-dioxothiomorpholinyl, and 1,1-dioxotetrahydrothiopyranyl. In some embodiments, the heterocyclyl group is one or more. It is optionally substituted with suitable substituents (e.g., 1 to 3). In some embodiments, the 3 to 8-membered heterocyclyl group is substituted with one heteroatom selected from oxygen, nitrogen, and sulfur. The contained 3- to 8-membered heterocyclyl groups, and in some embodiments, the 3- to 8-membered heterocyclyl groups are

[0091] [ka]

[0092] And among them, W A , R eA , R fA , WC , R eC , R fC This is as defined herein.

[0093] The term "alkoxy group" refers to an alkyl-O- such that the alkyl group is as defined herein. Typical alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. This includes, but is not limited to, xyloxy, pentyloxy, and hexyloxy groups.

[0094] The term "aryloxy group" refers to an aryl-O- group as defined herein.

[0095] The term "heteroaryloxy group" refers to a heteroaryl-O- group that is defined herein as such.

[0096] The term "cycloalkoxy group" refers to a cycloalkyl-O- such that the cycloalkyl group is defined herein.

[0097] The term "heterocyclyloxy group" refers to a heterocyclyl-O- group as defined herein.

[0098] The term "carbonyl group" refers to a group in which two atoms, carbon and oxygen, are linked by a double bond. It refers to the organic functional group -C(=O)-. The term "alkoxycarbonyl group" is a This refers to lucoxy-C(=O)-, meaning that this group is connected to the other parts of the compound via the carbonyl group. They are linked. The term "alkylcarbonyl group" refers to alkyl-C(=O)-, That is, the group is linked to the other part of the compound via a carbonyl group. Similarly, the term "arylcarbonyl group" refers to aryl-C(=O)-, that is, the group is The term "aryloxycarbonyl group" refers to an aryloxy-C(=O)- group that is linked to the other part of the compound via a carbonyl group. It is connected to other parts of the composite and similarly inferred.

[0099] The term "cyano group" refers to a -CN group in which a carbon atom and a nitrogen atom are linked by a triple bond.

[0100] The term "amidino group" means

[0101] [ka]

[0102] It refers to.

[0103] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0104] The term "haloalkyl group" refers to a group in which at least one hydrogen atom is replaced by a halogen atom. This refers to alkyl groups. In some embodiments, two or more hydrogen atoms are substituted with halogen atoms. In this case, the halogen atoms are homologous or different from each other. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, and trifluoroethyl groups.

[0105] The term "aminoalkyl group" refers to an alkyl group substituted with an amino group.

[0106] The term "alkylamino group" refers to an amino group that has been substituted with an alkyl group.

[0107] "C1~C6" or "C 1-6 The expression "C1-C6" encompasses the range of 1 to 6 carbon atoms, for example, C1-C6. 2~C6, C3~C6, C 4~ C6, C5~C6, C1~C5, C2~C5, C3~C5, C4~C5, C1~C4, C 2~ It should be understood that this includes C4, C3-C4, C1-C3, C2-C3, C1-C2, etc., as well as any sub-ranges within them, including C1, C2, C3, C4, C5, C6, etc., and the values ​​of each point. to, "C3~C8" or "C 3-8 The expression "C3" encompasses the range of 3-8 carbon atoms, for example, C3 The expression "3-8 members" should be understood to include any sub-range within rings such as ~C6, and C3, C4, C5, C6, C7, C8, etc., as well as the values ​​of each point. Similarly, the expression "5-14 members" should be understood to include any sub-range within rings such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 members, as well as the values ​​of each point. Other similar expressions in this specification should be understood in a similar manner.

[0108] The terms "optionally substituted" or "optionally substituted with..." mean that the referred base may or may not be substituted.

[0109] The terms "optionally substituted" or "substituted" mean that the group mentioned may be substituted with one or more additional groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, alkylthio groups, halogens, mercap groups, hydroxyl groups, nitro groups, amino groups, cyano groups, carboxyl groups, oxo groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, NH2C(=O)-, alkylamino groups, etc.

[0110] In the expressions "substituted with one or more groups selected from..." or "optionally substituted with one or more groups selected from...", "one or more" refers to the conditions that satisfy the valence requirement. This means that the item was replaced by 1 to 5 elements, or 1 to 4 elements, or 1 to 3 elements, or 1 to 2 elements.

[0111] Note that "C 6-14 "Arylcarbonyl group", "C 6-14 The term "aryloxycarbonyl group" refers to a group where the aryl group is C 6-14 It means that it is an aryl group, and "C 3-8 Cycloalkylcal Bonyl group, C 3-8 The term "cycloalkoxycarbonyl group" refers to a group where the cycloalkyl group is C 3-8 This means it is a cycloalkyl group, specifically a "5-14 member heteroarylcarbonyl group". The term "5-14 member heteroaryloxycarbonyl group" means that the heteroaryl group is a 5-14 member heteroaryl group, and also means "3-8 member heterocyclylcarbonyl group", "3 The term "~8-membered heterocyclyloxycarbonyl group" refers to a heterocyclyl group with 3 to 8 members. It means that it is a telocyclyl group, and "C 1-6 The term "alkoxycarbonyl group" refers to an alkyl group with C 1-6 It should be understood that this means it is an alkyl group. Similarly, "C 1-6 "Aminoalkyl group" is a group where the alkyl group is C 1-6 This means it is an alkyl group.

[0112] The term "pharmaceutically acceptable carrier" refers to a substance that does not have an apparent irritant effect on an organism and does not impair the biological activity and performance of the active compound. "pharmaceutically acceptable carriers" include, but are not limited to, flow enhancers, sweeteners, diluents, preservatives, dyes and colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0113] The names of the compounds disclosed herein, "Compound *-0" and "Compound *-100" (where * is the compound number), are stereoisomers of "Compound *," respectively. For example, Compound 3 is a racemic mixture. Compound 3-0 and Compound 3-100 are stereoisomers thereof, respectively.

[0114] In this invention, "*" indicates a connection point. For example, G in this disclosure is

[0115] [ka]

[0116] If that is the case,

[0117] [ka]

[0118] but

[0119] [ka]

[0120] This indicates that...

[0121] Note that the expression "G is -CR" 4C R 5C "-Selected from" means that the C atom is a ring atom, i.e.

[0122] [ka]

[0123] but

[0124] [ka]

[0125] This means that, similarly, "G is -S(=O)(=NR 6C ')-) Selected from' is S atom The fact that it is a ring atom, that is

[0126] [ka]

[0127] but

[0128] [ka]

[0129] It should be understood that this means...

[0130] Furthermore, the structure referred to in this disclosure

[0131] [ka]

[0132] Q refers to an aromatic ring, for example, 1A / Q 1C ~Q 4A / Q 4C If one of them is N and the rest is C, then the structure is a pyridine ring, and Q 1A / Q 1C ~Q 4A / Q 4C If both are C, the structure is It should be understood that it is a rhombic ring. Also, in the above expression, "the remainder is C" This means that the ring atom is C, and based on valence bond theory, the rest is actually CH. It should be understood that this means "to do".

[0133] The compound or salt thereof of the present invention may contain one or more stereocenters, each stereocenter These compounds exist independently in R or S configurations and can therefore produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined in absolute stereochemistry as (R)- or (S)- or (D)- or (L)- of an amino acid. The present invention is intended to include all possible isomeric forms or mixtures thereof, such as substantially pure enantiomers, diastereomers, racemates, or mixtures thereof. In some embodiments, preferred compounds are isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the compounds of the present invention are all within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0134] In some embodiments, the compounds of the Disclosure are racemates. In some embodiments, the compounds of the Disclosure are single enantiomers. In some embodiments, the compounds of the Disclosure are substantially free of other isomers. In some embodiments, the compounds of the Disclosure are a single isomer substantially free of other isomers. In some embodiments, the compounds of the Disclosure contain 25% or less of other isomers, or 20% or less of other isomers, or 15% or less of other isomers, or 10% or less of other isomers, or 5% or less of other isomers, or 1% or less of other isomers.

[0135] In some embodiments, the compounds of the present disclosure have a stereochemical purity of at least 75%. It has a stereochemical purity of at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least It also has a stereochemical purity of 99%.

[0136] In some embodiments, the chiral carbon atoms in the compounds of the Disclosure may exist in racemic or enantiomerically enriched forms, for example, in (R)-, (S)-, or (R,S)- configurations. In some embodiments, the (S)- or (R)- configured chiral carbon atoms in the compounds of the Disclosure may be at least 50% enantiomers. Having an excess ratio, an enantiomer excess ratio of at least 60%, an enantiomer excess ratio of at least 70%, an enantiomer excess ratio of at least 80%, an enantiomer excess ratio of at least 90%, an enantiomer excess ratio of at least 95%, or an enantiomer excess ratio of at least 99%.

[0137] As used herein, “substantially pure” or “substantially free of other isomers” means that the product contains less than 10% by weight, preferably less than 5% by weight, relative to the preferred isomer. This means that the compound contains less than 4% by weight, preferably less than 3% by weight, preferably less than 2% by weight, and preferably less than 1% by weight of other isomers. Where this disclosure refers to or indicates that a particular configuration of a compound is an absolute configuration, it should be understood that this means that it is substantially a pure absolute configuration, and similarly, where this disclosure refers to or indicates that a compound is a single enantiomer, it means that it is substantially a pure enantiomer.

[0138] The following detailed description is intended to illustrate non-limiting embodiments, enabling those skilled in the art to better understand the technical solutions, principles, and practical applications of the present invention.

[0139] compound This disclosure provides a compound represented by formula IA, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0140] [ka]

[0141] In some embodiments, R 1A is H or -COOH, preferably H, and R 2A -NR aA C(=O)OR bA or -NR aA S(=O)2OR bA And preferably -NR aA C(=O)OR bA And among them, R aA is H, or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxyl group, nitro group, cyano group, NH2C(=O)-, C 1-6 Selected from alkoxy groups C substituted with one or more groups 1-6 It is an alkyl group, preferably H, or an amino group, C 1-6 Alkylamino group, or C 1-6 C substituted with an alkoxy group 1-6 It is an alkyl group, more preferably H, or C 1-6 It is an aminoalkyl group, R bA C 1-6 Alkyl alkyl group, C 6-14 Aryl group, 5-14 member heteroaryl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups (preferably)

[0142] [ka]

[0143] Selected from, preferably C 1-6 Selected from alkyl groups and 3- to 8-membered heterocyclyl groups, more preferably C 1-6 alkyl group,

[0144] [ka]

[0145] Selected from, more preferably C 1-6alkyl group,

[0146] [ka]

[0147] Selected from, more preferably C 1-6 alkyl group,

[0148] [ka]

[0149] Selected from the above R bA The groups are halogen, hydroxyl, amino, nitro, and cyano groups. , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Selected from alkoxy groups It is optionally substituted with one or more groups, R eA and R fA These are each independently -(CH2) n1A - and -(CH2) n1A' -and in some embodiments, each -(CH2) n1A -and-(CH2) n1A’ -where n1A and n1A' are independently selected from 0, 1, 2, and 3, preferably 2, and n1A and n1A' are not 0 at the same time, W A is -NH-C(=O)- -NH-S(=O)2-, -NR 5A -, -O-, -S-, -S(=O)2- are selected, preferably -O-, -S(=O)2-, R 5A H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A - is selected from, and n3A is selected from 1, 2 and 3. In some embodiments, R aA H is H. In some embodiments, R aA is an amino group, C1-6 Alkylamino group, or C 1-6 Alcocy C substituted with a cy group 1-6 It is an alkyl group, such as a methoxyethyl group, a methylaminoethyl group, an aminopropyl group, or an aminoethyl group. In some embodiments, R aA is H or C 1-6 It is an aminoalkyl group. In some embodiments, R bA Haroge n, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 C is optionally substituted with one or more alkoxy groups. 1-6 It is an alkyl group, for example, a methyl group, an ethyl group, or a propyl group, and preferably a methyl group. In some embodiments, R bA is halogen, hydroxyl group, amine nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Optionally substituted with one or more alkoxy groups

[0150] [ka]

[0151] And W A -NH-C(=O)-, -NH-S(=O)2-, -NR 5A Choose from -, -O-, -S-, -S(=O)2- Preferably selected from -O- and -S(=O)2-, R 5A H, C 1-6 Alkyl alkyl, amidino Group, HOOC-(CH2) n3A - is selected from 1, 2, and 3, and n3A is selected from 1, 2, and 3.

[0152] In some embodiments, R 1A and R 2A These, together with the carbon atoms to which they are linked, form an optionally substituted 9-10 membered bicyclic moiety (specifically, a 9-10 membered fused ring). Preferably, the above bicyclic moiety, together with the piperidine ring to which they are linked,

[0153] [ka]

[0154] Form a structure selected from, Q 1A ~Q 4A If any one of them is N, the rest is either CH or Q 1A ~Q 4A All of them are CH, W 1A and W 2A These are independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, and -NR. 6A -, -NR 6A It is -CH2-, -NH2, -OH, halogen, nitro group, cy A group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2A - is either or does not exist, R 6A H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A - is selected from, and n3A is selected from 1, 2 and 3, preferably 1, preferably W 1A and W 2A It is impossible for them to exist simultaneously. W 3A NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2A - n2A is selected from 0, 1, 2, and 3.

[0155] More preferably, the bicyclic portion, together with the piperidine ring to which they are connected,

[0156] [ka]

[0157] Forms a structure selected from, comfortable

[0158] [ka]

[0159] Selected from, and more preferably

[0160] [ka]

[0161] Selected from.

[0162] In some embodiments, R 3A is H or -(CH2) mA NR cA R dA Selected from among , R cA and R dA H and C are independent of each other. 1-6 Alkyl groups (e.g., methyl group, isopropyl group) (such as a ru group), amidino group, C 1-6 The alkoxycarbonyl group is selected from (e.g., methoxycarbonyl group), and mA is selected from 0, 1, 2, 3, 4, or 5. In some embodiments, R 3A H is H. In some embodiments, R cA and R dA Each of them is independently H , C 1-6Selected from alkoxycarbonyl groups (e.g., methoxycarbonyl group). In some embodiments, R cA and R dA These are each H. In some embodiments , R cA H is R dA is C 1-6 Alkoxycarbonyl group, preferably methoxycarbonyl group In some embodiments, mA This is selected from 0, 1, 2, or 3, preferably 3. That is the case.

[0163] In some embodiments, R 4A These are halogen, NO2, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, cyano group, NH2C(=O)-, C 1-6 The group is selected from alkoxy groups, preferably from F, Cl, NO2, CH3, CF3, cyano groups, and NH2C(=O)-.

[0164] In some embodiments, nA is 0, 1, 2, 3, 4, or 5, preferably 0, 1, 2 or It is 3, and more preferably 0.

[0165] In some embodiments, formula IA is represented by formula IIA, preferably by formula IIIA, and further Preferably represented by formula IVA, and more preferably by formula VA,

[0166] [ka]

[0167] Preferably, R in formula IA, formula IIA, formula IIIA, formula IVA, or formula VA. bA C 1-6 alkyl group ,

[0168] [ka]

[0169] Selected from, preferably

[0170] [ka]

[0171] And among them, W A This is selected from -O- and -S(=O)2-.

[0172] In some embodiments, formula IA is represented by formula VIA,

[0173] [ka]

[0174] Preferably, R in formula VIA aA is H, or an amino group, C 1-6 Alkylamino group, Or C 1-6 C substituted with an alkoxy group 1-6 It is an alkyl group, more preferably H or C 1-6 It is an aminoalkyl group.

[0175] In some embodiments, the compound of the present invention is a compound represented by formula IIIA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of which R aA H is R bA C 1-6 Al Kill base,

[0176] [ka]

[0177] Selected from, R eA and R fA These are -(CH2) n1A-and-(CH2) n1A' - and n1A and n1A' are each independently selected from 0, 1, 2, and 3, preferably 2, and n1A and n1A' are not 0 at the same time, W A -NH-C(=O)-, -NH-S(=O)2-, -NR 5A -, -O-, -S-, -S(=O)2- are selected from R 5A H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A - is selected from, n3A is selected from 1, 2 and 3, R cA and R dA H and C are independent of each other. 1-6 Al Kill group, amidino group, C 1-6 Selected from alkoxycarbonyl groups.

[0178] In some embodiments, the compound of the present invention is a compound represented by formula IIIA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of which R aA H is R bA C 1-6 Al Kill base,

[0179] [ka]

[0180] Selected from, W A R is selected from -O- and -S(=O)2-. cA and R dA H and C are independent of each other. 1-6 Alkyl group, amidino group, C 1-6 Selected from alkoxycarbonyl groups.

[0181] In some embodiments, the compound of the present invention is a compound represented by formula IVA, the stereoisographic compound A substance or a pharmaceutically acceptable salt thereof, of which R aA H is R bA C 1-6 Al Kill base,

[0182] [ka]

[0183] Selected from, W A This is selected from -O- and -S(=O)2-.

[0184] In some embodiments, the compounds of the present invention are selected from the compounds shown below, their stereoisomers, or their pharmaceutically acceptable salts.

[0185] [ka]

[0186] [ka]

[0187] [ka]

[0188] This disclosure further provides intermediates for preparing the above-mentioned compounds of this disclosure, which are compounds of a general formula, stereoisomers thereof, or salts thereof.

[0189] [ka]

[0190] Eventually, R 1A ' is R 1A Or R protected by an amino protecting group 1A And R 2A ' is R 2A Or R protected by an amino protecting group 2A And R 3A ' is R 3A Or R protected by an amino protecting group 3AAnd R 1A , R 2A , R 3A , R 4A And nA are as defined above, R xA is an amino protecting group, The above amino protecting groups are, independently of each other, tert-butoxycarbonyl group (Boc), 9-fluorenylmethoxycarbonyl group (Fmoc), allyloxycarbonyl group (Alloc), and trichlorocarbonyl group. Roethoxycarbonyl group (Troc), trimethylsilylethoxycarbonyl group (Teoc), benzyloxycarbonyl group (CBz), p-toluenesulfonyl group (Tosyl), p-nitrobenzenesulfonyl group (Nosyl), tert-butyl group (t-Bu), trifluoroacetyl group (Tfa), Select from a methoxycarbonyl group, a tert-butylsulfinyl group, or an ethoxycarbonyl group. It is preferable that this be done.

[0191] Manufacturing method In some embodiments, the compounds shown in the present invention can be prepared by a method selected from the following: Method 1: Method 1 is,

[0192] [ka]

[0193] This includes the following steps: Method 2: Method 2 is,

[0194] [ka]

[0195] This includes the following steps: Eventually, R 1A ' is R 1A Or R protected by an amino protecting group 1A And R2A ' is R 2A Or R protected by an amino protecting group 2A And R 3A ' is R 3A Or R protected by an amino protecting group 3A And R 1A , R 2A , R 3A , R 4A And nA are as defined above, R xA is an amino protecting group,

[0196] The above amino protecting groups are, independently, a tert-butoxycarbonyl group and a 9-fluorenyl group. Methoxycarbonyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoroacetyl group, Select from a methoxycarbonyl group, a tert-butylsulfinyl group, or an ethoxycarbonyl group. It is preferable that this be done.

[0197] compound This disclosure provides compounds represented by formula IB, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0198] [ka]

[0199] R 1B H, C 1-6 Alkyl group (e.g., methyl group), C 1-6 Alkylcarbonyl group (e.g., methylcarbonyl group), C 1-6 Alkoxycarbonyl group (e.g., methoxycarbonyl group), C 6-14 Aryl group, C 6-14 Arylcarbonyl group, C 6-14 Aryloxycarbonyl group , C 3-8Cycloalkyl groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 Cycloalkoxycarbonyl group, 5-14 member heteroaryl group, 5-14 member heteroarylcarbonyl group, 5-14 member hetero Selected from a teloaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocycloxycarbonyl group, preferably H, C 1-6 Alkyl group (e.g., methyl group), C 1-6 Alkylcarbonyl group (e.g., methylcarbon) nyl group), C 1-6 Selected from alkoxycarbonyl groups (e.g., methoxycarbonyl group), more preferably C 1-6 Alkyl group (e.g., methyl group), C 1-6 Selected from alkylcarbonyl groups (e.g., methylcarbonyl group), the substituents are halogen, hydroxyl group, amino group, nitro group, cyano group, and C, respectively. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Optionally substituted with one or more alkoxy groups, R 2B and R 3B H and C are independent of each other. 1-6 Alkyl groups (e.g., methyl group, isopropyl group) (Lu group), amidino group, C 1-6 Selected from alkoxycarbonyl groups (e.g., methoxycarbonyl groups), R 4B These are halogen, NO2, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, cyano group, NH2C(=O)-, C 1-6 Selected from alkoxy groups, preferably F, Cl, NO2, CH3, CF3, cyano group, NH2C Selected from (=O)-, mB and nB are independently 0, 1, 2, 3, 4, or 5, for example, mB is 3, and ☐ or nB is 0.

[0200] In some embodiments, R 1B H, C 1-6 Alkyl alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 6-14 Aryl group, C 6-14 Arylcarbonyl group, C 6-14 a Reeloxycarbonyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 Select from cycloalkoxycarbonyl group, 5-14 member heteroaryl group, 5-14 member heteroarylcarbonyl group, 5-14 member heteroaryloxycarbonyl group, 3-8 member heterocyclyl group, 3-8 member heterocyclylcarbonyl group, and 3-8 member heterocyclyloxycarbonyl group. And preferably, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkylcarbonyl groups, preferably H, C 1-6 Alkyl alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 From the alkoxycarbonyl group Selected, more preferably, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkylcarbonyl groups, each of the above substituents may be a halogen, hydroxyl group, amino group, nitro group, cyano group, or C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 It is optionally substituted with one or more groups selected from alkoxy groups. In some embodiments, R 1B H is H. In some embodiments, R 1B These are halogens, hydroxyl groups, amino groups, nitro groups, and cyano groups. , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Selected from alkoxy groups C is optionally substituted with one or more groups. 1-6 It is an alkyl group, preferably a halogen. , hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 A methyl group, ethyl group, propyl group, or butyl group, which is optionally substituted with one or more groups selected from alkoxy groups, and more preferably a methyl group. In some embodiments, R 1B These are halogens, hydroxyl groups, amino groups, nitro groups, Cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 From the alkoxy group C is optionally substituted with one or more selected groups. 1-6 It is an alkylcarbonyl group, In addition, halogens, hydroxyl groups, amino groups, nitro groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 A methylcarbonyl group, ethylcarbonyl group, propylcarbonyl group, or butylcarbonyl group, which is optionally substituted with one or more groups selected from alkoxy groups, and more preferably a methylcarbonyl group.

[0201] In some embodiments, R 2B and R 3B H and C are independent of each other. 1-6 alkyl group, a Midino group, C 1-6 Selected from alkoxycarbonyl groups. In some embodiments, R 2B and R 3B H and C are independent of each other. 1-6 Selected from alkoxycarbonyl groups. Several In this embodiment, R 2B and R 3B In all of these, R 2B H is R 3B is C 1-6It is an alkoxycarbonyl group, preferably a methoxycarbonyl group.

[0202] In some embodiments, R 4B These are halogen, NO2, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, cyano group, NH2C(=O)-, C 1-6 The group is selected from alkoxy groups, preferably from F, Cl, NO2, CH3, CF3, cyano groups, and NH2C(=O)-.

[0203] In some embodiments, mB and nB are independently 0, 1, 2, 3, 4, or 5. In some embodiments, mB is 0, 1, 2, 3, 4, or 5, preferably 3. In some embodiments, nB is 0, 1, 2, or 3, preferably 0.

[0204] In some embodiments, formula IB is preferably represented by formula IIB,

[0205] [ka]

[0206] More preferably, represented by formula IIIB,

[0207] [ka]

[0208] More preferably represented by formula IIVB

[0209] [ka]

[0210] In some embodiments, in the above general formula, R 1B is halogen, hydroxyl group, Amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 C is optionally substituted with one or more alkoxy groups. 1-6 Alkyl alkyl group, C 1-6 Selected from alkylcarbonyl groups, preferably C 1-6 Alkyl alkyl group or C 1-6 It is an alkylcarbonyl group, more preferably a methyl group or a methylcarbonyl group.

[0211] In some embodiments, the compounds of the present invention are selected from the compounds shown below, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0212] [ka]

[0213] This disclosure further provides intermediates for preparing the compounds of the present invention, such as the compound of formula iB-1, its stereoisomers, or salts thereof.

[0214] [ka]

[0215] Eventually, R 1B , R 4B mB and nB are as previously defined, R xB and R yB These are amino protecting groups, preferably independently of each other: tert-butoxycarbonyl group (Boc), 9-fluorenylmethoxycarbonyl group (Fmoc), allyloxycarbonyl group (Alloc), and tri Chloroethoxycarbonyl group (Troc), trimethylsilylethoxycarbonyl group (Teoc), benzyloxycarbonyl group (CBz), p-toluenesulfonyl group (Tosyl), p-nitrobenzenesulfonyl group (Nosyl), tert-butyl group (t-Bu), trifluoroacetyl group (Tfa ), selected from a methoxycarbonyl group or an ethoxycarbonyl group.

[0216] Similarly, the present disclosure further provides compounds of formula iB-4, stereoisomers thereof, or salts thereof.

[0217] [ka]

[0218] , eventually, R 1B , R 2B , R 3B , R 4B , mB, nB and R xB This is as previously defined.

[0219] Manufacturing method In some embodiments, the compounds shown herein can be prepared by a method comprising the following steps:

[0220] [ka]

[0221] Eventually, R 1B , R 4B mB and nB are as previously defined, and R xB and R yB These are amino protecting groups, preferably independently of a tert-butoxycarbonyl group and a 9-fluorine group. Lenylmethoxycarbonyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoroacetyl A group selected from a hydroxyl group, a methoxycarbonyl group, or an ethoxycarbonyl group.

[0222] compound This disclosure provides compounds represented by , stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0223] [ka]

[0224] In some embodiments, ring A is C 3-8 Cycloalkyl groups, C 6-14 An aryl group (preferably a monocyclic aryl group), or a 5-14 membered heteroaryl group (preferably a monocyclic heteroaryl group) The ring A is an aryl group, for example, a cyclopropyl group, a cyclopentyl group, a phenyl group, a pyridinyl group, and a pyrimidinyl group. In some embodiments, ring A is a phenyl group. ru.

[0225] In some embodiments, Y is selected from CH or N. In some embodiments, Y is N.

[0226] In some embodiments, G is -S-, -O-, -CR 4C R 5C -, -NR 6C -, -S(=O)2-, -S(=O)(=NR 6C ')-、

[0227] [ka]

[0228] Selected from: In some embodiments, G is -O-, -CR 4C R 5C -, -NR 6C -, -S(=O)2-, -S(=O)(=NR 6C ')-、

[0229] [ka]

[0230] Selected from. In some embodiments, G is -O-. In some embodiments, G is -S(=O)2-.

[0231] In some embodiments, G is -S(=O)(=NR 6C ')- and among them, R 6C ' is H, C 1-6 Alkyl group (e.g., methyl group), C 1-6 Alkylcarbonyl group (e.g., methylcarbonyl) Bonyl group), C 1-6 Alkoxycarbonyl group (e.g., methoxycarbonyl group), C 6-14 a Reel base, C 6-14 Arylcarbonyl group, C 6-14 Aryloxycarbonyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 Cycloalkoxycarbonyl group, 5 ~14-membered heteroaryl group, 5-14-membered heteroarylcarbonyl group, 5-14-membered heteroaryloxycarbonyl group, 3-8-membered heterocyclyl group, 3-8-membered heterocyclylcarbonyl group, 3 Selected from ~8-membered heterocyclyloxycarbonyl groups, preferably H, C 1-6 Alkyl group (e.g., methyl group), C 1-6 Alkylcarbonyl group (e.g., methylcarbonyl group), C 1-6 Selected from alkoxycarbonyl groups (e.g., methoxycarbonyl group), more preferably C 1-6 Alkyl group (e.g., methyl group), C 1-6 Selected from alkylcarbonyl groups (e.g., methylcarbonyl group), each of the above substituents may be a halogen, hydroxyl group, amino group, nitro group, cyano group, or C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 It is optionally substituted with one or more alkoxy groups.

[0232] In some embodiments, G is -CR4C R 5C - and among them, R 4C and R 5C H and C are independent of each other. 1-6 Alkyl alkyl group, C 1-6 Alkyl-O-, hydroxyl group, -C(O)OR7, -NR8R9, -NR cC C(O)NR8R9, C 1-6 Alkylamino group, 3-8 member heterocyclyl-(CH2) mC -,halogen cyano group, -NR cC S(=O)2NR8R9, -NR cC C(O)OR dC , -NR cC S(=O)2OR dC , -NR cC C(O)R7', -NH(CH2) mC Selected from NR8R9, the alkyl group and heterocyclyl group are halogens. , hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalgorithm NH2C(=O)-,C 1-6 R7 and R7' are optionally substituted with one or more alkoxy groups, and R7 and R7' are independently H and C, respectively. 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-14 Selected from aryl groups and 5-14 membered heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 It is optionally substituted with one or more groups selected from alkoxy groups, and R8 and R9 are independently H, or halogen, hydroxyl group, amino group, Nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Arco C is optionally substituted with one or more groups selected from the xy group. 1-6 It is an alkyl group, R cC is H, or an amino group, C 1-6 Alkylamino group, C 1-6 Alkyl groups, halogens, hyphens hydroxy group, nitro group, cyano group, NH2C(=O)-, C 1-6 C substituted with one or more alkoxy groups selected from 1-6 It is an alkyl group, preferably H, or an amino group, C 1-6 a Calcylamino group or C 1-6 C substituted with an alkoxy group 1-6 Alkyl, more preferably H, or amino group, C 1-6 C substituted with alkylamino group 1-6 It is an alkyl group , R dC C 1-6 Alkyl alkyl group, C 6-14 Aryl group, 5-14 member heteroaryl group, C 3-8 Cycloa A lucyl group is selected from a 3- to 8-membered heterocyclyl group, preferably C 1-6 Selected from alkyl groups and 3- to 8-membered heterocyclyl groups, more preferably C 1-6 alkyl group,

[0233] [ka]

[0234] Selected from, more preferably C 1-6 alkyl group,

[0235] [ka]

[0236] Selected from the above R dC The groups are halogen, hydroxyl, amino, nitro, and cyano groups. , C 1-6 Alkyl alkyl group, C1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Selected from alkoxy groups It is optionally substituted with one or more groups, R eC and R fC These are each independently -(CH2) n1C - and -(CH2) n1C' -and in several embodiments, -(CH2) n1C -and-(CH2) n1C’ - and among them, n 1C and n 1C' Each is independently selected from 0, 1, 2, and 3, preferably 2, and n1C and n1C' are not 0 at the same time, W C -NH-C(=O)-, -NH-S(=O)2-, -NR 12 -, -O-, -S-, -S(=O)2- are selected, preferably -O-, -S(=O)2-, R 12 H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3C - Select from n3C is selected from 1, 2, and 3, and mC is selected from 1, 2, 3, and 4.

[0237] Or, CR 4C R 5C This refers to a 3-8 membered heterocyclic ring or a 9-10 membered bicyclic ring (specifically, a 9-10 membered fused ring). ) form the above 3-8 member heterocyclic ring or 9-10 member bicyclic ring portion, which are connected by piperi Along with the zinc ring,

[0238] [ka]

[0239] Form a structure selected from, Q 1C ~Q 4C If any one of them is N, the rest is either CH or Q 1C ~Q 4CAll of them are CH, W 1C and W 2C These are independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, and -NR. 12 -, -NR 12 It is -CH2-, -NH2, -OH, halogen, nitro group, cy A group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2C - is either or does not exist, R 12 H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3C - Selected from, preferably, W 1C and W 2C It is impossible for them to exist simultaneously. W 3C NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2C - It is either present or absent, preferably NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2C -and, W 4C and W 5C NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 -(CH2) is optionally substituted with one or more alkoxy groups. n2C - is either or does not exist, n2C is selected from 0, 1, 2, and 3. More preferably, the 3-8 member heterocyclic ring or 9-10 member bicyclic ring portion is connected to each other. Along with the piperidine ring,

[0240] [ka]

[0241] Forms a structure selected from, comfortable

[0242] [ka]

[0243] Selected from.

[0244] In some embodiments, G is -CR 4C R 5C - and among them, R 4C H is R 5C -NR cC C(O)OR dC And R cC and R dC This is as defined above.

[0245] In some embodiments, G is -CR 4C R 5C - and among them, R 4C is -NR8R9, and R 5C R7 is -C(O)OR7, and R7, R8 and R9 are as defined above. In some embodiments, R7 is H, or a halogen, hydroxyl group, amino group, nitro group, cyano group , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Selected from alkoxy groups C is optionally substituted with one or more groups. 1-6 It is an alkyl group, for example, H or C 1-6It is an alkyl group, for example, H or a methyl group. In some embodiments, R8 and R9 are All of them are H.

[0246] In some embodiments, G is -S(=O)(=NR 6C ')- and among them, R 6C ' is as defined above.

[0247] In some embodiments, R 1C is H or -(CH2) t NR aC R bC Selected from, of which, R aC and R bC H and C are independent of each other. 1-6 Alkyl groups (e.g., methyl group, isopropyl group) (e.g., groups), amidino group, C 1-6 The alkoxycarbonyl group is selected from (e.g., a methoxycarbonyl group), and t is selected from 0, 1, 2, 3, 4, or 5. In some embodiments... And, R 1C H is H. In some embodiments, R aC and R bC H and C are independent of each other. 1-6 Selected from alkoxycarbonyl groups (e.g., methoxycarbonyl groups). In one embodiment, R aC and R bC These are H, respectively. In some embodiments t is selected from 0, 1, 2, or 3, and is preferably 3.

[0248] In some embodiments, R 2C H, amino group, hydroxyl group, C 1-6 Alkyl alkyl group, C 1-6 Alkylamino group, C 1-6 Selected from aminoalkyl groups, of which alkyl groups include halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl alkyl group, C 1-6Haloalkyl group, NH2C(=O)-, C 1-6 It is optionally substituted with one or more alkoxy groups.

[0249] In some embodiments, if Y is CH, R 3C H, hydroxyl group, C 1-6 alkyl group , 3-8 membered heterocyclyl group, C 1-6 Selected from alkoxy groups, if Y is N, R 3C H, C 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl-(CH2) mC -, 3-8 member heterozygotes Cyclyl group, 3-8 member heterocyclyl-(CH2) mC -,-(CH2) mC NR 10 R 11 Selected from among alkyl groups, cycloalkyl groups, heterocyclyl groups, and alkoxy groups are halogens, hydroxyl groups, amino groups, nitro groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Alkoxy group, C 1-6 Optionally substituted with one or more alkylamino groups, R 10 and R 11 These are H or C, respectively, independently. 1-6 It is an alkyl group or R 10 and R 11 These, along with the nitrogen atom to which they are linked, form a 3- to 8-membered heterocyclyl group (for example,

[0250] [ka]

[0251] It forms a structure in which the alkyl group and heterocyclyl group are halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6Haloalkyl group, NH2C(=O)-, C 1-6 It is optionally substituted with one or more alkoxy groups, and each time mC appears, it is independently selected from 1, 2, 3, or 4.

[0252] In some embodiments, R0 is H, halogen, NO2, cyano group, NH2C(=O)-, C 1-6 Selected from alkoxy groups, including halogen, hydroxyl, amino, nitro, cyano, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 C is optionally substituted with one or more alkoxy groups. 1-6 Selected from alkyl groups, preferably H, F, Cl, NO2, CH3, CF3, cyano, NH2C(=O)-, C 1-6 Selected from aminoalkyl groups. In some embodiments, R 4C H is H.

[0253] In some embodiments, p is 0, 1, 2, 3, 4, or 5, preferably 0, 1, 2, or 3, and more preferably 0.

[0254] In some embodiments, formula IC is represented by formula IIC-1 or IIC-2.

[0255] [ka]

[0256] In some embodiments, in IIC-1, R 2C C 1-6 It is an aminoalkyl group or an amino group, R 3C is H or C 1-6 It is an alkyl group, and in some embodiments, R 2C is Ami It is a no-group, R 3C H is H.

[0257] In some embodiments, in formula IIC-2, R 2C C 1-6 It is an aminoalkyl group or an amino group, R 3C is H or C 1-6 It is an alkyl group, or R 2C is H or C 1-6 It is an alkyl group, R 3C C 1-6 Aminoalkyl groups or 3-8 member nitrogen-containing heterocyclines It is the basis.

[0258] In some embodiments, formula IC is represented by formula IIIC or formula IVC,

[0259] [ka]

[0260] In some embodiments, the above general formula satisfies one or more of the following terms: (1)R 1C ha-(CH2) t NR aC R bC It is preferably -(CH2)3NH2, (2) Ring A is a phenyl group, (3) p is 0.

[0261] In some embodiments, in the above general formula, G is selected from the following: (1) G is -S (=O) (=NR 6C ')- and, (2) G is -CR 4C R 5C - and R 4C H is R 5C -NR cC C(O)OR dC And, (3) G is -CR 4C R 5C - and R 4C is -NR8R9, and R 5C is -C(O)OR7, where R7 is H, C1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-14 Selected from aryl groups and 5-14 membered heteroaryl groups, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may be halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 Alkoxy R7 is optionally substituted with one or more groups selected from the group, where R7 is preferably H, or a halogen, hydroxyl group, amino group, nitro group, cyano group, or C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, NH2C(=O)-, C 1-6 C is optionally substituted with one or more alkoxy groups. 1-6 It is an alkyl group.

[0262] In some embodiments, formula IC is represented by formula IVC-1, IVC-2, or IVC-3.

[0263] [ka]

[0264] In some embodiments, the compounds of the present disclosure are selected from the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof shown below.

[0265] [ka]

[0266] [ka]

[0267] [ka]

[0268]

change

[0269]

change

[0270]

change

[0271]

change

[0272]

change

[0273]

change

[0274]

change

[0275]

change

[0276]

change

[0277]

change

[0278]

change

[0279] This disclosure further provides intermediates for preparing the above-mentioned compounds of this disclosure, compounds of the following general formulas, stereoisomers thereof, or salts thereof,

[0280] [ka]

[0281] Of these, R0' is R0 or R0 in which NH2 is protected with an amino protecting group, and R 1C ' is R 1C Or R protected by an amino protecting group 1C And R 2C ' is R 2C Alternatively, NH2 is protected by an amino protecting group. R 2C And R 3C ' is R 3C Alternatively, R is a group protected by an amino protecting group, such as NH2 or a cyclic imino group. 3C G' is G or NH2 and / or a cyclic imino group protected with an amino protecting group and / or a carboxyl group protected with a carboxyl protecting group, and ring A, Y, R0, R 1C , R 2C , R 3C , G and p is as previously defined, and Rv is selected from H and carboxyl protecting groups.

[0282] In some embodiments, formula iiC-2-X is,

[0283] [ka]

[0284] Selected from, Of these, Rs and Rt are independently selected from H and an amino protecting group, respectively.

[0285] In some embodiments, the above amino protecting group is independently tert-butoxyca Rubonyl group, 9-Fluorenyl methoxycarbonyl group, Allyloxycarbonyl group, Trichlorooxycarbonyl group, Trimethylsilylethoxycarbonyl group, Benzyloxycarbonyl Bonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, Trifluoroacetyl group, methoxycarbonyl group, tert-butylsulfinyl group, 1-Fe A ylethyl group or an ethoxycarbonyl group is selected.

[0286] In some embodiments, the carboxyl protecting group is independently C 1-6 The group is selected from alkyl groups, allyl groups, benzyl groups, 2,4-dimethoxybenzyl groups, p-methoxybenzyl groups, methoxyethoxymethyl groups, pentafluorophenyl groups, and 4-p-methylbenzyloxy groups.

[0287] Manufacturing method In some embodiments, the compounds shown in the present invention can be prepared by a method selected from the following: Method 1: Method 1 involves a compound represented by formula iC-2 and a compound represented by formula iC-3-a, iC-3-b, or iC-3-c. The process includes the step of condensing the two to produce a compound represented by formula iC-1, and then proceeding to a protecting group removal reaction to produce a compound represented by formula IC,

[0288] [ka]

[0289] Method 2: Method 2 includes the step of condensing the compound represented by formula iiC-2 and the compound represented by formula iiC-3 to produce the compound represented by formula iiC-1, and then producing the compound represented by formula IC through a protecting group removal reaction,

[0290] [ka]

[0291] Preferably, the compound of formula iiC-2 is prepared by a method selected from the following: Method 3: Method 3 involves a condensation reaction between the compound represented by formula iiC-4-a and the compound represented by formula iiC-5-a, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, using formula iiC-2 The step includes obtaining the compound shown,

[0292] [ka]

[0293] Method 4: Method 4 involves a condensation reaction between the compound represented by formula iiC-4-b and the compound represented by formula iiC-5-b, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, with formula iiC-2 The step includes obtaining the compound shown,

[0294] [ka]

[0295] Method 5: Method 5 involves a condensation reaction between the compound represented by formula iiC-4-c and the compound represented by formula iiC-5-c, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, with formula iiC-2 The step includes obtaining the compound shown,

[0296] [ka]

[0297] Method 6: Method 6 involves a condensation reaction between the compound represented by formula iiC-4-d and the compound represented by formula iiC-5-d, followed by hydration. Decomposition reaction, and optionally amino protecting group removal reaction, amino protecting reaction, with formula iiC-2 The step includes obtaining the compound shown,

[0298] [ka]

[0299] Preferably, the above formula iC-2 is

[0300] [ka]

[0301] And, Preferably, the above iiC-2 is

[0302] [ka]

[0303] Selected from, Of these, R0' is R0 or R0 in which NH2 is protected with an amino protecting group, and R 1C 'and R 1C ''teeth , R 1C Or R protected by an amino protecting group 1C And R 2C 'and R 2C '' is R 2C Or R protected by an amino protecting group 2C And R 3C 'and R 3C '' is R 3C Alternatively, R is a group protected by an amino protecting group, such as NH2 or a cyclic imino group. 3C G' is a group of G or NH2 and / or a cyclic imino group that holds an amino acid. G is protected by a protective group and / or the carboxyl group is protected by a carboxyl protecting group, and Rw is a carboxyl protecting group, and rings A, Y, R0, R 1C , R 2C , R 3C G and p are as defined above. Rs, Rt, and Ru are each independently selected from H and an amino protecting group. Preferably, the above amino protecting groups are independently a tert-butoxycarbonyl group and a 9- Fluorenyl methoxycarbonyl group, allyloxycarbonyl group, trichlorooxycarbonyl group, trimethylsilylethoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, p-nitrobenzenesulfonyl group, tert-butyl group, trifluoro Cetyl group, methoxycarbonyl group, tert-butylsulfinyl group, 1-phenylethyl group, Alternatively, selected from ethoxycarbonyl groups, the above carboxy protecting groups are each independently C 1-6 The group is selected from alkyl groups, allyl groups, benzyl groups, 2,4-dimethoxybenzyl groups, p-methoxybenzyl groups, methoxyethoxymethyl groups, pentafluorophenyl groups, and 4-p-methylbenzyloxybenzyl groups.

[0304] In methods 3, 4, 5, and 6 described above, the condensation reaction is iiC-4 (specifically This means that iiC-4-a, iiC-4-b, iiC-4-c, and iiC-4-d) are reacted with iiC-5 (specifically, iiC-5-a, iiC-5-b, iiC-5-c, and iiC-5-d) respectively to form condensation products, and the water content is added. The deconjugation reaction aims to remove the carboxyl protecting group Rw from the condensation product, but requires the addition of water. Depending on the hydrolysis conditions, it may be possible to remove the carboxyl protecting group Rw in the condensation product, as well as some or all of the amino protecting groups (if present) in the condensation product, and the product after the hydrolysis reaction is called the hydrolysis product. In some embodiments, the hydrolysis product is the compound shown in iiC-2. In some embodiments, the hydrolysis The product undergoes further amino protection to obtain the compound shown in formula iiC-2. Several implementations In this state, the hydrolysis product undergoes further amino protecting group removal and amino protecting reactions to obtain the compound represented by formula iiC-2. [Examples]

[0305] The following describes embodiments of the present invention in detail. The embodiments described below are illustrative and are for interpreting the present invention only, and should not be understood as limiting the present invention. Unless otherwise indicated, all proportions, percentages, etc., referred to herein are based on weight.

[0306] Unless otherwise specified, the reagents or equipment used in this application are all commercially available conventional products. Specifically, intermediate 2 (whose structure is shown below) ) was purchased from Hangzhou Taijia Biotech Co., Ltd.

[0307] [ka]

[0308] Furthermore, regarding the purification of the final product, each example mentions "purification by reversed-phase flash chromatography," "purification by preparative HPLC," "purification by reversed-phase column chromatography," "purification by high-performance liquid chromatography," and "purification by reversed-phase column chromatography," respectively, and the mobile phase conditions used for purification were, in some examples, "solvent ACN and Although the solvent is explicitly stated as "H2O(FA, 0.1%)", the same or similar mobile phase stripe is used in other examples. It should be understood that the following conditions are used. Under such chromatographic conditions, some of the compounds in the examples are formed as formate salts. However, those skilled in the art will understand that the compounds can be formed in their free state under conventional neutralization reaction conditions of the art.

[0309] Abbreviation: ACN: Acetonitrile BTC: (Trichloromethyl) Carbonate CDI: N,N-carbonyldiimidazole DCM: Dichloromethane DIEA: Diethylamine DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: Dimethylformamide HATU:2-(7-azabenzotriazazole)-N,N,N',N'-tetramethyluronium hexa Fluorophosphate HOBT: 1-hydroxybenzotriazole TBTU:O-benzotriazazole-N,N,N',N'-tetramethyluroniumtetrafluorob rate TEA: Triethylamine TFA: Trifluoroacetic acid TFE: 2,2,2-trifluoroethanol THF: Tetrahydrofuran

[0310] Example 1 Synthesis of Compound 1

[0311] [ka]

[0312] 1.1 Synthesis of Compound 1-1 At room temperature, dissolve 4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate ethyl hydrochloride (3.7 g, 12.552 mmol, 1.00 equiv) in DMF (37 mL) and prepare DIEA (4.87 g, 37.656 (5.73 g, 15.062 mmol, 1.2 equiv) (2R)-2-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid (5.73 g, 15.062 mmol, 1.2 equiv) and HATU (5.73 g, 15.062 mmol, 1.2 equiv) were added, respectively. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with dichloromethane (2 × 200 mL). The combined organic layer was then bran. Washed with 2 x 300 mL of water and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane and methanol (20:1) to obtain a grayish-white solid: 1-[(2R)-2-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate methyl (8.97 g, 94.63%, purity 82.0%). This was obtained. LC-MS-1-1(ES, m / z): [M+1]=621

[0313] 1.2 Synthesis of Compounds 1-3 (2R)-2-amino-4-methylpentanoate hydrochloride (5 g, 22.347 mmol, 1.00 equiv) and DIEA (8.66 g, 67.041 mmol, 3 equiv) were dissolved in DMF (50.00 mL, 646.052 mmol, 28.91 equiv) to obtain (2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanoic acid (10.39 g, 26.816 mmol, 1.2 equiv) and HATU (10.20 g, 26.816 mmol). , 1.2 equiv) was added. The resulting mixture was stirred overnight at room temperature. The resulting mixture was then mixed with acetic acid. Extraction was performed with ethyl acetate (1 × 500 mL). The combined organic layers were washed with brine (5 × 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (4:1) to obtain a white solid. The compound (2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamide]-4-methylpentanoate (13.94 g, 97.60%, purity 87.0%) Obtained. LC-MS-1-3 (ES, m / z): [M+1]=557

[0314] 1.3 Synthesis of Compounds 1-2 1-[(2R)-2-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl [(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-car Methyl phosphate (8.97 g, 14.450 mmol, 1.00 equiv) was dissolved in methanol (162.35 mL), and Pd / C (922.69 mg, w / t, 10%) was added. The resulting mixture was left overnight at room temperature under a hydrogen atmosphere. The mixture was stirred. The resulting mixture was filtered, and the filter cake was washed with methanol (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to obtain 1-[(2R)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate methyl (5.65 g, 76.53%, purity 95.0%). This was obtained. LC-MS-1-2(ES, m / z): [M+1]=487

[0315] 1.4 Synthesis of Compounds 1-4 (2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamide]-4-methylpentanoate (13.94 g, 25.040 mmol) in DCM (100 mL) Dissolve (1573.005 mmol, 62.82 equiv.) in the solution and add TFA (1.00 mL, 1346.304 mmol, 53.77 equiv.). Stir the resulting mixture overnight at room temperature. Concentrate the resulting mixture under reduced pressure. Recrystallize the crude product from water with dichloromethane / 1M hydrochloric acid, wash with 1 × 400 mL of water, and filter. Then, collect the solid and (2R)-2-[(2R)-2-{[(9H-fluorene-9-ylmethoxy)carbon [Amino-3-phenylpropanamide]-4-methylpentanoic acid (9.43 g, 74.48%, purity 98.8%) was obtained. LC-MS-1-4(ES, m / z): [M+1]=501

[0316] 1.5 Synthesis of Compounds 1-5 (2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamide]-4-methylpentanoic acid (4.78 g, 9.539 mmol, 1.1 equiv) and DIEA Dissolve (3.36 g, 26.016 mmol, 3 equiv) in DMF (40 mL, 516.870 mmol, 59.60 equiv). Then, 1-[(2R)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate methyl (4.22 g, 8.672 mmol, 1.00 equiv) and HATU (3.96 g, 10.406 mmol, 1.2 equiv) were added. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with ethyl acetate (1 × 400 mL). The organic layer was washed with brine (3 x 200 mL) and dried with anhydrous sodium sulfate. After filtration, The filtrate was concentrated under reduced pressure. The residue was eluted with petroleum ether / ethyl acetate (1:2) silica gel. The solution was purified by Lamb chromatography, fractional distillation, and rotational drying to obtain 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]]-2-[(2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-carboxylate methyl (8.39 g, 98.12%, purity 98.3%). LC-MS-1-5(ES, m / z): [M+1]=969

[0317] 1.6 Synthesis of Compounds 1-6 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2]-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4- Methyl carboxylate (8.93 g, 9.214 mmol, 1.00 equiv) was dissolved in DCM (80 mL), and piperidine (8.90 mL, 104.487 mmol, 11.34 equiv) was added in several portions. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was subjected to reverse-phase flash chromatography. Purified by tography, 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpro [Panamide]-4-methylpentanamide]-6-[(tert-butoxycarbonyl)amino]hexa [Noyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate methyl (5.74 A sample with a purity of 97.0% was obtained. LC-MS-1-6(ES, m / z): [M+1]=747

[0318] 1.7 Synthesis of Compounds 1-7 Carbonylimidazole (47.76 mg, 0.295 mmol, 1.1 equiv) in N,N-dimethylform Dissolve in amide (1.60 mL) and stir while 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamide]-4-methylpentanamide]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylic acid] Methyl (200 mg, 0.268 mmol, 1.00 equiv), N-methylbenzylamine (32.45 mg, 0.268 mmol, 1 equiv), and triethylamine (54.19 mg, 0.536 mmol, 2 equiv) were added. The resulting mixture was stirred overnight at room temperature. It was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography, fractional distillation, and rotational drying to obtain 1-[(2R)-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3-phenylpropanamide]-4-methylpentaneamide [d]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbon [Nyl]amino]piperidine-4-carboxylate methyl (136 mg, 55.67%, purity 66.7%) was obtained. Ta. LC-MS-1-7(ES, m / z): [M+1]=894

[0319] 1.8 Synthesis of Compounds 1-8 1-[(2R)-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3-fu [Phenylpropanamide]-4-methylpentanamide]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylic acid Chill (136 mg, 0.152 mmol, 1.00 equiv) was dissolved in dioxane (10.00 mL), and a 1,4-dioxane solution (15.0 mL) of 4 M HCl (gas) at room temperature was added in several portions. The resulting mixture The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-carboxylate methyl (115 mg, Crude product was obtained. LC-MS-1-8(ES, m / z): [M+1]=694

[0320] 1.9 Synthesis of Compound 1 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]pipe Methyl lysine-4-carboxylate (115 mg, 0.166 mmol, 1.00 equiv) mixed with THF (10 mL) Dissolve in water (2 mL) and add LiOH.H2O (13.933 mg, 0.332 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then acidified to pH=7 with 1 M HCl (aqueous solution). The resulting mixture was purified by reverse-phase flash chromatography, and 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3- [Phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-carb 60.0 mg of nitrate (49.23%, purity 95.2%) was obtained. LC-MS-1 (ES, m / z): [M+1]=680 1H NMR-1 (400 MHz, Deuterium Oxide) δ8.38(s, 1H), 7.36 - 7.22 (m, 6H), 7.18 (dd, J = 7.6, 2.0 Hz, 2H), 7.03 - 6.95 (m, 2H), 4.76 - 4.72 (m, 1H), 4.50 (ddd,J = 9.0, 5.7, 3.0 Hz, 1H), 4.43 (d, J = 16.5 Hz, 1H), 4.38 - 4.25 (m, 2H), 3.88 - 3.47 (m, 4H), 3.11 (dd, J = 13.9, 5.8 Hz, 1H), 2.97 - 2.85 (m, 3H), 2.77 (d, J= 2.9 Hz, 3H), 2.27 - 2.06 (m, 2H), 1.93 - 1.42 (m, 9H), 1.42 - 1.23 (m, 2H), 0.92 - 0.77 (m, 6H).

[0321] Example 2 Synthesis of Compound 2

[0322]

change

[0323] LC-MS-2-0(ES, m / z):[M+1]=710 1 H NMR (400 MHz, Deuterium Oxide) δ 8.30 (s, 1H), 7.51 - 7.20 (m, 8H), 7.18 - 6.96 (m, 2H), 5.52 (ddd, J = 19.0, 10.7, 4.7 Hz, 1H), 4.45 (dt, J= 8.9, 6.2 Hz, 1H), 4.30 (p, J = 4.7 Hz, 1H), 3.75 (dp, J = 18.4, 6.9 Hz, 2H), 3.68 - 3.38 (m, 4H), 3.10 (ddd, J = 14.6, 9.2, 6.3 Hz, 1H), 2.97 (dt, J = 13.9, 10.1 Hz, 1H), 2.87 (q, J = 7.8 Hz, 2H), 2.53 (d, J = 5.4 Hz, 3H), 2.30 - 2.05 (m, 2H), 1.96 - 1.43 (m, 9H), 1.32 (d, J= 20.6 Hz, 2H), 0.85 (dd, J = 16.8, 5.6 Hz, 6H).

[0324] LC-MS-2-100(ES, m / z):[M+1]=710 1 H NMR (400 MHz, Deuterium Oxide) δ8.35 (s, 2H), 7.50 - 7.10 (m, 8H), 7.03 - 6.72 (m, 2H), 5.53 (dd, J = 11.1, 4.2 Hz, 1H), 4.86 - 4.74 (m, 1H), 4.72 - 4.59 (m, 1H), 4.35 (dt, J= 9.3, 5.2 Hz, 1H), 4.06 - 3.66 (m, 3H), 3.68 - 3.37 (m, 3H), 3.34 - 3.14 (m, 1H), 3.07 - 2.73 (m, 3H), 2.43 (d, J = 6.2 Hz, 3H), 2.31 - 2.01 (m, 2H), 1.97 - 1.21 (m, 11H), 0.85 (dd, J = 16.8, 5.6 Hz, 6H).

[0325] Example 3 Synthesis of Compound 3

[0326]

change

[0327] LC-MS-3 (ES, m / z): [M+1]=681 1H NMR-3 (400 MHz, Deuterium Oxide) δ8.34 (s, 2H), 7.34 - 7.19 (m, 6H), 7.11 (dt, J = 7.3, 2.2 Hz, 2H), 7.09 - 7.01 (m, 2H), 4.53 (td, J = 6.9, 6.1, 3.1 Hz, 1H), 4.33 (ddd, J= 7.0, 4.9, 1.9 Hz, 1H), 4.30 - 4.21 (m, 1H), 3.88 - 3.46 (m, 4 H), 3.01 - 2.82 (m, 5H), 2.75 (ddd, J = 14.1, 7.1, 4.5 Hz, 1H), 2.28 - 2.04 (m, 2H), 1.95 - 1.55 (m, 6H), 1.57 - 1.26 (m, 5H), 0.82 (dd, J = 19.0, 5.2 Hz, 6H).

[0328] Example 4 Synthesis of Compound 4

[0329] [ka]

[0330] 4.1 Synthesis of Compound 4-1 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamide]-4-methylphenyl [Tanamide]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxy [Cicarbonyl)amino]piperidine-4-carboxylate methyl (120 mg, 0.161 mmol, 1.00 equiv) was dissolved in DMF (7 mL), and 3-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid (51.15 mg, 0.193 mmol, 1.2 equiv), HATU (73.30 mg, 0.193 mmol, 1.2 equiv), and DIEA (62.29 mg, 0.483 mmol, 3 equiv) were added. The resulting mixture was stirred overnight. Then, it was diluted with water (30 mL) and extracted with EA (3 × 20 mL). The combined organic layers were then subjected to anhydrous sulfur. Dried with sodium acid. Concentrated under reduced pressure to 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-{3-[(tert-but [Xycarbonyl]amino]-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-carboxylate methyl (256 mg, crude product) ) was obtained. LC-MS-4-1(ES, m / z): [M+1] =994

[0331] 4.2 Synthesis of Compound 4-2 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-{3-[(tert-butoxycarbonyl)amino]-3-phenyl [Propanamide]-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-carboxylate methyl (265 mg, 0.267 mmol, 1.00 equiv) was dissolved in dioxane (5.3 mL), and a solution of 1,4-dioxane in 4 M HCl (gas) at room temperature (8 mL) was added. The mixture was stirred at room temperature for 2 hours. It was then concentrated under reduced pressure. 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-(3-amino-3-phenylpropanamide)-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-carboxylate methyl (101 mg, crude product) was obtained. LC-MS-4-2(ES, m / z): [M+1] =694

[0332] 4.3 Synthesis of Compound 4-0 / 100 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-(3-amino-3-phenylpropane [Phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piper Methyl din-4-carboxylate (80 mg, 0.115 mmol, 1.00 equiv) was dissolved in THF (3 mL), and H2O (0.8 mL, 44.4075.15 mmol) and LiOH (5.52 mg, 0.230 mmol, 2 equiv) were added. The mixture was stirred at room temperature for 4 hours. The mixture was acidified to pH 7 with HCl (1 N). The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography. Fractional distillation and rotational drying yielded 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-((3R)-3-amino-3-phenylpropanamide)-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidi n-4-carboxylic acid (11 mg, 13.43%, purity 95.3%) and 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-[(3S)-3-amino-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-carboxylic acid (11 mg, 13.74%, purity 97.5%) were obtained.

[0333] LC-MS-4-0(ES, m / z): [M+1] =680 Compound 4-0: 1 H NMR (300 MHz, Deuterium Oxide) δ8.34 (s, 2H), 7.22 (t, J = 41.9 Hz, 10H), 4.27 (d, J = 80.8 Hz, 4H), 3.64 (d, J = 47.2 Hz, 4H), 2.89 (s, 6H), 2.13 (s, 2H), 1.90 - 1.48 (m, 6H), 1.37 (s, 5H), 0.76 (d, J = 20.6 Hz, 6H).

[0334] LC-MS-4-100(ES, m / z): [M+1] =680 Compound 4-100: 1 H NMR (300 MHz, Deuterium Oxide) δ8.34 (s, 2H), 7.50 - 6.77 (m, 10H), 4.59 - 4.16 (m, 4H), 3.67 (d, J = 40.1 Hz, 4H), 3.05 - 2.62 (m, 6H), 2.12 (d, J = 27.4 Hz, 2H), 1.96 - 1.52 (m, 6H), 1.54 - 1.16 (m, 5H), 0.93 - 0.66 (m, 6H).

[0335] Example 5 Synthesis of Compound 5

[0336]

change

[0337] LC-MS-5-0(ES, m / z): [M+1] =680 Compound 5-0: 1 H NMR (300 MHz, Deuterium Oxide) δ8.37 (s, 1H), 7.37 - 7.08 (m, 10H), 4.90 (t, J = 7.1 Hz, 1H), 4.48 - 4.39 (m, 2H), 4.20 (t, J = 7.3 Hz, 1H), 3.86 - 3.45 (m, 4H), 3.06 - 2.78 (m, 4H), 2.78 - 2.50 (m, 2H), 2.26 - 2.02 (m, 2H), 1.93 - 1.53 (m, 6H), 1.51 - 1.19 (m, 5H), 0.80 (dd, J = 17.5, 5.1 Hz, 6H).

[0338] LC-MS-5-100(ES, m / z): [M+1] =680 Compound 5-100: 1H NMR (300 MHz, Deuterium Oxide) δ7.39 - 7.01 (m, 10H), 4.94 (t, J = 7.1 Hz, 1H), 4.44 (t, J = 7.4 Hz, 2H), 4.24 (d, J = 8.8 Hz, 1H), 3.66 (d, J = 58.6 Hz, 4H), 2.99 - 2.56 (m, 6H), 2.14 (d, J = 20.9 Hz, 2H), 1.92 - 1.55 (m, 6H), 1.40 (d, J = 33.6 Hz, 5H), 0.81 (dd, J = 15.7, 4.9 Hz, 6H).

[0339] Example 6 Synthesis of Compound 6

[0340]

change

[0341] LC-MS-6-0(ES, m / z):[M+1]=734 1 H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H), 7.48 - 6.81 (m, 10H), 4.66 - 4.48 (m, 1H), 4.06 (q, J = 6.6, 5.5 Hz, 1H), 3.91 - 3.44 (m, 6H), 3.25 (dd, J = 13.1, 4.9 Hz, 1H), 3.16 - 2.48 (m, 9H), 2.35 - 1.97 (m, 2H), 1.98 - 1.18 (m, 15H), 0.91 (dd, J= 18.5, 5.3 Hz, 6H).

[0342] LC-MS-6-100(ES, m / z):[M+1]=734 1H NMR (400 MHz, Deuterium Oxide) δ8.38 (s, 3H), 7.45 - 6.86 (m, 10H), 4.68 - 4.57 (m, 1H), 4.10 (d, J = 2.8 Hz, 1H), 3.96 - 3.42 (m, 5H), 3.42 - 3.17 (m, 1H), 3.02 (dt, J = 12.5, 5.7 Hz, 1H), 2.97 - 2.77 (m, 4H), 2.71 - 2.48 (m, 1H), 2.14 (dd, J= 27.5, 13.5 Hz, 2H), 2.02 - 1.49 (m, 13H), 1.39 - 1.23 (m, 2H), 1.08 - 0.79 (m, 6H).

[0343] Example 7 Synthesis of Compound 7

[0344]

change

[0345] LC-MS-7(ES, m / z): [M+1]=695 1 H NMR (400 MHz, Deuterium Oxide) δ8.35 (s, 2H), 7.53 - 6.99 (m, 9H), 4.39 (ddd, J = 8.8, 5.6, 3.0 Hz, 1H), 4.32 - 3.97 (m, 5H), 3.94 - 3.63 (m, 2H), 3.58 - 3.29 (m, 2H), 3.04 (dt, J= 13.9, 5.1 Hz, 1H), 2.93 - 2.63 (m, 3H), 2.39 - 1.92 (m, 2H), 1.97 - 1.18 (m, 11H), 0.79 (dd, J = 19.1, 5.4 Hz, 6H).

[0346] Example 8 Synthesis of Compound 8

[0347]

change

[0348] 8.1 Synthesis of Compound 8-1 (2R)-2-amino-3-phenylpropionate tert-butyl (480 mg, 2.169 mmol, 1.00 equiv) and triethylamine (1.85 g, 18.282 mmol, 8.43 equiv) are dissolved in acetonitrile (19 Dissolve in mL, 361.469 mmol, 166.65 equiv) and stir at 0°C for 30 min under a nitrogen atmosphere. To the above mixture, add N,N'-carbonyldiimidazole (1.2 g, 7.401 mmol, 3.41 equiv) and 2,2,2-trifluoro-N-[2-(methylamino)-2-phenylethyl]acetamide (12.80 g, 51.991 mmol, 23.97 equiv). Stir the resulting mixture overnight at room temperature under a nitrogen atmosphere. The solution was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography, fractional distillation, and tumble drying to obtain (2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanoate (855 mg, 79.87%, purity 100%). Obtained. LC-MS-8-1(ES, m / z):[M+1]=494

[0349] 8.2 Synthesis of Compound 8-2 tert-butyl(2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamide) Ethyl]carbamoyl}amino)-3-phenylpropionate tert-butyl (67 mg, 0.136 mmol, 1 equiv) was dissolved in dichloromethane (7.70 mL), and trifluoroacetic acid (7.70 mL, 78.592 mmol, 45.09 equiv) was added dropwise. The resulting mixture was stirred in air for 3 hours. The mixture was concentrated under reduced pressure to obtain (2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanoic acid (600 mg, crude product). The crude product mixture was obtained and used directly in the next step without further purification. LC-MS-8-2(ES, m / z):[M+1]=438

[0350] 8.3 Synthesis of Compound 8-3 At room temperature, {4-[(4-methylphenyl)methoxy]phenyl}methyl(2R)-2-[(2R)-2-amine [no-4-methylpentanamide]-6-[(tert-butoxycarbonyl)amino]hexanoate (1445.79 mg, 2.538 mmol, 3 equiv), (2R)-2-({methyl[1-phenyl-2-(2,2,2-tri Fluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanoic acid (2600 mg, 5.944 mmol, 9.15 equiv) and HOBT (222 mg, 1.643 mmol, 2.53 equiv) were dissolved in DMF (50 mL, 64.609 mmol, 99.49 equiv), and TBTU (528 mg, 1.644 mmol) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and {4-[(4-methylphenyl)methoxy]phenylpropanoic acid was prepared. Nylmethyl(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-4-methyl-2-[(2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamide)ethyl]carbamyl] Il-amino)-3-phenylpropionamide]pentanamide]hexanoate (2.6 g, Crude product was obtained.

[0351] 8.4 Synthesis of Compound 8-4 At room temperature, {4-[(4-methylphenyl)methoxy]phenyl}methyl(2R)-6-[(tert-butoxy] [(2R)-4-methyl-2-[(2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamide)ethyl]carbamoyl}amino)-3-phenylpropion [Amide]pentanamide]hexanoate (2.8 g, 3.150 mmol, 1 equiv) was dissolved in DCM (20 mL), and trifluoroacetic acid (10 mL) was added. The resulting mixture was left at room temperature under an air atmosphere. The mixture was stirred for 2 hours to obtain (2R)-6-amino-2-[(2R)-4-methyl-2-[(2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanamide]pentanamide]hexanoic acid (470 mg, crude product). LC-MS-8-4(ES, m / z):[M+1]=679

[0352] 8.5 Synthesis of Compound 8-5 (2R)-6-amino-2-[(2R)-4-methyl-2[(2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanamide]pentanamide]hexanoic acid (470 mg, 0.692 mmol, 1 equiv), H2O (10 mL), and lithium hydroxide (33.17 mg, 1.384 mmol, 2 equiv) were added to a 50 mL round-bottom flask at room temperature. The mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure to obtain (2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-amino-1-phenylethyl)(methyl)carbamoyl]amine [-3-phenylpropanamide]-4-methylpentanamide]hexanoic acid (500 mg, crude product) (The object) was obtained. LC-MS-8-5(ES, m / z):[M+1]=583

[0353] 8.6 Synthesis of Compound 8-6 (2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-amino-1-phenylethyl)(methyl Carbamoyl]amino}-3-phenylpropanamide]-4-methylpentanamide]hexanoic acid (350 mg, 0.601 mmol, 1 equiv) and TEA (182.33 mg, 1.803 mmol, 3 equiv) are used in THF It was dissolved in (10 mL) and di-tert-butyl dicarbonate (262.1202 mg, 1 equiv) was added. The mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography, and (2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]]-1-phenylethyl}(methyl )Carbamoyl)amino]-3-phenylpropanamide]-4-methylpentanamide]hexa 260 mg of nitrate (55.29%, 100% purity) was obtained. LC-MS-8-6(ES, m / z):[M+1]=783

[0354] 8.7 Synthesis of Compound 8-7 (2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamide]-4-methylpentanamide]hexanoic acid (60 mg, 0.077 mmol, 1 equiv), 3-methyl-1-(piperidine-4-yl)urea (24.10 mg), and TEA (23.26 mg, 0.231 mmol, 3 equiv) were dissolved in DMF (5 mL, 64.609 mmol, 843.12 equiv) at room temperature and under nitrogen. Then, HATU (43.71 mg, 0.115 mmol, 3 equiv) was added. The resulting mixture was left at room temperature and under nitrogen. The mixture was stirred overnight under atmospheric conditions. The resulting mixture was purified by reverse-phase flash chromatography and obtained N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl)}(methyl)carbamoyl)amino]-3-phenylpropanamide]-4- Methylpentanamide]-6-{4-[(methylcarbamoyl)amino]piperidine-1-yl}-6-oxohexyl]carbamate tert-butyl (62 mg, 87.74%, purity 100%) was obtained. LC-MS-8-7(ES, m / z):[M+1]=922

[0355] 8.8 Synthesis of Compound 8 N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamide]-4-methyl [Pentanamide]-6-{4-[(methylcarbamoyl)amino]piperidine-1-yl}-6-oxohexyl]carbamate tert-butyl (62 mg, 0.067 mmol, 1 equiv) to dioxane (10 mL) The mixture was dissolved in HCl (gas) and 5 mL of 1,4-dioxane solution was added. The resulting mixture was heated in a chamber. The mixture was stirred at warm temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and subjected to reverse-phase flash chromatography. Purified by (2R)-2-[(2R)-2-{[(2-amino-1-phenylethyl)(methyl)carbamoyl)amino}-3-phenylpropanamide]-N-[(2R)-6-amino-1-{4-[(methyl car Bamoyl)amino]piperidine-1-yl}-1-oxohexyl-2-yl]-4-methylpentane Mid was obtained (13.6 mg, 26.73%, purity 95.0%). LC-MS-8(ES, m / z):[M+1]=722 1H NMR (400 MHz, Deuterium Oxide) δ8.33 (s, 2H), 7.50 - 7.15 (m, 8H), 7.10 (d, J = 7.2 Hz, 2H), 5.49 (dd, J= 10.8, 5.2 Hz, 1H), 4.42 (dd, J = 9.1, 6.2 Hz, 1H), 4.37 - 4.25 (m, 1H), 4.24 - 4.00 (m, 1H), 3.95 - 3.40 (m, 7H), 3.26 - 3.02 (m, 2H), 2.99 - 2.69 (m, 4H), 2.70 - 2.42 (m, 6H), 2.02 - 1.75 (m, 6H), 1.73 - 1.43 (m, 4H), 1.42 - 1.13 (m, 7H), 0.80 (ddd, J = 15.3, 6.0, 2.9 Hz, 6H).

[0356] Example 9 Synthesis of Compound 9

[0357]

change

[0358] LC-MS-9(ES, m / z): [M+1]=671.20 1 H NMR (300 MHz, Deuterium Oxide) δ8.37 (s, 1H), 7.43 - 6.81 (m, 10H), 4.49 (s, 2H), 4.46 - 3.55 (m, 6H), 3.60 - 2.94 (m, 5H), 3.03 - 2.52 (m, 6H), 1.83 - 1.10 (m, 9H), 0.78 (dd, J = 14.0, 5.0 Hz, 6H).

[0359] Example 10 Synthesis of Compound 10

[0360]

change

[0361] LC-MS-10(ES, m / z):[M+1]=699.20 1 H NMR (300 MHz, Deuterium Oxide) δ 7.42 - 6.89 (m, 10H), 5.51 (dd, J= 10.6, 4.8 Hz, 1H), 4.43 (dd, J = 9.0, 6.3 Hz, 1H), 4.34 - 4.12 (m, 2H), 4.10 - 3.71 (m, 2H), 3.65 - 3.44 (m, 3H), 3.32 (d, J = 19.3 Hz, 2H), 3.18 (d, J = 17.1 Hz, 2H), 3.09 (dd, J = 13.8, 6.1 Hz, 1H), 3.00 - 2.93 (m, 1H), 2.85 (t, J = 7.6 Hz, 2H), 2.57 (d, J = 31.2 Hz, 4H), 1.82 - 1.43 (m, 7H), 1.42 - 1.16 (m, 2H), 0.82 (dd, J = 12.3, 5.0 Hz, 6H).

[0362] Example 11 Synthesis of Compound 11

[0363]

change

[0364] LC-MS-11(ES, m / z):[M+1]=695 1H NMR (400 MHz, Deuterium Oxide) δ8.39 (s, 1H), 7.40 - 7.19 (m, 6H), 7.08 (ddt, J = 27.2, 5.4, 1.7 Hz, 4H), 4.59 - 4.47 (m, 1H), 4.30 (ddd, J = 28.1, 8.0, 5.5 Hz, 2H), 4.14 (dd, J = 47.0, 13.4 Hz, 1H), 3.88 (dd, J = 36.1, 13.4 Hz, 1H), 3.70 - 3.50 (m, 4H), 3.24 (q, J = 13.9, 12.7Hz, 1H), 2.99 - 2.70 (m, 7H), 2.01 - 1.80 (m, 2H), 1.76 - 1.55 (m, 4H), 1.48 (q, J = 9.6, 8.5 Hz, 3H), 1.41 - 1.17 (m, 4H), 0.83 (ddd, J = 16.8, 5.1, 2.1Hz, 6H).

[0365] Example 12 Synthesis of Compound 12

[0366] [ka]

[0367] 12.1 Synthesis of Compound 12-1 4-aminopiperidine-1-carboxylate tert-butyl (500 mg, 2.496 mmol, 1 equiv) was dissolved in DCM, and TEA (505.25 mg, 4.992 mmol, 2 equiv) was added. Methyl chloroformate (353.84 mg, 3.744 mmol, 1.5 equiv) was added in multiple portions at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (5:1), followed by fractional distillation and fractional distillation. The mixture was then dried to obtain 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate tert-butyl (522 mg, 80.94%, purity 100%). LC-MS-12-1(ES, m / z):[M+1]=259.32

[0368] 12.2 Synthesis of Compound 12-2 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate tert-butyl (552) at room temperature (mg, 2.137 mmol, 1 equiv) was added to a solution of 1,4-dioxane (5 mL) in 4 M HCl (gas). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at room temperature. The mixture was concentrated under reduced pressure. N-(piperidine-4-yl)carbamate methyl ester (455 mg, crude product) was obtained. The crude product was used directly in the next step without further purification. LC-MS-12-2(ES, m / z): [M+1]=159.20

[0369] 12.3 Synthesis of Compound 12-3 (2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamide]-4-methylpentanamide]hexanoic acid (70 mg, 0.089 mmol, 1 equiv), TEA (27.14 mg, 0.267 mmol, 3 equiv), and N-(piperidine-4-yl)carbamate methyl ester (21.22 mg, 0.134 mmol, 1.5 equiv) were added to DMF (1 mL) at room temperature. And HATU (50.99 mg, 0.134 mmol, 1.5 equiv) was added in multiple doses under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was quenched with water at room temperature. LC-MS was used. , the desired product could be detected. The reaction solution was purified by reverse-phase flash chromatography, and tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamide]-4-methylpentanamide]-6-{4-[(methoxycarbonyl)amino]piperidin-1-yl}-6- oxohexyl]carbamate (70 mg, 83.00%, purity 100%) was obtained. LC-MS-12-3(ES, m / z): [M+1]= 924.1

[0370] 12.4 Synthesis of Compound 12 Under room temperature and nitrogen atmosphere, tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpro panamide]-4-methylpentanamide]-6-{4-[(methoxycarbonyl)amino]piper idin-1-yl}-6-oxohexyl]carbamate (70 mg, 0.076 mmol, 1 equiv) was added to DCM (4 mL), and TFA (1 mL) was added dropwise. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography, fractionated, and rotary dried to obtain methyl N-{1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-amino-1-phenylethyl)(methyl)carbamoyl]amino}-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidin-4-yl}carbamate (42.1 mg, 72.07%, purity 93.9%). LC-MS-12(ES, m / z):[M+1]=723.15 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H), 7.58 - 6.75 (m, 10H), 5.52 (s, 1H), 4.79 - 4.73 (m, 1H), 4.50 - 3.99 (m, 3H), 3.87 (d, J = 32.6 Hz, 1H), 3.57 (s, 6 H), 3.35 - 3.03 (m, 2H), 3.02 - 2.68 (m, 4H), 2.48 (dd, J = 39.8, 5.2 Hz, 3H), 1.90 (s, 2H), 1.74 - 1.07 (m, 11H), 1.01 - 0.61 (m, 6H).

[0371] Example 13 Synthesis of Compound 13

[0372] [ka]

[0373] 13.1 Synthesis of Compound 13-1 At room temperature and under a nitrogen atmosphere, tert-butyl N-[2-(benzylamino)ethyl]carbamate (100 mg, 0.399 mmol, 2.98 equiv), TEA (40.64 mg, 0.402 mmol, 3 equiv), and N,N'-carbonyldiimidazole (23.88 mg, 0.147 mmol) were mixed in an ACN (3 mL) / DMF (3 mL) solution and 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamide]-4-methylpenta [(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxy [Carbonyl)amino]piperidine-4-carboxylate methyl ester (100 mg, 0.134 mmol, 1.00 equiv) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was purified by reverse-phase flash chromatography, fractionated and rotated dry to obtain methyl 1-[(2R)-2-[(2R)-2-[(2R)-2-{[benzyl({2-[(tert-butoxycarbonyl)amino] [N]ethyl]carbamoyl]amino]-3-phenylpropanamide]-4-methylpentaneamide [d]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbon Ethyl (nyl)amino]piperidine-4-carboxylate (120 mg, 87.59%, purity 100%) was obtained. LC-MS-13-1(ES, m / z):[M+1]=1024.28

[0374] 13.2 Synthesis of Compound 13-2 1-[(2R)-2-[(2R)-2-[(2R)-2-{[benzyl({2-[(tert-butoxycarbonyl)a [Mino]ethyl)carbamoyl]amino}-3-phenylpropanamide]-4-methylpentane Mido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl] Ethyl vonyl)amino]piperidine-4-carboxylate (120 mg, 0.117 mmol, 1 equiv) was dissolved in DCM (1 mL, 5.612 mmol), and TFA (1 mL) was added. The solution was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography and obtained 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-aminoethyl)(benzyl)carbamoyl]amino}-3-phenylpropanamide]-4-methylphenyl [Tanamide]hexanoyl]piperidine-4-carboxylate methyl (75 mg, 88.47%, purity 100%) was obtained. LC-MS-13-2(ES, m / z): [M+1]=723.93 1 H NMR (400 MHz, Deuterium Oxide) δ7.46 - 7.09 (m, 6H), 6.97 (dt, J = 14.3, 5.4 Hz, 4H), 4.52 - 4.36 (m, 2H), 4.31 (d, J = 17.5 Hz, 1H), 4.19 (p, J = 4.9, 4.1 Hz, 1H), 4.07 (d, J = 14.1 Hz, 1H), 3.92 (d, J = 14.4 Hz, 1H), 3.73 (dt, J= 12.4, 2.2 Hz, 3H), 3.64 (s, 1H), 3.60 - 3.31 (m, 3H), 3.30 - 3.16 (m, 1H), 3.10 - 2.89 (m,3H), 2.87 - 2.57 (m, 3H), 2.36 - 2.06 (m, 2H), 1.93-1.47 (m, 6H), 1.48 - 1.18 (m, 5H), 0.92 - 0.40 (m, 6H).

[0375] 13.3 Synthesis of Compound 13 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-aminoethyl)(benzyl)carbamoyl]amino}-3-phenylpropanamide]-4-methylpentanamide]hexa Noyl]piperidine-4-carboxylate ethyl (75 mg, 0.104 mmol, 1 equiv) in THF (1 mL) It was dissolved in H2O (1 mL), and lithium hydroxide (5 mg, 0.209 mmol, 2.01 equiv) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The residue was obtained by concentrating under reduced pressure. The residue was purified by reverse-phase flash chromatography, fractional distillation and rotary drying to obtain 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(aminoethyl)(benzyl)carbamoyl]]amino}-3-phenylpropanamide]-4-methylpentanamide]hexano Il]piperidine-4-carboxylic acid (25.5 mg, 29.28%, purity 84.5%) was obtained. LC-MS-13(ES, m / z):[M+1]=709.25 1 H NMR (300 MHz, Deuterium Oxide) δ8.33 (s, 2H), 7.33 - 7.15 (m, 6H), 7.00 (ddt, J = 12.9, 5.2, 2.6 Hz, 4H), 4.46 - 4.21 (m, 4H), 3.76 - 3.36 (m, 6H), 3.13 - 2.51 (m, 6H), 2.25 - 1.88 (m, 2H), 1.96 - 1.49 (m, 6H), 1.50 - 1.10 (m, 5H), 0.78 (dd, J = 14.4, 5.4 Hz, 6H).

[0376] Example 14 Synthesis of Compound 14

[0377] [ka]

[0378] LC-MS-14(ES, m / z):[M+1]=723.25 1H NMR (300 MHz, Deuterium Oxide) δ8.33(s, 3H), 7.45 - 6.79 (m, 10H), 5.62 - 5.41 (m, 1H), 4.49 - 4.19 (m, 2H), 4.05 - 3.35 (m, 8H), 3.35 - 2.59 (m, 5H), 2.45 (dd, J = 30.9, 2.3 Hz, 3H), 2.20 (t, J = 16.0 Hz, 2H), 2.00 - 1.10 (m, 11H), 0.81 (dt, J= 11.9, 5.9 Hz, 6H).

[0379] Example 15 Synthesis of Compound 15

[0380]

change

[0381] LC-MS-15 (ES, m / z): [M+1]=751 1 H NMR (400 MHz, Deuterium Oxide) δ8.32 (s, 2H), 7.52 - 6.72 (m, 10H), 5.70 - 5.31 (m, 2H), 4.48 - 4.09 (m, 3H), 4.11 - 3.34 (m, 7H), 3.29 - 3.14 (m, 1H), 3. 14 - 2.68 (m, 5H), 2.49 (d, J= 5.1 Hz, 2H), 2.44 - 2.28 (m, 1H), 2.17 (d, J = 18.8 Hz, 2H), 1.93 - 1.34 (m, 10H), 1.20 (dd, J = 9.0, 6.3 Hz, 8H), 1.00 - 0.59 (m, 6H).

[0382] Example 16 Synthesis of Compound 16

[0383]

change

[0384] 16.1 Synthesis of Compound 16-1 Compounds 1-3 (500 mg, 0.898 mmol, 1 equiv) were dissolved in DCM (5 mL), and then piperidine was added. (0.5 mL) was added dropwise to the above reaction system and stirred at room temperature for 3 hours. Then the reaction solution was rotated dry. A yellow crude product was obtained, and the obtained crude product was purified by reverse-phase column chromatography (conditions as follows: C18 chromatography column, mobile phase, solvent ACN and solvent H2O (FA, 0.1%), 10 min gradient from 10% to 50%, UV254 nano detector), fractional distillation and rotational drying were performed to obtain compound 16-1 (250 mg, 83.22%, purity 99%). LC-MS-16-1(ES, m / z):[M+1]=335

[0385] 16.2 Synthesis of Compound 16-3 Under nitrogen protection, at 0°C, compound 16-1 (1482 mg, 4.438 mmol, 1 equiv) and compound 16-2 (711 Add CDI (791.55 mg) to ACN (2 mL) / DMF (0.4 mL) solution of (mg, 4.438 mmol, 1.00 equiv) The reaction mixture was then stirred overnight at room temperature. (4.882 mmol, 1.1 equiv) was added in several portions. The mixture was dried to obtain a yellow, oily crude product. This crude product was purified by reverse-phase column chromatography (under the following conditions: C18 chromatography column, mobile phase, solvent ACN and solvent H2O (FA, 0.1%), 10 min gradient from 10% to 50%, UV254 nano detector), and then fractional distillation and rotational drying were performed to obtain compound 16-3 (950 mg, 35.05%, purity 99%). LC-MS-16-3 (ES, m / z):[M+1]=611

[0386] 16.3 Synthesis of Compound 16-4 Compound 16-3 (760 mg, 1.244 mmol, 1 equiv) was dissolved in DCM (5 mL), and then TFA (5 mL) was added. The compound ) was added dropwise to the above reaction system and stirred at room temperature for 2 hours. The reaction mixture was then rotated dry to obtain compound 16-4 (800 mg, crude product). LC-MS-16-4 (ES, m / z):[M+1]=455

[0387] 16.4 Synthesis of Compound 16-5 After dissolving compound 16-4 (600 mg, 1.320 mmol, 1 equiv) in THF (20 mL) at room temperature, add TEA (267.13 mg, 2.640 mmol, 2 equiv) and Boc2O (432.11 mg, 1.980 mmol, 1.5 equiv). The reaction mixture was added dropwise to the above reaction system and stirred at room temperature for 2 hours. The reaction mixture was then rotated dry to obtain the crude product. The crude product obtained was purified by silica gel column chromatography using PE / EA(1 / 1), fractional distillation, and rotational drying to obtain compound 16-5 (600 mg, 81.95%, purity 99%). LC-MS-16-5 (ES, m / z):[M+1]=555

[0388] 16.5 Synthesis of Compound 16-7 Compound 16-5 (600 mg, 1.320 mmol, 1 equiv), Compound 16-6 (1975.52 mg, 4.328 mmol, 4 equiv), HOBt (292.33 mg, 2.164 mmol, 2 equiv), DMF (50 mL), DIPEA (279.33 mg, 2.164 mmol, 2 equiv), and TBTU (694.64 mg, 2.164 mmol, 2 equiv) were added to a 100 mL necked flask at room temperature, and the mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered, and the residue was removed. They were washed with methanol and ether, and the residue was rotatably dried to obtain compound 16-7 (2.6 g, crude product). (The object) was obtained.

[0389] 16.6 Synthesis of Compound 16-8 Compound 16-7 (2.6 g, 2.618 mmol, 1 equiv), DCM (25 mL, 393.265 mmol, 150.24 equiv), and TFA (25 mL, 336.577 mmol, 128.58 equiv) were added to a 100 mL necked flask at room temperature, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was filtered, the residue was washed with TFA / DCM (v / v, 1 / 1), and the filtrate was rotate-dried to obtain compound 16-8 (1 g, crude product). LC-MS-16-8 (ES, m / z):[M+1]=583

[0390] 16.7 Synthesis of Compound 16-9 Compound 16-8 (1 g, 1.716 mmol, 1 equiv) was dissolved in THF (20 mL) at room temperature, then TEA (0.35 g, 3.432 mmol, 2 equiv) and Boc2O (0.75 g, 3.432 mmol, 2 equiv) were added dropwise to the reaction system, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then rotated dry to obtain the crude product of compound 10. The crude product was obtained and purified by silica gel column chromatography eluting with PE / EA(1 / 1), and the image was rotate-dried to obtain compound 16-9 (700 mg, 52.10%, purity 99%). Ta. LC-MS-16-9 (ES, m / z):[M+1]=783

[0391] 16.8 Synthesis of Compounds 16-11 Add compound 16-9 (60 mg, 0.076 mmol, 1 equiv), compound 16-10 (18.18 mg, 0.115 mmol, 1.5 equiv), TEA (15.51 mg, 0.154 mmol, 2 equiv), DMF (2 mL), and HATU (43.71 mg, 0.115 mmol, 1.5 equiv) to a 50 mL necked flask at room temperature and prepare under a nitrogen atmosphere at room temperature. The mixture was stirred overnight. The reaction mixture was subjected to reverse-phase column chromatography (conditions were as follows: C18). The compound 16-11 (50 mg) was purified by chromatography using a chromatography column, mobile phase, solvent ACN, and solvent H2O (FA, 0.1%), with a 10% to 50% gradient over 10 mins, and a UV254 nanometer. It was then fractionally distilled and tumble-dried. A product with a purity of 99% and a concentration of 70.68% was obtained. LC-MS-16-11(ES, m / z):[M+1]=923

[0392] 16.9 Synthesis of Compound 16 Compound 16-11 (60 mg, 0.065 mmol, 1 equiv), DCM (4 mL), and TFA (4 mL) were added to a 50 mL necked flask at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was rotated dry, and the crude product was back-dried. Phase column chromatography (Conditions are as follows: C18 chromatography column) Mobile phase, solvent ACN and solvent H2O(FA, 0.1%), 10 min gradient from 10% to 50%, UV254 nanodetection. The compound was purified using a filtration system, fractional distillation, and rotary drying to obtain compound 16 (25 mg, 53.21%, purity 99.8%). LC-MS-16 (ES, m / z):[M+1]=723 1 H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H), 7.49 - 7.17 (m, 6H), 7.06 (q , J = 14.0, 8.1 Hz, 4H), 4.58 - 4.33 (m, 3H), 4.33 - 3.99 (m, 2H), 3.87 (dd, J = 36.1, 13.2 Hz, 1H), 3.74 - 3.37 (m, 6H), 3.21 (t, J = 13.4 Hz, 1H), 3.13 - 2.68 (m, 7H), 2.02 - 1.77 (m, 2H), 1.80 - 1.16 (m, 11H), 0.82 (dd, J = 18.2, 5.7 Hz, 6H).

[0393] Example 17 Synthesis of Compound 17 Prepare the target compound according to steps similar to those in Example 16, and then react the starting material compound

[0394] [ka]

[0395] of

[0396] [ka]

[0397] Replace it with the following:

[0398] [ka]

[0399] LC-MS-17 (ES, m / z):[M+1]=721 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H), 7.32 (d, J = 7.3 Hz, 2H), 7.30 - 7.19 (m, 4H), 7.11 (d, J = 7.0 Hz, 1H), 7.05 (dd, J = 10.4, 6.5 Hz, 4H), 4.49 (d, J = 16.9 Hz, 2H), 4.45 - 4.35 (m, 1H), 4.27 (s, 1H), 3.83 (t, J = 13.7 Hz, 1H), 3.58 - 3.41 (m, 2H), 3.26 - 3.13 (m, 1H), 3.02 (did, J = 19.7, 11.6, 4.7 Hz, 3H), 2.96 - 2.87 (m, 3H), 2.87 - 2.75 (m, 2H), 2.62 - 2.56 (m, 2H), 2.54 (s, 1H), 1.87 (dd, J = 19.6, 8.9 Hz, 2H), 1.70 - 1.56 (m, 4H), 1.50 - 1.43 (m, 2H), 1.40 - 1.28 (m, 3H), 0.89 - 0.72 (m, 6H).

[0400] Example 18 Synthesis of Compound 18

[0401]

change

[0402] LC-MS-18(ES, m / z):[M+1]=709 1 H NMR (400 MHz, Deuterium Oxide) δ8.32 (s, 1H), 8.29 (s, 1H), 8.08 (d, J = 4.9 Hz, 1H), 7.46 - 7.35 (m, 1H), 7.29 (dd, J = 8.1, 5.1 Hz, 1H), 7.10 (dd, J = 4.4, 2.2 Hz, 3H), 6.96 (t, J = 4.3 Hz, 2H), 4.48 (s, 1H), 4.46 - 4.32 (m, 2H), 4.22 (t, J = 7.0 Hz, 1H), 3.85 - 3.22 (m, 7H), 3.05 - 2.87 (m, 3H), 2.83 (t, J= 7.7 Hz, 2H), 2.73 (ddd, J = 14.7, 9.6, 5.7 Hz, 1H), 2.27 - 1.94 (m, 2H), 1.88 - 1.09 (m, 11H), 0.86 - 0.64 (m, 6H).

[0403] Example 19 Synthesis of Compound 19

[0404]

change

[0405] LC-MS-19 (ES, m / z): [M+1] = 710 1 H NMR (400 MHz, Deuterium Oxide) δ8.95 (d, J = 2.4 Hz, 1H), 8.37 (s, 2H), 8.35 (s, 1H), 7.09 (dq, J = 45.5, 3.8, 3.3 Hz, 5H), 4.61 (d, J = 18.1 Hz, 2H), 4.52 - 4.40 (m, 2H), 4.31 (t, J = 6.7 Hz, 1H), 3.94 - 3.24 (m, 6H), 3.05 (dt, J = 22.4, 6.0 Hz, 3H), 2.91 (t, J = 7.7 Hz, 2H), 2.78 (ddd, J = 14.1, 10.2, 7.5 Hz, 1H), 2.14 (ddd, J = 35.9, 12.0, 5.5 Hz, 2H), 1.94 - 1.21 (m, 11H), 0.97 - 0.69 (m, 6H).

[0406] Example 20 Synthesis of Compound 20 The target compound was prepared according to steps similar to those in Example 16, and the reaction starting material compound

[0407]

Chem.

[0408] was

[0409]

Chem.

[0410] replaced with, specifically as follows.

[0411]

Chem.

[0412] LC-MS-20(ES, m / z):[M+1]=713 1 H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 2H), 7.33 (s, 1H), 7.33 - 7.23 (m, 2H), 7.27 - 7.21 (m, 2H), 7.10 - 7.00 (m, 5H), 4.74 (s, 1H), 4.54 - 4.44 (m, 2H), 4.39 (d, J = 17.5 Hz, 1H), 4.28 (s, 1H), 4.20 (d, J = 15.1 Hz, 1H), 4.05 (s, 1H), 3.98 - 3.76 (m, 1H), 3.72 (d, J = 14.2 Hz, 1H), 3.63 - 3.55 (m, 1H), 3.48 (dd, J = 13.9, 7.6 Hz, 2H), 3.36 (s, 2H), 3.32 - 3.21 (m, 1H), 3.02 (dq, J = 20.9, 5.7 Hz, 6H), 2.98 - 2.80 (m, 1H), 2.73 - 2.64 (m, 2H), 1.68 (d, J = 6.1 Hz, 1H), 1.62 (s, 5H), 1.47 (s, 4H), 1.35 (d, J = 12.0 Hz, 1H), 0.85 - 0.80 (d, J = 5.5 Hz, 6H).

[0413] Example 21 Synthesis of Compound 21

[0414]

change

[0415] 21.1 Synthesis of compound 21-2 A solution of intermediate 3 (50 mg, 0.064 mmol, 1 equiv) was dissolved in DMF (10 mL) at room temperature under the protection of acetone. Mixture 21-1 (34.53 mg, 0.256 mmol, 4 equiv) was added and the mixture was reacted with stirring for 2 hours. Then, HATU (36.42 mg, 0.096 mmol, 1.5 equiv) and DIPEA (16.51 mg, 0.128 mmol, 2 equiv) were added dropwise at room temperature. The resulting mixture was extracted with EA (3 × 100 mL), and the organic layer was separated by brine (3 Washed with 10 mL of water and dried with Na2SO4. The resulting filtrate was concentrated under reduced pressure to obtain the crude product. Reverse-phase column chromatography (conditions are as follows: C18 chromatography) Lamb, mobile phase, solvent ACN and solvent H2O (FA, 0.1%), 10 min gradient from 10% to 50%, UV200 nanometers. The compound was purified using a detector to obtain compound 21-2 (58 mg, crude product). LC-MS-21-2 (ES, m / z):[M+1]=900

[0416] 21.2 Synthesis of Compound 21 Under nitrogen protection, compound 21-2 (40 mg, 0.044 mmol, 1 equiv) was reacted with a mixed solution of TFA (1 mL) / DCM (4 mL) with stirring for 2 hours at room temperature. The resulting filtrate was concentrated under reduced pressure. The crude product obtained was then subjected to reverse-phase column chromatography (the conditions were as follows: C18) The compound was purified using a chromatography column, mobile phase, solvent ACN, and solvent H2O (FA, 0.1%), with a 10% to 50% gradient over 10 mins, and a UV200 nanometer. After fractional distillation and rotational drying, compound 21 (18.6 mg, 57.47%, purity 96.0%) was obtained. LC-MS-21 (ES, m / z):[M+1]=700 1H NMR (400 MHz, Deuterium Oxide) δ 8.36 (s, 2H), 7.31 (d, J = 7.3 Hz, 3H), 7.24 (q, J = 3.6, 3.1 Hz, 3H), 7.05 (dd, J = 12.4, 5.8 Hz, 4H), 4.74 (s, 2H), 4.49 (dt, J = 13.3, 4.4 Hz, 2H), 4.39 (d, J = 17.5 Hz, 1H), 4.28 (s, 3H), 4.19 (d, J = 14.8 Hz, 1H), 3.88 (q, J = 15.4, 14.7 Hz, 1H), 3.70 (d, J = 15.5 Hz, 1H), 3.67 - 3.51 (m, 1H), 3.48 (s, 1H), 3.28 (d, J= 16.0 Hz, 1H), 3.19 (s, 2H), 3.09 - 2.96 (m, 3H), 2.87 (dt, J = 27.6, 8.3 Hz, 3H), 1.69 (t, J = 7.4 Hz, 2H), 1.62 (q, J = 7.5 Hz, 2H), 1.47 (s, 4H), 1.35 (dt, J = 16.9, 8.0 Hz, 2H), 0.83 (dt, J = 19.1, 3.9 Hz, 6H).

[0417] Example 22 Synthesis of Compound 22

[0418]

change

[0419] LC-MS-22(ES, m / z):[M+1]=784 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 1H), 8.11 (s, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.40 (d, J= 3.4 Hz, 1H), 7.31 - 7.19 (m, 5H), 7.18 - 6.99 (m, 5H), 4.53 - 4.38 (m, 2H), 4.36 (s, 3H), 4.28 (t, J = 7.6 Hz, 1H), 4.00 (d, J = 13.8 Hz, 1H), 3.89 (s, 1H), 3.61 (d, J = 13.3 Hz, 1H), 3.55 (s, 1H), 3.47 (ddd, J= 21.8, 14.8, 6.7 Hz, 3H), 3.18 - 2.99 (m, 3H), 2.95 - 2.82 (m, 5H), 2.17 (s, 3H), 1.99 (d, J = 17.9 Hz, 3H), 1.92 (s, 2H), 1.62 (p, J = 6.8 Hz, 2H), 1.47 (d, J = 7.3 Hz, 1H), 1.37 (s, 4H), 1.20 (t, J = 7.3 Hz, 1H), 0.82 (dt, J = 16.5, 6.7 Hz, 6H), 0.67 (d, J = 6.2 Hz, 1H).

[0420] Example 23 Synthesis of Compound 23

[0421]

change

[0422] LC-MS-23(ES, m / z):[M+1]=840.46 1H NMR (400 MHz, Deuterium Oxide) δ8.29 (s, 2H), 7.31 - 7.08 (m, 6H), 7.00 (dd, J = 35.0, 7.4 Hz, 4H), 4.80 (s, 1H), 4.48 - 3.95 (m, 6H), 3.54 - 3.35 (m, 3H), 3.28 - 2.66 (m, 12H), 2.15 (s, 4H), 1.79 (s, 3H), 1.65 - 1.15 (m, 11H), 0.83 - 0.55 (m, 6H).

[0423] Example 24 Synthesis of Compound 24 Prepare the target compound according to steps similar to those in Example 16, and then react the starting material compound

[0424] [ka]

[0425] of

[0426] [ka]

[0427] Replace it with the following:

[0428] [ka]

[0429] LC-MS-24 (ES, m / z):[M+1]=793 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H), 7.31 (d, J = 7.4 Hz, 2H), 7.30 - 7.21 (m, 3H), 7.12 (d, J = 6.6 Hz, 1H), 7.04 (t, J = 9.5 Hz, 4H), 4.48 (d, J = 17.6 Hz, 3H), 4.39 (d, J = 17.8 Hz, 1H), 4.27 (s, 1H), 4.20 (d, J = 12.5 Hz, 1H), 4.07 (d, J = 13.1 Hz, 2H), 3.55 (s, 5H), 3.20 (d, J = 13.5 Hz, 1H), 2.96 (s, 6H), 2.89 (s, 1H), 1.86 (s, 4H), 1.60 (s, 6H), 1.46 (d, J = 6.9 Hz, 1H), 1.35 (s, 6H), 0.81-0.66 (dd, J = 17.8, 5.7 Hz, 6H).

[0430] Example 25 Synthesis of Compound 25

[0431]

change

[0432] LC-MS-25 (ES, m / z): [M+1]=853 1H NMR (400 MHz, Deuterium Oxide) δ8.38 (s, 2H), 7.32 (d, J = 7.3 Hz, 3H), 7.32 - 7.20 (m, 3H), 7.05 (d, J= 17.7 Hz, 1H), 7.05 (s, 3H), 4.27 (d, J = 7.3 Hz, 1H), 3.53 (s, 4H), 3.41 (s, 1H), 3.31 (s, 1H), 3.03 (dd, J = 15.0, 8.3 Hz, 3H), 2.89 (q, J= 12.2, 9.9 Hz, 3H), 2.49 (t, J = 12.5 Hz, 2H), 2.19 - 2.09 (m, 2H), 1.82 (s, 2H), 1.63 (s, 8H), 1.51 - 1.43 (m, 4H), 0.82 (dd, J = 18.6, 5.9 Hz, 6H).

[0433] Example 26 Synthesis of Compound 26 Prepare the target compound according to steps similar to those in Example 16, and then react the starting material compound

[0434] [ka]

[0435] of

[0436] [ka]

[0437] Replace it with the following:

[0438] [ka]

[0439] LC-MS-26(ES, m / z):[M+1]=758 1H NMR (400 MHz, Deuterium Oxide) δ8.39 (s, 2H), 7.40 - 7.18 (m, 6H), 7.16 - 7.00 (m, 4H), 4.56 - 4.47 (m, 2H), 4.47 - 4.35 (m, 2H), 4.30 (dq, J = 10.1, 5.2, 4.5 Hz, 1H), 4.20 (d, J= 12.0 Hz, 1H), 4.10 (td, J = 13.3, 11.5, 6.9 Hz, 1H), 3.58 (dd, J= 15.1, 6.5 Hz, 1H), 3.54 - 3.43 (m, 1H), 3.37 (dp, J = 11.2, 5.1 Hz, 1H), 3.28 - 3.14 (m, 1H), 3.10 - 2.94 (m, 3H), 2.92 (dd, J = 7.8, 4.0 Hz, 1H), 2.90 - 2.77 (m, 2H), 2.56 (dd, J = 11.6, 4.2 Hz, 3H), 2.00 (s, 1H), 1.94 (d, J = 8.6 Hz, 1H), 1.75 - 1.55 (m, 4H), 1.55 - 1.40 (m, 4H), 1.40 - 1.27 (m, 3H), 0.82 (ddd, J = 17.6, 6.3, 2.6 Hz, 4H), 0.74 (dd, J= 6.8, 3.3 Hz, 1H), 0.67 (t, J = 5.4 Hz, 1H).

[0440] Example 27 Synthesis of Compound 27

[0441]

change

[0442] LC-MS-27 (ES, m / z): [M+1]=736 1H NMR (400 MHz, Deuterium Oxide) δ8.33 (s, 1H), 7.52 - 7.10 (m, 6H), 6.98 (q, J = 4.8, 3.9 Hz, 4H), 4.57 - 4.26 (m, 4H), 4.21 (dd, J = 9.8, 4.8 Hz, 1H), 3.71 (tt, J = 13.0, 5.6 Hz, 3H), 3.63 - 3.31 (m, 3H), 3.25 (td, J = 12.2, 8.6 Hz, 1H), 3.17 - 2.90 (m, 3H), 2.91 - 2.58 (m, 3H), 2.39 - 1.98 (m, 3H), 1.94 - 1.15 (m, 12H), 0.96 - 0.44 (m, 6H).

[0443] Example 28 Synthesis of Compound 28

[0444]

change

[0445] LC-MS-28(ES, m / z):[M+1]=722 1H NMR (400 MHz, Deuterium Oxide) δ8.38 (s, 2H), 7.41 - 7.18 (m, 6H), 7.14 - 6.91 (m, 4H), 4.58 - 4.22 (m, 5H), 3.95 - 3.35 (m, 7H), 3.16 - 2.78 (m, 7H), 2.61 (s, 3H), 2.33 - 2.01 (m, 3H), 1.94 - 1.25 (m, 12H), 0.84 (dd, J = 18.5, 5.4 Hz, 6H).

[0446] Example 29 Synthesis of Compound 29

[0447]

change

[0448] LC-MS-29(ES, m / z):[M+1]=734 1 H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 2H), 7.32 (d, J = 7.5 Hz, 3H), 7.23 (dt, J = 7.7, 4.0 Hz, 3H), 7.04 (d, J = 7.1 Hz, 4H), 4.51 (s, 1H), 4.42 (dd, J = 22.2, 16.8 Hz, 1H), 4.31 - 4.20 (m, 3H), 4.09 - 3.97 (m, 2H), 3.94 (d, J= 10.0 Hz, 2H), 3.57 (s, 1H), 3.49 (dd, J = 9.9, 5.5 Hz, 1H), 3.33 (dd, J= 28.5, 14.0 Hz, 1H), 3.06 (d, J = 7.0 Hz, 1H), 3.01 (s, 3H), 2.95 - 2.80 (m, 3H), 1.88 (d, J = 9.0 Hz, 2H), 1.83 - 1.72 (m, 1H), 1.72 - 1.60 (m, 4H), 1.48 (s, 3H), 1.34 (s, 3H), 0.83 (dd, J = 19.5, 5.7 Hz, 6H).

[0449] Example 30 Synthesis of Compound 30

[0450]

change

[0451] LC-MS-30-0 (ES, m / z):[M+1]=749 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 1H), 7.68 - 6.76 (m, 10H), 5.47 (d, J = 11.3 Hz, 1H), 4.61 - 4.18 (m, 2H), 3.78 - 3.24 (m, 6H), 3.21 - 2.76 (m, 3H), 2.70 - 2.33 (m, 5H), 2.11 (dd, J = 14.2, 7.6 Hz, 2H), 1.95 - 1.15 (m, 14H), 1.15 - 0.39 (m, 6H).

[0452] LC-MS-30-100(ES, m / z):[M+1]=749 1 H NMR (400 MHz, Deuterium Oxide) δ 8.37 (s, 1H), 7.57 - 6.76 (m, 10H), 5.51 (d, J = 11.1 Hz, 1H), 4.35 (d, J = 6.8 Hz, 1H), 3.75 - 3.12 (m, 6H), 3.06 - 2.67 (m, 3H), 2.46 (d, J = 17.8 Hz, 5H), 2.12 (dd, J = 13.7, 7.4 Hz, 2H), 2.00 - 1.18 (m, 12H), 0.85 (dd, J= 17.1, 5.1 Hz, 6H).

[0453] Example 31 Synthesis of Compound 31

[0454]

change

[0455] LC-MS-31(ES, m / z):[M+1]=709 1 H NMR (400 MHz, Deuterium Oxide) δ8.34 (s, 2H), 7.76 - 6.68 (m, 10H), 5.15 - 4.80 (m, 2H), 4.56 - 3.67 (m, 6H), 3.61 (d, J = 16.4 Hz, 4H), 3.30 - 2.97 (m, 4H), 3.11 - 2.70 (m, 4H), 2.19 - 1.79 (m, 2H), 1.76 - 1.06 (m, 11H), 0.95 - 0.39 (m, 6H).

[0456] Example 32 Synthesis of Compound 32 Prepare the target compound according to steps similar to those in Example 8, and then prepare the reaction starting compound

[0457] [ka]

[0458] of

[0459] [ka]

[0460] Replace it with the following:

[0461] [ka]

[0462] LC-MS-32 (ES, m / z):[M+1]=782 1H NMR (400 MHz, Deuterium Oxide) δ8.51 (s, 1H), 8.36 (s, 1H), 7.93 (s, 1H), 7.57 (s, 1H), 7.35 (d, J = 7.2 Hz, 2H), 7.31 - 7.26 (m, 4H), 7.22 (d, J = 7.7 Hz, 2H), 7.13 (d, J = 7.4 Hz, 1H), 6.89 (d, J = 6.8 Hz, 1H), 5.57 - 5.49 (m, 1H), 4.49 - 4.41 (m, 1H), 4.33 (s, 2H), 4.24 - 4.16 (m, 1H), 3.94 (s, 1H), 3.69 - 3.50 (m, 1H), 3.49 (s, 3H), 3.24 (dd, J = 13.7, 5.2 Hz, 1H), 3.07 (s, 1H), 3.00 - 2.78 (m, 2H), 2.53 (d, J = 8.6 Hz, 3H), 2.43 (d, J = 2.8 Hz, 3H), 1.87 (s, 2H), 1.68 - 1.58 (m, 2H), 1.57 (s, 6H), 1.52 (s, 1H), 1.35 (s, 3H), 0.90 - 0.78 (m, 2H), 0.83 (s, 5H).

[0463] Example 33 Synthesis of Compound 33 Prepare the target compound according to steps similar to those in Example 8, and then prepare the reaction starting compound

[0464] [ka]

[0465] of

[0466] [ka]

[0467] Replace it with the following:

[0468]

change

[0469] LC-MS-33 (ES, m / z): [M+1]=793 1 H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 2H), 7.59 - 7.10 (m, 9H), 6.89 (d, J = 6.7 Hz, 1H), 5.54 (dd, J= 11.4, 4.5 Hz, 1H), 4.56 - 4.25 (m, 2H), 4.25 - 4.03 (m, 1H), 3.96 - 3.78 (m, 3H), 3.72 - 3.42 (m, 5H), 3.34 - 3.05 (m, 2H), 3.05 - 2.73 (m, 4H), 2.49 (d, J= 39.1 Hz, 3H), 1.87 (s, 4H), 1.57 (d, J = 31.1 Hz, 9H), 1.34 (dd, J= 24.6, 11.5 Hz, 4H), 0.85 (dt, J = 13.0, 7.0 Hz, 6H).

[0470] Example 34 Synthesis of Compound 34

[0471]

change

[0472] LC-MS-34(ES, m / z):[M+1]=712 1 H NMR (400 MHz, Deuterium Oxide) δ8.26 (s, 1H), 7.28 - 7.18 (m, 3H), 7.15 (td, J = 4.4, 1.9 Hz, 3H), 7.01 - 6.90 (m, 4H), 4.67 (s, 1H), 4.47 - 4.31 (m, 3H), 4.31 - 4.18 (m, 2H), 3.81 (s, 1H), 3.51 (dt, J = 15.1, 5.8 Hz, 1H), 3.35 (ddd, J = 28.0, 13.3, 7.3 Hz, 2H), 3.02 - 2.87 (m, 4H), 2.80 (dddd, J = 23.1, 13.9, 9.1, 4.7 Hz, 4H), 2.03 - 1.77 (m, 4H), 1.56 (ddt, J = 20.7, 8.8, 4.7 Hz, 4H), 1.44 - 1.20 (m, 5H), 0.74 (ddd, J = 15.8, 5.2, 2.4 Hz, 6H).

[0473] Example 35 Synthesis of Compound 35 Prepare the target compound according to steps similar to those in Example 16, and then react the starting material compound

[0474] [ka]

[0475] of

[0476] [ka]

[0477] Replace it with the following:

[0478] [ka]

[0479] LC-MS-35(ES, m / z): [M+1]=675 1H NMR (400 MHz, Deuterium Oxide) δ8.29 (s, 2H), 7.18 (dtd, J = 29.2, 8.0, 7.1, 2.7 Hz, 6H), 7.08 - 6.88 (m, 4H), 4.49 - 4.11 (m, 4H), 3.62 - 3.23 (m, 5H), 3.16 - 2.71 (m, 8H), 1.88 - 1.14 (m, 14H), 0.78 - 0.53 (m, 6H).

[0480] Example 36 Synthesis of Compound 36 Prepare the target compound according to steps similar to those in Example 8, and then prepare the reaction starting compound

[0481] [ka]

[0482] of

[0483] [ka]

[0484] Replace it with the following:

[0485] [ka]

[0486] LC-MS-36(ES, m / z):[M+1]=700 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 1H), 7.43 - 7.17 (m, 8H), 7.13 (d, J = 7.4 Hz, 1H), 6.91 - 6.85 (m, 1H), 5.56 - 5.49 (m, 1H), 4.45 (dd, J = 9.0, 6.2 Hz, 1H), 4.29 (d, J = 8.4 Hz, 2H), 4.17 (d, J = 15.9 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.67 (dd, J = 25.3, 12.6 Hz, 1H), 3.61 - 3.45 (m, 2H), 3.35 (t, J = 11.9 Hz, 1H), 3.28 (s, 1H), 3.20 (s, 5H), 3.18 - 3.06 (m, 1H), 3.01 - 2.72 (m, 3H), 2.54 (s, 2H), 2.43 (s, 1H), 1.63 (s, 1H), 1.61 - 1.49 (m, 4H), 1.34 (t, J = 7.9 Hz, 1H), 0.85 (ddd, J = 15.5, 9.9, 5.4 Hz, 6H).

[0487] Example 37 Synthesis of Compound 37 Prepare the target compound according to steps similar to those in Example 8, and then prepare the reaction starting compound

[0488] [ka]

[0489] of

[0490] [ka]

[0491] Replace it with the following:

[0492] [ka]

[0493] LC-MS-37(ES, m / z):[M+1]=652 1 H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 2H), 7.54 - 6.66 (m, 10H), 5.52 (dd, J = 11.4, 5.7 Hz, 1H), 4.64 - 4.13 (m, 2H), 3.91 - 3.30 (m, 10H), 3.35 - 2.73 (m, 4H), 2.48 (d, J= 40.5 Hz, 3H), 1.95 - 1.22 (m, 9H), 0.84 (dt, J = 15.4, 7.6 Hz, 6H).

[0494] Example 38 Synthesis of Compound 38

[0495]

change

[0496] LC-MS-38(ES, m / z):[M+1]=651 1 H NMR (400 MHz, Deuterium Oxide) δ8.38 (s, 1H), 7.57 - 6.68 (m, 10H), 5.52 (dd, J = 11.0, 4.5 Hz, 1H), 4.70 - 4.10 (m, 2H), 4.13 - 3.32 (m, 6H), 3.27-2.73 (m, 8H), 2.73 - 2.30 (m, 3H), 1.90 - 1.41 (m, 9H), 1.44 - 1.01 (m, 3H), 1.01 - 0.42 (m, 6H).

[0497] Example 39 Synthesis of Compound 39 Example 16: Preparation of the target compound similar to the target compound and reaction raw material compound

[0498]

change

[0499] of

[0500] [ka]

[0501] Replace it with the following:

[0502] [ka]

[0503] LC-MS-39(ES, m / z):[M+1]=652 1 H NMR (400 MHz, Deuterium Oxide) δ7.68 - 6.57 (m, 10H), 4.50 - 3.83 (m, 4H), 3.77 - 3.21 (m, 10H), 3.16 - 2.57 (m, 6H), 1.76 - 1.03 (m, 9H), 0.98 - 0.23 (m, 6H).

[0504] Example 40 Synthesis of Compound 40

[0505] [ka]

[0506] LC-MS-40(ES, m / z):[M+1]=651 1H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 1H), 7.53 - 7.15 (m, 6H), 7.08 - 6.79 (m, 4H), 4.58 - 4.15 (m, 5H), 3.96 - 3.34 (m, 6H), 3.34 - 2.77 (m, 10H), 1.77-21.22 (m, 9H), 0.80 (dd, J= 19.9, 5.3 Hz, 6H).

[0507] Example 41 Synthesis of Compound 41

[0508]

change

[0509] LC-MS-41(ES, m / z):[M+1]=723 1H NMR (400 MHz, Deuterium Oxide) δ 8.37 (s, 2H), 7.32 (q, J = 7.1 Hz, 3H), 7.26 - 7.20 (m, 3H), 7.06 (t, J = 4.7 Hz, 4H), 4.54 - 4.46 (m, 2H), 4.40 (d, J = 17.4 Hz, 2H), 4.28 (d, J = 6.8 Hz, 1H), 4.01 (s, 2H), 3.67 - 3.54 (m, 4H), 3.48 (dt, J = 15.2, 6.8 Hz, 1H), 3.28 - 3.11 (m, 3H), 2.95 (dqd, J = 44.1, 15.2, 14.4, 6.9 Hz, 6H), 2.67 (t, J = 13.1 Hz, 1H), 1.87 - 1.59 (m, 6H), 1.48 (t, J = 7.5 Hz, 3H), 1.26 (dt, J = 13.0, 6.8 Hz, 3H), 0.83 (dq, J = 18.4, 3.4 Hz, 6H).

[0510] Example 42 Synthesis of Compound 42

[0511]

change

[0512] LC-MS-42(ES, m / z):[M+1]=666 1 H NMR (400 MHz, Deuterium Oxide) δ 8.38 (s, 1H), 7.32 (q, J = 7.0 Hz, 3H), 7.23 (q, J = 3.8 Hz, 3H), 7.05 (t, J = 5.2 Hz, 4H), 4.53 - 4.45 (m, 2H), 4.40 (d, J = 17.5 Hz, 1H), 4.28 (t, J = 6.9 Hz, 1H), 4.21 - 4.09 (m, 1H), 3.84 (d, J = 16.9 Hz, 1H), 3.57 (t, J = 8.5 Hz, 5H), 3.45 (dq, J = 15.4, 5.4, 5.0 Hz, 1H), 3.23 (d, J = 13.5 Hz, 1H), 3.03 (dd, J = 13.0, 6.4 Hz, 1H), 2.97 (d, J = 6.6 Hz, 2H), 2.91 - 2.79 (m, 1H), 2.86 (s, 1H), 1.93 (d, J = 12.6 Hz, 1H), 1.86 (d, J = 15.1 Hz, 1H), 1.48 (s, 2H), 1.49 - 1.44 (m, 2H), 1.24 (q, J = 7.0 Hz, 4H), 0.88 - 0.77 (m, 6H).

[0513] Example 43 Synthesis of Compound 43

[0514]

change

[0515] LC-MS-43(ES, m / z):[M+1]=723 1H NMR (400 MHz, Deuterium Oxide) δ8.35 (s, 2H), 7.35 (dd, J = 12.2, 5.2 Hz, 3H), 7.30 - 6.81 (m, 7H), 5.70 - 5.42 (m, 1H), 4.46 - 4.28 (m, 2H), 4.12 - 3.83 (m, 2H), 3.61 (d, J = 11.6 Hz, 3H), 3.50 (q, J = 11.8, 9.2 Hz, 2H), 3.30 - 3.02 (m, 4H), 2.91 (h, J = 10.1, 9.2 Hz, 3H), 2.70 - 2.50 (m, 3H), 2.43 (d, J = 4.9 Hz, 1H), 2.00 - 1.63 (m, 5H), 1.60 - 1.44 (m, 3H), 1.37 - 0.98 (m, 3H), 0.95 - 0. 50 (m, 6H).

[0516] Example 44 Synthesis of Compound 44

[0517]

change

[0518] LC-MS-44(ES, m / z):[M+1]=706 1 H NMR (400 MHz, Deuterium Oxide) δ8.28 (s, 2H), 7.28 - 7.09 (m, 6H), 7.07 - 6.90 (m, 4H), 4.49 - 4.10 (m, 5H), 4.04 - 3.79 (m, 2H), 3.59 - 3.28 (m, 2H), 3.13 (ddt, J = 36.4, 14.4, 7.9 Hz, 3H), 2.99 - 2.67 (m, 6H), 2.68 - 2.52 (m, 2H), 2.13 - 1.94 (m, 3H), 1.86 - 1.02 (m, 12H), 0.84 - 0.51 (m, 6H).

[0519] Example 45 Synthesis of Compound 45 Prepare the target compound according to steps similar to those in Example 16, and then react the starting material compound

[0520] [ka]

[0521] of

[0522] [ka]

[0523] Replace it with the following:

[0524] [ka]

[0525] LC-MS-45(ES, m / z):[M+1]=708 1 H NMR (400 MHz, Deuterium Oxide) δ8.29 (s, 1H), 7.29 - 7.07 (m, 6H), 7.07 - 6.91 (m, 4H), 4.46 - 4.25 (m, 3H), 4.25 - 3.93 (m, 2H), 3.90 - 3.58 (m, 2H), 3.58 - 3.29 (m, 2H), 3.13 (t, J= 13.6 Hz, 1H), 3.02 - 2.64 (m, 7H), 1.79 (dd, J = 19.2, 5.9 Hz, 5H), 1.64 - 1.08 (m, 11H), 0.79 - 0.54 (m, 6H).

[0526] Example 46 Synthesis of Compound 46 Prepare the target compound according to steps similar to those in Example 16, and then react the starting material compound

[0527] [ka]

[0528] of

[0529] [ka]

[0530] Replace it with the following:

[0531] [ka]

[0532] LC-MS-46 (ES, m / z): [M+1]=709 1 H NMR (400 MHz, Deuterium Oxide) δ8.34 (d, J = 2.0 Hz, 2H), 7.33 - 7.17 (m, 6H), 7.01 (dq, J = 13.1, 5.3, 4.5 Hz, 4H), 4.52 - 4.41 (m, 2H), 4.35 (dd, J = 17.6, 4.9 Hz, 1H), 4.25 (dd, J = 8.8, 5.9 Hz, 1H), 3.61 (d, J = 3.0 Hz, 6H), 3.50 (t, J = 6.6 Hz, 3H), 3.38 (s, 1H), 3.01 (dt, J = 14.3, 4.5 Hz, 1H), 2.96 - 2.76 (m, 5H), 1.68 - 1.52 (m, 4H), 1.43 (q, J = 10.1, 8.0 Hz, 3H), 1.35 - 1.25 (m, 2H), 0.84 - 0.74 (m, 6H).

[0533] Example 47 Synthesis of Compound 47 Prepare the target compound according to steps similar to those in Example 16, and then react the starting material compound

[0534] [ka]

[0535] を

[0536]

change

[0537] The specific items are as follows.

[0538]

change

[0539] LC-MS-47(ES, m / z):[M+1]=693 1H NMR (400 MHz, Deuterium Oxide) δ8.33 (s, 2H), 7.31 - 7.14 (m, 6H), 7.00 (dd, J = 11.1, 5.8 Hz, 4H), 4.47 (dd, J = 13.2, 7.5 Hz, 2H), 4.38 - 4.22 (m, 2H), 3.68 - 3.51 (m, 5H), 3.38 (tdt, J = 24.0, 18.3, 9.2 Hz, 5H), 3.05 - 2.79 (m, 6H), 2.03 (t, J = 6.9 Hz, 3H), 1.70 - 1.53 (m, 4H), 1.43 (hept, J = 6.6, 5.9 Hz, 3H), 1.36 - 1.22 (m, 2H), 0.79 (dd, J = 18.2, 5.9 Hz, 6H).

[0540] Example 48 Synthesis of Compound 48

[0541]

change

[0542] LC-MS-48(ES, m / z):[M+1]=673.43 1 H NMR (400 MHz, Deuterium Oxide) δ7.28 - 7.14 (m, 5H), 4.70 (s, 1H), 4.65 (s, 2H), 4.43 (dd, J = 9.5, 5.7 Hz, 1H), 4.28 - 4.21 (m, 1H), 3.56 (s, 2H), 3.35 (dt, J = 14.1, 7.2 Hz, 2H), 3.13 - 2.89 (m, 2H), 2.87 (s, 2H), 2.86 (d, J = 7.6 Hz, 2H), 2.85 - 2.75 (m, 2H), 1.98 (dd, J = 13.5, 6.8 Hz, 1H), 1.87 (d, J = 9.5 Hz, 1H), 1.55 (dq, J = 15.0, 7.6 Hz, 6H), 1.45 (s, 5H), 0.77 (dd, J= 17.0, 5.1 Hz, 7H), 0.66 - 0.59 (m, 1H), 0.33 (d, J = 7.8 Hz, 2H).

[0543] Example 49 Synthesis of Compound 49

[0544]

change

[0545] LC-MS-49 (ES, m / z): [M+1]=700 1 H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.23 (dd, J = 17.4, 7.3 Hz, 3H), 4.76 (d, J = 6.2 Hz, 1H), 4.69 (s, 1H), 4.49 (dd, J = 9.7, 5.4 Hz, 1H), 4.30 (d, J = 8.6 Hz, 1H), 3.74 (s, 2H), 3.56 (ddd, J = 29.1, 13.5, 7.1 Hz, 2H), 3.34 (ddt, J = 16.1, 10.9, 5.8 Hz, 1H), 3.14 (dd, J = 14.4, 6.6 Hz, 2H), 2.93 (dq, J = 14.1, 6.5 Hz, 6H), 2.22 - 2.11 (m, 1H), 2.09 (s, 1H), 1.72 (s, 5H), 1.62 (t, J = 7.7 Hz, 2H), 1.47 (s, 10H), 1.37 (s, 1H), 0.94 (s, 1H), 0.84 (dd, J = 17.7, 5.3 Hz, 7H).

[0546] Example 50 Synthesis of Compound 50

[0547]

change

[0548] LC-MS-50(ES, m / z):[M+1]=726 1H NMR (400 MHz, Deuterium Oxide) δ 8.29 (s, 2H), 7.18 - 7.12 (m, 3H), 6.98 (d, J = 5.5 Hz, 2H), 6.91 (td, J = 8.0, 6.9, 3.2 Hz, 4H), 4.45 - 4.34 (m, 2H), 4.31 - 4.17 (m, 2H), 3.75 - 3.57 (m, 3H), 3.51 (dq, J = 13.0, 6.3, 5.7 Hz, 2H), 3.35 (dtt, J = 21.5, 10.9, 6.0 Hz, 1H), 2.97 (dt, J = 14.0, 4.6 Hz, 1H), 2.90 (q, J = 5.4 Hz, 2H), 2.83 (t, J = 7.7 Hz, 2H), 2.75 (ddd, J = 13.5, 9.2, 3.4 Hz, 1H), 2.15 - 2.06 (m, 1H), 2.01 (dd, J = 13.5, 7.7 Hz, 1H), 1.75 (dt, J = 13.3, 5.6 Hz, 1H), 1.68 - 1.59 (m, 2H), 1.56 (s, 1H), 1.53 (d, J = 7.5 Hz, 1H), 1.40 (q, J = 9.4, 8.3 Hz, 3H), 1.35 - 1.22 (m, 2H), 0.74 (dd, J = 18.9, 5.1 Hz, 6H).

[0549] Example 51 Synthesis of Compound 51 Example 16: Preparation of the target compound similar to the target compound and reaction raw material compound

[0550]

change

[0551] を

[0552]

change

[0553] The specific items are as follows.

[0554]

change

[0555] LC-MS-51(ES, m / z): [M+1]=829 1 H NMR (400 MHz, Deuterium Oxide) δ 8.34 (s, 2H), 7.34 - 7.22 (m, 3H), 7.21 ( dt, J = 6.3, 2.6 Hz, 3H), 7.07 - 6.97 (m, 4H), 4.52 - 4.42 (m, 2H), 4.36 (d, J = 17.5 Hz, 1H), 4.25 (dd, J = 8.8, 5.7 Hz, 1H), 3.74 (d, J = 13.5 Hz, 2H), 3.63 - 3.37 (m, 4H), 3.28 (ddd, J = 17.5, 11.7, 4.4 Hz, 2H), 3.16 (td, J = 8.7, 8.2, 4.1 Hz, 1H), 3.04 (ddt, J = 20.9, 12.1, 5.0 Hz, 2H), 2.99 - 2.77 (m, 7H), 1.71 - 1.63 (m, 1H), 1.60 (ddd, J = 14.5, 9.7, 5.6 Hz, 3H), 1.44 (s, 3H), 1.35 (ddd, J= 30.9, 14.8, 7.2 Hz, 1H), 0.79 (dd, J = 18.9, 5.7 Hz, 6H).

[0556] Example 1A Synthesis of Compound 1A

[0557]

change

[0558] 1.1 Synthesis of compound 1A-1 Benzyl 4-aminopiperidine-1-carboxylate (100 mg, 0.427 mmol, 1.00 equiv) Dissolve ) and TEA (0.2 mL, 2.693 mmol, 6.31 equiv) in DCM (15 mL) and chloroformate me Chill (60.49 mg, 0.640 mmol, 1.5 equiv) was added in several portions. The mixture was stirred at room temperature for 2 hours. Then, saturated ammonium chloride solution was added to quench the reaction. Extraction was performed with DCM (15 mL x 3), the organic phases were combined and dried, and the mixture was rotated to obtain the crude product. The crude product was purified by silica gel column chromatography eluted with PE / EA (1:1), fractional distillation, and rotational drying. This yields benzyl 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate. Ta. LC-MS-1A-1(ES, m / z):[M+1]=293

[0559] 1.2 Synthesis of Compound 1A-2 A stirred solution of benzyl 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate (180 mg, 0.616 mmol, 1.00 equiv) in THF (12 mL) was mixed with Pd / C (18 mg, w / t, 10%). The mixture was stirred under a hydrogen atmosphere for 13 hours. The resulting mixture was washed with MeOH (7 × 50 mL). The filtrate was concentrated under reduced pressure to obtain methyl N-(piperidine-4-yl)carbamate. (100 mg, crude product) was obtained. LC-MS-1A-2(ES, m / z):[M+1]=159

[0560] 1.3 Synthesis of Compound 1A-3 Methyl N-(piperidine-4-yl)carbamate methyl ester (19.51 mg, 0.123 mmol) Add DIPEA (1.48 mg, 0.123 mmol, 3 equiv) to a stirred solution of DMF (10 mL) of 3.00 equiv. Intermediate 2 (31 mg, 0.041 mmol, 1.00 equiv) and HATU (23.45 mg, 0.061 mmol, 1.5 equiv) were added. The reaction was carried out at room temperature under a nitrogen atmosphere for 3 hours. Water (12 mL) was added to complete the reaction. The solution was quenched and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and dried, and the crude product was obtained by tumble drying. The crude product was purified by reverse-phase chromatography eluting with CH3CN / H2O (0.1% FA) (6:1), fractional distillation, and tumble drying yielded N-[(5R)-5-[(2R))-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]-6-{4-[(methoxycarbonyl))amino]piperidine-1-yl}-6-oxohexyl]carbamate tert-butyl. LC-MS-1A-3(ES, m / z): [M+1]=894

[0561] 1.4 Synthesis of Compound 1A N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]-6-{4-[(methoxycarbonyl)amino]piperidine-1-yl}-6-oxohexyl]carbamate tert-butyl (350 mg, 0.391 mmol, 1 equiv) was dissolved in 4 M HCl (gas) / 1,4-dioxane (5 mL) and reacted at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC, fractional distillation, and rotational drying to obtain N-{1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-[(2R)-2-amino-3]-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]hexanoyl]piperidine-4-yl}carbamate methyl ester (169.1 mg, 62.01%, purity 99.2%). LC-MS-1A(ES, m / z):[M+1]=693 1H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 2H), 7.45 - 6.86 (m, 10H), 4.63 - 4.47 (m, 2H), 4.27 - 4.06 (m, 3H), 3.85 (dd, J = 37.5, 14.1 Hz, 1H), 3.55 (d, J = 3.6 Hz, 4H), 3.32 - 2.69 (m, 8H), 2.14 - 1.71 (m, 2H), 1.73 - 1.13 (m, 11H), 0.82 (dq, J = 20.0, 2.6 Hz, 6H).

[0562] Example 2A Synthesis of Compound 2A

[0563] [ka]

[0564] 2.1 Synthesis of Compound 2A-1 At 0°C and under a nitrogen atmosphere, in a stirred solution of indene (1.16 g, 9.986 mmol, 1.00 equiv) in THF (12.00 mL, 148.116 mmol, 14.83 equiv), bis(trimethylsilyl)lithium ammonium compounds were added. Mid (19.97 mL, 119.348 mmol, 11.95 equiv) was added dropwise. The resulting mixture was prepared under a nitrogen atmosphere. The mixture was stirred at 0°C for 1 hour under gas pressure. N,N-bis(2-chloroethyl)carbamide was added to the above mixture at 0°C. Tert-butyl acid (2.42 g, 9.994 mmol, 1.00 equiv) was added dropwise. The resulting mixture was stirred at 0°C for a further 1 hour. The crude product was obtained by concentration under reduced pressure. The crude product was mixed with petroleum ether / acetic acid. Purified by silica gel column chromatography eluting with ethyl(9:1), fractional distillation and... Rotary drying yielded tert-butylspiro[indene-1,4'-piperidine]-1'-carboxylate tert-butyl (2.22 g, 77.90%, purity 99%). LC-MS-2A-1(ES, m / z): [M+1]=286

[0565] 2.2 Synthesis of Compound 2A-2 At 0°C, under a nitrogen atmosphere, a stirring solution of spiro[indene-1,4'-piperidine]-1'-carboxylate tert-butyl (2.22 g, 7.779 mmol, 1.00 equiv) in THF (22 mL) was prepared with 2 M boranedimethyl sulfate. Rufide complex (THF) (19.45 mL, 38.895 mmol, 5 equiv) was added. The resulting mixture The mixture was stirred at 0°C for 4 hours under a nitrogen atmosphere. Sodium hydroxide (2 M) (23.34 mL, 46.674 mmol, 6 equiv) and hydrogen peroxide solution (6.66 mL, 285.878 mmol, 36.75 equiv) were added dropwise to the mixture at 0°C. The resulting mixture was stirred for a further 30 minutes at 0°C. The mixture was then extracted with ethyl acetate (1 × 150 mL), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1), fractional distillation, and rotational drying to obtain 2-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate tert-butyl (959 mg, 40.63%, purity 99%). It was done. LC-MS-2A-2(ES, m / z):[M+1]=304

[0566] 2.3 Synthesis of Compound 2A-3 Under room temperature conditions, 2-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-cal Dess-Martin reagent (2180.81 mg, 5.142 mmol, 2 equiv) was added in several portions to a solution of tert-butyl vonate (780 mg, 2.571 mmol, 1.00 equiv) in dichloromethane (16 mL). The resulting mixture was stirred at room temperature for 12 hours. The mixture was filtered, and the filter cake was washed with dichloromethane (1 × 20 mL). The combined organic phases were washed with aqueous sodium bicarbonate (1 × 15 mL) and brine (1 × 15 mL), extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was petroleum ether / ethyl acetate. Purified by silica gel column chromatography eluting at a (4:1) ratio, followed by fractional distillation and rotary drying. Dry 2-oxo-3H-spiro[indene-1,4'-piperidine]-1'-carboxylate tert-butyl (550 mg, 70.98%, and 99% purity were obtained. LC-MS-2A-3 (ES, m / z): [M+1]=302

[0567] 2.4 Synthesis of Compound 2A-4 At room temperature, tert-butyl 2-oxo-3H-spiro[indene-1,4'-piperidine]-1'-carboxylate (1.72 g, 5.707 mmol, 1.00 equiv) and ethyl titanate (4 mL) were stirred together, and tert-butanesulfenamide (2.08 g, 17.121 mmol, 3 equiv) was added in several portions. The resulting mixture was stirred at 85°C for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was filtered. After filtering, the filtered cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phase (1 × 40 mL) was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was petroleum ether / ethyl acetate. Purified by silica gel column chromatography eluting in a (2:1) ratio, followed by fractional distillation and rotary drying. By drying, (2E)-2-[(2-methylpropane-2-sulfinyl)imino]-3H-spiro[idene-1,4'-piperidine]-1'-carboxylate tert-butyl (450 mg, 19.49%, purity 99%) was obtained. LC-MS-2A-4 (ES, m / z):[M+1]=405

[0568] 2.5 Synthesis of Compound 2A-5 (2E)-2-[(2-methylpropane-2-sulfinyl)imino]-3H- Spiro[indene-1,4'-piperidine]-1'-carboxylate tert-butyl (350 mg, 0.865 mmol) BH3.THF (1.73 mL, 1.730 mmol, 2 equiv) was added to a stirred solution of tetrahydrofuran (5 mL). The mixture was added in several portions. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 2 hours. The reaction was quenched with methanol at room temperature. The resulting mixture was concentrated under reduced pressure to obtain 2-[(2-methylpropane [-2-sulfinyl)amino]-2,3-dihydrospiro[inden-1,4'-piperidine]-1'-cal tert-butyl benzoate (380 mg, crude product) was obtained. LC-MS-2A-5 (ES, m / z): [M+1]=407

[0569] 2.6 Synthesis of Compound 2A-6 At room temperature, 2-[(2-methylpropane-2-sulfinyl)amino]-2,3-dihydrospiro[inde To a stirred solution of tert-butyl n-1,4'-piperidine]-1'-carboxylate (100 mg, 0.246 mmol) in dichloromethane (1.7 mL), TFA (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated under vacuum to obtain N-{2,3-dihydrospiro[inden-1,4'-piperidine]-2-yl}-2-methylpropane-2-sulfinamide (100 mg, crude product). . LC-MS-2A-6 (ES, m / z):[M+1]=307

[0570] 2.7 Synthesis of Compound 2A-7 Dimethylformamide (2) of N-{2,3-dihydrospiro[inden-1,4'-piperidine]-2-yl}-2-methylpropan-2-sulfinamide (100.00 mg, 0.327 mmol, 1.1 equiv) at room temperature In a mL solution, diisopropylethylamine (115.01 mg, 0.891 mmol, 3 equiv), intermediate Composition 2 (22 mg, 3.64 mg, 0.297 mmol, 1.00 equiv) and HATU (135.34 mg, 0.3156 mmol, 1.2 equiv) were added in several portions. The resulting mixture was reacted overnight at room temperature with stirring. The obtained solution was purified by reverse-phase flash chromatography, fractional distillation, and rotational drying to obtain N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]-6-{2-[(2-methylpropan-2-sulfinyl)amino]-2,3-dihydrospiro[inden-1,4'-piperidine]-1'-yl}-6-oxohexyl] tert-butyl carbamate (70 mg, 22.64%, purity 99%). LC-MS-2A-7 (ES, m / z):[M+1]=1042

[0571] 2.8 Synthesis of Compound 2A At room temperature, tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]-6-{2-[(2-methylpropan-2-sulfinyl)amino]-2,3-dihydrospiro[inden-1,4'-piperidine]-1'-yl}-6-oxohexyl]carbamate tert-butyl (70 mg, 0.067 mmol, 1.00 equiv) was added to a stirred solution of dioxane (2 mL) with 4 M HCl (gas) / 1,4-dioxane (2 mL) in several portions. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC to obtain (2R)-N-[(2R)-6-amino-1-{2-amino-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl}-1-oxy Sohexyl-2-yl]-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide (24.7 mg, 41.65%, purity 83.3%) was obtained. LC-MS-2A (ES, m / z):[M+1]=738 1 H NMR-2 (400 MHz, Deuterium Oxide) δ8.26 (s, 3H), 7.48 - 6.89 (m, 14H), 4.52 (ddt, J = 25.9, 13.0, 7.1 Hz, 2H), 4.14 (dq, J = 17.7, 5.4, 4.2 Hz, 2H), 3.99 (q, J = 8.3, 7.1 Hz, 2H), 3.86 - 3.23 (m, 3H), 3.16 - 2.65 (m, 7H), 2.25 - 1.18 (m, 13H), 0.97 - 0.56 (m, 6H).

[0572] Example 3A Synthesis of Compound 3A

[0573] [ka]

[0574] 3.1 Synthesis of Compound 3A-1 Dissolve (3-bromopyridine-2-yl)methanol (1 g, 5.318 mmol, 1.00 equiv) at 0°C. Thionyl chloride (1.27 g, 10.636 mmol, 2.0 equiv) was added to the stirred solution of dissolved DCM multiple times. The mixture was added in separate portions. The resulting mixture was stirred at 0°C for 4 hours. The mixture was neutralized to pH 7 with saturated NaHCO3 (aq.). The crude product was purified by silica gel column chromatography eluting with PE / EA (5:1), fractional distillation, and rotational drying to obtain 3-bromo-2-(chloromethyl)pyridine (700 mg, 64.4%, purity 99%). LC-MS-3A-1(ES, m / z):[M+1]=205

[0575] 3.2 Synthesis of Compound 3A-2 1-tert-butyl4-methylpiperidine-1,4-dicarboxylic acid ester under -30°C and nitrogen protection. To THF (50 mL) in which 2.65 g, 10.897 mmol, 1.5 equiv of ru (dissolved), LDA (10 mL, 73.747) was added. Add mmol (10.15 equiv) dropwise to the solution, and after 30 minutes, add 3-bromo-2-(chloromethyl)pyriol to the solution. A THF solution of din (1.5 g, 7.265 mmol, 1 equiv) was added dropwise and stirred overnight at room temperature. The reaction was quenched with saturated NH4Cl (aqueous solution). Extraction with ethyl acetate and mixing of the organic phases were performed. Rotary drying was performed, and the crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), then fractional distillation and rotation drying were performed to obtain 1-tert-butyl 4-methyl 4-[(3-bromopyridine-2-yl )methyl]piperidine-1,4-dicarboxylic acid ester (3.7 g, 82.4%, purity 99%) was obtained. . LC-MS-3A-2(ES, m / z):[M+1]=413

[0576] 3.3 Synthesis of Compound 3A-3 LiOH (0.37 g, 8.709 mmol, 3 equiv) was added to methanol containing 1.2 g, 2.903 mmol, 1.00 equiv, of 1-tert-butyl 4-methyl 4-[(3-bromopyridine-2-yl)methyl]piperidine-1,4-dicarboxylic acid ester, dissolved at 70°C. The mixture was stirred at 70°C for 6 hours. The reaction mixture was cooled, and then the pH of the mixture was adjusted to 6 with HCl (aq.). The organic phase was extracted with ethyl acetate. The mixture was dried and then rotated-dried. The crude product was purified by silica gel column chromatography eluting PE / EA (1:1), fractional distillation, and rotational drying to obtain 4-[(3-bromopyridine-2-yl)methyl]-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (630 mg, 54.34%, purity 99%). LC-MS-3A-3(ES, m / z):[M+1]=399

[0577] 3.4 Synthesis of Compound 3A-4 At room temperature and under nitrogen protection, N,O-dimethylhydroxylamine hydrochloride (200 mg, 2.029 mmol, 1 equiv) and 4-[(3-bromopyridine-2-yl)methyl]-1-(tert-butoxycarbonyl Stirring of DMF containing piperidine-4-carboxylic acid (1604.22 mg, 4.058 mmol, 2 equiv). The solution contains DIPEA (786.87 mg, 6.087 mmol, 3 equiv) and HATU (1543.30 mg, 4.058 mmol, 2 equiv). Equiv) was added. The mixture was stirred at 0°C for 3 hours under nitrogen protection. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined and dried, and the mixture was tumble-dried. The crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), fractional distillation and tumble-drying to obtain 4-[(3-bromopyridine-2-yl)methyl]-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate tert-butyl (120 mg, 13.52%, purity 99%). LC-MS-3A-4(ES, m / z):[M+1]=442

[0578] 3.5 Synthesis of Compound 3A-5 4-[(3-bromopyridine-2-yl)methyl]-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate tert-butyl (1.2 g, 2.713 mmol, 1 equiv) under nitrogen protection at -78°C. Butyllithium (1.74 mL, 27.130 mmol, 10 equiv) was added to the THF mixture in which ) was dissolved. The mixture was stirred at -78°C under nitrogen protection for 3 hours. The reaction was quenched by adding saturated NH4Cl (aq.) (2 mL) solution at room temperature. Extraction was performed with ethyl acetate, the organic phases were combined and dried, and the mixture was rotated dry. The crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), fractional distillation, and rotated dry to obtain 5-oxo-7H-spiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylate tert-butyl (590 mg, 71.93%, purity 99%). LC-MS-3A-5(ES, m / z):[M+1]=303

[0579] 3.6 Synthesis of Compound 3A-6 Under air conditions, tert-butane is added to a stirred solution of tert-butyl 5-oxo-7H-spiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylate (25 mg, 0.083 mmol, 1 equiv). Sulfenamide (30.06 mg, 0.249 mmol, 3 equiv) was added dropwise. The mixture was then subjected to nitrogen protection. The mixture was stirred at 110°C for 4 hours. After the reaction mixture was cooled to room temperature, water was added to quench the reaction. Ethyl acetate was extracted, the organic phases were combined and dried, and the mixture was tumble-dried. The crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), fractional distillation, and tumble-dried to obtain (5Z)-5-[(2-methylpropane-2-sulfinyl)imino]-7H-spiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylate tert-butyl (10 mg, 29.82%, purity 99%). LC-MS-3A-6(ES, m / z):[M+1]=413

[0580] 3.7 Synthesis of Compound 3A-7 Under 0°C and nitrogen protection, (5Z)-5-[(2-methylpropane-2-sulfinyl)imino]-7H- Spiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylate tert-butyl ester (20 mg, 0.049 mmol, 1 equiv) and BH3-THF (0.2 mL, 2.327 mmol, 47.19 equiv) were dissolved in THF and stirred for 3 hours. The reaction was quenched by adding MeOH (2 mL) at room temperature. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column: silica column, mobile phase: MeCN / aqueous solution, 10% to 100% gradient over 10 min, detector: UV 220 nm. After fractional distillation and rotational drying, 5-[(2-methylpropane-2-sulfinyl)amino]-5,7-dihydride was obtained. Rospiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylate tert-butyl ester (10 mg, 49.75%, purity 99%) was obtained. LC-MS-3A-7(ES, m / z):[M+1]=408

[0581] 3.8 Synthesis of Compound 3A-8 Under room temperature and air conditions, 5-[(2-methylpropane-2-sulfinyl)amino]-5,7-dihydrospiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylate tert-butyl ester (180 mg, 0.4421 mmol, 1 equiv) and TFA (1 mL, 13.463 mmol, 30.48 equiv) The mixture was dissolved in DCM and stirred for 3 hours. The resulting mixture was concentrated under reduced pressure. N-{5,7-dihydros Pyrro[cyclopentadiene[b]pyridine-6,4'-piperidine]-5-yl}-2-methylpropane-2- Sulfinamide (66 mg, crude product) was obtained and proceeded to the next step without further purification. I used it directly. LC-MS-3A-8(ES, m / z):[M+1]=308

[0582] 3.9 Synthesis of Compound 3A-9 Under room temperature and air conditions, stir the DMF solution containing N-{5,7-dihydrospiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-5-yl}-2-methylpropane-2-sulfinamide (66 mg, 0.107 mmol, 1 equiv) and intermediate 2 (126.70 mg, 0.086 mmol, 0.8 equiv) for 1 minute. The mixture was stirred. At room temperature, DIPEA (41.62 mg, 0.323 mmol, 1.5 equiv) and HATU (163.24 mg, 0.430 mmol, 2 equiv) were added to the mixture. The mixture was stirred for 3 hours at room temperature under nitrogen protection. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions: Column: silica column, mobile phase: MeCN aqueous solution, gradient from 10% to 50% over 10 min, detector: UV 220 nm. After fractional distillation and rotational drying, the N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarb [nyl)amino]-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpenta [Namide]-6-{5-[(2-methylpropane-2-sulfinyl)amino]-5,7-dihydrospiro[cyclopentadiene[c]pyridine-6,4'-piperidine]-1'-yl}-6-oxohexyl]carbamide Tert-butyl acid (30 mg, 13.39%, purity 99%) was obtained. LC-MS-3A-9(ES, m / z):[M+1]=1043

[0583] 3.10 Synthesis of Compound 3A N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide]-6-{5-[(2-methyl To tert-butyl hydroxyl (110 mg, 0.105 mmol, 1 equiv) of tert-butyl lupropane-2-sulfinyl)amino]-5,7-dihydrospiro[cyclopentadiene[c]pyridine-6,4'-piperidine]-1'-yl}-6-oxohexyl]carbamate, 4 M HCl (gas) / 1,4-dioxane (5 mL) was added dropwise, and the mixture was stirred at room temperature under nitrogen protection for 3 hours. The crude product was obtained by concentration under reduced pressure. The crude product (100 mg) was divided... The sample was purified by HPLC under the following conditions: column: C18 silica gel, mobile phase: acetonitrile / aqueous solution, gradient from 10% to 50% over 10 min, detector: UV220 nm). After fractional distillation and rotational drying, (2R)-N-[(2R)-6-amino-1-{5-amino-5,7-dihydrospiro[cyclopentadiene[c]pyridine-6,4'-piperidine]-1'-yl}-1-oxohexane-2-yl]-2-[(2R)-2-amino-3-phenylpropanamide]-3-phenylpropanamide]-4-methylpentanamide (20.1 mg, 18.2%, purity 70.3%). LC-MS-3A(ES, m / z):[M+1]=739 1H NMR (400 MHz, Deuterium Oxide) δ8.40 (s, 1H), 8.27 (s, 3H), 7.81 (dd, J = 8.2, 4.4 Hz, 1H), 7.41 - 6.90 (m, 11H), 4.58 - 4.38 (m, 2H), 4.36 - 4.16 (m, 2H), 4.10 (s, 2H), 3.98 - 3.71 (m, 1H), 3.39 (d, J = 12.4 Hz, 1H), 3.23 - 2.72 (m, 9H), 1.81 - 1.20 (m, 13H), 0.79 (dt, J = 20.4, 5.1 Hz, 6H).

[0584] Example 4A Synthesis of Compound 4A

[0585] [ka]

[0586] 4.1 Synthesis of Compound 4A-1 Under a nitrogen atmosphere, at 0°C, a stirred solution of 6-chloropyridine-2-amine (500 mg, 3.889 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) was mixed with sodium bis(trimethylsilyl)amine. D (1426.37 mg, 7.778 mmol) was added. Di-tert-butyl dicarbonate (933.69 mg, 4.278 mmol, 1.1 equiv) was added dropwise to the above mixture. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water / ice at 0°C. The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (10:1), fractional distillation and rotational drying were performed to obtain N-(6-chloropyridine-2- tert-butyl ylcarbamate (800 mg, 89.95%, purity: 99%) was obtained. LC-MS-4A-1 (ES, m / z): [M+1]=229

[0587] 4.2 Synthesis of Compound 4A-2 In a two-necked round-bottom flask, tetramethylethylenediamine (3353.91 mg, 28.862 mmol, 2.2 equiv) was dissolved in tetrahydrofuran (78.43 mL). The mixture was then infused at -78°C. Butyllithium (1848.71 mg, 28.862 mmol, 2.2 equiv) was added dropwise. The mixture was left at -20°C. The mixture was stirred for another 30 minutes. 4-oxopiperidine-1-carboxylate benzyl ester (4590.26 mg, 19.678 mmol, 1.5 equiv) was added dropwise to the mixture at -78°C. The mixture was stirred for another hour at -78°C. N-(6-chloropyridine-2-yl)carbamic acid tert-butyric acid was added to the mixture at -50°C. 3000 mg, 13.119 mmol, 1.00 equiv of ru (3000 mg) was added dropwise. The resulting mixture was stirred overnight at 40°C. The resulting mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (2:1) to obtain 7'-chloro-2'-oxo-1'H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxylate benzyl ester (3000 mg, 58.97%, purity 99%). LC-MS-4A-2 (ES, m / z): [M+1]=388

[0588] 4.3 Synthesis of Compound 4A-3 7'-chloro-2'-oxo-1'H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxylate benzyl ester (230 mg, 0.612 mmol, 1.00 equiv) was dissolved in methanol (20 mL), Pd / C (12.62 mg, w / t, 10%) was added, and hydrogen was replaced three times. The resulting mixture The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-2'(1'H)-one (110 mg, crude product). LC-MS-4A-3 (ES, m / z): [M+1]=220

[0589] 4.4 Synthesis of Compound 4A-4 Spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-2'(1'H)-one (44 mg, 0.138 mmol, 1.00 equiv) and intermediate 2 (100 mg, 0.067 mmol, 0.5 equiv) in DMF (2 mL) The mixture was dissolved, and diisopropylethylamine (34 mg, 0.4 mmol, 3.00 equiv) and HATU (76 mg, 0.207 mmol, 1.50 equiv) were added in several portions. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was combined, dried, and concentrated in a vacuum. ((10R,13R,16R,19R)-16-ben Zyl-13-isobutyl-2,2-dimethyl-4,12,15,18-tetraoxo-10-(2'-oxo-1',2'dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carbonyl)-20-fe Tert-butyl yl-3-oxa-5,11,14,17-tetraazaeikosan-19-yl)carbamate was obtained (120 mg, crude product). LC-MS-4A-4 (ES, m / z): [M+1]=955

[0590] 4.5 Synthesis of Compound 4A In a 50 mL round-bottom flask, add ((10R,13R,16R,19R)-16-benzyl-13-isobutyl-2,2-dimethyl Tyl-4,12,15,18-tetraoxo-10-(2'-oxo-1',2'dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carbonyl)-20-phenyl-3-oxa-5,11,14,17-tetraoxa 120 mg, 0.126 mmol, 1.00 equiv) of tert-butyl traazaeicosan-19-yl carbamidate and a solution of 1,4-dioxane (4 mL) in 4 M HCl (gas) were added. The resulting mixture was prepared by adding tert-butyl traazaeicosan-19-yl carbamidate (120 mg, 0.126 mmol, 1.00 equiv) and a solution of 1,4-dioxane (4 mL) in 4 M HCl (gas). The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and subjected to reverse flash chromatography. The following methods were used to purify the material, followed by fractional distillation and rotary drying: (2R)-N-[(2R)-6-amino-1-oxo-1-{2'-O Xo-1'H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-yl}hexa-2-yl]-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamide]-3-phenylpropanamide Mido-4-methylpentanamide (7 mg, 7.31%, purity 99.2%) was obtained. LC-MS-4A (ES, m / z):[M+1]=755 1 H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 2H), 8.10 (dd, J = 10.1, 5.0 Hz, 1H), 7.58 (dd, J = 15.2, 7.7 Hz, 1H), 7.24 (h, J = 7.1 Hz, 6H), 7.12 (q, J = 7.7 Hz, 5H), 4.67 (s, 1H), 4.55 (q, J = 7.5 Hz, 1H), 4.33 (d, J = 13.6 Hz, 1H), 4.25 - 4.16 (m, 1H), 4.07 - 3.82 (m, 2H), 3.66 - 3.43 (m, 1H), 3.09 (q, J = 13.2 Hz, 1H), 3.04 - 2.82 (m, 6H), 2.15 (d, J = 27.4 Hz, 2H), 2.05 - 1.82 (m, 2H), 1.78 - 1.55 (m, 4H), 1.57 - 1.23 (m, 5H), 0.84 (dt, J= 20.5, 5.2 Hz, 6H).

[0591] Example 5A Synthesis of Compound 5A

[0592]

change

[0593] LC-MS-5A(ES, m / z):[M+1]=753 1 H NMR (300 MHz, Deuterium Oxide) δ8.55 - 8.39 (m, 1H), 8.35 (s, 2H), 7.97 - 7.74 (m, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.37 - 7.00 (m, 10H), 4.85-4.70(m, 2H), 4.58 - 4.46 (m, 1H), 4.33 - 4.13 (m, 2H), 4.05 - 3.79 (m, 2H), 3.71 - 3.54 (m, 2H), 3.50 - 3.26 (m, 1H), 3.02 - 2.82 (m, 6H), 1.95 - 1.17 (m, 13H), 0.83 (dd, J = 14.9, 6.7 Hz, 6H).

[0594] Example 6A Synthesis of Compound 6A

[0595]

change

[0596] LC-MS-6A(ES, m / z):[M+1]=753 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H), 8.23 ​​- 7.98 (m, 1H), 7.77 (dd, J = 27.3, 7.8 Hz, 1H), 7.47 - 6.96 (m, 11H), 4.85 - 4.77 (m, 1H), 4.58 (t, J = 7.5 Hz, 1H), 4.34 - 4.01 (m, 3H), 3.86 (dd, J = 53.3, 14.0 Hz, 1H), 3.46 (q, J = 12.7, 12.2 Hz, 1H), 3.25 - 2.68 (m, 9H), 2.10 - 1.58 (m,8H), 1.47 (d, J= 6.9 Hz, 5H), 1.13 - 0.44 (m, 6H).

[0597] Example 7A Synthesis of Compound 7A

[0598]

change

[0599] LC-MS-7A(ES, m / z):[M+1]=753 1 H NMR (400 MHz, Deuterium Oxide) δ8.38 (s, 2H), 7.88 - 7.37 (m, 2H), 7.42 - 7.00 (m, 10H), 6.90 - 6.47 (m, 1H), 4.57 (t, J = 7.4 Hz, 2H), 4.37 - 3.97 (m, 3H), 3.86 (dd, J = 44.1, 13.8 Hz, 1H), 3.63 - 3.34 (m, 3H), 3.20 - 2.66 (m, 9H), 2.28 - 1.11 (m, 15H), 0.84 (dd, J = 20.1, 5.4 Hz, 6H).

[0600] Example 8A Synthesis of Compound 8A

[0601]

change

[0602] 8.1 Synthesis of Compound 8A-1 4-aminopiperidine-1-carboxylate benzyl ester (500 mg, 2.134 mmol, 1 equiv) was dissolved in toluene (5 mL), diphosgene (260 μL, 1.314 mmol, 0.62 equiv) was added, and the mixture was stirred at 90°C for 3 hours. Then, tetrahydropyran-4-ol (205 μL, 2.007 mmol, 0.94 equiv) was added dropwise. The resulting mixture was stirred overnight at 90°C under nitrogen protection. The reaction mixture was cooled to room temperature, then poured into ice water, and the resulting mixture was extracted with siRNA (3 × 10 mL). The combined organic layers were washed with ethyl acetate (3 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0603] 8.2 Synthesis of Compound 8A-2 Compound 8A-1 (433 mg, 1.195 mmol, 1 equiv) and Pd / C (100 mg, w / t, 10%) were methylated. Add to (10 mL, 246.988 mmol, 206.73 equiv) and stir overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the filtrate was rotated dry to obtain oxa-4-yl N-(piperidine-4-yl)carbamate (448 mg, crude product).

[0604] 8.3 Synthesis of Compound 8A-3 Under nitrogen protection at room temperature, dioxan-4-yl N-(piperidine-4-yl)carbamate (113 mg, 0.495 mmol, 1.5 equiv) was dissolved in DMF (10 mL) to obtain intermediate 2 (248.79 mg, 0.330 mmol). Add (1 equiv) and stir, then add DIPEA (85.30 mg, 0.660 mmol, 2 equiv) and HATU (188.21 mg, 0.495 mmol, 1.5 equiv), and stir overnight after the additions are complete. Add water and mix. The mixture was entrenched and extracted with toluene (3 × 20 mL). The combined organic layer was then ethyl acetate. The solution was washed with ether (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: silica gel, mobile phase: aqueous MeCN, gradient from 10% to 50% over 10 min, detector: UV 254 nm. Compound 8A-3 (104 mg, 32.69%, purity 99%) was obtained by fractional distillation and tumble drying.

[0605] 8.4 Synthesis of Compound 8A At room temperature under nitrogen protection, compound 8A-3 (104 mg, 0.108 mmol, 1 equiv) and TFA (4 mL) were added to DCM (16 mL) and stirred for 3 hours. The resulting mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flash chromatography under the following conditions: column: silica gel, mobile phase: aqueous MeCN, gradient from 10% to 50% over 10 minutes, detector: UV 254 nm. Compound 8A (19.7 mg, 22.73%, purity 95.0%) was obtained by fractional distillation and rotational drying. LC-MS-8A(ES, m / z):[M+1]=764 1 H NMR (400 MHz, Deuterium Oxide) δ8.36 (s, 1H), 7.26 (h, J = 6.6 Hz, 6H), 7.13 (t, J = 7.1 Hz, 4H), 4.55 (dt, J = 8.0, 4.0 Hz, 2H), 4.30 - 3.99 (m, 2H), 3.98 - 3.72 (m, 4H), 3.56 (d, J = 10.5 Hz, 3H), 3.22 (q, J = 13.9 Hz, 1H), 2.96 (t, J = 6.7 Hz, 3H), 2.90 (td, J = 7.6, 2.7 Hz, 3H), 1.85 (s, 4H), 1.74 - 1.52 (m, 6H), 1.52 - 1.17 (m, 7H), 0.93 - 0.75 (m, 6H).

[0606] Example 9A Synthesis of Compound 9A

[0607] [ka]

[0608] LC-MS-9A(ES, m / z):[M+1]=812.25 1 H NMR (300 MHz, Deuterium Oxide) δ8.41 (s, 2H), 7.38 - 7.16 (m, 10H), 4.92 (s, 1H), 4.60 (s, 2H), 4.26 (s, 2H), 4.02 (d, J = 38.6 Hz, 2H), 3.67 (s, 1H), 3.41 - 2.90 (m, 12H), 2.28 (s, 4H), 1.93 (d, J = 21.3 Hz, 2H), 1.71 - 1.28 (m, 11H), 0.95 - 0.83 (m, 6H).

[0609] Example 10A Synthesis of Compound 10A

[0610] [ka]

[0611] 10.1 Synthesis of Compound 10A-3 Compound 10A-2 (1 g) was added to a 100 mL round-bottom flask and stirred in DCM (40 mL) at room temperature for 30 minutes until swollen. The mixture was filtered, the solid was washed with DCM, and dried. After dissolving the solid in DMF (40 mL), Compound 10A-1 (2 g, 8.761 mmol, 1.00 equiv), DCC (5.42 g, 26.283 mmol, 3 equiv) HOBT (2.37 g, 17.522 mmol, 2 equiv) was added and the mixture was stirred at room temperature for 3 hours. Finally, DMAP (0.54 g, 4.380 mmol, 0.5 equiv) was added and the mixture was stirred overnight at room temperature. The resulting mixture was filtered, washed with MeOH, and the solid was collected to obtain compound 10A-3 (3 g, crude product), which was a white solid. The resulting mixture was then directly added to the next step without further purification.

[0612] 10.2 Synthesis of Compound 10A-4 Under nitrogen protection at room temperature, compound 10A-3 (2.9 g, 5.560 mmol, 1 equiv) was mixed with DMF (40 mL) and The mixture was stirred for 6 hours in a solution of piperidine (10 mL). The resulting mixture was filtered, washed with MeOH, and the solid was collected and tumble-dried. The resulting white crude product (2 g) was then taken to the next step. I added it directly.

[0613] 10.3 Synthesis of Compound 10A-6 Under nitrogen protection, at room temperature, a solution of compound 10A-4 (2 g, 6.681 mmol, 1 equiv) in DMF (10 mL) was prepared. Compound 10A-5 (3.54 g, 10.021 mmol, 1.5 equiv) was added, and DIEA (1.30 g, 10.021 mmol, 1.5 equiv), HOBT (1.35 g, 10.021 mmol, 1.5 equiv), and TBTU (3.22 g, 10.021 mmol, 1.5 equiv) were added at room temperature. After stirring for 2 hours at room temperature, the resulting mixture was filtered, washed with MeOH, and the solid was collected. Compound 10A-6 (2.9 g, crude product) was obtained by concentrating under reduced pressure.

[0614] 10.4 Synthesis of Compound 10A-7 Under nitrogen protection at room temperature, compound 10A-6 (2 g, 3.151 mmol, 1 equiv) was reacted with a mixed solution of TFA (10 mL, 134.631 mmol, 42.73 equiv) and DCM (40 mL, 629.224 mmol, 199.71 equiv) by stirring for 4 hours. The resulting mixture was concentrated under reduced pressure and rotated dry to form the compound. Product 10A-7 (1.6 g, crude product) was obtained. LC-MS-10A-7(ES, m / z): [M+1]=424

[0615] 10.5 Synthesis of Compound 10A-9 Under nitrogen protection, compound 10A-8 (229.60 mg, 0.728 mmol, 1.5 equiv) was added to a solution of compound 10A-7 (206 mg, 0.485 mmol, 1 equiv) in DMF (10 mL) at room temperature. HATU (276.78 mg, 0.728 mmol, 1.5 equiv) and DIPEA (125.44 mg, 0.970 mmol, 2 equiv) were then added at room temperature. After reacting with stirring for 4 hours, water was added to quench the reaction. The resulting mixture was extracted with EA (3 × 100 mL), the organic layer was washed with EA (3 × 10 mL), and dried over Na₂SO₄. The mixture was filtered, the resulting liquid was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (under the following conditions: C18 chromatography column, mobile phase, solvent ACN and solvent H2O (0.1% FA), 10 min gradient from 10% to 50%, UV254 nano detector). Compound 10A-9 (165 mg, 47.10%) was obtained by fractional distillation and rotational drying. LC-MS-10A-9(ES, m / z):[M+1]=721

[0616] 10.6 Synthesis of Compound 10A-10 Under nitrogen protection at room temperature, compound 10A-9 (165 mg, 0.229 mmol, 1 equiv) was reacted with a solution of piperidine (1 mL) and DCM (10 mL) by stirring for 3 hours. The resulting liquid was concentrated under reduced pressure. The product was reduced, and the resulting crude product was subjected to reverse-phase column chromatography using C18 chromatography. - Column, mobile phase, solvent ACN and solvent H2O (0.1% FA), 10 min gradient from 10% to 50%, UV254 The compound 10A-10 (100 mg, 87.5%) was purified under conditions of a detector, then fractional distillation and rotational drying were performed. This was obtained. LC-MS-10A-10(ES, m / z):[M+1]=499

[0617] 10.7 Synthesis of Compound 10A-13 Under nitrogen protection, compound 10A-12 (1.93 g, 4.981 mmol, 1.28 equiv) was added to a solution of compound 10A-11 (1 g, 3.880 mmol, 1 equiv) in DMF (10 mL) at room temperature. HATU (2.1 g, 8.712 mmol, 2.25 equiv) and DIPEA (1.8 g, 13.927 mmol, 3.59 equiv) were added dropwise, and the mixture was stirred overnight to allow it to react. The resulting mixture was quenched with water and extracted with EA (3 × 100 mL). The mixture was dried in phase, rotary dried, filtered, and the resulting liquid was concentrated under reduced pressure. The crude product was then subjected to reverse-phase column chromatography (under the following conditions: C18 chromatography). - Column, mobile phase, solvent ACN and solvent H2O (0.1% FA), 10 min gradient from 10% to 50%, UV254 The compound 10A-13 (1.86 g, 81.16%, purity 99%) was obtained by purification using a detector, fractional distillation, and rotational drying. LC-MS-10A-13(ES, m / z):[M+1]=590

[0618] 10.8 Synthesis of Compound 10A-14 Under nitrogen protection at room temperature, compound 10A-13 (1.86 g, 3.149 mmol, 1 equiv) was reacted with a mixed solution of TFA (6 mL, 61.209 mmol, 19.44 equiv) / DCM (24 mL, 377.534 mmol, 119.90 equiv) by stirring for 3 hours. The resulting mixture was concentrated under reduced pressure to obtain compound 10A-14 (2.7 g, crude product). LC-MS-10A-14(ES, m / z):[M+1]=535

[0619] 10.9 Synthesis of Compound 10A-15 Under nitrogen protection, compound 10A-14 (74.90 mg, 0.140 mmol, 1 equiv) was added to a solution of compound 10A-10 (70 mg, 0.140 mmol, 1 equiv) in DMF (10 mL) at room temperature. HATU (53.27 mg, 0.140 mmol, 1.5 equiv) and DIPEA (24.14 mg, 0.187 mmol, 1.25 equiv) were added, and the mixture was stirred for 4 hours to allow the reaction to proceed. Water was added to the reaction mixture to quench it, and the organic phase was extracted with EA (3 × 100 mL). The two components were combined and dried, then rotary dried. The resulting crude product was subjected to reverse-phase column chromatography (conditions were as follows: C18 chromatography column, mobile phase, solvent ACN and solvent H2O). Purified by (0.1% FA), 10 min gradient of 10% to 50%, UV254 nano detector), followed by fractional distillation and rotation. After drying, compound 10A-15 (118 mg, 83.1%, purity 99%) was obtained. LC-MS-10A-15(ES, m / z):[M+1]=1017

[0620] 10.10 Synthesis of compound 10A-16 Under nitrogen protection at room temperature, compound 10A-15 (118 mg, 0.116 mmol, 1 equiv) was dissolved in piperidine (1 The reaction was carried out by stirring for 2 hours in a solution of (mL) and DCM (10 mL). The resulting liquid was concentrated under reduced pressure to obtain compound 10A-16 (94 mg, crude product), and the obtained crude product was used in the next step. I added it directly. LC-MS-10A-16(ES, m / z):[M+1]=916

[0621] 10.11 Synthesis of Compound 10A Under nitrogen protection at room temperature, compound 10A-16 (94 mg, 0.118 mmol, 1 equiv) was reacted with a mixed solution of TFA (1 mL) / DCM (5 mL) by stirring for 2 hours. The resulting filtrate was concentrated under reduced pressure. The product was reduced, and the resulting crude product was purified by reverse-phase column chromatography (conditions as follows: C18 chromatography column, mobile phase, solvent ACN and solvent H2O (0.1% FA), 10 min gradient from 10% to 50%, UV254 nano detector), fractional distillation, and rotational drying to obtain compound 10A (0.0233 g). A solution with a purity of 99.0% and a concentration of 28.22% was obtained. LC-MS-10A (ES, m / z):[M+1]=694 1H NMR (400 MHz, Deuterium Oxide) δ 8.37 (s, 1H), 7.30 (s, 3H), 7.30 - 7.19 (m, 4H), 7.14 (dd, J = 6.8, 4.0 Hz, 3H), 4.61 (t, J = 6.7 Hz, 1H), 4.53 (t, J = 7.5 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 4.22 (t, J = 7.9 Hz, 1H), 4.00 (t, J = 13.1 Hz, 2H), 3.91 (d, J = 5.7 Hz, 1H), 3.64 (s, 3H), 3.21 (s, 2H), 3.13 (d, J = 13.5 Hz, 1H), 2.94 (ddd, J = 15.8, 9.8, 4.5 Hz, 6H), 2.66 (s, 1H), 1.81 (q, J = 7.3 Hz, 3H), 1.74 (d, J = 14.4 Hz, 2H), 1.46 (d, J = 8.1 Hz, 4H), 1.26 (dd, J = 14.7, 7.1 Hz, 3H), 0.85 (dt, J = 20.3, 5.0 Hz, 6H).

[0622] Example 11A Synthesis of Compound 11A

[0623]

change

[0624] LC-MS-11A (ES, m / z): [M+1]=680 1H NMR (400 MHz, Deuterium Oxide) δ8.35 (s, 1H), 7.24 (ddd, J = 11.2, 7.7, 5.5 Hz, 6H), 7.10 (t, J = 9.0 Hz, 4H), 4.69 (s, 2H), 4.58 (t, J = 7.1 Hz, 1H), 4.48 (t, J = 7.4 Hz, 1H), 4.36 (s, 1H), 4.20 (t, J = 8.0 Hz, 1H), 4.08 (s, 1H), 4.00 (d, J = 13.6 Hz, 1H), 3.68 (d, J = 6.7 Hz, 1H), 3.64 (s, 1H), 3.47 - 3.39 (m, 2H), 3.14 (t, J = 13.3 Hz, 1H), 3.06 - 2.98 (m, 2H), 2.90 (s, 2H), 2.85 (dd, J = 17.8, 6.6 Hz, 2H), 2.65 (s, 1H), 1.75 (s, 2H), 1.51 (s, 3H), 1.43 (s, 3H), 1.24 (dd, J = 12.7, 7.0 Hz, 3H), 0.82 (dt, J = 20.9, 5.0 Hz, 6H).

[0625] Example 12A Synthesis of Compound 12A

[0626]

change

[0627] LC-MS-12A(ES, m / z):[M+1]=637 1 H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 1H), 7.32 - 7.17 (m, 6H), 7.12 (dd, J = 7.2, 3.8 Hz, 4H), 4.68 (s, 1H), 4.61 - 4.46 (m, 1H), 3.88 (t, J = 6.9 Hz, 2H), 3.61 (s, 2H), 3.56 (s, 4H), 3.21 (q, J = 13.1 Hz, 3H), 2.98 - 2.88 (m, 4H), 1.93 (s, 1H), 1.84 (d, J = 13.1 Hz, 1H), 1.43 (s, 2H), 1.30 (s, 2H), 1.23 (t, J = 7.0 Hz, 4H), 0.85 - 0.80 (d, J = 4.9 Hz, 6H).

[0628] Example 1B Synthesis of Compound 1B

[0629] [ka]

[0630] 1.1 Synthesis of Compound 1B-2 Under room temperature and nitrogen protection conditions, intermediate 2 (750 mg, 0.995 mmol, 1.00 equiv) and DIEA (192.85 mg, 1.492 mmol, 1.5 equiv) were dissolved in DMF (30 mL), and HATU (567.37 mg, 1.492 mmol, 1.5 equiv) and compound 1B-1 (200 mg, 1.492 mmol, 1.5 equiv) were added in multiple portions. The resulting mixture was stirred overnight under room temperature and nitrogen conditions. The resulting crude product was purified by reverse-phase column chromatography under the following conditions: C18 column, mobile phase, solvent ACN and solvent H2O. (0.1% formic acid), 10 min gradient from 10% to 50%, UV200 nanometer, obtained fractional distillation and rotation After drying, N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3]-phenylpropanamide]-3-phenylpropanamide]-4-methylpenta [Iminamide]-6-(1-imino-1-oxo-1λ6-thiomorpholin-4-yl)-6-oxohexyl]carbamate tert-butyl (600 mg, 69.32%, purity 99%) was obtained, exhibiting a pale yellow solid. LC-MS-1B-2 (ES, m / z):[M+1]=870

[0631] 1.2 Synthesis of Compound 1B In a 25 mL round-bottom flask, add N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoki [Cicarbonyl)amino]-3]-phenylpropanamide]-3-phenylpropanamide]-4-Me [Tylpentanamide]-6-(1-imino-1-oxo-1λ6-thiomorpholin-4-yl)-6-oxo 80 mg, 0.092 mmol, 1.00 equiv tert-butyl hexylcarbamate and 8 mL of 1,4-dioxane solution in 4 M HCl were added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography under the following conditions: C18 column, mobile phase, solvent ACN and solvent H2O (0.1% formic acid), 10 min gradient from 10% to 50%. The detector is UV200 nanometers, and (R)-N-((R)-6-amino-1-(1-imino-1-oxo-1λ6-thiomorpholin)-1-oxohexy-2-yl)-2-((R)-2-((R)-2-amino-3-fu Phenylpropanamide-3-phenylpropanamide-4-methylpentanamide (10.2 mg, 15.90%, purity 95.9%) was obtained. LC-MS-1B (ES, m / z):[M+1]=670 1H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 2H)(HCOOH), 7.63 - 7.01 (m, 10H), 4.56 (t, J = 7.5 Hz, 1H), 4.37 - 3.87 (m, 5H), 3.85 - 3.67 (m, 1H), 3.52 (t, J = 12.4 Hz, 1H), 3.40 - 3.07 (m, 4H), 3.11 - 2.81 (m, 6H), 1.64 (tt, J = 15.1, 7.8 Hz, 4H), 1.52 - 1.17 (m, 5H), 0.85 (dd, J = 21.2, 5.0 Hz, 6H).

[0632] Example 2B Synthesis of Compound 2B

[0633] [ka]

[0634] Prepare the target compound according to steps similar to those in Example 1B, and then prepare the reaction raw materials.

[0635] [ka]

[0636] of

[0637] [ka]

[0638] It differed in that it was replaced with something else. LC-MS-2B (ES, m / z):[M+1]=684.20 1 H NMR (400 MHz, Deuterium Oxide) δ8.30 (d, J = 6.9 Hz, 1H), 7.51 - 7.05 (m, 10H), 4.62 (dt, J = 15.2, 7.6 Hz, 2H), 4.33 - 4.12 (m, 3H), 4.12 - 3.90 (m, 1H), 3.87 - 3.66 (m, 1H), 3.62 - 3.36 (m, 4H), 3.36 - 3.04 (m, 3H), 2.98 (dq, J = 24.6, 7.8 Hz, 4H), 2.73 (s, 3H), 1.92 - 1.60 (m, 4H), 1.57 - 1.21 (m, 5H), 0.87 (dd, J= 20.8, 5.0 Hz, 6H).

[0639] Example 3B Synthesis of Compound 3B

[0640] [ka]

[0641] Prepare the target compound according to steps similar to those in Example 1B, and then prepare the reaction raw materials.

[0642] [ka]

[0643] of

[0644] [ka]

[0645] It differed in that it was replaced with something else. LC-MS-3B (ES, m / z):[M+1]=712.20 1 H NMR (400 MHz, Deuterium Oxide) δ8.37 (s, 1H), 7.43 - 7.01 (m, 10H), 4.63 - 4.50 (m, 1H), 4.43 (s, 1H), 4.33 - 3.98 (m, 4H), 3.98 - 3.26 (m, 6H), 3.12 - 2.70 (m, 6H), 2.18 - 1.91 (m, 3H), 1.74 - 1.27 (m, 9H), 0.98 - 0.72 (m, 6H).

[0646] Example 4B Synthesis of Compound 4B

[0647] [ka]

[0648] Prepare the target compound according to steps similar to those in Example 1B, and then prepare the reaction raw materials.

[0649] [ka]

[0650] of

[0651] [ka]

[0652] It differed in that it was replaced with something else. LC-MS-4B (ES, m / z):[M+1]=728.10 1 H NMR (300 MHz, Deuterium Oxide) δ8.34 (s, 2H), 7.38 - 7.07 (m, 10H), 4.63 - 4.04 (m, 5H), 3.96 (q, J = 6.5 Hz, 1H), 3.86 - 3.30 (m, 8H), 3.22 (s, 1H), 3.12 - 2.59 (m, 6H), 1.90 - 1.09 (m, 9H), 0.89 (dd, J = 13.9, 5.0 Hz, 6H).

[0653] This specification provides illustrative examples of the preparation of the above compounds, and those skilled in the art will understand that other unexecuted compounds of the present invention can also be prepared by referring to the above general methods and specific examples.

[0654] Comparative example 1B

[0655] [ka]

[0656] The compound was prepared by referring to the method of Example 5 of CN108290926A.

[0657] Biological testing and evaluation The present invention will be further explained and interpreted below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0658] This disclosure describes how the following CR845 is prepared with reference to the method of Example 2 of CN101627049A shown below.

[0659] [ka]

[0660] Test Example 1. In vitro receptor binding experiment 1.1 Experimental Objectives In vitro isotope labeling was used to detect the affinity of compounds for μ, Kappa, and delta receptors.

[0661] 1.2 Experimental Materials Cell lines: CHO-K1-μ, CHO-K1-Kappa, CHO-K1-delta stable transformed cell lines (Nanjing Jinsuishu) Materials Technology Co., Ltd.)

[0662] [Table 1]

[0663] [Table 2]

[0664] [Table 3]

[0665] [Table 4]

[0666] 1.3 Experimental Method 1.3.1 Buffer preparation A: (Preparation of μ, Kappa, and delta receptor membranes): Weigh 11.7 mg of EDTA and 380.84 mg of MgCl2, add 50 mM of Tris-HCl buffer to make a total volume of 400 mL, and adjust the pH to 7.4. The final concentration was then determined. These were converted to EDTA 0.1 mM and MgCl2 10 mM, respectively.

[0667] B: Compound preparation: The theoretical amount of compound to be charged was calculated according to the design concentration and desired volume. 5.0 × 10 -3 M is used as the initial formulation dose, dissolved in DMSO, and then diluted with DMSO for 5.0 × 10⁻⁶ times. -4 M~5.0×10 -9 Dilute the DMSO solution sequentially with M, and then use Buffer to reach a working concentration of 5.0 × 10⁻¹⁰. -5 M~5.0×10 -11 Diluted to M, the final concentration of the working solution DMSO was 1% (the final concentration of the reaction system DMSO was 0.2%). After sample preparation, at 4°C It was saved and discarded after the exam.

[0668] 1.3.2 Preparation of receptor membranes Cells such as CHO-μ, Kappa, and delta were removed from a -80°C refrigerator, allowed to thaw naturally, and then centrifuged at 1000 g at 4°C for 10 minutes. The precipitate was removed, and the supernatant was discarded. Buffer was added to the precipitate, homogenized for 20-30 seconds, and then centrifuged at 50000 g at 4°C for 15 minutes. The upper layer was carefully discarded, buffer was added again, mixed uniformly, and centrifuged at 50000 g at 4°C for 15 minutes. This process was repeated three times. I returned it. I stored it at -80°C.

[0669] 1.3.3 Receptor competitive binding test 3.3.1 μ-receptor affinity test Step 1: Add 50 μL of vehicle (1% DMSO) to a fully bound tube (TB) and nonspecific 50 μL of DAMGO (final concentration 1.0 × 10) in a binding tube (NB). -5 M) was added, and 50 μL of the test compound was added to each test compound tube (CB). Step 2: 100 μL of buffer (homogenate A) was added to each reaction tube. Step 3: First, the prepared membrane homogenate A was prepared into a 10 mg / mL membrane suspension for use. Step 4: Add a radioactive ligand to each reaction tube. 3 50 μL of [H] DAMGO was added at a final concentration of 2 nM. Step 5: 50 μL of membrane solution was added to each reaction tube. Step 6: Incubate each reaction tube at 25°C for 90 minutes, and after the reaction is complete, the bound ri The Gand was rapidly filtered under reduced pressure, the UniFilter GF / C plate was prematurely saturated with 0.5% PEI solution for 1 hour, thoroughly washed with ice-cold Tris buffer, filtered by vacuum, and then dried in a constant temperature drying box for 30 minutes. The filtered plate was removed and MICROSCINT PS scintillation solution was added at a rate of 40 μL / well. Step 7: Place the scintillation cup into the liquid scintillation counter. It undone.

[0670] 3.3.2 Kappa receptor competitive binding test Step 1: Add 50 μL of vehicle (1% DMSO) to a fully bound tube (TB) and nonspecific 50 μL of U69593 (final concentration 1.0 × 10) in a binding tube (NB). -5 Add M) and each test compound 50 μL of the test compound was added to tube (CB). Step 2: 100 μL of buffer (homogenate A) was added to each reaction tube. Step 3: First, the prepared membrane homogenate A was prepared into a 15 mg / mL membrane suspension for use. Step 4: A radioactive ligand is placed in each reaction tube. 3 50 μL of H-U69593 was added at a final concentration of 2 nM. Step 5: 50 μL of membrane solution was added to each reaction tube. Step 6: Incubate each reaction tube at 25°C for 90 minutes, and after the reaction is complete, the bound ri The Gand was rapidly filtered under reduced pressure, the UniFilter GF / C plate was prematurely saturated with 0.5% PEI solution for 1 hour, thoroughly washed with ice-cold Tris buffer, filtered by vacuum, and then dried in a constant temperature drying box for 30 minutes. The filtered plate was removed and MICROSCINT PS scintillation solution was added at a rate of 40 μL / well. Step 7: The filtration plate was placed in a liquid scintillation counter and counted. .

[0671] 3.3.3 Delta receptor competitive binding study Step 1: Add 50 μL of vehicle (1% DMSO) to a fully bound tube (TB) and nonspecific 50 μL of DADLE (final concentration 1.0 × 10) in a binding tube (NB). -5 M) was added, and 50 μL of the test compound was added to each test compound tube (CB). Step 2: 100 μL of buffer (homogenate A) was added to each reaction tube. Step 3: First, the prepared membrane homogenate A was prepared into a 10 mg / mL membrane suspension for use. Step 4: A radioactive ligand is placed in each reaction tube. 3 50 μL of H-DADLE at a final concentration of 4 nM Added. Step 5: 50 μL of membrane solution was added to each reaction tube. Step 6: Incubate each reaction tube at 25°C for 90 minutes, and after the reaction is complete, the bound ri The Gand was rapidly filtered under reduced pressure, the UniFilter GF / C plate was prematurely saturated with 0.5% PEI solution for 1 hour, thoroughly washed with ice-cold Tris buffer, filtered by vacuum, and then dried in a constant temperature drying box for 30 minutes. The filtered plate was removed and MICROSCINT PS scintillation solution was added at a rate of 40 μL / well. Step 7: The filtration plate was placed in a liquid flush counter and counted.

[0672] 1.4 Data Analysis Based on the effect values ​​at test points of different concentrations of the compound sample, the action curve of the compound sample on the receptor was fitted using GraphPad Prism software, and the Ki value was calculated. The results are shown in Table 5.

[0673] [Table 5-1]

[0674] [Table 5-2]

[0675] As can be seen from this, the compounds of the present invention exhibit excellent selectivity for κ-opioid receptors and high affinity for κ-opioid receptors.

[0676] Test Example 2. In vitro functional testing 2.1 Experimental Objectives Using the Cisbio HTRF cAMP-Gi kit, κ-opioids are detected by a microplate reader. We detect changes in cAMP concentration in the receptor (Kappa) signaling pathway and the EC of compounds. 50 We will calculate the value. The agonist effects of compounds on κ-opioid receptors were evaluated.

[0677] 2.2 Experimental materials: Cell line: CHO-K1-OPRK1 stably transformed cell line (Nanjing Jinsirui Biological Technology Co., Ltd.) Cell culture conditions: F12, 10% FBS, 200 μg / mL Zeocin, 100 μg / mL Hygromycin B Reagents and consumables: F12(meilunbio, MA0229) FBS (BOVOGEN, SFBS) Zeocin (invitrogen, R25001) Hygromycin B (invitrogen, 10687010) PBS (meilunbio, MA0015) Pancreatin (Gibco, 25200-072) 96-cell plate (cisbio, 66PL96025) cAMP-Gi kit (cisbio, 62AM9PEB) CO2 incubator (Thermo, 311) Centrifugal separator (Shanghai Anting, TGL-16C) Site meter (Countstar, IC1000) Microplate readers (PerkinElmer, EnVision)

[0678] 2.3 Experimental Method (1) Preparation of reaction buffer (1x Stimulation buffer) required for the experiment: 5x Stimulation buffer and ddH2O from the Cisbio cAMP-Gi kit were diluted in a 1:4 ratio and prepared for use. (2) Preparation of the compound: The compound was diluted with DMSO to a 5 mM stock solution, then diluted 3.16 times in 10 gradients, and the prepared compound was then diluted with Stimulation buffer to the corresponding concentration (2.5 x) for use. (3) Cell preparation: CHO-K1-OPRK1 cells on a culture dish are treated with trypsin and lysed in culture medium. The cells were extracted and collected in a 5 mL centrifuge tube. Centrifuge at 1000 rpm for 5 min and discard the supernatant. Add 3 mL of PBS and mix thoroughly by light pipetting. Centrifuge again at 1000 rpm for 5 min and discard the supernatant. Resuspend the cells in 1 x Stimulation buffer and Countstar The cell density was measured using a lithometer, and the cell density was calculated to be 6 × 10⁻⁶. 5 The amount was adjusted to 1 / mL and prepared for use. (4) Cell addition: The cell suspension was added to the experimental plate at a rate of 5 μL / well (i.e., approximately 3000 cells / well). (5) Compound addition: Add the compound diluted in Stimulation buffer to the above experimental plate in 4 μL / well. It was added. (6) Reaction incubation: After shaking gently, incubate the experimental plate at 37°C for 20 minutes. It was incubated. (7) Addition of the agonist Forskolin: A 10x adenylyl cyclase agonist (Forskolin, final concentration 1 μM) solution was added at a rate of 1 μL / well. (8) Reaction incubation: After shaking gently, incubate the experimental plate at 37°C for 45 minutes. It was incubated. (9) Adding detection reagents: Dilute cAMP-cryptate and Anti-cAMP-d2 1:20 with Lysis & detection buffer from the Cisbio cAMP-Gi detection kit, respectively, and add the above dilutions to the experimental plates. cAMP-cryptate and Anti-cAMP-d2 were added at a concentration of 5 μL / well. After shaking, the experimental plate was opened. The sample was left to stand at room temperature for 60 minutes. (10) Experimental readings: The plate was read using Envision, and readings for the 665 nm and 615 nm channels were detected. The ratio of the 665 nm / 615 nm readings was calculated.

[0679] 2.4 Data Analysis Based on the agonist effect values ​​at test points with different concentrations of compound samples, GraphPad Prism Using software, the agonist action curves of compound samples against κ-opioid receptors were fitted, and EC 50 The calculation was performed. The experimental results are shown in Table 6.

[0680] [Table 6-1]

[0681] [Table 6-2]

[0682] As can be seen from this, the compounds of the present invention have a strong agonist effect on κ-opioid receptors.

[0683] Test Example 3. Sedation Safety Window Test 3.1 Mouse Acetate Rising Test 3.1.1 Test Objectives The analgesic effect of the compound after a single administration was investigated using a mouse acetate lithography test, and its ED 50 They sought it.

[0684] 3.1.2 Test System 3.1.2.1 Laboratory Animal Information Species and strain: ICR mouse Grade: Standard Grade Number and sex: Male, 100 individuals (depending on the circumstances) Age range: 6-8 weeks old Weight range: 23-32 g Supplier: SPF (Beijing) Biotechnology Co., Ltd Animal use permit: SYXK (Su) 2019-053 Disposal of remaining animals: The remaining animals were moved to the experimental system section and processed.

[0685] 3.1.2.2 Equipment and Reagents

[0686] [Table 7]

[0687] 3.1.3 Test Method The mouse acetate rising test is a classic visceral pain test model. Intraperitoneal injection of a 0.6% aqueous acetate solution into mice stimulates the peritoneum, inducing a sustained pain response and a rising response. Analgesics can suppress this rising response. After injecting the drug into the tail vein of the mice, they are first allowed to adapt for 15 minutes, then a 0.6% acetic acid solution (0.1 mL / 10 g) is injected intraperitoneally. A vehicle control group (0.9% sodium chloride injection) is established, and acetic acid is injected into the control group. The number of times mice rose after injection was observed and recorded for 15 minutes, and the rate of inhibition of rising by the test compound was calculated to perform an initial evaluation of the analgesic effect of a single dose. Rising suppression rate % = (Number of sessions in vehicle group - Number of sessions in administration group) × 100% / Number of sessions in vehicle group.

[0688] 3.1.4 Data Processing The mean ± standard deviation (Mean ± SD) of the experimental data was calculated using one-way ANOVA with GraphPad Prism8 statistical software, comparing pairs of data and using Dunnett's t-test, followed by nonlinear fitting to obtain the ED. 50 We calculate this and show that a difference of P<0.05 is statistically significant.

[0689] 3.2 Mouse spontaneous activity test 3.2.1 Test Objectives The effect of a single dose of a compound on the spontaneous activity of mice was measured, and its ED 50 They sought it.

[0690] 3.2.2 Test System 3.2.2.1 Laboratory Animal Information Species and strain: ICR mouse Grade: Standard Grade Number and sex: Male, 200 individuals (depending on the circumstances) Age range: 6-8 weeks old Weight range: 23-35 g Supplier: SPF (Beijing) Biotechnology Co., Ltd Animal use permit: SYXK (Su) 2019-053 Disposal of remaining animals: The remaining animals were moved to the experimental system section and processed.

[0691] 3.2.2.2 Equipment and Reagents

[0692] [Table 8]

[0693] 3.2.3 Test Method The mouse spontaneous motility test is a classic test model for evaluating the degree of central nervous system inhibition by compounds. A sample solution of the appropriate concentration (prepared at the time of use) is administered to mice via tail vein injection. A vehicle (0.9% sodium chloride injection) is administered to the blank group, and immediately after administration, the mice are placed in a spontaneous motility box (a black polyethylene box measuring 29 cm x 29 cm x 30 cm). The mice were recorded for 30 minutes, and after the recording was completed, video analysis was performed to evaluate their spontaneous activity after administration.

[0694] 3.2.4 Data Processing The mean ± standard deviation (Mean ± SD) of the experimental data was calculated using GraphPad Prism8 statistical software. We then performed a one-way ANOVA, compared pairs of data, used a Dunnett t-test, and applied a nonlinear fitting method to ED. 50 We calculate this and show that a difference of P<0.05 is statistically significant.

[0695] 3.3 Safety window Sedation is the most prominent side effect of peripheral Kappa receptor agonists, and ED is a side effect of sedation.50 (From the activity test) / Drug efficacy ED 50 (Lysine acetate test), the sedative safety window can be obtained. It is predicted that the larger the safety window, the higher the safety, and the possibility of clinically occurring sedative side effects at the same dose is reduced. The experimental results are shown in Table 9.

[0696]

Table 9

[0697] As can be seen from this, the compound of the present invention has a large safety window, that is, it has a safer dosage range or a lower possibility of side effects occurring at the same dose.

[0698] Test Example 4 Mouse PK and Brain Penetration 4.1 Purpose of the test: The pharmacokinetic characteristics and blood-brain barrier permeability of the compounds of the present disclosure in mice were investigated.

[0699] 4.2 Test equipment

[0700]

Table 10

[0701] [[ID=4I]]4.3 Test methods and data processing Healthy male ICR mice were randomly divided into groups of 6 animals per group. Each test compound was used in 3 groups of animals. The animals in Group 1 were used to collect blood and brains 5 minutes after administration , and the animals in Groups 2 and 3 were used for cross-blood collection at subsequent time points. The test compounds were intravenously administered to the corresponding group of mice (at 1 mg / kg), and blood was collected from the submandibular vein of the mice at different time points. The drug contents in plasma and brain tissues at different time points were measured by the LC-MS / MS method. The brain-blood ratio B / P was calculated using EXCEL software, and the pharmacokinetic parameters were calculated using DAS3.0 software. The experimental results are shown in Table 11.

[0702]

Table 11

[0703] As can be seen from this, the compounds of the present invention have excellent pharmacokinetic properties. Specifically, compared with CR845, the brain-blood ratio B / P of the compounds of the present invention is equivalent to or lower than that of CR845, and can selectively act on the peripheral Kappa receptor. Moreover, the compounds of the present invention significantly have improved pharmacokinetic properties and a significantly longer half-life.

[0704] Test Example 5 Single-dose Toxicity Test in Mice 5.1 Purpose of the Test: Safety data was supplemented by examining the toxic reaction after a single intravenous administration of the compounds of the present invention to mice.

[0705] 5.2 Test System Species and Strain: ICR mice Grade: SPF grade Gender: Male Body Weight Range: 24 - 28 g Supplier: SPF (Beijing) Biotechnology Co., Ltd Animal Production License: SCXK(Beijing) 2019 - 0010 Animal Use License: SYXK(Suzhou) 2019 - 0053 Treatment of the Remaining Animals: The remaining animals were transferred to the test system section for treatment.

[0706] 5.3 Equipment and Reagents <A <A

[0707] <A <A

Table 12

[0708] <A 5.4 Test Method <A ICR mice were selected, randomly divided into groups of 10 mice each, and administered via tail vein at a dose of 10 mL / kg. Observe and record the condition of the object and the circumstances of death, LD 50 The medication was administered sequentially based on the recommended dosage of the AOT425 software until the value was determined. This process continued until the value was determined.

[0709] 5.5 Data Processing Using AOT425 software 50 The calculation was performed. The results are shown in Table 13.

[0710] [Table 13]

[0711] As can be seen from this, the compounds of the present invention have improved safety because they have low single-dose toxicity.

[0712] Study Example 6: Investigation of the effects of compounds on hERG potassium channels 6.1 Test Objectives This experiment detected the inhibitory effect of compounds on hERG channels using manual patch-clamp techniques.

[0713] 6.2 Test System Non-cardiac drugs inhibit the duration of myocardial action potentials by inhibiting hERG (IKr) channels. The possibility of prolonging and developing life-threatening torsades de pointes (TdP) ventricular arrhythmias. This may increase the risk. In this experiment, the HEK293 cell line, which does not contain endogenous IKr current, was used with host cells. This cell line is used in this manner and is widely used for the detection of hERG.

[0714] HEK293 cells, which stably express hERG channels, were cultured in 35 mm culture dishes and placed in a 37°C / 5% CO2 incubator for at least 24 hours before being used in experiments. The hERG cell line was then used in experiments with 10% bovine cells. The cells were routinely cultured and subcultured in DMEM containing fetal serum and 250 μg / mL of G418.

[0715] 6.3 Liquid formulation The extracellular fluid components used in the whole-cell patch-clamp experiment are (mM): NaCl 145, MgCl21, KCl 4, Glucose 10, HEPES 10, CaCl22, with the pH adjusted to 7.4 with NaOH, and sucrose The osmotic pressure was then adjusted to 300 mOsm.

[0716] The intracellular fluid components were (mM): KCl 140, MgCl21, EGTA 5, HEPES 10, and Na2ATP 4. The pH was adjusted to 7.2 with KOH, and the osmotic pressure was adjusted to 290 mOsm with sucrose.

[0717] [Table 14]

[0718] 6.4 Test Method Electrophysiological recording: One culture dish was removed for each experiment, washed twice with extracellular fluid, and placed on an inverted microscope stage. Whole-cell patch-clamp experiments were performed at room temperature, and the tip resistance of the borosilicate glass microelectrodes used was 3–5 MΩ.

[0719] Voltage stimulation protocol and current recording: After whole-cell recording mode, the membrane potential is clamped to -80 mV, and the cells are stimulated with a depolarizing voltage of +50 mV every 30 seconds, lasting for 2 seconds before repolarizing to -50 mV. And, if it was sustained for 3 seconds, it was possible to extract the hERG tail current. Before the depolarization voltage stimulation, A repolarization voltage of -50 mV was applied to the cell for 50 ms, and the current recorded at this voltage was used as the hERG tail current. This served as the baseline for calculations. Only cells that met the recording criteria were applied to the detection of the test compound. Before adding the compound, the hERG tail current was allowed to subside in extracellular fluid for at least 3 minutes. It was recorded precisely. If the change in hERG tail current amplitude after perfusion administration is less than <5%, the drug effect is considered fixed. It is considered to have reached a normal state. If the current does not reach a steady state within 6 minutes, The detection of the compound by concentration has also been completed.

[0720] 6.5 Data Processing Raw data was recorded using Clampex 10.2, and data acquisition and analysis were performed using pCLAMP 10.1 software. A software program was used. The current before compound addition was in a steady state for 4-5 sweeps. Selected and the average of the peak values ​​was calculated as the control current amplitude. Four to five sweeps where the current before compound addition was in a steady state were selected, and the average of the peaks was calculated as the residual amplitude after current suppression. The inhibition rate of the test compound against hERG current was calculated based on the following formula: % suppression rate = {1 - (residual current amplitude) / (control current amplitude)} × 100

[0721] Based on the calculation method described above, the suppression rate of the hERG current at a 10 μM concentration of the test compound was obtained. The results are shown in Table 15.

[0722] [Table 15]

[0723] As can be seen from this, the compounds of the present invention have improved safety because they have low cardiotoxicity.

[0724] The above examples merely illustrate the activity data of some representative compounds of the present invention; other compounds provided by the present invention will exhibit similar effects when tested in a similar manner.

Claims

1. A compound represented by formula IB, its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, R 1B is H, C 1-6 alkyl group, C 1-6 alkylcarbonyl group, C 1-6 alkoxycarbonyl group, C 6-14 aryl group, C 6-14 arylcarbonyl group, C 6-14 aryloxycarbonyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkylcarbonyl group, C 3-8 cycloalkoxycarbonyl group, 5- to 14-membered heteroaryl group, 5- to 14-membered heteroarylcarbonyl group, 5- to 14-membered heteroaryloxycarbonyl group, 3- to 8-membered heterocyclyl group, 3- to 8-membered heterocyclylcarbonyl group, and 3- to 8-membered heterocyclyloxycarbonyl group, and each of the substituents is optionally substituted with one or more groups selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, NH 2 C(=O)-, and C 1-6 alkoxy group R 2B and R 3B H and C are independent of each other. 1-6 Alkyl groups, amidino groups, and C 1-6 Selected from alkoxycarbonyl groups, R 4B Halogen, NO 2 , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, cyano group, NH 2 C(=O)- and C 1-6 Selected from alkoxy groups, mB and nB are independently 0, 1, 2, 3, 4, or 5. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof.

2. Selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts: 【Chemistry 2】 The compound described in claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound described in claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or excipient, and optionally another therapeutic agent.

4. A pharmaceutical composition for use in the prevention and / or treatment of related diseases mediated by κ-opioid receptors, Preferably, the disease is selected from pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma, and more preferably pain; More preferably, the pain is selected from neuropathic pain, trunk pain, visceral pain, skin pain, arthritis pain, kidney stone pain, uterine spasms, dysmenorrhea, endometriosis, indigestion, postoperative pain, pain after medical procedure, eye pain, otitis media pain, cancer explosion pain, and GI disorder-related pain, as described in claim 3.

5. Use in the manufacture of a pharmaceutical product of a pharmaceutical composition comprising, optionally, a compound according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, and optionally another therapeutic agent, In particular, the pharmaceutical product is used for the prevention and / or treatment of related diseases mediated by κ-opioid receptors. Preferably, the disease is selected from pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma, and more preferably pain. More preferably, the pain is selected from neuropathic pain, trunk pain, visceral pain, skin pain, arthritis pain, kidney stone pain, uterine spasms, dysmenorrhea, endometriosis, indigestion, postoperative pain, pain after medical procedures, eye pain, otitis media pain, cancer explosion pain, and GI disorder-related pain.

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