Polyamide compounds, their preparation process and medical uses

Abstract

The present invention relates to the pharmaceutical field, in particular to synthetic polyamide compounds represented by formulas IA, IB and IC or their pharma- ceutically acceptable salts, stereoisomers and compositions containing same, their preparation methods, and applications in the pharmaceutical field. JPEG2025510081000298.jpg13095

Description

[Technical Field]

[0001] The present invention relates to the medical field, and more particularly to a synthetic polyamide compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a composition containing the same, and applications in the pharmaceutical field. [Background technology]

[0002] Opioid receptors are an important class of G protein-coupled receptors that are the binding targets of endogenous opioid peptides and opioid drugs. After activation, opioid receptors exert regulatory effects on the nervous, immune, and endocrine systems. Opioid drugs are currently the most potent and commonly used central nervous system 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 sensory neurons, dorsal root ganglion cells, and peripheral primary afferent neurons. It is involved in important physiological activities such as pain sensation, neuroendocrine and emotional behavior, and cognition.

[0004] KOR agonists have good prospects for application in the pharmaceutical industry as drugs.For example, CN108290926A discloses phenylpropionamide derivatives that can be KOR agonists, and CN101627049A discloses synthetic peptide amides that can be KOR agonists, among which the compound D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH (R&D code CR845) has entered clinical research.

[0005] Although several KOR agonists already exist in the prior art, there remains a need for new KOR agonists with improved activity and / or druggability. Summary of the Invention

[0006] The present invention provides novel kappa opioid receptor (KOR receptor) agonist compounds that surprisingly exhibit excellent efficacy and activity. Specifically, such novel amide bond-containing compounds not only have excellent KOR receptor agonist activity (high affinity for the KOR receptor), but also have very good hydrophilicity, and therefore have a lower ability to penetrate the blood-brain barrier and enter the brain. In some embodiments, the compounds of the present invention also have higher selectivity for the K opioid receptor compared to the μ and δ opioid receptors. In some embodiments, the compounds of the present invention have lower addictive potential, better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., cytochrome P 450 In some embodiments, the compounds of the present invention have improved safety, i.e., lower acute toxicity and cardiac toxicity. In some embodiments, the compounds of the present invention have improved safety (e.g., a wider safe dosage 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).

[0007] One aspect of the present invention provides a compound of 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 R2A is -NR aA C(=O)OR bA or -NR aA S(=O)2OR bA and preferably -NR aA C(=O)OR bA Among them, R aA is H or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxy group, nitro group, cyano group, NHC(=O)-, C 1-6 C substituted with one or more groups selected from alkoxy groups 1-6 an alkyl group, preferably H, or an amino group, C 1-6 Alkylamino group or C 1-6 Alkoxy-substituted C 1-6 is an alkyl group, more preferably H, or an amino group, C 1-6 C substituted with alkylamino group 1-6 is an alkyl group, and R bA is C 1-6 Alkyl group, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-8 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, preferably C 1-6 alkyl groups, and 3- to 8-membered heterocyclyl groups, more preferably C 1-6 alkyl groups,

[0010] [ka]

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

[0012] [ka]

[0013] R above is selected from bAThe groups are halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups, and R eA and R fA are each independently -(CH2) n1A - and -(CH2) n1A' n1A and n1A' are each independently selected from 0, 1, 2 and 3, preferably 2, and n1A and n1A' are not simultaneously 0; W A -NH-C(=O)-, -NH-S(=O)2-, -NR 5A -, -O-, -S-, -S(=O)2-, preferably -O-, -S(=O)2-, R 5A is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A and n3A is selected from 1, 2 and 3; or R 1A and R 2A together with the carbon atoms to which they are attached form an optionally substituted 9-10 membered bicyclic moiety, preferably said bicyclic moiety together with the piperidine ring to which they are attached forms

[0014] [ka]

[0015] forming a structure selected from Q 1A ~Q 4A If any one of is N, the rest is C or Q 1A ~Q 4A are both C, W 1A and W 2A are each independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, or -NR 6A -, -NR 6A-CH2-, -NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2A - or absent, among which R 6A is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A -, preferably W 1A and W 2A cannot exist at the same time, W 3A is NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2A - and

[0016] n2A is selected from 0, 1, 2 and 3; More preferably, the bicyclic moieties together with the piperidine ring to which they are attached are:

[0017] [ka]

[0018] and more preferably forms a structure selected from

[0019] [ka]

[0020] and more preferably selected from

[0021] [ka]

[0022] is selected from R3A is H or -(CH2) mA NR cA R dA is selected from R cA and R dA are independently H, C 1-6 Alkyl group, amidino group, C 1-6 alkoxycarbonyl groups, R 4A are halogens, NO2, C 1-6 Alkyl group, C 1-6 Haloalkyl group, cyano group, NHC(=O)-, C 1-6 alkoxy groups, mA and nA are each independently 0, 1, 2, 3, 4, or 5.

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

[0024] [ka]

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

[0026] [ka]

[0027] This includes the steps: Among them, R 1A ' is R 1A or R in which NH2 is protected with an amino protecting group 1A and R 2A ' is R 2A or R in which NH2 is protected with an amino protecting group 2A and R 3A ' is R 3A or R in which NH2 is protected with an amino protecting group3A and R 1A , R 2A , R 3A , R 4A and nA are as defined above, and R xA is an amino protecting group, The amino-protecting groups are preferably each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, and an ethoxycarbonyl group.

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

[0029] [ka]

[0030] Among them, R 1A ' is R 1A or R in which NH2 is protected with an amino protecting group 1A and R 2A ' is R 2A or R in which NH2 is protected with an amino protecting group 2A and R 3A ' is R 3A or R in which NH2 is protected with 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, The amino-protecting groups are preferably each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, and an ethoxycarbonyl group.

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

[0032] [ka]

[0033] Among them, R 1B is H, C 1-6 Alkyl groups (e.g., methyl groups), 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 groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 is selected from a cycloalkoxycarbonyl group, a 5- to 14-membered heteroaryl group, a 5- to 14-membered heteroarylcarbonyl group, a 5- to 14-membered heteroaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocyclyloxycarbonyl group, and is preferably H, C 1-6 Alkyl groups (e.g., methyl groups), C 1-6 Alkylcarbonyl group (e.g., methylcarbonyl group), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups), more preferably C 1-6Alkyl groups (e.g., methyl groups), C 1-6 alkylcarbonyl groups (e.g., methylcarbonyl groups), and the substituents are selected from halogen, hydroxyl groups, amino groups, nitro groups, cyano groups, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R 2B and R 3B are independently H, C 1-6 Alkyl groups (e.g., methyl groups, isopropyl groups), amidino groups, C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups); R 4B are halogens, NO2, C 1-6 Alkyl group, C 1-6 Haloalkyl group, cyano group, NHC(=O)-, C 1-6 alkoxy groups, mB and nB are each independently 0, 1, 2, 3, 4, or 5, e.g., mB is 3 and / or nB is 0.

[0034] Yet another aspect of the present invention provides a method for preparing a compound of the present invention, comprising the steps of:

[0035] [ka]

[0036] Among them, R 1B , R 4B , mB and nB are as defined above, and R xB and R yBare amino-protecting groups, preferably each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl 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] Among them, R 1B , R 4B , mB and nB are as defined above, and R xB and R yB are amino-protecting groups, preferably each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, or an ethoxycarbonyl group.

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

[0041] [ka]

[0042] Among them, Ring A is C 3-8 Cycloalkyl groups, C 6-14an aryl group or a 5- to 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] 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 is selected from R 2C is H, amino group, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkylamino group, C 1-6 The alkyl group is selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R 3C When Y is CH, H, hydroxyl group, C 1-6 Alkyl group, 3- to 8-membered heterocyclyl group, C 1-6alkoxy groups, and when Y is N, H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl-(CH2) mC -, 3- to 8-membered heterocyclyl group, 3- to 8-membered heterocyclyl-(CH2) mC -, -(CH2) mC NR 10 R 11 Among these, alkyl, cycloalkyl, heterocyclyl and alkoxy groups are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 Alkoxy group, C 1-6 optionally substituted with one or more groups selected from alkylamino groups; R 4C and R 5C are independently H, C 1-6 Alkyl group, C 1-6 Alkyl-O-, hydroxy group, -C(O)OR7, -NR8R9, -NR cC C(O)NR8R9, C 1-6 Alkylamino group, 3-8 membered 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 NR8R9, and the alkyl group and heterocyclyl group are selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; Or, CR 4C R 5Cform a 3- to 8-membered heterocyclic ring or a 9- to 10-membered bicyclic moiety, and the 3- to 8-membered heterocyclic ring or the 9- to 10-membered bicyclic moiety, together with the piperidine ring to which they are linked,

[0047] [ka]

[0048] forming a structure selected from Q 1C ~Q 4C If any one of is N, the rest are C or Q 1C ~Q 4C are both C, W 1C and W 2C are each independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, or -NR 12 -, -NR 12 -CH2-, -NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C - or absent, R 12 is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3C -, preferably W 1C and W 2C cannot exist at the same time, W 3C is NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C - or absent, preferably NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6-(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C - and W 4C and W 5C is NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C -or not present, n2C is selected from 0, 1, 2 and 3; More preferably, the 3- to 8-membered heterocyclic or 9- to 10-membered bicyclic moiety, together with the piperidine ring to which it is attached, is

[0049] [ka]

[0050] and more preferably forms a structure selected from

[0051] [ka]

[0052] is selected from R aC and R bC are independently H, C 1-6 Alkyl group, amidino group, C 1-6 alkoxycarbonyl groups, R cC is H or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxy group, nitro group, cyano group, NHC(=O)-, C 1-6 C substituted with one or more groups selected from alkoxy groups 1-6 an alkyl group, preferably H, or an amino group, C 1-6 Alkylamino group or C 1-6 Alkoxy-substituted C 1-6is an alkyl group, more preferably H, or an amino group, C 1-6 C substituted with alkylamino group 1-6 is an alkyl group, R dC is C 1-6 Alkyl group, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-8 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, preferably C 1-6 alkyl groups, and 3- to 8-membered heterocyclyl groups, more preferably C 1-6 alkyl groups,

[0053] [ka]

[0054] and more preferably selected from C 1-6 alkyl groups,

[0055] [ka]

[0056] R above is selected from dC The groups are halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups, and R eC and R fC are each independently -(CH2) n1C - and -(CH2) n1C' n1C and n1C' are each independently selected from 0, 1, 2 and 3, preferably 2, and n1C and n1C' are not simultaneously 0; W C -NH-C(=O)-, -NH-S(=O)2-, -NR 12 -, -O-, -S-, -S(=O)2-, preferably -O-, -S(=O)2-, R 12 is H, C1-6 Alkyl group, amidino group, HOOC-(CH2) n3C and n3C is selected from 1, 2 and 3; R 6C and R 6C ' is independently H, C 1-6 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 Cycloalkylcarbonyl group, C 3-8 a cycloalkoxycarbonyl group, a 5- to 14-membered heteroaryl group, a 5- to 14-membered heteroarylcarbonyl group, a 5- to 14-membered heteroaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocyclyloxycarbonyl group, and each of the above substituents is selected from a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R7 and R7' are each independently H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-14 aryl group and 5- to 14-membered heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R8 and R9 are each independently H, or a halogen, a hydroxy group, an amino group, a nitro group, a cyano group, C 1-6Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 is an alkyl group, R 10 and R 11 are each independently H or C 1-6 is an alkyl group, or R 10 and R 11 form a 3- to 8-membered heterocyclyl group together with the nitrogen atom to which they are attached, and the alkyl and heterocyclyl groups are not limited to halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; p and t are each independently selected from 0, 1, 2, 3, 4, or 5; mC is independently selected from 1, 2, 3, and 4 at each occurrence; R0 is H, halogen, NO2, cyano group, NH2C(=O)-, C 1-6 alkoxy groups, halogens, hydroxy groups, amino groups, nitro groups, cyano groups, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 The alkyl group is selected from the group consisting of:

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

[0058] [ka]

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

[0060] [ka]

[0061] This includes the steps: Preferably, the compound of formula iiC-2 is prepared by a method selected from: Method 3: Method 3 comprises the steps of subjecting a compound of formula iiC-4-a and a compound of formula iiC-5-a to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0062] [ka]

[0063] Method 4: Method 4 comprises the steps of subjecting a compound of formula iiC-4-b and a compound of formula iiC-5-b to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0064] [ka]

[0065] Method 5: Method 5 comprises the steps of subjecting a compound of formula iiC-4-c and a compound of formula iiC-5-c to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0066] [ka]

[0067] Method 6: Method 6 comprises the steps of subjecting a compound of formula iiC-4-d and a compound of formula iiC-5-d to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0068] [ka]

[0069] Preferably, the formula iC-2 is

[0070] [ka]

[0071] and Preferably, iiC-2 above is

[0072] [ka]

[0073] is selected from wherein R' is R or R in which NH is protected with an amino-protecting group, and R 1C ' and R 1C '' is R 1C or R in which NH2 is protected with an amino protecting group 1C and R 2C ' and R 2C '' is R 2C or R in which NH2 is protected with an amino protecting group 2C and R 3C ' and R 3C '' is R 3C or R in which NH2 or cyclic imino group is protected with an amino protecting group 3C G' is G or G in which NH and / or the cyclic imino group is protected with an amino-protecting group and / or the carboxy group is protected with a carboxy-protecting group, Rw is a carboxy-protecting group, and the rings A, Y, R, R 1C , R 2C , R 3C, G and p are as defined above, and Rs, Rt and Ru are each independently selected from H and an amino protecting group; Preferably, the amino protecting groups are each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichlorooxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, a 1-phenylethyl group, and an ethoxycarbonyl group, and the carboxy protecting groups are each independently selected from a C 1-6 It is selected from an alkyl group, an allyl group, a benzyl group, a 2,4-dimethoxybenzyl group, a p-methoxybenzyl group, a methoxyethoxymethyl group, a pentafluorophenyl group, and a 4-p-methylbenzyloxybenzyl group.

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

[0075] [ka]

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

[0077] [ka]

[0078] is selected from wherein R' is R or R in which NH is protected with an amino-protecting group, and R 1C ' is R 1C or R in which NH2 is protected with an amino protecting group 1C and R 2C ' is R 2C or R in which NH2 is protected with an amino protecting group 2C and R 3C ' is R3C or R in which NH2 or cyclic imino group is protected with an amino protecting group 3C G' is G or G in which NH and / or cyclic imino group is protected with an amino-protecting group and / or carboxy group is protected with a carboxy-protecting group, and the rings A, Y, R, R 1C , R 2C , R 3C , G and p are as defined above, Rs, Rt are each independently selected from H and an amino protecting group, and Rv is selected from H and a carboxy protecting group; Preferably, the amino protecting groups are each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichlorooxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, a 1-phenylethyl group, and an ethoxycarbonyl group, and the carboxy protecting groups are each independently selected from a C 1-6 It is selected from an alkyl group, an allyl group, a benzyl group, a 2,4-dimethoxybenzyl group, a p-methoxybenzyl group, a methoxyethoxymethyl group, a pentafluorophenyl group, and a 4-p-methylbenzyloxybenzyl group.

[0079] Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, its stereoisomer 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 a compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a medicament for agonizing a kappa opioid receptor.

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

[0082] Another aspect of the present invention provides the use of a compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a medicament, particularly wherein the medicament is used for the prevention and / or treatment of an associated disease mediated by the kappa opioid receptor.

[0083] In the present disclosure, the related diseases mediated by kappa opioid receptors are selected from pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough, and glaucoma, preferably pain. In the present disclosure, the pain is selected from neuropathic pain, truncal pain, visceral pain, cutaneous pain, arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, postoperative pain, pain after medical procedures, eye pain, otitis media pain, cancer eruption pain, and pain associated with GI disorders. DETAILED DESCRIPTION OF THE INVENTION

[0084] term Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0085] Unless otherwise indicated, the present invention employs conventional methods, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, within the skill of the art. Unless specific definitions are provided, the chemically related nomenclature and laboratories and techniques described herein, such as analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry, are known to those of skill in the art. In general, the techniques and steps described above are well known in the art and can be carried out by conventional methods as described in various general and more specific references, which are cited and discussed herein.

[0086] The term "alkyl group" refers to an aliphatic hydrocarbon group, and may be a branched or straight-chain alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "lower alkyl group" having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like. The term "alkyl group" referred to herein includes such alkyl groups in all possible configurations and conformations. For example, the term "propyl group" referred to herein includes n-propyl and isopropyl groups, the term "butyl group" includes n-butyl, isobutyl, and tert-butyl groups, and the term "pentyl group" includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pentyl-3-yl, and the like. In some embodiments, alkyl groups are optionally substituted with one or more (eg, 1 to 3) suitable substituents.

[0087] The term "aryl group" refers to an all-carbon monocyclic or polycyclic aromatic group with 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. 6-14 The aryl group is C 6-10 An aryl group is preferred. Examples of the aryl group may include a phenyl group, a naphthyl group, an anthracene group, etc. In some embodiments, the aryl group is optionally substituted with one or more (e.g., 1 to 3) suitable substituents.

[0088] The term "heteroaryl group" refers to a monocyclic or polycyclic aromatic group containing one or more heteroatoms, whether homologous or different, such as oxygen, nitrogen, or sulfur. For example, the term "5- to 14-membered heteroaryl group" as used herein refers to a heteroaryl group having 5 to 14 ring atoms. Furthermore, the heteroaryl group refers to a monocyclic, bicyclic, or tricyclic aromatic group having 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 containing at least one heteroatom, whether homologous or different, such as oxygen, nitrogen, or sulfur; the heteroaryl group may also be a benzofused group. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof, or selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof. In some embodiments, the heteroaryl group is optionally substituted with one or more (e.g., 1 to 3) suitable substituents.

[0089] The term "cycloalkyl group" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring group (e.g., monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl; or bicyclic groups containing spirocyclic, fused, or bridged ring systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, and decalinyl). Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the cycloalkyl group is optionally substituted with one or more (e.g., 1 to 3) suitable substituents.

[0090] The term "heterocyclyl group" refers to a saturated or unsaturated monocyclic or polycyclic group having 3 to 12 ring atoms or 3 to 8 ring atoms, including, for example, carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, within the ring; the heterocyclyl group can be linked to the remainder of the molecule through any one of the carbon atoms or a nitrogen atom, if present. Carbon atoms in the heterocyclyl group can be optionally substituted with an oxo (=O) group. Sulfur atoms in the ring can be optionally oxidized to S-oxides such as SO, SO, etc. Nitrogen atoms in the ring can be optionally oxidized to N-oxygen compounds. 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, oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrimidinedione, 2-oxopyrrolidinyl, 3,5-dioxopiperidinyl, sulfolane, 1,1-dioxothiomorpholinyl, and 1,1-dioxotetrahydrothiopyranyl. In some embodiments, the heterocyclyl group is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. In some embodiments, the 3- to 8-membered heterocyclyl group is a 3- to 8-membered heterocyclyl group containing one heteroatom selected from oxygen, nitrogen, and sulfur; in some embodiments, the 3- to 8-membered heterocyclyl group is

[0091] [ka]

[0092] Among them, W A , R eA , R fA , W C , R eC , R fC is as defined herein.

[0093] The term "alkoxy" refers to alkyl-O-, where alkyl is as defined herein. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.

[0094] The term "aryloxy group" refers to an aryl-O- group, in which the aryl group is as defined herein.

[0095] The term "heteroaryloxy group" refers to a heteroaryl-O- group, in which the heteroaryl group is as defined herein.

[0096] The term "cycloalkoxy" refers to a cycloalkyl-O- group, wherein the cycloalkyl group is as defined herein.

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

[0098] The term "carbonyl group" refers to an organic functional group, -C(=O)-, in which two atoms, carbon and oxygen, are connected by a double bond. The term "alkoxycarbonyl group" refers to alkoxy-C(=O)-, i.e., the group is connected to the rest of the compound via a carbonyl group. The term "alkylcarbonyl group" refers to alkyl-C(=O)-, i.e., the group is connected to the rest of the compound via a carbonyl group. Similarly, the term "arylcarbonyl group" refers to aryl-C(=O)-, i.e., the group is connected to the rest of the compound via a carbonyl group, and the term "aryloxycarbonyl group" refers to aryloxy-C(=O)-, i.e., the group is connected to the rest of the compound via a carbonyl group, and so forth.

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

[0100] The term "amidino group" means

[0101] [ka]

[0102] Refers to...

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

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

[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 substituted with an alkyl group.

[0107] "C1~C6" or "C 1-6 " encompasses a range of 1 to 6 carbon atoms, e.g., C1-C6, C 2~ C6, C3 to C6, C 4~ C6, C5~C6, C1~C5, C2~C5, C3~C5, C4~C5, C1~C4, C 2~ It should be understood that any subranges therein, including C4, C3-C4, C1-C3, C2-C3, C1-C2, etc., and C1, C2, C3, C4, C5, C6, etc., are encompassed, as are any subranges therein, and the values ​​of each point. Similarly, "C3-C8" or "C3-8 The expression "is a cyclic ring having 3 to 8 carbon atoms" should be understood to include any subranges therein, such as C3 to C6, and including C3, C4, C5, C6, C7, C8, etc., as well as any point values. The expression "3 to 8-membered" should be understood to include any subranges therein, such as 3 to 7-membered, 3 to 6-membered, 3 to 5-membered, 4 to 8-membered, and 3, 4, 5, 6, 7, and 8-membered, as well as any point values. Similarly, the expression "5 to 14-membered" should be understood to include any subranges therein, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered rings, as well as any point values. Other similar expressions herein should be understood in an analogous manner.

[0108] The term "optionally substituted" or "optionally substituted with" means that the referenced group may be substituted or unsubstituted.

[0109] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups each independently selected from alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, alkylthio groups, halogens, mercapto groups, hydroxy groups, nitro groups, amino groups, cyano groups, carboxy groups, oxo groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, NHC(=O)-, alkylamino groups, and the like.

[0110] The term "one or more" in the phrase "substituted with one or more groups selected from" or "optionally substituted with one or more groups selected from" means substituted with 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 groups, provided that valency requirements are met.

[0111] In addition, "C 6-14 arylcarbonyl group," "C 6-14 The term "aryloxycarbonyl group" refers to a group in which the aryl group is C 6-14 It means that it is an aryl group, and "C 3-8cycloalkylcarbonyl group, "C 3-8 The term "cycloalkoxycarbonyl group" refers to a cycloalkyl group having a C 3-8 The terms "5- to 14-membered heteroarylcarbonyl group" and "5- to 14-membered heteroaryloxycarbonyl group" mean that the heteroaryl group is a 5- to 14-membered heteroaryl group, and the terms "3- to 8-membered heterocyclylcarbonyl group" and "3- to 8-membered heterocyclyloxycarbonyl group" mean that the heterocyclyl group is a 3- to 8-membered heterocyclyl group. 1-6 The term "alkoxycarbonyl group" refers to the alkyl group C 1-6 It should be understood that "C" means an alkyl group. 1-6 "Aminoalkyl group" is a group in which the alkyl group is C 1-6 It means that it is an alkyl group.

[0112] The term "pharmaceutically acceptable carrier" refers to a substance that has no apparent irritating effect on an organism and does not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, a glidant, a sweetener, a diluent, a preservative, a dye colorant, a flavoring agent, a surfactant, a wetting agent, a dispersant, a disintegrant, a stabilizer, a solvent, or an emulsifier.

[0113] The names of the compounds disclosed herein, "Compound *-0" and "Compound *-100" (where * is the compound number), are each stereoisomers of "Compound *." For example, Compound 3 is a racemate, and Compound 3-0 and Compound 3-100 are its respective stereoisomers.

[0114] In the present invention, "*" indicates the point of attachment. For example, in the present disclosure, G is

[0115] [ka]

[0116] If

[0117] [ka]

[0118] but

[0119] [ka]

[0120] This indicates that

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

[0122] [ka]

[0123] but

[0124] [ka]

[0125] Similarly, "G is -S(=O)(=NR 6C 'Selected from)-)' means that the S atom is a ring atom, i.e.

[0126] [ka]

[0127] but

[0128] [ka]

[0129] It should be understood that this means that

[0130] Also, structures referred to in this disclosure

[0131] [ka]

[0132] refers to an aromatic ring, e.g., Q 1A / Q 1C ~Q 4A / Q 4C When one of Q is N and the rest are C, the structure is a pyridine ring, and Q 1A / Q 1C ~Q 4A / Q 4C are both C, the structure is understood to be a benzene ring. In addition, in the above expression, "the remainder is C" means that the ring atoms are C, and it should be understood that based on the valence bond theory, it actually means that "the remainder is CH."

[0133] The compounds of the present invention, or salts thereof, may contain one or more stereocenters, each of which may exist independently in the R or S configuration and thus produce enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- of amino acids. The present invention is intended to encompass all possible isomers 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 of the compounds of the present invention, or racemic or diastereomeric mixtures, are all within the scope of the present invention. Purification and separation of such materials can be achieved by standard techniques known in the art.

[0134] In some embodiments, the compounds of the present disclosure are racemic. In some embodiments, the compounds of the present disclosure are single enantiomers. In some embodiments, the compounds of the present disclosure are substantially free of other isomers. In some embodiments, the compounds of the present disclosure are single isomers substantially free of other isomers. In some embodiments, the compounds of the present 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, compounds of the present disclosure have at least 75% stereochemical purity, or at least 80% stereochemical purity, or at least 85% stereochemical purity, or at least 90% stereochemical purity, or at least 95% stereochemical purity, or at least 96% stereochemical purity, or at least 97% stereochemical purity, or at least 98% stereochemical purity, or at least 99% stereochemical purity.

[0136] In some embodiments, the asymmetric carbon atoms in the compounds of the present disclosure may be present in either racemic or enantiomerically enriched form, for example, in the (R)-, (S)-, or (R,S)-configuration. In some embodiments, the asymmetric carbon atoms in the (S)- or (R)-configuration in the compounds of the present disclosure have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[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%, preferably less than 4%, preferably less than 3%, preferably less than 2%, preferably less than 1% by weight of other isomers relative to the preferred isomer. It should be understood that when the present disclosure refers to or indicates that a particular configuration of a compound is an absolute configuration, it means that it is in the form of a substantially pure absolute configuration; similarly, when the present disclosure refers to or indicates that a compound is a single enantiomer, it means that it is in the substantially pure enantiomeric form.

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

[0139] compound The present disclosure provides a compound of formula IA, its stereoisomers, or its pharmaceutically acceptable salts:

[0140] [ka]

[0141] In some embodiments, 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 preferably -NR aA C(=O)OR bA Among them, R aA is H or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxy group, nitro group, cyano group, NHC(=O)-, C 1-6 C substituted with one or more groups selected from alkoxy groups 1-6an alkyl group, preferably H, or an amino group, C 1-6 Alkylamino group or C 1-6 Alkoxy-substituted C 1-6 is an alkyl group, more preferably H, or C 1-6 is an aminoalkyl group, and R bA is C 1-6 Alkyl group, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups (preferably

[0142] [ka]

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

[0144] [ka]

[0145] and more preferably selected from C 1-6 alkyl groups,

[0146] [ka]

[0147] and more preferably selected from C 1-6 alkyl groups,

[0148] [ka]

[0149] R above is selected from bA The groups are halogen, hydroxyl, amino, nitro, cyano, C 1-6Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups, and R eA and R fA are each independently -(CH2) n1A - and -(CH2) n1A' -, and in some embodiments, each -(CH) n1A - and -(CH2) n1A’ wherein n1A and n1A' are each independently selected from 0, 1, 2 and 3, preferably 2, and n1A and n1A' are not simultaneously 0; W A -NH-C(=O)-, -NH-S(=O)2-, -NR 5A -, -O-, -S-, -S(=O)2-, preferably -O-, -S(=O)2-, R 5A is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A - and n3A is selected from 1, 2, and 3. In some embodiments, R aA is H. In some embodiments, R aA is an amino group, C 1-6 Alkylamino group, or C 1-6 Alkoxy-substituted C 1-6 In some embodiments, R is an alkyl group, such as a methoxyethyl group, a methylaminoethyl group, an aminopropyl group, or an aminoethyl group. aA is H or C 1-6 In some embodiments, R bA is a halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 In some embodiments, R is an alkyl group, such as a methyl group, an ethyl group, or a propyl group, preferably a methyl group. bAis a halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups

[0150] [ka]

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

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

[0153] [ka]

[0154] forming a structure selected from Q 1A ~Q 4A If any one of the groups is N, the rest are CH or Q 1A ~Q 4A are both CH, W 1A and W 2Aare each independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, or -NR 6A -, -NR 6A -CH2-, -NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2A - or absent, R 6A is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A -, n3A is selected from 1, 2 and 3, preferably 1, and preferably W 1A and W 2A cannot exist at the same time, W 3A is NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2A - and n2A is selected from 0, 1, 2 and 3.

[0155] More preferably, the bicyclic moieties together with the piperidine ring to which they are attached are:

[0156] [ka]

[0157] and more preferably forms a structure selected from

[0158] [ka]

[0159] and more preferably selected from

[0160] [ka]

[0161] is selected from.

[0162] In some embodiments, R 3A is H or -(CH2) mA NR cA R dA are selected from, among which R cA and R dA are independently H, C 1-6 Alkyl groups (e.g., methyl groups, isopropyl groups, etc.), amidino groups, C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups), and mA is selected from 0, 1, 2, 3, 4, or 5. In some embodiments, R 3A is H. In some embodiments, R cA and R dA are independently H, C 1-6 In some embodiments, R is selected from alkoxycarbonyl groups (e.g., methoxycarbonyl groups, etc.). cA and R dA are each H. In some embodiments, R cA is H and R dA is C 1-6 It is an alkoxycarbonyl group, preferably a methoxycarbonyl group. mA is selected from 0, 1, 2, or 3, and is preferably 3.

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

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

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

[0166] [ka]

[0167] Preferably, R in Formula IA, Formula IIA, Formula IIIA, Formula IVA, or Formula VA bA is C 1-6 alkyl groups,

[0168] [ka]

[0169] is selected from, preferably

[0170] [ka]

[0171] Among them, W A is selected from —O—, —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 Alkoxy-substituted C1-6 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 of formula IIIA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R aA is H and R bA is C 1-6 alkyl groups,

[0176] [ka]

[0177] Selected from R eA and R fA are -(CH2), respectively. n1A - and -(CH2) n1A' n1A and n1A' are each independently selected from 0, 1, 2 and 3, preferably 2, and n1A and n1A' are not simultaneously 0; W A -NH-C(=O)-, -NH-S(=O)2-, -NR 5A -, -O-, -S-, -S(=O)2-, R 5A is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3A n3A is selected from 1, 2 and 3; R cA and R dA are independently H, C 1-6 Alkyl group, amidino group, C 1-6 The alkyl group is selected from alkoxycarbonyl groups.

[0178] In some embodiments, the compound of the present invention is a compound of formula IIIA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R aA is H and R bA is C 1-6 alkyl groups,

[0179] [ka]

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

[0181] In some embodiments, the compound of the present invention is a compound of formula IVA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R aA is H and R bA is C 1-6 alkyl groups,

[0182] [ka]

[0183] Selected from W A is selected from —O—, —S(═O)2—.

[0184] In some embodiments, the compound of the present invention is selected from the compounds shown below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0185] [ka]

[0186] [ka]

[0187] [ka]

[0188] The present disclosure further provides compounds of the general formula, stereoisomers thereof, or salts thereof, which are intermediates for preparing the above compounds of the present disclosure:

[0189] [ka]

[0190] Among them, R 1A ' is R 1A or R in which NH2 is protected with an amino protecting group 1A and R 2A ' is R 2A or R in which NH2 is protected with an amino protecting group 2A and R 3A ' is R 3A or R in which NH2 is protected with 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, The amino-protecting groups are preferably each independently selected from a tert-butoxycarbonyl group (Boc), a 9-fluorenylmethoxycarbonyl group (Fmoc), an allyloxycarbonyl group (Alloc), a trichloroethoxycarbonyl group (Troc), a trimethylsilylethoxycarbonyl group (Teoc), a benzyloxycarbonyl group (CBz), a p-toluenesulfonyl group (Tosyl), a p-nitrobenzenesulfonyl group (Nosyl), a tert-butyl group (t-Bu), a trifluoroacetyl group (Tfa), a methoxycarbonyl group, a tert-butylsulfinyl group, and an ethoxycarbonyl group.

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

[0192] [ka]

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

[0194] [ka]

[0195] This includes the steps: Among them, R 1A ' is R 1A or R in which NH2 is protected with an amino protecting group 1A and R 2A ' is R 2A or R in which NH2 is protected with an amino protecting group 2A and R 3A ' is R 3A or R in which NH2 is protected with 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,

[0196] The amino-protecting groups are preferably each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, and an ethoxycarbonyl group.

[0197] compound The present disclosure provides a compound of formula IB, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0198] [ka]

[0199] R 1B is H, C 1-6 Alkyl groups (e.g., methyl groups), 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 groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 is selected from a cycloalkoxycarbonyl group, a 5- to 14-membered heteroaryl group, a 5- to 14-membered heteroarylcarbonyl group, a 5- to 14-membered heteroaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocyclyloxycarbonyl group, and is preferably H, C 1-6 Alkyl groups (e.g., methyl groups), C 1-6 Alkylcarbonyl group (e.g., methylcarbonyl group), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups), more preferably C 1-6 Alkyl groups (e.g., methyl groups), C 1-6 alkylcarbonyl groups (e.g., methylcarbonyl groups), and the substituents are selected from halogen, hydroxyl groups, amino groups, nitro groups, cyano groups, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R 2B and R 3B are independently H, C 1-6 Alkyl groups (e.g., methyl groups, isopropyl groups), amidino groups, C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups); R4B are halogens, NO2, C 1-6 Alkyl group, C 1-6 Haloalkyl group, cyano group, NHC(=O)-, C 1-6 alkoxy groups, preferably F, Cl, NO2, CH3, CF3, cyano groups, NH2C(=O)-; mB and nB are each independently 0, 1, 2, 3, 4, or 5, e.g., mB is 3 and / or nB is 0.

[0200] In some embodiments, 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 groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 is selected from a cycloalkoxycarbonyl group, a 5- to 14-membered heteroaryl group, a 5- to 14-membered heteroarylcarbonyl group, a 5- to 14-membered heteroaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocyclyloxycarbonyl group, and preferably 1-6 Alkyl group, C 1-6 alkylcarbonyl groups, preferably H, C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, C 1-6 alkoxycarbonyl groups, more preferably C 1-6 Alkyl group, C 1-6 alkylcarbonyl groups, each of the above substituents being selected from halogen, hydroxy, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 In some embodiments, R is optionally substituted with one or more groups selected from an alkoxy group. 1Bis H. In some embodiments, R 1B is a halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 It is an alkyl group, and preferably a halogen, a hydroxy group, an amino group, a nitro group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 In some embodiments, R is a methyl group, an ethyl group, a propyl group, or a butyl group optionally substituted with one or more groups selected from an alkoxy group, and more preferably a methyl group. 1B is a halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 alkylcarbonyl group, preferably halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 Examples of the alkyl group include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, and a butylcarbonyl group, each of which is optionally substituted with one or more groups selected from an alkoxy group, and more preferably a methylcarbonyl group.

[0201] In some embodiments, R 2B and R 3B are independently H, C 1-6 Alkyl group, amidino group, C 1-6 In some embodiments, R is selected from the group consisting of alkoxycarbonyl groups. 2B and R 3B are independently H, C 1-6 In some embodiments, R is selected from the group consisting of alkoxycarbonyl groups. 2B and R3B are both H. In some embodiments, R 2B is H and R 3B is C 1-6 It is an alkoxycarbonyl group, preferably a methoxycarbonyl group.

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

[0203] In some embodiments, mB and nB are each 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, it is represented by formula IIIB:

[0207] [ka]

[0208] More preferably, the compound is represented by formula IVB

[0209] [ka]

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

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

[0212] [ka]

[0213] The present disclosure further provides a compound of formula iB-1, a stereoisomer thereof, or a salt thereof, which is an intermediate for preparing the compounds of the present invention:

[0214] [ka]

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

[0216] Similarly, the present disclosure further provides a compound of formula iB-4, a stereoisomer thereof, or a salt thereof:

[0217] [ka]

[0218] , among which, R 1B , R 2B , R 3B , R 4B , mB, nB and R xB is as defined above.

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

[0220] [ka]

[0221] Among them, R 1B , R 4B , mB and nB are as defined above, and R xB and R yBare amino-protecting groups, preferably each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, or an ethoxycarbonyl group.

[0222] compound The present disclosure provides a compound represented by the formula:

[0223] [ka]

[0224] In some embodiments, ring A is C 3-8 Cycloalkyl groups, C 6-14 Ring A is an aryl group (preferably a monocyclic aryl group) or a 5- to 14-membered heteroaryl group (preferably a monocyclic heteroaryl group), such as a cyclopropyl group, a cyclopentyl group, a phenyl group, a pyridinyl group, or a pyrimidinyl group. In some embodiments, ring A is a phenyl group.

[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-, or -CR 4C R 5C -, -NR 6C -, -S(=O)2-, -S(=O)(=NR 6C ')-,

[0227] [ka]

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

[0229] [ka]

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

[0231] In some embodiments, G is —S(═O)(═NR 6C ')-, among which R 6C ', H, C 1-6 Alkyl groups (e.g., methyl groups), 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 groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 is selected from a cycloalkoxycarbonyl group, a 5- to 14-membered heteroaryl group, a 5- to 14-membered heteroarylcarbonyl group, a 5- to 14-membered heteroaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocyclyloxycarbonyl group, and is preferably H, C 1-6 Alkyl groups (e.g., methyl groups), C 1-6 Alkylcarbonyl group (e.g., methylcarbonyl group), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups), more preferably C 1-6 Alkyl groups (e.g., methyl groups), C 1-6alkylcarbonyl groups (e.g., methylcarbonyl groups), and each of the above substituents is selected from halogen, hydroxyl groups, amino groups, nitro groups, cyano groups, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 Optionally substituted with one or more groups selected from alkoxy groups.

[0232] In some embodiments, G is -CR 4C R 5C -, among which R 4C and R 5C are independently H, C 1-6 Alkyl group, C 1-6 Alkyl-O-, hydroxy group, -C(O)OR7, -NR8R9, -NR cC C(O)NR8R9, C 1-6 Alkylamino group, 3-8 membered 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 NR8R9, and the alkyl group and heterocyclyl group are selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 R7 and R7' are each independently selected from H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-14 aryl group and 5- to 14-membered heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C1-6 R8 and R9 are each independently H or a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 is an alkyl group, and R cC is H or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxy group, nitro group, cyano group, NHC(=O)-, C 1-6 C substituted with one or more groups selected from alkoxy groups 1-6 an alkyl group, preferably H, or an amino group, C 1-6 Alkylamino group or C 1-6 Alkoxy-substituted C 1-6 alkyl, more preferably H, or an amino group, C 1-6 C substituted with alkylamino group 1-6 is an alkyl group, and R dC is C 1-6 Alkyl group, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-8 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, preferably C 1-6 alkyl groups, and 3- to 8-membered heterocyclyl groups, more preferably C 1-6 alkyl groups,

[0233] [ka]

[0234] and more preferably selected from C 1-6 alkyl groups,

[0235] [ka]

[0236] R above is selected from dC The groups are halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups, and R eC and R fC are each independently -(CH2) n1C - and -(CH2) n1C' -, and in some embodiments, each is -(CH) n1C - and -(CH2) n1C’ -, where n 1C and n 1C' are each independently selected from 0, 1, 2 and 3, preferably 2, and n1C and n1C' are not simultaneously 0; W C -NH-C(=O)-, -NH-S(=O)2-, -NR 12 -, -O-, -S-, -S(=O)2-, preferably -O-, -S(=O)2-, R 12 is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3C -, nC is selected from 1, 2 and 3, and mC is selected from 1, 2, 3 and 4;

[0237] Or, CR 4C R 5C form a 3- to 8-membered heterocyclic ring or a 9- to 10-membered bicyclic moiety (specifically, a 9- to 10-membered fused ring), and the 3- to 8-membered heterocyclic ring or the 9- to 10-membered bicyclic moiety, together with the piperidine ring to which they are linked,

[0238] [ka]

[0239] forming a structure selected from Q 1C ~Q 4C If any one of the groups is N, the rest are CH or Q1C ~Q 4C are both CH, W 1C and W 2C are each independently -C(=O)-NH-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S-, -O-, or -NR 12 -, -NR 12 -CH2-, -NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C - or absent, R 12 is H, C 1-6 Alkyl group, amidino group, HOOC-(CH2) n3C -, preferably W 1C and W 2C cannot exist at the same time, W 3C is NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C - or absent, preferably NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C - and W 4C and W 5C is NH2, -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 -(CH2) optionally substituted with one or more groups selected from alkoxy groups n2C -or not present, n2C is selected from 0, 1, 2 and 3; More preferably, the 3- to 8-membered heterocyclic or 9- to 10-membered bicyclic moiety, together with the piperidine ring to which it is attached, is

[0240] [ka]

[0241] and more preferably forms a structure selected from

[0242] [ka]

[0243] is selected from.

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

[0245] In some embodiments, G is -CR 4C R 5C -, among which R 4C is -NR8R9, and R 5C is —C(O)OR7, where R7, R8, and R9 are as defined above. In some embodiments, R7 is H, or is selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 is an alkyl group, such as H or C 1-6 In some embodiments, R and R are both H.

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

[0247] In some embodiments, R 1C is H or -(CH2) t NR aC R bC are selected from, among which R aC and R bC are independently H, C 1-6 Alkyl groups (e.g., methyl groups, isopropyl groups, etc.), amidino groups, C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl groups), and t is selected from 0, 1, 2, 3, 4, or 5. In some embodiments, R 1C is H. In some embodiments, R aC and R bC are independently H, C 1-6 In some embodiments, R is selected from alkoxycarbonyl groups (e.g., methoxycarbonyl groups, etc.). aC and R bC are each H. In some embodiments, t is selected from 0, 1, 2, or 3, and is preferably 3.

[0248] In some embodiments, R 2C is H, amino group, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkylamino group, C 1-6 The alkyl group is selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 Optionally substituted with one or more groups selected from alkoxy groups.

[0249] In some embodiments, when Y is CH, R 3C is H, hydroxyl group, C1-6 Alkyl group, 3- to 8-membered heterocyclyl group, C 1-6 alkoxy groups, and when Y is N, R 3C is H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl-(CH2) mC -, 3- to 8-membered heterocyclyl group, 3- to 8-membered heterocyclyl-(CH2) mC -, -(CH2) mC NR 10 R 11 Among these, alkyl, cycloalkyl, heterocyclyl and alkoxy groups are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 Alkoxy group, C 1-6 alkylamino groups, and R 10 and R 11 are each independently H or C 1-6 is an alkyl group, or R 10 and R 11 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclyl group (e.g.,

[0250] [ka]

[0251] wherein the alkyl group and heterocyclyl group are selected from the group consisting of halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 each occurrence of mC is independently selected from 1, 2, 3, 4, optionally substituted with one or more groups selected from alkoxy groups;

[0252] In some embodiments, R is H, a halogen, NO, a cyano group, NHC(=O)-, C 1-6alkoxy groups, halogens, hydroxy groups, amino groups, nitro groups, cyano groups, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 alkyl groups, preferably H, F, Cl, NO, CH, CF, cyano, NHC(=O)-, C 1-6 In some embodiments, R is selected from the group consisting of an aminoalkyl group. 4C 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 is C 1-6 is an aminoalkyl group or an amino group, and R 3C is H or C 1-6 is an alkyl group, and in some embodiments, R 2C is an amino group, and R 3C is H.

[0257] In some embodiments, in Formula IIC-2, R 2C is C 1-6 an aminoalkyl group or an amino group, and R 3C is H or C 1-6 is an alkyl group, or R 2C is H or C 1-6 is an alkyl group, and R 3C is C 1-6It is an aminoalkyl group or a 3- to 8-membered nitrogen-containing heterocyclyl group.

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

[0259] [ka]

[0260] In some embodiments, in the above general formula, one or more of the following conditions are satisfied: (1)R 1C Ha-(CH2) t NR aC R bC is preferably —(CH)NH, (2) Ring A is a phenyl group; (3) p is 0.

[0261] In some embodiments, in the above general formula, G is selected from one of the following: (1) G is -S(=O)(=NR 6C ')- and (2) G is -CR 4C R 5C - and R 4C is H and R 5C Ha-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, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-14 aryl group and 5- to 14-membered heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are selected from halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6Haloalkyl group, NHC(=O)-, C 1-6 R7 is preferably H or a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NHC(=O)-, C 1-6 C optionally substituted with one or more groups selected from 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 compound of the present disclosure is selected from the compounds shown below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0265] [ka]

[0266] [ka]

[0267] [ka]

[0268] [ka]

[0269] [ka]

[0270] [ka]

[0271] [ka]

[0272] [ka]

[0273] [ka]

[0274] [ka]

[0275] [ka]

[0276] [ka]

[0277] [ka]

[0278] [ka]

[0279] The present disclosure further provides a compound of the following general formula, a stereoisomer thereof, or a salt thereof, which is an intermediate for preparing the above compounds of the present disclosure:

[0280] [ka]

[0281] wherein R' is R or R in which NH is protected with an amino-protecting group, and R 1C ' is R 1C or R in which NH2 is protected with an amino protecting group 1C and R 2C ' is R 2C or R in which NH2 is protected with an amino protecting group 2C and R 3C ' is R 3C or R in which NH2 or cyclic imino group is protected with an amino protecting group 3C G' is G or G in which NH and / or cyclic imino group is protected with an amino-protecting group and / or carboxy group is protected with a carboxy-protecting group, and the rings A, Y, R, R 1C , R 2C , R 3C , G and p are as defined above, and R v is selected from H and a carboxy protecting group.

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

[0283] [ka]

[0284] is selected from wherein Rs and Rt are each independently selected from H and an amino-protecting group.

[0285] In some embodiments, the amino protecting groups are each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichlorooxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, a 1-phenylethyl group, or an ethoxycarbonyl group.

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

[0287] Manufacturing method In some embodiments, compounds according to the present invention can be prepared by a method selected from: Method 1: Method 1 includes the steps of: condensing a compound represented by formula iC-2 with a compound represented by formula iC-3-a, iC-3-b, or iC-3-c to produce a compound represented by formula iC-1; and then removing a protecting group to produce a compound represented by formula IC;

[0288] [ka]

[0289] Method 2: Method 2 comprises the steps of condensing a compound of formula iiC-2 with a compound of formula iiC-3 to produce a compound of formula iiC-1, followed by deprotection to produce a compound of formula IC;

[0290] [ka]

[0291] Preferably, the compound of formula iiC-2 is prepared by a method selected from: Method 3: Method 3 comprises the steps of subjecting a compound of formula iiC-4-a and a compound of formula iiC-5-a to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0292] [ka]

[0293] Method 4: Method 4 comprises the steps of subjecting a compound of formula iiC-4-b and a compound of formula iiC-5-b to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0294] [ka]

[0295] Method 5: Method 5 comprises the steps of subjecting a compound of formula iiC-4-c and a compound of formula iiC-5-c to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0296] [ka]

[0297] Method 6: Method 6 comprises the steps of subjecting a compound of formula iiC-4-d and a compound of formula iiC-5-d to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound of formula iiC-2;

[0298] [ka]

[0299] Preferably, the formula iC-2 is

[0300] [ka]

[0301] and Preferably, iiC-2 above is

[0302] [ka]

[0303] is selected from wherein R' is R or R in which NH is protected with an amino-protecting group, and R 1C ' and R 1C '' is R 1C or R in which NH2 is protected with an amino protecting group 1C and R 2C ' and R 2C '' is R 2C or R in which NH2 is protected with an amino protecting group 2C and R 3C ' and R 3C '' is R 3C or R in which NH2 or cyclic imino group is protected with an amino protecting group 3C G' is G or G in which NH and / or the cyclic imino group is protected with an amino-protecting group and / or the carboxy group is protected with a carboxy-protecting group, Rw is a carboxy-protecting group, and the rings A, Y, R, R 1C , R 2C , R 3C , G and p are as defined above, and Rs, Rt and Ru are each independently selected from H and an amino protecting group; Preferably, the amino protecting groups are each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichlorooxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, a 1-phenylethyl group, and an ethoxycarbonyl group, and the carboxy protecting groups are each independently selected from a C 1-6It is selected from an alkyl group, an allyl group, a benzyl group, a 2,4-dimethoxybenzyl group, a p-methoxybenzyl group, a methoxyethoxymethyl group, a pentafluorophenyl group, and a 4-p-methylbenzyloxybenzyl group.

[0304] In the above Methods 3, 4, 5, and 6, the condensation reaction refers to the condensation reaction of iiC-4 (specifically, iiC-4-a, iiC-4-b, iiC-4-c, and iiC-4-d) with iiC-5 (specifically, iiC-5-a, iiC-5-b, iiC-5-c, and iiC-5-d), respectively, to form a condensation product. The hydrolysis reaction aims to remove the carboxyl-protecting group Rw in the condensation product. Depending on the hydrolysis conditions, the carboxyl-protecting group Rw in the condensation product may be removed simultaneously with the removal of some or all of the amino-protecting groups (if present) in the condensation product. The product after the hydrolysis reaction is referred to as the hydrolysis product. In some embodiments, the hydrolysis product is a compound represented by Formula iiC-2. In some embodiments, the hydrolysis product further undergoes an amino-protection reaction to obtain a compound represented by Formula iiC-2. In some embodiments, the hydrolysis product further undergoes an amino-protecting group removal reaction and an amino-protection reaction to obtain a compound represented by Formula iiC-2. [Example]

[0305] Examples of the present invention will be described in detail below. The examples described below are illustrative and are intended to explain the present invention only, and should not be understood as limiting the present invention. Unless otherwise indicated, all ratios, percentages, etc. referred to in this specification are by weight.

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

[0307] [ka]

[0308] Furthermore, the purification of the final product is referred to in each example as "purification by reversed-phase flash chromatography," "purification by preparative HPLC," "purification by reversed-phase column chromatography," "purification by high-performance liquid chromatography," or "purification by reversed-phase column chromatography," respectively. The mobile phase conditions used for the purification are explicitly stated in some examples as "solvent ACN and solvent HO (FA, 0.1%)," but it should be understood that the same or similar mobile phase conditions are used in other examples. Under these chromatographic conditions, the compounds in some examples are formed as formate salts. However, those skilled in the art will understand that the free compounds may also be formed by conventional neutralization reaction conditions in 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 hexafluorophosphate HOBT: 1-hydroxybenzotriazole TBTU: O-Benzotriazazole-N,N,N',N'-tetramethyluronium tetrafluoroborate 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 Ethyl 4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate hydrochloride (3.7 g, 12.552 mmol, 1.00 equiv) was dissolved in DMF (37 mL) at room temperature, and DIEA (4.87 g, 37.656 mmol, 3 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 at room temperature overnight. The resulting mixture was extracted with dichloromethane (2 × 200 mL). The combined organic layer was washed with brine (2 × 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 dichloromethane, methanol (20:1) to give an off-white solid, methyl 1-[(2R)-2-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (8.97 g, 94.63%, purity 82.0%). 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), and (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) were added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with ethyl acetate (1 × 500 mL). The combined organic layer was 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 give a white solid, (2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamido]-4-methylpentanoate (13.94 g, 97.60%, purity 87.0%). LC-MS-1-3 (ES, m / z): [M+1]=557

[0314] 1.3 Synthesis of Compound 1-2 Methyl 1-[(2R)-2-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (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 stirred under a hydrogen atmosphere at room temperature overnight. 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 give methyl 1-[(2R)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (5.65 g, 76.53%, purity 95.0%). 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-phenylpropanamido]-4-methylpentanoate (13.94 g, 25.040 mmol) was dissolved in DCM (100 mL, 1573.005 mmol, 62.82 equiv.), and TFA (1.00 mL, 1346.304 mmol, 53.77 equiv.) was added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The crude product was recrystallized from dichloromethane / 1 M aqueous hydrochloric acid, washed with 1 × 400 mL of water, filtered, and the solid collected to give (2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamido]-4-methylpentanoic acid (9.43 g, 74.48%, purity 98.8%). 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-phenylpropanamido]-4-methylpentanoic acid (4.78 g, 9.539 mmol, 1.1 equiv) and DIEA (3.36 g, 26.016 mmol, 3 equiv) were dissolved in DMF (40 mL, 516.870 mmol, 59.60 equiv), and methyl 1-[(2R)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (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 at room temperature overnight. The resulting mixture was extracted with ethyl acetate (1 × 400 mL). The combined organic layers were washed with brine (3 × 200 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 (1:2), fractionated, and rotary evaporated to give methyl 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]]-2-[(2R)-2-[(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (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 Methyl 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2]-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-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 at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give methyl 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamido]-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (5.74 g, 80.98%, purity 97.0%). 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) was dissolved in N,N-dimethylformamide (1.60 mL) and methyl 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamido]-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (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 with stirring at room temperature overnight. After concentration under reduced pressure, the residue was purified by reverse-phase flash chromatography, fractionated, and rotary evaporated to give methyl 1-[(2R)-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (136 mg, 55.67%, purity 66.7%). LC-MS-1-7(ES, m / z): [M+1]=894

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

[0320] 1.9 Synthesis of Compound 1 Methyl 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (115 mg, 0.166 mmol, 1.00 equiv) was dissolved in a mixture of THF (10 mL) and water (2 mL), and LiOH.HO (13.933 mg, 0.332 mmol, 2.00 equiv) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH = 7 with 1 M HCl (aq). The resulting mixture was purified by reverse-phase flash chromatography to give 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[benzyl(methyl)carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylic acid (60.0 mg, 49.23%, purity 95.2%). LC-MS-1 (ES, m / z): [M+1]=680 1 H 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 1H 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 1 H 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, 4H), 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]

change

[0330] 4.1 Synthesis of compound 4-1 Methyl 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamido]-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (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 diluted with water (30 mL), and extracted with EA (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-{3-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (256 mg, crude product). LC-MS-4-1(ES, m / z): [M+1] =994

[0331] 4.2 Synthesis of Compound 4-2 Methyl 4-[(tert-butoxycarbonyl)amino]-1-[(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-{3-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (265 mg, 0.267 mmol, 1.00 equiv) was dissolved in dioxane (5.3 mL) and a 4 M solution of HCl (gas) in 1,4-dioxane (8 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Methyl 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-(3-amino-3-phenylpropanamido)-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (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 Methyl 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-(3-amino-3-phenylpropanamido)-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (80 mg, 0.115 mmol, 1.00 equiv) was dissolved in THF (3 mL), and HO (0.8 mL, 44.4075.15 mmol) and LiOH (5.52 mg, 0.230 mmol, 2 equiv) were added. The resulting 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 rotary evaporation gave 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-((3R)-3-amino-3-phenylpropanamido)-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-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-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylic acid (11 mg, 13.74%, purity 97.5%).

[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 tert-Butyl (2R)-2-amino-3-phenylpropionate (480 mg, 2.169 mmol, 1.00 equiv) and triethylamine (1.85 g, 18.282 mmol, 8.43 equiv) were dissolved in acetonitrile (19 mL, 361.469 mmol, 166.65 equiv) and stirred at 0 °C for 30 min under a nitrogen atmosphere. To the above mixture was added 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography, fractionated, and rotary evaporated to give (2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanoate (855 mg, 79.87%, 100% pure). LC-MS-8-1(ES, m / z):[M+1]=494

[0349] 8.2 Synthesis of Compound 8-2 Tert-butyl tert-butyl (2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropionate (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 resulting mixture was concentrated under reduced pressure to give (2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanoic acid (600 mg, crude). The crude product mixture was 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 {4-[(4-methylphenyl)methoxy]phenyl}methyl(2R)-2-[(2R)-2-amino-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoate (1445.79 mg, 2.538 mmol, 3 equiv), (2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)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) at room temperature, and TBTU (528 mg, 1.644 mmol) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight to give {4-[(4-methylphenyl)methoxy]phenyl}methyl(2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-4-methyl-2-[(2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropionamido]pentanamido]hexanoate (2.6 g, crude product).

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

[0352] 8.5 Synthesis of Compound 8-5 To a 50 mL round-bottom flask was added (2R)-6-amino-2-[(2R)-4-methyl-2[(2R)-2-({methyl[1-phenyl-2-(2,2,2-trifluoroacetamido)ethyl]carbamoyl}amino)-3-phenylpropanamido]pentanamido]hexanoic acid (470 mg, 0.692 mmol, 1 equiv), HO (10 mL), and lithium hydroxide (33.17 mg, 1.384 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure to give (2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-amino-1-phenylethyl)(methyl)carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoic acid (500 mg, crude product). 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-phenylpropanamido]-4-methylpentanamido]hexanoic acid (350 mg, 0.601 mmol, 1 equiv) and TEA (182.33 mg, 1.803 mmol, 3 equiv) were dissolved in THF (10 mL), and di-tert-butyl dicarbonate (262.1202 mg, 1 equiv) was added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography to afford (2R)-6-[(tert-butoxycarbonyl)amino]-2-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamido]-4-methylpentanamido]hexanoic acid (260 mg, 55.29%, 100% pure). 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-phenylpropanamido]-4-methylpentanamido]hexanoic acid (60 mg, 0.077 mmol, 1 equiv), 3-methyl-1-(piperidin-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) under room temperature and nitrogen atmosphere, and HATU (43.71 mg, 0.115 mmol, 3 equiv) was added. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was purified by reverse-phase flash chromatography to afford tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl)}(methyl)carbamoyl)amino]-3-phenylpropanamido]-4-methylpentanamido]-6-{4-[(methylcarbamoyl)amino]piperidin-1-yl}-6-oxohexyl]carbamate (62 mg, 87.74%, 100% pure). LC-MS-8-7(ES, m / z):[M+1]=922

[0355] 8.8 Synthesis of Compound 8 Tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamido]-4-methylpentanamido]-6-{4-[(methylcarbamoyl)amino]piperidin-1-yl}-6-oxohexyl]carbamate (62 mg, 0.067 mmol, 1 equiv) was dissolved in dioxane (10 mL) and a solution of HCl (gas) in 1,4-dioxane (5 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography to give (2R)-2-[(2R)-2-{[(2-amino-1-phenylethyl)(methyl)carbamoyl)amino}-3-phenylpropanamido]-N-[(2R)-6-amino-1-{4-[(methylcarbamoyl)amino]piperidin-1-yl}-1-oxohexyl-2-yl]-4-methylpentanamide (13.6 mg, 26.73%, purity 95.0%). LC-MS-8(ES, m / z):[M+1]=722 1 H 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 1H 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 tert-Butyl 4-aminopiperidine-1-carboxylate (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 several portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water at room temperature. After concentration under reduced pressure, the residue was purified by silica gel column chromatography eluting with PE / EA (5:1), fractionated, and rotary evaporated to give tert-butyl 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate (522 mg, 80.94%, 100% pure). LC-MS-12-1(ES, m / z):[M+1]=259.32

[0368] 12.2 Synthesis of Compound 12-2 At room temperature, tert-butyl 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate (552 mg, 2.137 mmol, 1 equiv) was added to a solution of 4 M HCl (gas) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at room temperature. Concentration under reduced pressure gave N-(piperidin-4-yl)carbamic acid methyl ester (455 mg, crude product). 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-phenylpropanamido]-4-methylpentanamido]hexanoic acid (70 mg, 0.089 mmol, 1 equiv), TEA (27.14 mg, 0.267 mmol, 3 equiv), and N-(piperidin-4-yl)carbamic acid methyl ester (21.22 mg, 0.134 mmol, 1.5 equiv) were added to DMF (1 mL), and HATU (50.99 mg, 0.134 mmol, 1.5 equiv) was added in several portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched with water at room temperature. LCMS showed the desired product. The reaction mixture was purified by reverse-phase flash chromatography to give tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamido]-4-methylpentanamido]-6-{4-[(methoxycarbonyl)amino]piperidin-1-yl}-6-oxohexyl]carbamate (70 mg, 83.00%, 100% pure). LC-MS-12-3(ES, m / z): [M+1]= 924.1

[0370] 12.4 Synthesis of Compound 12 Under a nitrogen atmosphere at room temperature, tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[({2-[(tert-butoxycarbonyl)amino]-1-phenylethyl}(methyl)carbamoyl)amino]-3-phenylpropanamido]-4-methylpentanamido]-6-{4-[(methoxycarbonyl)amino]piperidin-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 evaporated to give N-{1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-amino-1-phenylethyl)(methyl)carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidin-4-yl}carbamic acid methyl ester (42.1 mg, 72.07%, purity 93.9%). LC-MS-12(ES, m / z):[M+1]=723.15 1 H 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 To a solution of 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) in ACN (3 mL) / DMF (3 mL) was added 1-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamido]-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylic acid methyl ester (100 mg, 0.134 mmol, 1.00 equiv) at room temperature under a nitrogen atmosphere. 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 rotary evaporated to give methyl 1-[(2R)-2-[(2R)-2-[(2R)-2-{[benzyl({2-[(tert-butoxycarbonyl)amino]ethyl})carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)amino]piperidine-4-carboxylate (120 mg, 87.59%, 100% pure). LC-MS-13-1(ES, m / z):[M+1]=1024.28

[0374] 13.2 Synthesis of Compound 13-2 Ethyl 1-[(2R)-2-[(2R)-2-[(2R)-2-{[benzyl({2-[(tert-butoxycarbonyl)amino]ethyl})carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]-6-[(tert-butoxycarbonyl)amino]hexanoyl]-4-[(tert-butoxycarbonyl)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 to give methyl 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-aminoethyl)(benzyl)carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (75 mg, 88.47%, 100% pure). 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 Ethyl 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(2-aminoethyl)(benzyl)carbamoyl]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylate (75 mg, 0.104 mmol, 1 equiv) was dissolved in THF (1 mL) and HO (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. Concentration under reduced pressure gave a residue. The residue was purified by reverse-phase flash chromatography, fractionated, and rotary evaporated to give 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-{[(aminoethyl)(benzyl)carbamoyl]]amino}-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylic acid (25.5 mg, 29.28%, 84.5% purity). 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 1 H 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 Compound 1-3 (500 mg, 0.898 mmol, 1 equiv) was dissolved in DCM (5 mL), and piperidine (0.5 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 3 h. The reaction mixture was then rotary evaporated to give a yellow crude product. The crude product was purified by reverse-phase column chromatography (conditions: C18 chromatography column, mobile phase, solvent: ACN and solvent: HO (FA, 0.1%), 10 min gradient from 10% to 50%, UV254 nanodetector), fractionated, and rotary evaporated to give 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 To a solution of compound 16-1 (1482 mg, 4.438 mmol, 1 equiv) and compound 16-2 (711 mg, 4.438 mmol, 1.00 equiv) in ACN (2 mL) / DMF (0.4 mL) was added CDI (791.55 mg, 4.882 mmol, 1.1 equiv) in several portions at 0 °C under nitrogen protection and stirred overnight at room temperature. The reaction mixture was evaporated to dryness to give a yellow crude oil. The crude product was purified by reverse-phase column chromatography (conditions: C18 chromatography column, mobile phase, ACN and HO (0.1%), 10% to 50% gradient over 10 min, UV254 nanodetector), fractionated distillation, and evaporated to give 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 TFA (5 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 h. The reaction mixture was then rotary evaporated to give 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 Compound 16-4 (600 mg, 1.320 mmol, 1 equiv) was dissolved in THF (20 mL) at room temperature. Then, TEA (267.13 mg, 2.640 mmol, 2 equiv) and BocO (432.11 mg, 1.980 mmol, 1.5 equiv) were added dropwise to the reaction mixture and stirred at room temperature for 2 h. The crude product was then purified by silica gel column chromatography using PE / EA (1 / 1), followed by fractional distillation and rotary evaporation to give 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 single-neck flask at room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered, and the residue was washed with methanol and ether, respectively. The residue was then rotary evaporated to give compound 16-7 (2.6 g, crude product).

[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 single-neck flask at room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered, the residue was washed with TFA / DCM (v / v, 1 / 1), and the filtrate was rotary evaporated to give 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. TEA (0.35 g, 3.432 mmol, 2 equiv) and BocO (0.75 g, 3.432 mmol, 2 equiv) were added dropwise to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was then spun down to give crude compound 10. The crude product was purified by silica gel column chromatography eluting with PE / EA (1 / 1). The fraction was spun down to give compound 16-9 (700 mg, 52.10%, purity 99%). LC-MS-16-9 (ES, m / z):[M+1]=783

[0391] 16.8 Synthesis of Compound 16-11 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) were added to a 50 mL single-neck flask at room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was purified by reverse-phase column chromatography (C18 chromatography column, mobile phase, solvent, ACN and solvent, HO (FA, 0.1%), 10 min 10% to 50% gradient, UV254 nanodetector), fractionated, and rotary evaporated to afford compound 16-11 (50 mg, 70.68%, purity 99%). 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 single-neck flask at room temperature and stirred for 2 h. The reaction mixture was then spun down, and the crude product was purified by reverse-phase column chromatography (conditions: C18 chromatography column, mobile phase, solvent: ACN and solvent: HO (0.1%), 10% to 50% FA gradient over 10 min, UV254 nanodetector). Compound 16 (25 mg, 53.21%, purity: 99.8%) was obtained by fractional distillation and spun down. LC-MS-16 (ES, m / z): [M+1] = 723 1H 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 The target compound was prepared according to steps similar to those in Example 16, and the starting compound

[0394] [ka]

[0395] of

[0396] [ka]

[0397] Specifically, it is replaced as follows:

[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 1H 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 1H 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 starting compound

[0407] [ka]

[0408] of

[0409] [ka]

[0410] Specifically, it is replaced as follows:

[0411] [ka]

[0412] LC-MS-20(ES, m / z):[M+1]=713 1H 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 Compound 21-1 (34.53 mg, 0.256 mmol, 4 equiv) was added to a solution of intermediate 3 (50 mg, 0.064 mmol, 1 equiv) in DMF (10 mL) under nitrogen protection at room temperature. The mixture was stirred for 2 h, followed by the dropwise addition of HATU (36.42 mg, 0.096 mmol, 1.5 equiv) and DIPEA (16.51 mg, 0.128 mmol, 2 equiv). The resulting mixture was extracted with EA (3 × 100 mL). The organic layer was washed with brine (3 × 10 mL) and dried over NaSO. The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (conditions: C18 chromatography column, mobile phase, solvent: ACN and solvent: HO (FA, 0.1%), 10% to 50% gradient over 10 min, UV200 nanodetector) to give compound 21-2 (58 mg, crude product). LC-MS-21-2 (ES, m / z):[M+1]=900

[0416] 21.2 Synthesis of Compound 21 Compound 21-2 (40 mg, 0.044 mmol, 1 equiv) was reacted with a mixture of TFA (1 mL) and DCM (4 mL) under nitrogen protection at room temperature for 2 hours with stirring. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography (conditions: C18 chromatography column, mobile phase, solvent, ACN and solvent, HO (FA, 0.1%), 10 min 10% to 50% gradient, UV200 nano detector), fractionated, and rotary evaporated to give compound 21 (18.6 mg, 57.47%, purity 96.0%). 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 The target compound was prepared according to steps similar to those in Example 16, and the starting compound

[0424] [ka]

[0425] of

[0426] [ka]

[0427] Specifically, it is replaced as follows:

[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 The target compound was prepared according to steps similar to those in Example 16, and the starting compound

[0434] [ka]

[0435] of

[0436] [ka]

[0437] Specifically, it is replaced as follows:

[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 1H 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 The target compound was prepared according to steps similar to those in Example 8, and the starting compound

[0457] [ka]

[0458] of

[0459] [ka]

[0460] Specifically, it is replaced as follows:

[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 The target compound was prepared according to steps similar to those in Example 8, and the starting compound

[0464] [ka]

[0465] of

[0466] [ka]

[0467] Specifically, it is replaced as follows:

[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 1H 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 The target compound was prepared according to steps similar to those in Example 16, and the starting compound

[0474] [ka]

[0475] of

[0476] [ka]

[0477] Specifically, it is replaced as follows:

[0478] [ka]

[0479] LC-MS-35(ES, m / z): [M+1]=675 1 H 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 The target compound was prepared according to steps similar to those in Example 8, and the starting compound

[0481] [ka]

[0482] of

[0483] [ka]

[0484] Specifically, it is replaced as follows:

[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 The target compound was prepared according to steps similar to those in Example 8, and the starting compound

[0488] [ka]

[0489] of

[0490] [ka]

[0491] Specifically, it is replaced as follows:

[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] Specifically, it is replaced as follows:

[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 The target compound was prepared according to steps similar to those in Example 16, and the starting compound

[0520] [ka]

[0521] of

[0522] [ka]

[0523] Specifically, it is replaced as follows:

[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 The target compound was prepared according to steps similar to those in Example 16, and the starting compound

[0527] [ka]

[0528] of

[0529] [ka]

[0530] Specifically, it is replaced as follows:

[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 The target compound was prepared according to steps similar to those in Example 16, and the starting 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 1H 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 1H 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) and TEA (0.2 mL, 2.693 mmol, 6.31 equiv) were dissolved in DCM (15 mL), and methyl chloroformate (60.49 mg, 0.640 mmol, 1.5 equiv) was added in several portions. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of saturated ammonium chloride solution. Extraction with DCM (15 mL × 3) was performed. The combined organic phase was dried and rotary evaporated to give the crude product, which was purified by silica gel column chromatography eluting with PE / EA (1:1), followed by fractional distillation and rotary evaporation to give benzyl 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate. LC-MS-1A-1(ES, m / z):[M+1]=293

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

[0560] 1.3 Synthesis of Compound 1A-3 To a stirred solution of methyl N-(piperidin-4-yl)carbamate methyl ester (19.51 mg, 0.123 mmol, 3.00 equiv) in DMF (10 mL) was added DIPEA (1.48 mg, 0.123 mmol, 3 equiv), Intermediate 2 (31 mg, 0.041 mmol, 1.00 equiv), and HATU (23.45 mg, 0.061 mmol, 1.5 equiv). The reaction was carried out at room temperature under a nitrogen atmosphere for 3 h. The reaction was quenched by the addition of water (12 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried and rotary evaporated to give the crude product, which was purified by reverse-phase chromatography eluting with CHCN / HO (0.1% FA) (6:1), fractionated, and rotary evaporated to give tert-butyl N-[(5R)-5-[(2R))-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-{4-[(methoxycarbonyl))amino]piperidin-1-yl}-6-oxohexyl]carbamate. LC-MS-1A-3(ES, m / z): [M+1]=894

[0561] 1.4 Synthesis of Compound 1A Tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-{4-[(methoxycarbonyl)amino]piperidin-1-yl}-6-oxohexyl]carbamate (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, fractionated, and rotary evaporated to give N-{1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-[(2R)-2-amino-3]-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidin-4-yl}carbamic acid methyl ester (169.1 mg, 62.01%, purity 99.2%). LC-MS-1A(ES, m / z):[M+1]=693 1 H 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 To 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) at 0°C and under a nitrogen atmosphere was added bis(trimethylsilyl)lithium amide (19.97 mL, 119.348 mmol, 11.95 equiv) dropwise. The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. To the above mixture at 0°C was added tert-butyl N,N-bis(2-chloroethyl)carbamate (2.42 g, 9.994 mmol, 1.00 equiv) dropwise. The resulting mixture was stirred at 0°C for an additional 1 hour. Concentration under reduced pressure gave the crude product. The crude product was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (9:1), fractionated, and rotary evaporated to give tert-butyl tert-butyl spiro[indene-1,4′-piperidine]-1′-carboxylate (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 To a stirred solution of tert-butyl spiro[indene-1,4'-piperidine]-1'-carboxylate (2.22 g, 7.779 mmol, 1.00 equiv) in THF (22 mL) was added 2 M borane dimethyl sulfide complex (THF) (19.45 mL, 38.895 mmol, 5 equiv) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 4 h. To the above mixture was added dropwise sodium hydroxide (2 M) (23.34 mL, 46.674 mmol, 6 equiv) and aqueous hydrogen peroxide (6.66 mL, 285.878 mmol, 36.75 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min. 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), fractionated, and rotary evaporated to give tert-butyl 2-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (959 mg, 40.63%, purity 99%). LC-MS-2A-2(ES, m / z):[M+1]=304

[0566] 2.3 Synthesis of compound 2A-3 Dess-Martin reagent (2180.81 mg, 5.142 mmol, 2 equiv) was added in several portions to a solution of tert-butyl 2-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (780 mg, 2.571 mmol, 1.00 equiv) in dichloromethane (16 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (1 × 20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (1 × 15 mL) and brine (1 × 15 mL), extracted with ethyl acetate, and the combined organic layers were 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), fractionated, and rotary evaporated to give tert-butyl 2-oxo-3H-spiro[indene-1,4′-piperidine]-1′-carboxylate (550 mg, 70.98%, purity 99%). LC-MS-2A-3 (ES, m / z): [M+1]=302

[0567] 2.4 Synthesis of Compound 2A-4 To a stirred mixture of 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) at room temperature, 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, and the filter 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 purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (2:1), fractionated, and rotary evaporated to give tert-butyl (2E)-2-[(2-methylpropane-2-sulfinyl)imino]-3H-spiro[indene-1,4'-piperidine]-1'-carboxylate (450 mg, 19.49%, purity 99%). LC-MS-2A-4 (ES, m / z):[M+1]=405

[0568] 2.5 Synthesis of Compound 2A-5 To a stirred solution of tert-butyl (2E)-2-[(2-methylpropane-2-sulfinyl)imino]-3H-spiro[indene-1,4'-piperidine]-1'-carboxylate (350 mg, 0.865 mmol) in tetrahydrofuran (5 mL) at 0°C and a nitrogen atmosphere, BH3.THF (1.73 mL, 1.730 mmol, 2 equiv) 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 give tert-butyl 2-[(2-methylpropane-2-sulfinyl)amino]-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (380 mg, crude product). LC-MS-2A-5 (ES, m / z): [M+1]=407

[0569] 2.6 Synthesis of Compound 2A-6 To a stirred solution of tert-butyl 2-[(2-methylpropane-2-sulfinyl)amino]-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (100 mg, 0.246 mmol) in dichloromethane (1.7 mL) was added TFA (0.3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated in vacuo to give N-{2,3-dihydrospiro[indene-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 To a solution of N-{2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl}-2-methylpropane-2-sulfinamide (100.00 mg, 0.327 mmol, 1.1 equiv) in dimethylformamide (2 mL) at room temperature, diisopropylethylamine (115.01 mg, 0.891 mmol, 3 equiv), Intermediate 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 with stirring at room temperature overnight. The resulting solution was purified by reverse-phase flash chromatography, fractionated, and rotary evaporated to give tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-{2-[(2-methylpropane-2-sulfinyl)amino]-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl}-6-oxohexyl]carbamate (70 mg, 22.64%, 99% purity). LC-MS-2A-7 (ES, m / z):[M+1]=1042

[0571] 2.8 Synthesis of Compound 2A To a stirred solution of tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-{2-[(2-methylpropane-2-sulfinyl)amino]-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl}-6-oxohexyl]carbamate (70 mg, 0.067 mmol, 1.00 equiv) in dioxane (2 mL) at room temperature, 4 M HCl (gas) in 1,4-dioxane (2 mL) was added in several portions. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC to give (2R)-N-[(2R)-6-amino-1-{2-amino-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl}-1-oxohexyl-2-yl]-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamide (24.7 mg, 41.65%, purity 83.3%). 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 To a stirred solution of (3-bromopyridin-2-yl)methanol (1 g, 5.318 mmol, 1.00 equiv) in DCM at 0 °C was added thionyl chloride (1.27 g, 10.636 mmol, 2.0 equiv) in several portions. The resulting mixture was stirred at 0 °C for 4 h. The mixture was neutralized to pH 7 with saturated NaHCO (aq.). The crude product was purified by silica gel column chromatography eluting with PE / EA (5:1), fractionated, and rotary evaporated to give 3-bromo-2-(chloromethyl)pyridine (700 mg, 64.4%, 99% pure). LC-MS-3A-1(ES, m / z):[M+1]=205

[0575] 3.2 Synthesis of Compound 3A-2 LDA (10 mL, 73.747 mmol, 10.15 equiv) was added dropwise to 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (2.65 g, 10.897 mmol, 1.5 equiv) in THF (50 mL) at -30 °C under nitrogen protection. After 30 min, a THF solution of 3-bromo-2-(chloromethyl)pyridine (1.5 g, 7.265 mmol, 1 equiv) was added dropwise to the above solution and stirred overnight at room temperature. The reaction was quenched with saturated NH4Cl (aq) at room temperature. After extraction with ethyl acetate, the combined organic phases were rotary evaporated, and the crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), fractionated, and rotary evaporated to give 1-tert-butyl 4-methyl 4-[(3-bromopyridin-2-yl)methyl]piperidine-1,4-dicarboxylate (3.7 g, 82.4%, purity 99%). 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 1-tert-butyl 4-methyl 4-[(3-bromopyridin-2-yl)methyl]piperidine-1,4-dicarboxylate (1.2 g, 2.903 mmol, 1.00 equiv) in methanol at 70 °C. The mixture was stirred at 70 °C for 6 h. The reaction was cooled, and then the pH of the mixture was adjusted to 6 with HCl (aq.). After extraction with ethyl acetate, the combined organic phases were dried and rotary evaporated. The crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), fractionated, and rotary evaporated to give 4-[(3-bromopyridin-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 To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (200 mg, 2.029 mmol, 1 equiv) and 4-[(3-bromopyridin-2-yl)methyl]-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1604.22 mg, 4.058 mmol, 2 equiv) in DMF at room temperature under nitrogen protection was added DIPEA (786.87 mg, 6.087 mmol, 3 equiv) and HATU (1543.30 mg, 4.058 mmol, 2 equiv). The mixture was stirred under nitrogen protection at 0°C for 3 h. The reaction was quenched with water and extracted with ethyl acetate, the combined organic phases were dried and rotary evaporated, and the crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), fractionated and rotary evaporated to give tert-butyl 4-[(3-bromopyridin-2-yl)methyl]-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (120 mg, 13.52%, purity 99%). LC-MS-3A-4(ES, m / z):[M+1]=442

[0578] 3.5 Synthesis of Compound 3A-5 To a mixture of tert-butyl 4-[(3-bromopyridin-2-yl)methyl]-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.2 g, 2.713 mmol, 1 equiv) in THF was added butyllithium (1.74 mL, 27.130 mmol, 10 equiv) at −78°C under nitrogen protection. The mixture was stirred at −78°C under nitrogen protection for 3 hours. The reaction was quenched at room temperature by the addition of saturated aqueous NH₄Cl (aq.) (2 mL). After extraction with ethyl acetate, the combined organic phase was dried and rotary evaporated. The crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), followed by fractional distillation and rotary evaporation to give tert-butyl 5-oxo-7H-spiro[cyclopentadiene[b]pyridine-6,4′-piperidine]-1′-carboxylate (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-butanesulfenamide (30.06 mg, 0.249 mmol, 3 equiv) was added dropwise 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). The mixture was stirred at 110°C under nitrogen protection for 4 hours. After cooling to room temperature, the reaction was quenched by the addition of water. Ethyl acetate was extracted, the combined organic phases were dried and rotary evaporated, and the crude product was purified by silica gel column chromatography eluting with PE / EA (1:1), fractionated and rotary evaporated to give tert-butyl (5Z)-5-[(2-methylpropane-2-sulfinyl)imino]-7H-spiro[cyclopentadiene[b]pyridine-6,4′-piperidine]-1′-carboxylate (10 mg, 29.82%, purity 99%). LC-MS-3A-6(ES, m / z):[M+1]=413

[0580] 3.7 Synthesis of Compound 3A-7 (5Z)-5-[(2-methylpropane-2-sulfinyl)imino]-7H-spiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylic acid 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 at 0 °C under nitrogen protection for 3 h. The reaction was quenched by the addition of MeOH (2 mL) at room temperature. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: column: silica column, mobile phase: MeCN / water solution, 10% to 100% gradient over 10 min, detector: UV 220 nm. Fractional distillation and rotary evaporation gave 5-[(2-methylpropane-2-sulfinyl)amino]-5,7-dihydrospiro[cyclopentadiene[b]pyridine-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester (10 mg, 49.75%, 99% purity). LC-MS-3A-7(ES, m / z):[M+1]=408

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

[0582] 3.9 Synthesis of Compound 3A-9 A solution of N-{5,7-dihydrospiro[cyclopentadiene[b]pyridine-6,4'-piperidin]-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) in DMF was stirred for 1 min at room temperature under air. DIPEA (41.62 mg, 0.323 mmol, 1.5 equiv) and HATU (163.24 mg, 0.430 mmol, 2 equiv) were added to the above mixture at room temperature. The mixture was stirred at room temperature under nitrogen protection for 3 h. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: column: silica column, mobile phase: aqueous MeCN, 10% to 50% gradient over 10 min, detector: UV 220 nm. Fractional distillation and rotary evaporation afforded tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-{5-[(2-methylpropane-2-sulfinyl)amino]-5,7-dihydrospiro[cyclopentadiene[c]pyridine-6,4'-piperidine]-1'-yl}-6-oxohexyl]carbamate (30 mg, 13.39%, 99% pure). LC-MS-3A-9(ES, m / z):[M+1]=1043

[0583] 3.10 Synthesis of Compound 3A tert-Butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-{5-[(2-methylpropane-2-sulfinyl)amino]-5,7-dihydrospiro[cyclopentadiene[c]pyridine-6,4'-piperidine]-1'-yl}-6-oxohexyl]carbamate (110 mg, 0.105 mmol, 1 equiv) was added dropwise to 4 M HCl (gas) in 1,4-dioxane (5 mL) and stirred at room temperature under nitrogen protection for 3 hours. Concentration under reduced pressure gave the crude product. The crude product (100 mg) was purified by preparative HPLC using a C18 silica gel column, a mobile phase of acetonitrile / water, a 10 min gradient from 10% to 50%, and a UV detector at 220 nm. After fractional distillation and rotary evaporation, (2R)-N-[(2R)-6-amino-1-{5-amino-5,7-dihydrospiro[cyclopentadiene[c]pyridine-6,4'-piperidin]-1'-yl}-1-oxohexan-2-yl]-2-[(2R)-2-amino-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamide (20.1 mg, 18.2%, purity 70.3%) was obtained. LC-MS-3A(ES, m / z):[M+1]=739 1 H 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, sodium bis(trimethylsilyl)amide (1426.37 mg, 7.778 mmol) was added to a stirred solution of 6-chloropyridin-2-amine (500 mg, 3.889 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at 0 °C. 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 at room temperature overnight. 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 eluting with petroleum ether / ethyl acetate (10:1), followed by fractional distillation and rotary evaporation to give tert-butyl N-(6-chloropyridin-2-yl)carbamate (800 mg, 89.95%, purity: 99%). LC-MS-4A-1 (ES, m / z): [M+1]=229

[0587] 4.2 Synthesis of compound 4A-2 In a two-neck round-bottom flask, tetramethylethylenediamine (3353.91 mg, 28.862 mmol, 2.2 equiv) was dissolved in tetrahydrofuran (78.43 mL). To the mixture was added n-butyllithium (1848.71 mg, 28.862 mmol, 2.2 equiv) dropwise at −78° C. The mixture was stirred for an additional 30 min at −20° C. To the mixture was added 4-oxopiperidine-1-carboxylic acid benzyl ester (4590.26 mg, 19.678 mmol, 1.5 equiv) dropwise at −78° C. The mixture was stirred for an additional 1 h at −78° C. To the mixture was added tert-butyl N-(6-chloropyridin-2-yl)carbamate (3000 mg, 13.119 mmol, 1.00 equiv) dropwise at −50° C. The resulting mixture was stirred at 40° C. overnight. The resulting mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (2:1) to give 7'-chloro-2'-oxo-1'H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxylic acid 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-carboxylic acid 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 the mixture was purged with hydrogen three times. The resulting 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 give spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-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]oxazin]-2'(1'H)-one (44 mg, 0.138 mmol, 1.00 equiv) and Intermediate 2 (100 mg, 0.067 mmol, 0.5 equiv) were dissolved in DMF (2 mL), and diisopropylethylamine (34 mg, 0.4 mmol, 3.00 equiv) and HATU (76 mg, 0.207 mmol, 1.50 equiv) were added in portions. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried, and concentrated in vacuo. tert-Butyl ((10R,13R,16R,19R)-16-benzyl-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-phenyl-3-oxa-5,11,14,17-tetraazaeicosan-19-yl)carbamate was obtained (120 mg, crude). LC-MS-4A-4 (ES, m / z): [M+1]=955

[0590] 4.5 Synthesis of Compound 4A To a 50 mL round-bottom flask was added tert-butyl ((10R,13R,16R,19R)-16-benzyl-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-phenyl-3-oxa-5,11,14,17-tetraazaeicosan-19-yl)carbamate (120 mg, 0.126 mmol, 1.00 equiv) and a 4 M solution of HCl (gas) in 1,4-dioxane (4 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and purified by reverse flash chromatography, fractionated, and rotary evaporated to give (2R)-N-[(2R)-6-amino-1-oxo-1-{2'-oxo-1'H-spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl}hex-2-yl]-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamide (7 mg, 7.31%, purity 99.2%). LC-MS-4A (ES, m / z): [M+1] = 755 1H 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 1H 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 1 H 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] [ka]

[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, 5.4Hz, 6H).

[0600] Example 8A Synthesis of Compound 8A

[0601] [ka]

[0602] 8.1 Synthesis of Compound 8A-1 4-Aminopiperidine-1-carboxylic acid 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. Tetrahydropyran-4-ol (205 μL, 2.007 mmol, 0.94 equiv) was then added dropwise. The resulting mixture was stirred overnight at 90° C. under nitrogen protection. The reaction mixture was cooled to room temperature and then poured into ice water. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with ethyl acetate (3×10 mL) and dried over anhydrous NaSO. 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 added to methanol (10 mL, 246.988 mmol, 206.73 equiv) and stirred overnight at room temperature under a hydrogen atmosphere. The resulting 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 rotary evaporated to give ox-4-yl N-(piperidin-4-yl)carbamate (448 mg, crude product).

[0604] 8.3 Synthesis of Compound 8A-3 Dioxan-4-yl N-(piperidin-4-yl)carbamate (113 mg, 0.495 mmol, 1.5 equiv) was dissolved in DMF (10 mL) at room temperature under nitrogen protection, and Intermediate 2 (248.79 mg, 0.330 mmol, 1 equiv) was added. The mixture was stirred, followed by DIPEA (85.30 mg, 0.660 mmol, 2 equiv) and HATU (188.21 mg, 0.495 mmol, 1.5 equiv). After the addition was complete, the mixture was stirred overnight. After quenching with water, the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with diethyl 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 using a silica gel column, a MeCN aqueous solution as the mobile phase, a 10% to 50% MeCN gradient over 10 min, and a UV detector at 254 nm. Fractional distillation and rotary evaporation gave compound 8A-3 (104 mg, 32.69%, purity 99%).

[0605] 8.4 Synthesis of Compound 8A Compound 8A-3 (104 mg, 0.108 mmol, 1 equiv) and TFA (4 mL) were added to DCM (16 mL) under nitrogen protection at room temperature and stirred for 3 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash chromatography using a silica gel column, a MeCN aqueous solution as the mobile phase, a 10% to 50% gradient in 10 min, and a UV detector at 254 nm. Fractional distillation and rotary evaporation afforded compound 8A (19.7 mg, 22.73%, purity 95.0%). 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 1H 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) for 30 min. The mixture was filtered, the solid was washed with DCM, and dried. The solid was dissolved in DMF (40 mL), and then compound 10A-1 (2 g, 8.761 mmol, 1.00 equiv), DCC (5.42 g, 26.283 mmol, 3 equiv), and HOBT (2.37 g, 17.522 mmol, 2 equiv) were added and stirred at room temperature for 3 h. Finally, DMAP (0.54 g, 4.380 mmol, 0.5 equiv) was added and stirred at room temperature overnight. The resulting mixture was filtered, washed with MeOH, and the solid was collected to give compound 10A-3 (3 g, crude product) as a white solid. The resulting mixture was directly used in the next step without further purification.

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

[0613] 10.3 Synthesis of Compound 10A-6 Under nitrogen protection, compound 10A-5 (3.54 g, 10.021 mmol, 1.5 equiv) was added to a solution of compound 10A-4 (2 g, 6.681 mmol, 1 equiv) in DMF (10 mL) at room temperature, and then 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 at room temperature for 2 hours, the resulting mixture was filtered and washed with MeOH. The solid was collected and concentrated under reduced pressure to give compound 10A-6 (2.9 g, crude product).

[0614] 10.4 Synthesis of Compound 10A-7 Compound 10A-6 (2 g, 3.151 mmol, 1 equiv) was reacted in a mixture of TFA (10 mL, 134.631 mmol, 42.73 equiv) and DCM (40 mL, 629.224 mmol, 199.71 equiv) under nitrogen protection at room temperature for 4 hours. The filtrate was concentrated under reduced pressure and rotary evaporated to give compound 10A-7 (1.6 g, crude product). LC-MS-10A-7(ES, m / z): [M+1]=424

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

[0616] 10.6 Synthesis of Compound 10A-10 Compound 10A-9 (165 mg, 0.229 mmol, 1 equiv) was reacted in a solution of piperidine (1 mL) and DCM (10 mL) under nitrogen protection at room temperature for 3 h. The resulting solution was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography using a C18 chromatography column, ACN and HO (0.1% FA) as the mobile phase, a 10% to 50% gradient in 10 min, and a UV254 nanodetector. Compound 10A-10 (100 mg, 87.5%) was obtained after fractional distillation and rotary evaporation. LC-MS-10A-10(ES, m / z):[M+1]=499

[0617] 10.7 Synthesis of Compounds 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, and HATU (2.1 g, 8.712 mmol, 2.25 equiv) and DIPEA (1.8 g, 13.927 mmol, 3.59 equiv) were added dropwise at room temperature, followed by stirring overnight. The resulting mixture was quenched with water and extracted with EA (3 × 100 mL). The combined organic phases were dried, rotary evaporated, and filtered. The resulting liquid was concentrated under reduced pressure. The resulting crude product was purified by reverse-phase column chromatography (conditions: C18 chromatography column, mobile phase, solvent: ACN and solvent: HO (0.1% FA), 10% to 50% gradient in 10 min, UV254 nanodetector), fractionated, and rotary evaporated to give compound 10A-13 (1.86 g, 81.16%, purity: 99%). LC-MS-10A-13(ES, m / z):[M+1]=590

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

[0619] 10.9 Synthesis of Compounds 10A-15 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) under nitrogen protection at room temperature, followed by the addition of HATU (53.27 mg, 0.140 mmol, 1.5 equiv) and DIPEA (24.14 mg, 0.187 mmol, 1.25 equiv) at room temperature. The mixture was stirred for 4 hours. The reaction mixture was quenched with water and extracted with EA (3 × 100 mL). The combined organic phase was dried and rotovapped. The obtained crude product was purified by reverse-phase column chromatography (conditions were as follows: C18 chromatography column, mobile phase, solvent ACN and solvent HO (0.1% FA), 10% to 50% gradient in 10 min, UV254 nano detector), fractionated, and dried by rotary evaporation to obtain compound 10A-15 (118 mg, 83.1%, purity 99%). LC-MS-10A-15(ES, m / z):[M+1]=1017

[0620] 10.10 Synthesis of Compounds 10A-16 Compound 10A-15 (118 mg, 0.116 mmol, 1 equiv) was reacted in a solution of piperidine (1 mL) and DCM (10 mL) at room temperature under nitrogen protection with stirring for 2 hours. The resulting liquid was concentrated under reduced pressure to give compound 10A-16 (94 mg, crude product), which was directly used in the next step. LC-MS-10A-16(ES, m / z):[M+1]=916

[0621] 10.11 Synthesis of Compound 10A Compound 10A-16 (94 mg, 0.118 mmol, 1 equiv) was reacted in a mixture of TFA (1 mL) and DCM (5 mL) under nitrogen protection at room temperature for 2 h. The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (conditions: C18 chromatography column, mobile phase, ACN and HO (0.1% FA), 10 min gradient from 10% to 50%, UV254 nanodetector), fractionated, and rotary evaporated to give compound 10A (0.0233 g, 28.22%, purity 99.0%). LC-MS-10A (ES, m / z): [M+1] = 694 1 H 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] [ka]

[0624] LC-MS-11A (ES, m / z):[M+1]=680 1 H 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 1H 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]

change

[0630] 1.1 Synthesis of compound 1B-2 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) at room temperature under nitrogen protection, 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 several portions, and the resulting mixture was stirred at room temperature under nitrogen protection overnight. The crude product was purified by reverse-phase column chromatography under the following conditions: C18 column, mobile phase, solvent, ACN and solvent, HO (0.1% formic acid), 10 min 10% to 50% gradient, UV200 nanodetector. After fractional distillation and rotary drying, N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3]-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-(1-imino-1-oxo-1λ6-thiomorpholin-4-yl)-6-oxohexyl]tert-butylcarbamate (600 mg, 69.32%, purity 99%) was obtained as a pale yellow solid. LC-MS-1B-2 (ES, m / z):[M+1]=870

[0631] 1.2 Synthesis of Compound 1B A 25 mL round-bottom flask was charged with tert-butyl N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3]-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]-6-(1-imino-1-oxo-1λ6-thiomorpholin-4-yl)-6-oxohexyl]carbamate (80 mg, 0.092 mmol, 1.00 equiv) and a 4 M solution of HCl in 1,4-dioxane (8 mL). 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, HO (0.1% formic acid), 10 min 10% to 50% gradient, detector, UV 200 nm. (R)-N-((R)-6-amino-1-(1-imino-1-oxo-1λ6-thiomorpholine)-1-oxohex-2-yl)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-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] The target compound was prepared according to steps similar to those in Example 1B.

[0635] [ka]

[0636] of

[0637] [ka]

[0638] It differed in that it replaced 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] The target compound was prepared according to steps similar to those in Example 1B.

[0642] [ka]

[0643] of

[0644] [ka]

[0645] It differed in that it replaced 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] The target compound was prepared according to steps similar to those in Example 1B.

[0649] [ka]

[0650] of

[0651] [ka]

[0652] It differed in that it replaced 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] The present specification exemplifies the preparation of the above compounds, and those skilled in the art will understand that other unexemplified compounds of the present invention can also be prepared by reference to the above general methods and specific examples.

[0654] Comparative example 1B

[0655] [ka]

[0656] The compound was prepared with reference to the method of Example 5 of CN108290926A.

[0657] Biological Testing and Evaluation The present invention will be further explained and interpreted in conjunction with the following test examples, but these examples do not limit the scope of the present invention.

[0658] The present disclosure relates to the following CR845 prepared by referring to the method of Example 2 of CN101627049A:

[0659] [ka]

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

[0661] 1.2 Experimental materials Cell lines: CHO-K1-μ, CHO-K1-Kappa, CHO-K1-delta stably transformed cell lines (Nanjing Jinsirui Biotechnology 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): 11.7 mg of EDTA and 380.84 mg of MgCl2 were weighed out and added to 50 mM Tris-HCl buffer to a total volume of 400 mL, adjusted to pH 7.4, with final concentrations of 0.1 mM EDTA and 10 mM MgCl2, respectively.

[0667] B: Compound preparation: The theoretical charge amount was calculated according to the design concentration and desired volume. 5.0 × 10 -3 M was dissolved in DMSO as the initial compounding dose, and then 5.0 × 10 -4 M~5.0×10 -9 Serially dilute the diluted DMSO solution with Buffer A to a working concentration of 5.0 x 10. -5 M~5.0×10 -11 The final concentration of DMSO in the working solution was 1% (the final concentration of DMSO in the reaction system was 0.2%). After sample preparation, the samples were stored at 4°C and discarded after the test was completed.

[0668] 1.3.2 Preparation of receptor membranes CHO-μ, Kappa, Delta, and other cells were removed from a -80°C refrigerator, thawed naturally, and centrifuged at 1000 g for 10 minutes at 4°C. The precipitate was collected and the supernatant discarded. Buffer was added to the precipitate, homogenized for 20-30 seconds, and then centrifuged at 50,000 g for 15 minutes at 4°C. The supernatant was carefully discarded, and buffer was added again. The mixture was mixed uniformly and centrifuged at 50,000 g for 15 minutes at 4°C. This process was repeated three times. The sample was then stored at -80°C.

[0669] 1.3.3 Receptor competitive binding assay 3.3.1 μ receptor affinity test First step: Add 50 µL of vehicle (1% DMSO) to the total binding tube (TB) and 50 µL of DAMGO (final concentration 1.0 × 10) to the nonspecific binding tube (NB). -5 M) was added, and 50 μL of test compound was added to each test compound tube (CB). Second step: 100 μL of buffer (homogenate A) was added to each reaction tube. Third step: The first prepared membrane homogenate A was prepared into a 10 mg / mL membrane suspension for use. Fourth step: Add radioactive ligand [ 3 50 μL of [H]DAMGO was added at a final concentration of 2 nM. Fifth step: 50 μL of membrane solution was added to each reaction tube. Sixth step: Each reaction tube was incubated at 25°C for 90 min. After the reaction was completed, the bound ligand was rapidly filtered under reduced pressure. The UniFilter GF / C plate was pre-saturated with 0.5% PEI solution for 1 h, thoroughly washed with ice-cold Tris buffer, and then dried in a constant temperature drying box for 30 min. The filter plate was removed and 40 μL of MICROSCINT PS scintillation fluid was added per well. Seventh step: The scintillation cup was placed in a liquid scintillation counter and counted.

[0670] 3.3.2 Kappa receptor competitive binding assay First step: Add 50 µL of vehicle (1% DMSO) to the total binding tube (TB) and 50 µL of U69593 (final concentration 1.0 × 10) to the nonspecific binding tube (NB). -5 M) was added, and 50 μL of test compound was added to each test compound tube (CB). Second step: 100 μL of buffer (homogenate A) was added to each reaction tube. Third step: The first prepared membrane homogenate A was prepared into a 15 mg / mL membrane suspension for use. Fourth step: Add radioactive ligand to each reaction tube. 3 50 μL of H-U69593 was added at a final concentration of 2 nM. Fifth step: 50 μL of membrane solution was added to each reaction tube. Sixth step: Each reaction tube was incubated at 25°C for 90 min. After the reaction was completed, the bound ligand was rapidly filtered under reduced pressure. The UniFilter GF / C plate was pre-saturated with 0.5% PEI solution for 1 h, thoroughly washed with ice-cold Tris buffer, and then dried in a constant temperature drying box for 30 min. The filter plate was removed and 40 μL of MICROSCINT PS scintillation fluid was added per well. Seventh step: The filter plates were placed in a liquid scintillation counter and counted.

[0671] 3.3.3 Delta receptor competitive binding assay First step: Add 50 µL of vehicle (1% DMSO) to the total binding tube (TB) and 50 µL of DADLE (final concentration 1.0 × 10) to the nonspecific binding tube (NB). -5 M) was added, and 50 μL of test compound was added to each test compound tube (CB). Second step: 100 μL of buffer (homogenate A) was added to each reaction tube. Third step: The first prepared membrane homogenate A was prepared into a 10 mg / mL membrane suspension for use. Fourth step: Add radioactive ligand to each reaction tube. 3 50 μL of H-DADLE was added at a final concentration of 4 nM. Fifth step: 50 μL of membrane solution was added to each reaction tube. Sixth step: Each reaction tube was incubated at 25°C for 90 min. After the reaction was completed, the bound ligand was rapidly filtered under reduced pressure. The UniFilter GF / C plate was pre-saturated with 0.5% PEI solution for 1 h, thoroughly washed with ice-cold Tris buffer, and then dried in a constant temperature drying box for 30 min. The filter plate was removed and 40 μL of MICROSCINT PS scintillation fluid was added per well. Seventh step: The filter plates were placed in a liquid flash counter and counted.

[0672] 1.4 Data analysis Based on the effect values ​​of the test points of different concentrations of the compound samples, the GraphPad Prism software was used to fit the action curves of the compound samples to the receptors, and the Ki values ​​were 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 have excellent selectivity for the κ opioid receptor and high affinity for the κ opioid receptor.

[0676] Test Example 2. In vitro functional test 2.1 Experimental Objectives The Cisbio HTRF cAMP-Gi kit was used to detect changes in cAMP concentration in the kappa opioid receptor (Kappa) signaling pathway using a microplate reader, and the EC 50 The values ​​were calculated to evaluate the agonistic activity of the compounds on the kappa opioid receptor.

[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) Centrifuge (Shanghai Anting, TGL-16C) Cytometer (Countstar, IC1000) Microplate reader (PerkinElmer, EnVision)

[0678] 2.3 Experimental Method (1) Preparation of reaction buffer (1 x stimulation buffer) required for the experiment: 5 x stimulation buffer in the Cisbio cAMP-Gi kit was diluted with ddH2O at a ratio of 1:4 and prepared for use. (2) Compound preparation: The compounds were diluted to a 5 mM stock solution in DMSO, then diluted 3.16-fold in 10 gradients, and then diluted to the corresponding concentration (2.5x) in stimulation buffer for use. (3) Cell preparation: CHO-K1-OPRK1 cells on a culture dish were trypsinized, eluted with medium, and collected in a 5 mL centrifuge tube. The cells were centrifuged at 1000 rpm for 5 minutes and the supernatant was discarded. 3 mL of PBS was added and mixed evenly by gently pipetting with a pipette. The cells were centrifuged again at 1000 rpm for 5 minutes and the supernatant was discarded. The cells were resuspended in 1x stimulation buffer and counted using a Countstar cytometer to determine a cell density of 6 x 10 5 The concentration was adjusted to 1 / mL and prepared for use. (4) Cell addition: The cell suspension was added to the experimental plate at 5 μL / well (i.e., approximately 3000 cells / well). (5) Compound addition: Compounds diluted with stimulation buffer were added to the above experimental plate at 4 μL / well. (6) Reaction incubation: After gentle shaking, the experimental plate was incubated at 37°C for 20 min. (7) Addition of agonist Forskolin: 10x adenylate cyclase agonist solution (final concentration: 1 µM Forskolin) was added at 1 µL / well. (8) Reaction incubation: After gentle shaking, the experimental plate was incubated at 37°C for 45 min. (9) Addition of detection reagent: cAMP-cryptate and anti-cAMP-d2 were diluted 1:20 with the lysis and detection buffer in the Cisbio cAMP-Gi detection kit, and 5 μL of each diluted cAMP-cryptate and anti-cAMP-d2 were added to the experimental plate at each well. After shaking, the experimental plate was left at room temperature for 60 minutes. (10) Experimental readings: The plate was read on Envision to detect the readings of the 665 nm and 615 nm channels, and the ratio of the 665 nm / 615 nm readings was calculated.

[0679] 2.4 Data analysis Based on the agonistic effect values ​​of the test points of different concentrations of the compound samples, the agonistic effect curves of the compound samples on the kappa opioid receptor were fitted using GraphPad Prism software, and the EC 50 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 strong agonistic activity against the κ opioid receptor.

[0683] Test Example 3: Sedation Safety Window Test 3.1 Mouse acetic acid writhing test 3.1.1 Test Purpose The analgesic effect of the compound after a single administration was examined using the mouse acetic acid writhing test, and its ED 50 asked for.

[0684] 3.1.2 Test system 3.1.2.1 Laboratory Animal Information Species and strain: ICR mouse Grade: General grade Number and sex: Male, 100 (in some cases) Age range: 6-8 weeks Weight range: 23-32 g Supplier: SPF (Beijing) Biotechnology Co., Ltd Animal use permit: SYXK (Su) 2019-053 Processing of the remaining animals: The remaining animals were transferred to the test system section and processed.

[0685] 3.1.2.2 Equipment and Reagents

[0686] [Table 7]

[0687] 3.1.3 Test Method The mouse acetic acid writhing test is a classic visceral pain model. Intraperitoneal injection of 0.6% acetic acid solution into mice stimulates the peritoneum, causing a sustained pain response and resulting in writhing. Analgesics can inhibit the writhing response in mice. After drug injection into the tail vein, mice were allowed to adapt for 15 minutes. A 0.6% acetic acid solution (0.1 mL / 10 g) was then intraperitoneally injected. A vehicle control group (0.9% sodium chloride injection) was also included. The number of writhing movements in the mice was recorded over a 15-minute period after the acetic acid injection. The writhing inhibition rate of the test compound was calculated to provide an initial assessment of the analgesic effect of a single dose. Writhing inhibition rate %=(number of times in vehicle group−number of times in administration group)×100% / number of times in vehicle group.

[0688] 3.1.4 Data Processing The mean ± standard deviation (Mean ± SD) of the experimental data was calculated using one-way analysis of variance (ANOVA) with GraphPad Prism GraphPad Prism 8 statistical software, followed by pairwise comparisons using Dunnett's t-test and nonlinear fitting. 50 The difference was calculated with P<0.05 indicating statistical significance.

[0689] 3.2 Spontaneous activity test in mice 3.2.1 Test Purpose The effect of a single dose of the compound on the spontaneous activity of mice was measured, and its ED 50 asked for.

[0690] 3.2.2 Test system 3.2.2.1 Laboratory Animal Information Species and strain: ICR mouse Grade: General grade Number and sex: Male, 200 (in some cases) Age range: 6-8 weeks Weight range: 23-35 g Supplier: SPF (Beijing) Biotechnology Co., Ltd Animal use permit: SYXK (Su) 2019-053 Processing of the remaining animals: The remaining animals were transferred to the test system section and processed.

[0691] 3.2.2.2 Equipment and Reagents

[0692] [Table 8]

[0693] 3.2.3 Test Method The mouse locomotor activity test is a classic test model for evaluating the central inhibitory effects of compounds. Mice were administered a test solution (prepared at the time of use) at the appropriate concentration via tail vein injection, and a blank group was administered a vehicle (0.9% sodium chloride injection). Immediately after administration, the mice were placed in a locomotor activity box (a black polyethylene box measuring 29 cm x 29 cm x 30 cm) and videotaped. The video recording was performed for 30 minutes, and video analysis was performed after the recording to evaluate the locomotor activity of the mice.

[0694] 3.2.4 Data Processing The mean ± standard deviation (Mean ± SD) of the experimental data was calculated by one-way analysis of variance using GraphPad Prism8 statistical software, followed by pairwise comparisons using Dunnett's t-test and nonlinear fitting. 50 The difference was calculated with P<0.05 indicating statistical significance.

[0695] 3.3 Safety Window Sedation is the most prominent side effect of peripheral kappa receptor agonists, and sedative side effects of ED 50 (Spontaneous Activity Test) / Drug Efficacy ED 50 The sedative safety window was obtained in the acetic acid writhing test, and a larger safety window predicted higher safety and reduced the likelihood of clinical sedative side effects occurring at the same dose. The experimental results are shown in Table 9.

[0696] [Table 9]

[0697] As can be seen from this, the compounds of the present invention have a large safety window, ie, a safer dosage range or are less likely to cause side effects at the same dose.

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

[0699] 4.2 Test equipment

[0700] [Table 10]

[0701] 4.3 Test Methods and Data Processing Healthy male ICR mice were randomly divided into groups with 6 animals per group, and each test compound was assigned to 3 groups of animals, and the animals in group 1 were used to collect blood and brain samples 5 minutes after administration, and the animals in group 2 and group 3 were used for cross-sectional blood sampling at later time points. Test compound was intravenously administered to the mice in the corresponding groups (1 mg / kg), and blood was collected from the submandibular vein of mice at different time points, and the drug content in plasma and brain tissue at different time points was measured by LC-MS / MS method, and the brain-blood ratio B / P was calculated using EXCEL software, and its 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 cerebrospinal blood ratio (B / P) of the compounds of the present invention is equal to or lower than that of CR845, they can selectively act on peripheral Kappa receptors, and the compounds of the present invention have significantly improved pharmacokinetic properties and significantly longer half-lives.

[0704] Test Example 5 Single-dose toxicity test in mice 5.1 Purpose of the test: Safety data were supplemented by examining the toxicity response of compounds of the invention after a single intravenous administration to mice.

[0705] 5.2 Test System Species and strain: ICR mouse Grade: SPF grade Gender: Male Weight range: 24-28 g Supplier: SPF (Beijing) Biotechnology Co., Ltd Animal Production Permit: SCXK(Kyoto)2019-0010 Animal use permit: SYXK (Su) 2019-0053 Processing of the remaining animals: The remaining animals were transferred to the test system section and processed.

[0706] 5.3 Equipment and Reagents

[0707] [Table 12]

[0708] 5.4 Test Method ICR mice were randomly divided into groups of 10 mice each, and administered 10 mL / kg of the drug via the tail vein. The condition and mortality of the animals were observed and recorded, and the LD 50 The doses were administered sequentially based on the recommended doses in the AOT425 software until the value was determined.

[0709] 5.5 Data Processing LD using AOT425 software 50 The results are shown in Table 13.

[0710] [Table 13]

[0711] As can be seen, the compounds of the present invention have improved safety due to their low single dose toxicity.

[0712] Test Example 6 Study of the effect of compounds on the hERG potassium channel 6.1 Test Purpose This experiment detected the inhibitory effect of compounds on the hERG channel by using the manual patch clamp technique.

[0713] 6.2 Test System Non-cardiac drugs may prolong the duration of cardiac action potentials by inhibiting the hERG (IKr) channel, potentially increasing the likelihood of life-threatening torsade de pointes (TdP) ventricular arrhythmias. This experiment used the HEK293 cell line, which does not contain endogenous IKr current, as a host cell and is widely used to detect hERG.

[0714] HEK293 cells stably expressing the hERG channel were cultured in 35 mm culture dishes and placed in a 37°C / 5% CO2 incubator for at least 24 hours before use. The hERG cell line was routinely cultured and passaged in DMEM containing 10% fetal bovine serum and 250 μg / mL G418.

[0715] 6.3 Liquid formulation The components of the extracellular solution used for whole-cell patch clamp experiments were (mM): NaCl 145, MgCl2 1, KCl 4, Glucose 10, HEPES 10, CaCl2 2, with the pH adjusted to 7.4 with NaOH and the osmolality adjusted to 300 mOsm with sucrose.

[0716] The components of the intracellular solution were (mM): KCl 140, MgCl 2 1, EGTA 5, HEPES 10, and Na 2 ATP 4, and the pH was adjusted to 7.2 with KOH and the osmolality was adjusted to 290 mOsm with sucrose.

[0717] [Table 14]

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

[0719] Voltage Stimulation Protocol and Current Recording: After whole-cell recording, the membrane potential was clamped at -80 mV. Every 30 seconds, cells were subjected to a depolarizing voltage stimulus of +50 mV, lasting 2 seconds, followed by a repolarization to -50 mV, lasting 3 seconds, to elicit hERG tail currents. Prior to the depolarizing voltage stimulus, cells were subjected to a repolarizing voltage of -50 mV for 50 ms, and the current recorded at this voltage served as the baseline for calculating hERG tail currents. Only cells that met the recording criteria were subjected to test compound detection. Before compound addition, hERG tail currents were stably recorded in extracellular solution for at least 3 min. Drug effects were considered to have reached steady state if the hERG tail current amplitude changed by less than 5% after perfusion administration. If the current did not reach steady state within 6 min, compound detection at that concentration was also terminated.

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

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

[0722] [Table 15]

[0723] As can be seen, the compounds of the present invention have improved safety due to their reduced cardiotoxicity.

[0724] The above examples merely show the activity data of some representative compounds of the present invention for illustrative purposes, and other compounds provided by the present invention have similar effects when tested in the same manner.

Claims

1. A compound of formula IA, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Among them, R 1A is H or -COOH, preferably H; R 2A -NR aA C(=O)OR bA or -NR aA S (=O) 2 OR bA and preferably -NR aA C(=O)OR bA Among them, R aA is H or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxy group, nitro group, cyano group, NH 2 C(=O)-, C 1-6 C substituted with one or more groups selected from alkoxy groups 1-6 an alkyl group, preferably H, or an amino group, C 1-6 Alkylamino group or C 1-6 Alkoxy-substituted C 1-6 is an alkyl group, more preferably H, or amino, C 1-6 C substituted with alkylamino groups 1-6 is an alkyl group, R bA is C 1-6 Alkyl group, C 6-14 Aryl groups, 5- to 14-membered heteroaryl groups, C 3-8 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, preferably C 1-6 alkyl groups, 3- to 8-membered heterocyclyl groups, more preferably C 1-6 Alkyl groups, 【Chemistry 2】 More preferably, 1-6 Alkyl groups, 【Chemistry 3】 wherein R is selected from bA The groups are halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 Optionally substituted with one or more groups selected from alkoxy groups, R eA and R fA are each independently -(CH 2 ) n1A - and - (CH 2 ) n1A' n1A and n1A' are each independently selected from 0, 1, 2 and 3, preferably 2, and n1A and n1A' are not simultaneously 0; W A is -NH-C(=O)-, -NH-S(=O) 2 -, -NR 5A -, -O-, -S-, -S (=O) 2 -, preferably -O-, -S(=O) 2 - selected from R 5A , H, C 1-6 Alkyl group, amidino group, HOOC-(CH 2 ) n3A - and n3A is selected from 1, 2 and 3; or R 1A and R 2A together with the carbon atoms to which they are attached form an optionally substituted 9-10 membered bicyclic moiety, preferably said bicyclic moiety together with the piperidine ring to which they are attached forms 【Chemistry 4】 forming a structure selected from Q 1A ~Q 4A If any one of is N, the rest is C or Q 1A ~Q 4A are both C, W 1A and W 2A are each independently -C(=O)-NH-, -NH-C(=O)-, -S(=O) 2 -NH-, -NH-S (=O) 2 -, -S-, -O-, -NR 6A -, -NR 6A -CH 2 -NH 2 , -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 -(CH 2 ) n2A - or absent, of which R 6A , H, C 1-6 Alkyl group, amidino group, HOOC-(CH 2 ) n3A -, preferably W 1A and W 2A cannot exist at the same time, W 3A NH 2 , -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 -(CH 2 ) n2A - and n2A is selected from 0, 1, 2, and 3; More preferably, the bicyclic moieties, together with the piperidine ring to which they are attached, 【Chemistry 5】 and more preferably, 【Chemistry 6】 and more preferably selected from 【Chemistry 7】 is selected from R 3A is H or -(CH 2 ) mA NR cA R dA is selected from R cA and R dA are independently H, C 1-6 Alkyl group, amidino group, C 1-6 alkoxycarbonyl groups, R 4A is halogen, NO 2 , C 1-6 Alkyl group, C 1-6 Haloalkyl group, cyano group, NH 2 C(=O)-, C 1-6 alkoxy groups, mA and nA are each independently 0, 1, 2, 3, 4, or 5; A compound, its stereoisomer or a pharma- ceutically acceptable salt thereof.

2. A compound of formula IIA, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 8】 ,Of which, R 1A , R 2A , R cA and R dA is as defined in claim 1, Preferably, the compound is represented by formula IIIA, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof: 【Chemistry 9】 Among them, R bA , R aA , R cA and R dA is as defined in claim 1, More preferably, the compound of formula IVA, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 10】 Among them, R bA and R aA is as defined in claim 1, More preferably, it is a compound of formula VA, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, 【Chemistry 11】 Among them, R bA is as defined in claim 1, 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

3. R bA is C 1-6 is selected from an alkyl group or a 3- to 8-membered heterocyclyl group, preferably 1-6 Alkyl group or 【Chemistry 12】 More preferably, C 1-6 Alkyl group or 【Chemistry 13】 and more preferably 【Chemistry 14】 , W A is -O- or -S (=O) 2 - selected from, among which R eA and R fA is as defined in claim 1, and R aA , R cA and R dA is as defined in claim 1, 3. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

4. A compound of formula VIA, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 15】 ,Of which, R aA is H or an amino group, C 1-6 Alkylamino group or C 1-6 Alkoxy-substituted C 1-6 is an alkyl group, more preferably H or C 1-6 is an aminoalkyl group, R bA is as defined in claim 1, 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

5. 【Chemical 16】 【Chemistry 17】 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof, 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

6. A process for preparing a compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 5, selected from the following processes: Method 1: Method 1 is, 【Chemistry 19】 This includes the steps: Method 2: Method 2 is, 【Chemistry 20】 This includes the steps: Among them, R 1A ' is R 1A or NH 2 is protected with an amino protecting group 1A and R 2A ' is R 2A or NH 2 is protected with an amino protecting group 2A and R 3A ' is R 3A or NH 2 is protected with an amino protecting group 3A and R 1A , R 2A , R 3A , R 4A and nA are as defined in any one of claims 1 to 5, and R xA is an amino protecting group, It is preferable that the amino protecting groups are each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, or an ethoxycarbonyl group. method.

7. A compound represented by the following general formula, a stereoisomer thereof, or a salt thereof: 【Chemistry 21】 Among them, R 1A ' is R 1A or NH 2 is protected with an amino protecting group 1A and R 2A ' is R 2A or NH 2 is protected with an amino protecting group 2A and R 3A ' is R 3A or NH 2 is protected with an amino protecting group 3A and R 1A , R 2A , R 3A , R 4A and nA are as defined in any one of claims 1 to 5, and R xA is an amino protecting group, It is preferable that the amino protecting groups are each independently selected from a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trichloroethoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a p-nitrobenzenesulfonyl group, a tert-butyl group, a trifluoroacetyl group, a methoxycarbonyl group, a tert-butylsulfinyl group, or an ethoxycarbonyl group. A compound, its stereoisomer or its salt.

8. A compound of formula IB, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemical 22】 Among them, R 1B , 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 groups, C 3-8 Cycloalkylcarbonyl group, C 3-8 a cycloalkoxycarbonyl group, a 5- to 14-membered heteroaryl group, a 5- to 14-membered heteroarylcarbonyl group, a 5- to 14-membered heteroaryloxycarbonyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclylcarbonyl group, and a 3- to 8-membered heterocyclyloxycarbonyl group, each of said substituents being selected from a halogen, a hydroxy group, an amino group, a nitro group, a cyano group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R 2B and R 3B are independently H, C 1-6 Alkyl group, amidino group, C 1-6 alkoxycarbonyl groups, R 4B is halogen, NO 2 , C 1-6 Alkyl group, C 1-6 Haloalkyl group, cyano group, NH 2 C(=O)-, C 1-6 alkoxy groups, mB and nB are each independently 0, 1, 2, 3, 4, or 5; A compound, its stereoisomer or a pharma- ceutically acceptable salt thereof.

9. A compound of formula IIB, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 23】 Preferably, the compound of formula IIIB, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, 【Chemistry 24】 Preferably, the compound of formula IVB, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof is 【Chemistry 25】 9. The compound according to claim 8, its stereoisomer or a pharma- ceutically acceptable salt thereof.

10. R 1B However, halogens, hydroxyl groups, amino groups, nitro groups, cyano groups, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 Alkyl group, C 1-6 alkylcarbonyl groups, preferably C 1-6 Alkyl group or C 1-6 an alkylcarbonyl group, more preferably selected from a methyl group or a methylcarbonyl group; 10. The compound according to any one of claims 8 to 9, its stereoisomer or a pharma- ceutically acceptable salt thereof.

11. A compound selected from the following compounds, their stereoisomers, or pharma- ceutically acceptable salts: 【Chemistry 26】 9. The compound according to claim 8, its stereoisomer, or a pharma- ceutically acceptable salt thereof.

12. A method for preparing a compound, its stereoisomer or a pharma- ceutically acceptable salt thereof according to any one of claims 8 to 11, comprising the steps of: 【Chemical 27】 Among them, R 1B , R 4B , mB and nB are as defined in any one of claims 8 to 11, and R xB and R yB are amino protecting groups, preferably each independently selected from tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; method.

13. A compound of formula iB-1, its stereoisomer or a salt thereof, 【Chemistry 28】 Among them, R 1B , R 4B , mB and nB are as defined in any one of claims 8 to 11, and R xB and R yB are amino protecting groups, preferably each independently selected from tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; A compound, its stereoisomer or its salt.

14. A compound of formula IC, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemical 29】 Among them, Ring A is C 3-8 Cycloalkyl groups, C 6-14 an aryl group or a 5- to 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 ') -, 【Chemistry 30】 Preferably, -O-, -CR 4C R 5C -, -NR 6C -, -S (=O) 2 -, -S (=O) (=NR 6C ') -, 【Chemistry 31】 and R 1C is H or -(CH 2 ) t NR aC R bC is selected from R 2C is H, amino group, hydroxyl group, C 1-6 Alkyl group, C 1-6 Alkylamino group, C 1-6 The alkyl group is selected from halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R 3C When Y is CH, H, hydroxyl group, C 1-6 Alkyl groups, 3- to 8-membered heterocyclyl groups, C 1-6 alkoxy groups; when Y is N, H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl-(CH 2 ) mC -, 3- to 8-membered heterocyclyl group, 3- to 8-membered heterocyclyl-(CH 2 ) mC -, -(CH 2 ) mC NR 10 R 11 Among these, the alkyl group, the cycloalkyl group, the heterocyclyl group, and the alkoxy group are selected from halogen, a hydroxy group, an amino group, a nitro group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 Alkoxy group, C 1-6 optionally substituted with one or more groups selected from alkylamino groups; R 4C and R 5C are independently H, C 1-6 Alkyl group, C 1-6 Alkyl-O-, hydroxy group, -C(O)OR 7 , -NR 8 R 9 , -NR cC C(O)NR 8 R 9 , C 1-6 Alkylamino group, 3-8 membered heterocyclyl-(CH 2 ) mC -, halogen, cyano group, -NR cC S (=O) 2 NR 8 R 9 , -NR cC C(O)OR dC , -NR cC S (=O) 2 OR dC , -NR cC C(O)R 7 ', -NH(CH 2 ) mC NR 8 R 9 The alkyl group and the heterocyclyl group are selected from halogen, hydroxyl group, amino group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; Or, CR 4C R 5C form a 3- to 8-membered heterocyclic or 9- to 10-membered bicyclic moiety, which together with the piperidine ring to which they are attached form 【Chemistry 32】 forming a structure selected from Q 1C ~Q 4C If any one of is N, the rest is C or Q 1C ~Q 4C are both C, W 1C and W 2C are each independently -C(=O)-NH-, -NH-C(=O)-, -S(=O) 2 -NH-, -NH-S (=O) 2 -, -S-, -O-, -NR 12 -, -NR 12 -CH 2 -NH 2 , -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 -(CH 2 ) n2C - or absent, R 12 , H, C 1-6 Alkyl group, amidino group, HOOC-(CH 2 ) n3C -, preferably W 1C and W 2C cannot exist at the same time, W 3C NH 2 , -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 -(CH 2 ) n2C - or absent, preferably NH 2 , -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 -(CH 2 ) n2C - and W 4C and W 5C NH 2 , -OH, halogen, nitro group, cyano group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 -(CH 2 ) n2C -or absent, n2C is selected from 0, 1, 2, and 3; More preferably, the 3- to 8-membered heterocyclic or 9- to 10-membered bicyclic moieties together with the piperidine ring to which they are attached are 【Chemical 33】 and more preferably, 【Chemical Formula 34】 is selected from R aC and R bC are independently H, C 1-6 Alkyl group, amidino group, C 1-6 alkoxycarbonyl groups, R cC is H or an amino group, C 1-6 Alkylamino group, C 1-6 Alkoxy group, halogen, hydroxy group, nitro group, cyano group, NH 2 C(=O)-, C 1-6 C substituted with one or more groups selected from alkoxy groups 1-6 an alkyl group, preferably H, or an amino group, C 1-6 Alkylamino group or C 1-6 C1-6 alkyl substituted with an alkoxy group, more preferably H, or an amino group, C 1-6 C substituted with alkylamino groups 1-6 is an alkyl group, R dC is C 1-6 Alkyl group, C 6-14 Aryl groups, 5- to 14-membered heteroaryl groups, C 3-8 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, preferably C 1-6 alkyl groups, 3- to 8-membered heterocyclyl groups, more preferably C 1-6 Alkyl groups, 【Chemistry 35】 More preferably, 1-6 Alkyl groups, 【Chemical 36】 wherein R is selected from dC The groups are halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 Optionally substituted with one or more groups selected from alkoxy groups, R eC and R fC are each independently -(CH 2 ) n1C - and - (CH 2 ) n1C' - and n 1C and n 1C' are each independently selected from 0, 1, 2 and 3, preferably 2, and n1C and n1C' are not 0 at the same time; W C is -NH-C(=O)-, -NH-S(=O) 2 -, -NR 12 -, -O-, -S-, -S (=O) 2 -, preferably -O-, -S(=O) 2 - selected from R 12 , H, C 1-6 Alkyl group, amidino group, HOOC-(CH 2 ) n3C - selected from n 3C is selected from 1, 2 and 3; R 6C and R 6C ' is independently H, C 1-6 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 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, each of which is selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, and a C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R 7 and R 7 ' are independently H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-14 aryl and 5- to 14-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; R 8 and R 9 are each independently H, or a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 is an alkyl group, R 10 and R 11 are each independently H or C 1-6 is an alkyl group or R 10 and R 11 form, together with the nitrogen atom to which they are attached, a 3- to 8-membered heterocyclyl group, of which the alkyl and heterocyclyl groups are not limited to halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 optionally substituted with one or more groups selected from alkoxy groups; p and t are each independently selected from 0, 1, 2, 3, 4, or 5; mC is independently selected from 1, 2, 3, 4 at each occurrence; R 0 H, halogen, NO 2 , cyano group, NH 2 C(=O)-, C 1-6 alkoxy groups, halogens, hydroxy groups, amino groups, nitro groups, cyano groups, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 selected from alkyl groups, A compound, its stereoisomer or a pharma- ceutically acceptable salt thereof.

15. A compound represented by formula IIC-1 or IIC-2, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemical 37】 Preferably, in IIC-1, R 2C is C 1-6 R is an aminoalkyl group or an amino group. 3C is H or C 1-6 More preferably, R 2C is an amino group, and R 3C is H, 【Chemical 38】 , preferably in IIC-2, R 2C is C 1-6 R is an aminoalkyl group or an amino group. 3C is H or C 1-6 is an alkyl group, or R 2C is H or C 1-6 is an alkyl group, R 3C is C 1-6 an aminoalkyl group or a 3- to 8-membered nitrogen-containing heterocyclyl group; More preferably, formula IIC-2 is formula IIIC or formula IVC: 【Chemical 39】 【Chemistry 40】 15. The compound according to claim 14, its stereoisomer or a pharma- ceutically acceptable salt thereof.

16. One or more of the following conditions are met: (1) R 1C Ha-(CH 2 ) t NR aC R bC and preferably -(CH 2 ) 3 NH 2 and (2) Ring A is a phenyl group; (3) p is 0; 16. The compound according to claim 14 or 15, its stereoisomer or a pharma- ceutically acceptable salt thereof.

17. G is selected from one of the following: (1) G is -S(=O)(=NR 6C ')--and (2) G is -CR 4C R 5C - and R 4C is H and R 5C Ha-NR cC C(O)OR dC and (3) G is -CR 4C R 5C - and R 4C Ha-NR 8 R 9 and R 5C -C(O)OR 7 and R 7 , H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-14 aryl and 5- to 14-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 Optionally substituted with one or more groups selected from alkoxy groups, R 7 is preferably H, or a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, NH 2 C(=O)-, C 1-6 C optionally substituted with one or more groups selected from alkoxy groups 1-6 is an alkyl group, 17. The compound according to any one of claims 14 to 16, its stereoisomer or a pharma- ceutically acceptable salt thereof.

18. A compound represented by the following general formula, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: 【Chemistry 41】 and more preferably 【Chemistry 42】 and even more preferably 【Chemistry 43】 That is, 18. The compound according to any one of claims 14 to 17, its stereoisomer or a pharma- ceutically acceptable salt thereof.

19. 【Catalogue 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical Formula 54】 【Chemistry 55】 【Chemistry 56】 【Chemistry 57】 or a pharma- ceutically acceptable salt thereof, 15. The compound according to claim 14, its stereoisomer or a pharma- ceutically acceptable salt thereof.

20. The method is selected from the following: Method 1: Method 1 is, 【Chemistry 58】 This includes the steps: Method 2: Method 2 is, 【Chemistry 59】 This includes the steps: Preferably, the compound of formula iiC-2 is prepared by a method selected from: Method 3: Method 3 comprises subjecting a compound of formula iiC-4-a and a compound of formula iiC-5-a to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction, an amino-protection reaction to obtain a compound of formula iiC-2; 【Chemistry 60】 Method 4: Method 4 comprises subjecting a compound of formula iiC-4-b and a compound of formula iiC-5-b to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction, an amino-protection reaction to obtain a compound of formula iiC-2; 【Chemistry 61】 Method 5: Method 5 comprises subjecting a compound of formula iiC-4-c and a compound of formula iiC-5-c to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction, an amino-protection reaction to obtain a compound of formula iiC-2; 【Chemistry 62】 Method 6: Method 6 comprises subjecting a compound of formula iiC-4-d and a compound of formula iiC-5-d to a condensation reaction, a hydrolysis reaction, and optionally an amino-protecting group removal reaction, an amino-protection reaction to obtain a compound of formula iiC-2; 【Chemistry 63】 Preferably, the formula iC-2 is 【Chemistry 64】 and Preferably, iiC-2 is 【Chemistry 65】 is selected from Among them, R 0 ' is R 0 or NH 2 is protected with an amino protecting group 0 and R 1C ' and R 1C '' is R 1C or NH 2 is protected with an amino protecting group 1C and R 2C ' and R 2C '' is R 2C or NH 2 is protected with an amino protecting group 2C and R 3C ' and R 3C '' is R 3C or NH 2 or R in which the cyclic imino group is protected with an amino protecting group 3C and G' is G or NH 2 and / or G in which the cyclic imino group is protected with an amino-protecting group and / or the carboxy group is protected with a carboxy-protecting group, Rw is a carboxy-protecting group, and the rings A, Y, and R 0 , R 1C , R 2C , R 3C , G and p are as defined in any one of claims 14 to 19, and Rs, Rt and Ru are each independently selected from H and an amino protecting group; Preferably, the amino protecting groups are each independently selected from tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichlorooxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, tert-butylsulfinyl, 1-phenylethyl, or ethoxycarbonyl, and the carboxy protecting groups are each independently selected from C 1-6 selected from an alkyl group, an allyl group, a benzyl group, a 2,4-dimethoxybenzyl group, a p-methoxybenzyl group, a methoxyethoxymethyl group, a pentafluorophenyl group, and a 4-p-methylbenzyloxybenzyl group; A process for preparing a compound, its stereoisomer or a pharma- ceutically acceptable salt thereof according to any one of claims 14 to 19.

21. A compound represented by the following general formula, a stereoisomer thereof, or a salt thereof: 【Chemistry 66】 Preferably, formula iiC-2-X is 【Chemistry 67】 is selected from Among them, R 0 ' is R 0 or NH 2 is protected with an amino protecting group 0 and R 1C ' is R 1C or NH 2 is protected with an amino protecting group 1C and R 2C ' is R 2C or NH 2 is protected with an amino protecting group 2C and R 3C ' is R 3C or NH 2 or R in which the cyclic imino group is protected with an amino protecting group 3C and G' is G or NH 2 and / or G in which the cyclic imino group is protected with an amino-protecting group and / or the carboxy group is protected with a carboxy-protecting group; and rings A, Y, R 0 , R 1C , R 2C , R 3C , G and p are as defined in any one of claims 14 to 19, Rs, Rt are each independently selected from H and an amino protecting group, and Rv is selected from H and a carboxy protecting group; Preferably, the amino protecting groups are each independently selected from tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichlorooxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, tert-butylsulfinyl, 1-phenylethyl, or ethoxycarbonyl, and the carboxy protecting groups are each independently selected from C 1-6 selected from an alkyl group, an allyl group, a benzyl group, a 2,4-dimethoxybenzyl group, a p-methoxybenzyl group, a methoxyethoxymethyl group, a pentafluorophenyl group, and a 4-p-methylbenzyloxybenzyl group; A compound, its stereoisomer or its salt.

22. A compound according to any one of claims 1 to 5, 8 to 11, 14 to 19, its stereoisomer or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier or excipient, and optionally other therapeutic agents. Pharmaceutical compositions.

23. Use of a compound according to any one of claims 1 to 5, 8 to 11, 14 to 19, its stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the preparation of a medicament, in particular said medicament being used to agonize the kappa opioid receptor. use.

24. Use of the compound according to any one of claims 1 to 5, 8 to 11, 14 to 19, its stereoisomer or its pharma- ceutically acceptable salt, or the pharmaceutical composition according to claim 22, in the preparation of a medicament, in particular the medicament is used for the prophylaxis and / or treatment of associated diseases mediated by kappa opioid receptors, preferably the diseases are selected from pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough and glaucoma, preferably pain, preferably the pain is selected from neuropathic pain, truncal pain, visceral pain, skin pain, arthritis pain, kidney stone pain, uterine spasms, dysmenorrhea, endometriosis, dyspepsia, post-operative pain, pain after medical procedures, eye pain, otitis media pain, cancer eruption pain and pain associated with GI disorders; use.

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