Substituted derivatives of 2-(pyrrolidine-3-yl)acetic acid, method of preparation thereof, and use

Abstract

The present invention provides a compound represented by formula (I) and pharmaceutically acceptable salts of said compound. The compound of the present invention has a strong inhibitory effect on the assembly of Lp(a) and can be used to treat cardiovascular disease (CVD). [Formula 1] TIFF2026514875000578.tif39129

Description

[Technical Field]

[0001] (Cross-reference of related applications) This invention claims priority to the invention patent application filed with the China Patent Office on November 17, 2023, with application number 202311536343.5; the invention patent application filed with the China Patent Office on February 7, 2024, with application number 202410174573.X; the invention patent application filed with the China Patent Office on June 21, 2024, with application number 202410811526.1; and the invention patent application filed with the China Patent Office on September 6, 2024, with all contents of said patent applications incorporated herein by reference.

[0002] The present invention relates to the pharmaceutical technology, and more specifically to compounds as Lp(a) inhibitors, particularly substituted 2-(pyrrolidine-3-yl)acetic acid derivatives, methods for preparing the same, and their use. [Background technology]

[0003] Lipoprotein (a) (Lp(a)) is a lipoprotein particle synthesized in the liver, composed of cholesterol-rich low-density lipoprotein (LDL-C)-like particles attached to apolipoprotein (a). Lp(a) levels are primarily determined by genes, vary significantly among individuals, and are largely unaffected by lifestyle interventions.

[0004] Lp(a) is associated with an increased risk of coronary artery disease, ischemic stroke, aortic stenosis, heart failure, atrial fibrillation, and peripheral artery disease. Approximately 20% of people have elevated blood Lp(a) levels (≥30 mg / dL). The increased risk of cardiovascular disease (CVD) associated with Lp(a) is mainly due to the double coagulation-promoting effect of Apo(a) (the Apo(a) structure is similar to plasminogen) and the pro-inflammatory effects of components of Apo B (apolipoprotein B) that cause atherosclerosis (AS) and oxidized phospholipids (OxPL). Lp(a) is not only a pathogenic factor for atherosclerotic cardiovascular disease (ASCVD) but also for calcified aortic valve disease. Elevated Lp(a) plasma levels are an independent risk factor for CVD.

[0005] There are few approved treatment options for patients with elevated Lp(a) levels. Plasma apheresis can be used to filter blood to remove LDL and Lp(a), but its effects are temporary, it usually needs to be repeated every two weeks, and patient compliance is poor. To date, no drug therapies to reduce Lp(a) levels have been approved. Therefore, there is a need to provide pharmaceutically acceptable compounds and treatment options to reduce plasma Lp(a) levels in patients suffering from CVD. [Overview of the Initiative]

[0006] The object of the present invention is to provide a new compound for reducing plasma Lp(a) levels, a method for preparing this compound, and its use in the treatment of Lp(a)-mediated diseases. The new compound is biochemically effective and physiologically active.

[0007] In one aspect of the present invention, a compound represented by the following formula (I) or a pharmaceutically acceptable salt of said compound is provided.

[0008] [ka] however,

[0009] [Chemistry] is a single bond or a double bond, A is CRX, P, P(O), N, C , , 1~3 , 1~3 , 1~3 , , , , 1~3 , 1~3 , 6~10 ,

[0012] , an aryl group, a 5- to 14-member heteroaryl group, C 3~8 a carbocyclic group, a 5- to 18-member heterocyclic group, and the aryl group, heteroaryl group, carbocyclic group, and heterocyclic group may each be substituted with one or more substituents independently selected from deuterium, halogen, -CN, C 1~3 an alkyl group, C 1~3 an alkoxy group,

[0010] [Chemistry] <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A. L2 is -C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0013] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and A, R is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 12-membered heteroaryl group, C 1~6 alkyl group,

[0014] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkoxy group, C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between R and A, L3 is -C 1~6 Alkylene-,-C 2~6 Alkenylene-,-C 2~6 Alkinylene-,-C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkilen-5~12 member heteroaryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0015] [ka] Selected from, the alkylene group, alkenylene group, and alkynylene group are each independently one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.* is the junction of L3 and A, The rings W1, W2, and W3 are each independently a C 6~12 aryl group, a 5- to 12-member heteroaryl group, a C 6~14 cycloalkyl group, or a 5- to 12-member heterocyclic group, and the aryl group, heteroaryl group, cycloalkyl group, and heterocyclic group may each be substituted with one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NH2, -CHO, a C1-3 alkyl group, a C 1~3 alkoxy group, a C 1~3 haloalkyl group, a C 1~3 haloalkoxy group, -N(C 1~3 alkyl)2, -NH(C 1~3 alkyl), -C(O)C 1~3 alkyl group; Z 11 、Z 12 、Z 21 、Z 22 、Z 31 、Z 32 are each independently a bond, -O-, -S-, -NH-, -Se-, -C 1~4 alkylene-, -C 1~8 oxyalkylene-, -C1-4 thioalkylene-, -C 1~4 azaalkylene-, -C 1~4 selenoalkylene- and are each independently selected therefrom, and the alkylene group, oxyalkylene group, thioalkylene group, azaalkylene group, and selenoalkylene group may each be substituted with one or more substituents selected from Z41, and Z 41 is independently deuterium, halogen, an oxo group, a thio group, -CN, -OH, -NH2, C 1~3 alkyl group, a C 1~3 haloalkyl group, a C 1~3 s alkoxy group, a C 1~3 haloalkoxy group, or any two Z 41 together with the atoms to which they are attached form a C 3~6 cycloalkyl group, a 3- to 6-member heterocyclic group, a phenyl group, or a 5- to 6-member heteroaryl group; R 31 、R 32 、R 33is independently hydrogen, deuterium, halogen, C 1~6 alkyl group, C 1~6 haloalkyl group, C 1~6 deuterated alkyl group, C 1~6 alkoxy group, C 1~6 haloalkoxy group, C 1~6 deuterated alkoxy group, and is selected from h1, h2, h3, h4, h5, h6 are each independently 0, 1, 2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 are each independently H, deuterium, -CN, -OH, -NH2, halogen, C 1~6 alkyl group, C 1~6 haloalkyl group, C 1~6 alkoxy group, C 1~6 haloalkoxy group, -N(C 1~3 alkyl)2, -NH(C 1~3 alkyl) and is selected from R 50 , R 51 , R 52 are each independently H, deuterium, C 1~6 alkyl group, C 2~6 ​​​​​​​​​​​​​​​​The conditions are that A is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 If L1, L2, and L3 are simultaneously H

[0016] [ka] This will not happen. The conditions are that A is N and R is

[0017] [ka] So, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 41 , R 42 If both are H at the same time, then L1 and L2 are simultaneously

[0018] [ka] This will not happen. * This is the junction between R and A, The conditions are,

[0019] [ka] Instead, The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0020] In one embodiment of the compound represented by formula (I) above, R is a group containing L3, and L1, L2, and L3 are Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0021] In some embodiments, the following compounds represented by formula (I-1-P1) or pharmaceutically acceptable salts of said compounds are provided:

[0022] [ka] however,

[0023] [ka] It is either a single bond or a double bond. A is CR X , P, P(O) or N,

[0024] [ka] If it is a single bond, R X H, -OH, C 1~3 It is an alkoxy group,

[0025] [ka] If R is a double bond, X It does not exist. L1 is -C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0026] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A. L2 is -C 1~3 Alkylene-C 6~10Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0027] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and A, R is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 12-membered heteroaryl group, C 1~6 alkyl group,

[0028] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkoxy group, C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between R and A, L3 is -C 1~6 Alkylene-,-C 2~6 Alkenylene-,-C 2~6 Alkinylene-,-C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkilen-5~12 member heteroaryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0029] [ka] Selected from, the alkylene group, alkenylene group, and alkynylene group are each independently one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L3 and A. Rings W1, W2, and W3 are each independently C 6~12 Aryl group, 5-12 membered heteroaryl group, C 6~14Selected from cycloalkyl groups and 5-12 membered heterocyclic groups, the aryl group, heteroaryl group, cycloalkyl group, and heterocyclic group are each independently one or more of deuterium, halogen, -CN, and C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are joined independently, -C 1~4 Alkylene-,-C 1~4 Selected from oxyalkylene, the alkylene group and oxyalkylene group are each independently one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 Each is independently selected from H and deuterium. The condition is that if A is N, then L1, L2, and L3 are simultaneously

[0030] [ka] This will not happen. The conditions are that A is N and R is

[0031] [ka] If so, L1 and L2 simultaneously

[0032] [ka] This will not happen. * This is the junction between R and A, The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is one, two, or three.

[0033] In one embodiment of the compound represented by the above formula (I-1-P1), R is a group containing L3, and L1, L2, and L3 are each Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0034] In some embodiments, the following compounds represented by formula (I-1-P2) or pharmaceutically acceptable salts of said compounds are provided:

[0035] [ka] however,

[0036] [ka] It is either a single bond or a double bond. A is CR X , P, P(O) or N,

[0037] [ka] If it is a single bond, R X H, -OH, C 1~3 It is an alkoxy group,

[0038] [ka] If R is a double bond, X It does not exist. L1 is -C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0039] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A. L2 is -C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0040] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and A, R is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 12-membered heteroaryl group, C 1~6 alkyl group,

[0041] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3Alkoxy group, C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between R and A, L3 is -C 1~6 Alkylene-,-C 2~6 Alkenylene-,-C 2~6 Alkinylene-,-C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkilen-5~12 member heteroaryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0042] [ka] Selected from, the alkylene group, alkenylene group, and alkynylene group are each independently one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L3 and A. Rings W1, W2, and W3 are each independently C 6~12Aryl group, 5-12 membered heteroaryl group, C 6~14 Selected from cycloalkyl groups and 5-12 membered heterocyclic groups, the aryl group, heteroaryl group, cycloalkyl group, and heterocyclic group are each independently one or more of deuterium, halogen, -CN, and C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are joined independently, -C 1~4 Alkylene-,-C 1~4 Oxyalkylene-,-C 1~4 Thioalkylene-,-C 1~4 Selected from azaalkylene, the alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group are one or more independently comprising deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 Each is independently selected from H and deuterium. The condition is that if A is N, then L1, L2, and L3 are simultaneously

[0043] [ka] This will not happen. The conditions are that A is N and R is

[0044] [ka] If so, L1 and L2 simultaneously

[0045] [ka] This will not happen. * This is the junction between R and A, The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is one, two, or three.

[0046] In one embodiment of the compound represented by the above formula (I-1-P2), R is a group containing L3, and L1, L2, and L3 are each Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0047] In some embodiments, the following compounds represented by formula (I-1-P3) or pharmaceutically acceptable salts of said compounds are provided:

[0048] [ka] however,

[0049] [ka] It is either a single bond or a double bond. A is CRX, P, P(O), N, C 6~12 The group is an aryl group, a 5-14 membered heteroaryl group, or a 5-18 membered heterocyclic group, and each of the aryl group, heteroaryl group, and heterocyclic group is independently composed of one or more deuterium, halogen, -CN, and C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0050] [ka] If it is a single bond, R X H, -OH, C 1~3 It is an alkoxy group,

[0051] [ka] If R is a double bond, X It does not exist. L1 is -C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0052] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A. L2 is -C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0053] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and A, R is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 12-membered heteroaryl group, C 1~6 alkyl group,

[0054] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkoxy group, C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between R and A, L3 is -C 1~6 Alkylene-,-C 2~6 Alkenylene-,-C 2~6 Alkinylene-,-C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkilen-5~12 member heteroaryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0055] [ka] Selected from, the alkylene group, alkenylene group, and alkynylene group are each independently one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L3 and A. Rings W1, W2, and W3 are each independently C 6~12 Aryl group, 5-12 membered heteroaryl group, C 6~14 Selected from cycloalkyl groups and 5-12 membered heterocyclic groups, the aryl group, heteroaryl group, cycloalkyl group, and heterocyclic group are each independently one or more of deuterium, halogen, -CN, and C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are joined independently, -C 1~4 Alkylene-,-C 1~4 Oxyalkylene-,-C 1~4 Thioalkylene-,-C 1~4 Selected from azaalkylene, the alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group are one or more independently comprising deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 Alkyl alkyl group, C 1~3 Haloalkyl group, C 1~3 Alkoxy group, C 1~3 It may be substituted with substituents selected from the haloalkoxy group. R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 Each is independently selected from H and deuterium. The conditions are that A is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 If L1, L2, and L3 are simultaneously H

[0056] [ka] This will not happen. The conditions are that A is N and R is

[0057] [ka] So, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 If both are H at the same time, then L1 and L2 are simultaneously

[0058] [ka] This will not happen. * This is the junction between R and A, The conditions are,

[0059] [ka] Instead, The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0060] In one embodiment of the compound represented by the above formula (I-1-P3), R is a group containing L3, and L1, L2, and L3 are each Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0061] In some embodiments, the following compounds represented by formula (I-1-P4) or pharmaceutically acceptable salts of said compounds are provided:

[0062] [ka] however,

[0063] [ka] It is either a single bond or a double bond. A is CRX, P, P(O), N, C 6~12The group is an aryl group, a 5-14 membered heteroaryl group, or a 5-18 membered heterocyclic group, and each of the aryl group, heteroaryl group, and heterocyclic group is independently composed of one or more deuterium, halogen, -CN, and C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0064] [ka] If it is a single bond, R X H, -OH, C 1~3 It is an alkoxy group,

[0065] [ka] If R is a double bond, X It does not exist. L1 is -C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0066] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A. L2 is -C1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0067] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and A, R is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 12-membered heteroaryl group, C 1~6 alkyl group,

[0068] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkoxy group, C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between R and A, L3 is -C 1~6 Alkylene-,-C 2~6 Alkenylene-,-C 2~6 Alkinylene-,-C 1~3 Alkylene-C 6~10 Aryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-C 6~10 aryl-5~12 member heteroaryl-C 1~3 Alkylene-,-C 1~3 Alkilen-5~12 member heteroaryl-C 6~10 Aryl-C 1~3 Alkylene-,-C 1~3 Alkylene-5~12 member heteroaryl-5~12 member heteroaryl-C 1~3 Alkylene-,

[0069] [ka] Selected from, the alkylene group, alkenylene group, and alkynylene group are each independently one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L3 and A. Rings W1, W2, and W3 are each independently C 6~12 Aryl group, 5-12 membered heteroaryl group, C 6~14Selected from cycloalkyl groups and 5-12 membered heterocyclic groups, the aryl group, heteroaryl group, cycloalkyl group, and heterocyclic group are each independently one or more of deuterium, halogen, -CN, -OH, -NH2, -CHO, C1-3 alkyl groups, and C 1~3 Alkoxy group, C 1~3 Haloalkyl group, C 1~3 Haloalkoxy group, -N(C) 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 It may be substituted with substituents selected from alkyl groups. Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are bonded independently: -O-, -S-, -NH-, -Se-, -C 1~4 Alkylene-,-C 1~8 Oxyalkylene-, -C1~4 thioalkylene-, -C 1~4 Azaalkilene-,-C 1~4 Selected from selenoalkylene, the alkylene group, oxyalkylene group, thioalkylene group, azaalkylene group, and selenoalkylene group may be substituted with one or more substituents selected from Z41, Z 41 These are independently deuterium, halogen, oxo group, thio group, -CN, -OH, -NH2, and C 1~3 Alkyl alkyl group, C 1~3 Haloalkyl group, C 1~3 Alkoxy group, C 1~3 Selected from haloalkoxy groups, or any two Z groups 41 along with the atoms linked to them, C 3~6 Forming a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, and a 5-6 membered heteroaryl group, R 31 , R 32 , R 33 These are hydrogen, deuterium, halogen, and C, respectively, independently. 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 1~6 Deuterated alkyl groups, C 1~6 Alkoxy group, C1~6 Haloalkoxy group, C 1~6 Selected from deuterated alkoxy groups, h1, h2, h3, h4, h5, and h6 are independently 0, 1, and 2, respectively. R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 Each is independently selected from H and deuterium. The conditions are that A is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 If L1, L2, and L3 are simultaneously H

[0070] [ka] This will not happen. The conditions are that A is N and R is

[0071] [ka] So, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 If both are H at the same time, then L1 and L2 are simultaneously

[0072] [ka] This will not happen. * This is the junction between R and A, The conditions are,

[0073] [ka] Instead, The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0074] In one embodiment of the compound represented by the above formula (I-1-P4), R is a group containing L3, and L1, L2, and L3 are each Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0075] In some embodiments, the following compounds represented by formula (I-2) or pharmaceutically acceptable salts of said compounds are provided:

[0076] [ka] However, A,

[0077] [ka] L1, L2, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 31 , R 32 This is as described for the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4).

[0078] In one embodiment of the compound represented by formula (I-2) above, R is a group containing L3, and L1, L2, and L3 are each Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0079] In some embodiments, the following compounds represented by formula (I-3) or pharmaceutically acceptable salts of said compounds are provided:

[0080] [ka] However, A,

[0081] [ka] L1, L2, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 This is as described for the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4).

[0082] In one embodiment of the compound represented by formula (I-3) above, R is a group containing L3, and L1, L2, and L3 are each Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0083] In one embodiment of the present invention, A is CR X The group is P, P(O), N, a phenyl group, a 5-6 membered heterocyclic group, or a 12 membered heterocyclic group, where the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2, 3, or 4.

[0084] In one embodiment of the present invention, A is CR X P, P(O), N, phenyl group, piperazinyl group,

[0085] [ka] That is the case.

[0086] In one embodiment of the present invention, A is CR X , P, P(O), N,

[0087] [ka] And A is N,

[0088] [ka] It is preferable that this be the case.

[0089] In one embodiment of the present invention, A is CR X , P, P(O), N.

[0090] In one embodiment of the present invention, A is N.

[0091] In one embodiment of the present invention, A is P(O).

[0092] In one embodiment of the present invention, A is CR X Selected from, R X These are H, -OH, and methoxy groups.

[0093] In one embodiment of the present invention, A is selected from C-OH and C-OCH3.

[0094] In one embodiment of the present invention, A is a 6- to 12-membered heterocyclic group.

[0095] In one embodiment of the present invention, A is a 6-membered heterocyclic group, preferably A is a piperazinyl group.

[0096] [ka] It is preferable that this be the case.

[0097] In one embodiment of the present invention, A is

[0098] [ka] That is the case.

[0099] In one embodiment of the present invention, A is a phenyl group,

[0100] [ka] It is preferable that this be the case.

[0101] In one embodiment of the present invention, R X These are H, -OH, and methoxy groups.

[0102] In one embodiment of the present invention, L1 is -methylene-C 6~10 Aryl-C 6~10 Aryl-methylene-,-methylene-5~12 member heteroaryl-5~12 member heteroaryl-methylene-,

[0103] [ka] Selected from, the methylene group is one or more independently of deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A.

[0104] In one embodiment of the present invention, L1 is -C 1~3 Alkylene-phenyl-phenyl-C 1~3 Alkylene-,-C 1~3 Alkylene-5-6 member heteroaryl-5-6 member heteroaryl-C 1~3 Alkylene-,

[0105] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more halogens, -CN, and C 1~3 It may be substituted with substituents selected from alkoxy groups.* This is the junction between L1 and N.

[0106] In one embodiment of the present invention, L1 is -methylene-phenyl-phenyl-methylene-, -ethylene-phenyl-phenyl-ethylene-, -methylene-5~6 member heteroaryl-5~6 member heteroaryl-methylene-, -ethylene-5~6 member heteroaryl-5~6 member heteroaryl-ethylene-

[0107] [ka] Selected from, the methylene group and ethylene group are each independently one or more deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more halogens, -CN, and C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A.

[0108] In one embodiment of the present invention, L1 is -methylene-phenyl-phenyl-methylene-, -methylene-6-membered heteroaryl-6-membered heteroaryl-methylene-,

[0109] [ka] Selected from, the methylene group is one or more independently of deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more deuterium, halogen, -CN, or C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L1 and A.

[0110] In one embodiment of the present invention, L1 is -methylene-phenyl-phenyl-methylene-, -methylene-pyridyl-pyridyl-methylene-,

[0111] [ka] Selected from, * This is the junction between L1 and A.

[0112] In one embodiment of the present invention, L1 is

[0113] [ka] Selected from, * This is the junction between L1 and A.

[0114] In one embodiment of the present invention, L1 is

[0115] [ka] And, * This is the junction between L1 and A.

[0116] In one embodiment of the present invention, L2 is -methylene-C 6~10 Aryl-C 6~10 Aryl-methylene-,-methylene-5~12 member heteroaryl-5~12 member heteroaryl-methylene-,

[0117] [ka] Selected from, the methylene group is one or more independently of deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 It may be substituted with substituents selected from alkoxy groups. *This is the junction between L2 and A.

[0118] In one embodiment of the present invention, L2 is -C 1~3 Alkylene-phenyl-phenyl-C 1~3 Alkylene-,-C 1~3 Alkylene-5-6 member heteroaryl-5-6 member heteroaryl-C 1~3 Alkylene-,

[0119] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more halogens, -CN, and C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and N.

[0120] In one embodiment of the present invention, L2 is -methylene-phenyl-phenyl-methylene-, -ethylene-phenyl-phenyl-ethylene-, -methylene-5~6 member heteroaryl-5~6 member heteroaryl-methylene-, -ethylene-5~6 member heteroaryl-5~6 member heteroaryl-ethylene-,

[0121] [ka] Selected from, the methylene group and ethylene group are each independently one or more deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more halogens, -CN, and C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and A.

[0122] In one embodiment of the present invention, L2 is -methylene-phenyl-phenyl-methylene-, -methylene-6-membered heteroaryl-6-membered heteroaryl-methylene-,

[0123] [ka] Selected from, the methylene group is one or more independently of deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more deuterium, halogen, -CN, or C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L2 and A.

[0124] In one embodiment of the present invention, L2 is -methylene-phenyl-phenyl-methylene-, -methylene-pyridyl-pyridyl-methylene-,

[0125] [ka] Selected from, * This is the junction between L2 and A.

[0126] In one embodiment of the present invention, L2 is

[0127] [ka] Selected from, * This is the junction between L2 and A.

[0128] In one embodiment of the present invention, L2 is

[0129] [ka] Selected from, * This is the junction between L2 and A.

[0130] In one embodiment of the present invention, R is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 12-membered heteroaryl group, C 1~6 alkyl group,

[0131] [ka] Selected from, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkoxy group, C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between R and A.

[0132] In one embodiment of the present invention, R is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 10-membered heteroaryl group, C 1~6 alkyl group,

[0133] [ka] Selected from, the C 1~3The alkylene group may be substituted with one or more substituents independently selected from deuterium, halogen, oxo group, -CN, -OH, and -NH2, and the aryl group and heteroaryl group may be substituted with one or more substituents independently selected from deuterium, halogen, -CN, methoxy group, and C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between R and A.

[0134] In one embodiment of the present invention, R is H, a methylene-phenyl group, an ethylene-phenyl group, a methylene-5-6 membered heteroaryl group, an ethylene-5-6 membered heteroaryl group, and C 1~6 alkyl group,

[0135] [ka] The methylene group and ethylene group may be selected from and each independently substituted with one or more substituents selected from halogen, oxo group, -CN, -OH, and -NH2, and the phenyl group and heteroaryl group may be selected from and each independently substituted with one or more substituents selected from halogen, -CN, methoxy group,

[0136] [ka] The C may be substituted with a substituent selected from the above. 1~6 The alkyl group may be substituted with one or more substituents independently selected from halogens, oxo groups, carboxyl groups, -CN, -OH, and -NH2. * This is the junction between R and A.

[0137] In one embodiment of the present invention, R is H, -methylene-phenyl group, -ethylene-phenyl group, -methylene-pyridyl group, -ethylene-pyridyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, n-hexyl group,

[0138] [ka] Selected from, the phenyl group and pyridyl group are each independently one or more halogens, methoxy groups,

[0139] [ka] The methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, and n-hexyl group may be substituted by one or more substituents independently selected from carboxyl group and -NH2. * This is the junction between R and A.

[0140] In one embodiment of the present invention, R is H, -C 1~3 Alkylene-phenyl group, -C 1~3 Alkylene-5 to 6-membered heteroaryl group, C 1~6 Selected from alkyl groups, the C 1~3 The alkylene group is one or more, each independently consisting of a halogen, an oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more halogens, -CN, and C 1~3 Alkoxy group, C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6 The alkyl group may be substituted with one or more substituents independently selected from halogens, carboxyl groups, -NH2 groups, methyl groups, and methoxy groups.

[0141] In one embodiment of the present invention, R is H,

[0142] [ka] Selected from, * This is the junction between R and A.

[0143] In one embodiment of the present invention, R is H,

[0144] [ka] Selected from,

[0145] [ka] It is preferable that this be the case.

[0146] [ka] It is preferable that this be the case.

[0147] [ka] It is preferable that this be the case.

[0148] [ka] It is preferable that this be the case.

[0149] [ka] It is preferable that this be the case, however, * This is the connection point with A.

[0150] In one embodiment of the present invention, L3 is -C 1~6 Alkylene-,-C 2~6 Alkynylene-,-methylene-C 6~10 Aryl-C 6~10Aryl-methylene-,-methylene-5~12 member heteroaryl-5~12 member heteroaryl-methylene-,

[0151] [ka] Selected from, the alkylene group, methylene group, and alkynylene group are each independently one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, and C 1~3 They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. * This is the junction between L3 and A.

[0152] In one embodiment of the present invention, L3 is -C 1~6 Alkylene-,-C 2~6 Alkynylene-,-methylene-phenyl-phenyl-methylene-,-ethylene-phenyl-phenyl-ethylene-,-methylene-5-6 member heteroaryl-5-6 member heteroaryl-methylene-,-ethylene-5-6 member heteroaryl-5-6 member heteroaryl-ethylene-,

[0153] [ka] The alkylene-, methylene group, ethylene group, alkylylene group, and one or more substituents independently selected from halogen, oxo group, -CN, -OH, -NH2, methyl group, and ethyl group are not required to be substituted with such substituents, and the phenyl group and heteroaryl group are not required to be substituted with one or more substituents independently selected from halogen, -CN, methyl group, ethyl group, methoxy group, and ethoxy group. * This is the junction between L3 and A.

[0154] In one embodiment of the present invention, L3 is -C 1~6Alkylene-,-C 2~6 Alkynylene-,-methylene-phenyl-phenylmethylene-,-methylene-6-membered heteroaryl-6-membered heteroaryl-methylene-

[0155] [ka] The alkylene group and methylene group may be independently substituted with one or more substituents selected from fluorine, chlorine, bromine, oxo group, -CN, -OH, and -NH2, and the phenyl group and heteroaryl group may be independently substituted with one or more substituents selected from fluorine, chlorine, bromine, -CN, methyl group, ethyl group, methoxy group, and ethoxy group. * This is the junction between L3 and A.

[0156] In one embodiment of the present invention, L3 is a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an n-pentylene group, an n-hexylene group, an n-propynylene group, an n-butylylene group, an n-pentynylene group, an n-hexynylene group, -methylene-phenyl-phenyl-methylene-, -methylene-pyridyl-pyridyl-methylene-,

[0157] [ka] Selected from, * This is the junction between L3 and A.

[0158] In one embodiment of the present invention, L3 is

[0159] [ka] Selected from, * This is the junction between L3 and A.

[0160] In one embodiment of the present invention, L3 is

[0161] [ka] Selected from, * This is the junction between L3 and A.

[0162] In one embodiment of the present invention, rings W1, W2, and W3 are each independently C 6~12 Aryl group, 5-12 membered heteroaryl group, C 6~14 Selected from cycloalkyl groups, the aryl group, heteroaryl group, and cycloalkyl group are each independently one or more of deuterium, halogen, -CN, and C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0163] In one embodiment of the present invention, rings W1, W2, and W3 are each independently C 6~10 Aryl group, 5-10 membered heteroaryl group, C 6~10 Selected from cycloalkyl groups, the aryl group, heteroaryl group, and cycloalkyl group may each be independently substituted with one or more substituents selected from fluorine, chlorine, bromine, -CN, methyl group, ethyl group, methoxy group, and ethoxy group.

[0164] In one embodiment of the present invention, rings W1, W2, and W3 are independently a phenyl group, a naphthyl group, an 8-10 membered bicyclic heteroaryl group, and C 8~10 Selected from bicyclic cycloalkyl groups and 5-6 membered monocyclic heteroaryl groups, the phenyl group, naphthyl group, heteroaryl group, and cycloalkyl group are each independently one or more halogens, -CN, and C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0165] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a phenyl group, a naphthyl group, a 5-membered / 5-membered condensed heteroaryl group, a 5-membered / 6-membered condensed heteroaryl group, a 6-membered / 5-membered condensed heteroaryl group, a 6-membered / 6-membered condensed heteroaryl group, a 4-membered / 6-membered spirocycloalkyl group, a 6-membered / 4-membered spirocycloalkyl group, a 5-membered / 5-membered spirocycloalkyl group, a 5-membered / 6-membered spirocycloalkyl group, a 6-membered / 5-membered spirocycloalkyl group, a 6-membered / 6-membered spirocycloalkyl group, and a 5-6 membered monocyclic heteroaryl group. The phenyl group, naphthyl group, condensed heteroaryl group, spirocycloalkyl group, and monocyclic heteroaryl group may each be independently substituted with one or more substituents selected from fluorine, chlorine, bromine, -CN, methyl group, ethyl group, methoxy group, and ethoxy group.

[0166] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from one or more phenyl groups, naphthyl groups, 5-membered / 5-membered condensed heteroaryl groups, 5-membered / 6-membered condensed heteroaryl groups, 6-membered / 5-membered condensed heteroaryl groups, 6-membered / 6-membered condensed heteroaryl groups, 4-membered / 6-membered spirocycloalkyl groups, 6-membered / 4-membered spirocycloalkyl groups, and 5-6 membered monocyclic heteroaryl groups. The phenyl groups, naphthyl groups, condensed heteroaryl groups, spirocycloalkyl groups, and monocyclic heteroaryl groups are not necessarily substituted with one or more substituents independently selected from fluorine, chlorine, bromine, methyl groups, ethyl groups, methoxy groups, and ethoxy groups.

[0167] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a phenyl group and a 5-6 membered monocyclic heteroaryl group, and the phenyl group and heteroaryl group are each independently selected from one or more deuterium, halogen, -CN, -OH, -NH2, -CHO, and C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3The heteroaryl group may be substituted with substituents selected from alkyl groups, and the heteroatoms in the heteroaryl group are O, N, or S, and the number of heteroatoms is one or two.

[0168] In one embodiment of the present invention, rings W1, W2, and W3 may each be substituted independently:

[0169] [ka] Selected from, and "may be substituted" means unsubstituted, or one or more independently of deuterium, halogen, -CN, -OH, -NH2, -CHO, C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 This means that the alkyl group is substituted with a substituent selected from the alkyl group.

[0170] In one embodiment of the present invention, rings W1, W2, and W3 may each be substituted independently:

[0171] [ka] Selected from, and "may be substituted" means either unsubstituted or substituted by one or more substituents independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl group, ethyl group, methoxy group, ethoxy group, -N(CH3)2, -NH(CH3), and -C(O)CH3.

[0172] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a phenyl group and a thienyl group, and the phenyl group and thienyl group may be each independently substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl group, ethyl group, methoxy group, ethoxy group, -N(CH3)2, -NH(CH3), and -C(O)CH3.

[0173] In one embodiment of the present invention, rings W1, W2, and W3 may each be substituted independently:

[0174] [ka] Selected from, and "may be substituted" means either unsubstituted or substituted by one or more substituents independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl group, ethyl group, methoxy group, ethoxy group, -N(CH3)2, -NH(CH3), and -C(O)CH3.

[0175] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from phenyl groups, and each phenyl group may be substituted with one or more substituents independently selected from fluorine, chlorine, bromine, methyl, ethyl, methoxy, and ethoxy groups.

[0176] In one embodiment of the present invention, W1, W2, and W3 are each independently

[0177] [ka] They are selected from among them.

[0178] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32These are bonded independently: -O-, -S-, -NH-, -Se-, -C 1~4 Alkylene-,-C 1~6 Oxyalkylene-,-C 1~4 Thioalkylene-,-C 1~4 Azaalkilene-,-C 1~4 Selected from selenoalkylene, the alkylene group, oxyalkylene group, thioalkylene group, azaalkylene group, and selenoalkylene group are Z 41 It may be substituted with one or more substituents selected from Z 41 These are independently deuterium, halogens (e.g., fluorine, chlorine), oxo groups, thio groups, -CN, -OH, -NH2, and C 1~3 Alkyl alkyl group, C 1~3 Haloalkyl group, C 1~3 Alkoxy group, C 1~3 Selected from haloalkoxy groups, or any two Z groups 41 along with the atoms linked to them, C 3~6 A cycloalkyl group or a 3- to 6-membered heterocyclic group (e.g., an oxetanyl group) is formed, and the heteroatoms in the heterocyclic group are O, N, or S, and the number of heteroatoms is one or two.

[0179] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are joined independently, -C 1~3 Alkylene-,-C 1~3 Oxyalkylene-,-C 1~3 Thioalkylene-,-C 1~3 The alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group are selected from azaalkylene, and each alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be substituted with one or more substituents selected independently from deuterium, halogen, oxo group, -CN, -OH, -NH2, methyl group, and methoxy group. Preferably, each alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be substituted with one or more substituents selected independently from deuterium and oxo group.

[0180] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are each independently of -C 1~2 Alkylene-,-C 1~2 Oxyalkylene-,-C 1~2 Thioalkylene-,-C 1~2 The alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be substituted with one or more substituents independently selected from deuterium and oxo groups.

[0181] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are joined independently, -C 1~3 Alkylene-,-C 1~3 The alkylene group and oxyalkylene group are selected from oxyalkylene, and each alkylene group and oxyalkylene group may be substituted with one or more substituents selected independently from deuterium, halogen, oxo group, -CN, -OH, -NH2, methyl group, and methoxy group, and preferably the alkylene group and oxyalkylene group may be substituted with one or more substituents selected independently from deuterium and oxo group.

[0182] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are each independently of -C 1~2 Alkylene-,-C 1~3 Oxyalkylene-,-C 1~3 Selected from azaalkylene-, the alkylene group, oxyalkylene group, and azaalkylene group may be substituted with one or more substituents independently selected from oxo groups.

[0183] In one embodiment of the present invention, the compound is given Z 11 , Z 21 and Z 31 If both exist simultaneously, Z 11 , Z 21 and Z 31 The combinations defined as include at least one heteroatom or heteroatomic group, the heteroatom or heteroatomic group being selected from -O-, -S-, -Se-, -NH-, -CO-, and -C(S)-.

[0184] In one embodiment of the present invention, the compound is given Z 11 , Z 21 and Z 31 If both exist simultaneously, Z 11 , Z 21 and Z 31 The combinations defined as include at least one heteroatom or heteroatomic group, and the heteroatom or heteroatomic group is selected from -CO- or -C(S)-.

[0185] In one embodiment of the present invention, the compound is given Z 11 , Z 21 and Z 31 If both exist simultaneously, Z 11 , Z 21 and Z 31 The combinations consisting of the definitions include:

[0186] [ka] It includes at least one that is arbitrarily selected from,

[0187] [ka] This is preferable. * This represents the connection point with A.

[0188] In one embodiment of the present invention, the compound is given Z 11 , Z 21and Z 31 If both exist simultaneously, Z 11 , Z 21 and Z 31 The combinations defined include at least one heteroatom or heteroatomic group, and the heteroatom or heteroatomic group is selected from -O-, -NH-, and -CO-.

[0189] In one embodiment of the present invention, the compound is given Z 11 , Z 21 and Z 31 If both exist simultaneously, Z 11 , Z 21 and Z 31 The combinations defined include 1 to 4 heteroatoms or heteroatomic groups, the heteroatoms or heteroatomic groups are selected from -O-, -S-, -Se-, -NH-, -CO-, and -C(S)-, specifically 1, 2, 3, or 4, with 1 to 3 heteroatoms or heteroatomic groups preferred, specifically 1, 2, or 3, with 2 to 4 heteroatoms or heteroatomic groups more preferred, specifically 2, 3, or 4, with 2 or 3 heteroatoms or heteroatomic groups more preferred, the heteroatoms or heteroatomic groups are preferably -O-, -S-, -NH-, or -CO-, the heteroatoms or heteroatomic groups are more preferably -O- or -CO-, and preferably the heteroatoms or heteroatomic groups include at least -CO- or -C(S)-.

[0190] In one embodiment of the present invention, Z 21 It contains a heteroatom or heteroatomic group selected from -O-, -S-, -Se-, and -NH-, and Z 31 It contains a heteroatom or heteroatomic group selected from -CO- and -C(S)-, and Z 21 and Z 31 The total number of heteroatoms or heteroatomic groups in the combination is 1 to 4.

[0191] In one embodiment of the present invention, the compound is given Z 11 , Z 21 and Z 31If both exist simultaneously, Z 11 , Z 21 and Z 31 The combinations defined include 1 to 4 heteroatoms or heteroatomic groups, the heteroatoms or heteroatomic groups being selected from -O-, -NH-, and -CO-, preferably 1 to 3, more preferably 2 to 3, and preferably at least -CO-.

[0192] In one embodiment of the present invention, Z 11 , Z 21 and Z 31 It contains a total of 1 to 4 heteroatoms or heteroatomic groups, and the heteroatoms or heteroatomic groups are selected from -O-, -NH-, and -CO-, specifically 1, 2, 3, or 4.

[0193] In one embodiment of the present invention, Z 11 , Z 21 and Z 31 It contains a total of 1 to 3 heteroatoms or heteroatomic groups, and the heteroatoms or heteroatomic groups are selected from -O-, -NH-, and -CO-, specifically 1, 2, or 3.

[0194] In one embodiment of the present invention, Z 11 , Z 21 and Z 31 The material contains a total of 2 to 3 heteroatoms or heteroatomic groups, the heteroatoms or heteroatomic groups being selected from -O-, -NH-, and -CO-, specifically 2 or 3, and preferably containing at least -CO-.

[0195] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are -CD2- and -C, respectively, independently. 1~4 Alkylene-,-OC 1~3 Alkylene-, -C(O)-, -C 1~3 Alkylene-C(O)-,-OC1~3 alkylene-C(O)-, -NH-C 1~3 alkylene-C(O)-, -S-C 1~3 alkylene-C(O)-, -O-C 1~2 alkylene-C(O)-C 1~3 alkylene-, -C 1~2 alkyl-O-C 1~3 alkylene-, -NH-C 1~3 alkylene-, -S-C 1~3 alkylene-, -C 1~3 alkylene-NH-C(O)-, -C 1~3 alkylene-O-C(O)-, -NH-C(O)-, -O-C(O)-, -S-C(O)-, -C 1~3 alkylene-C(S)-, -Se-C 1~3 alkylene-

[0196]

Chemical formula

[0197] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 are each independently -CD2-, -C 1~3 alkylene-, -OC 1~3 alkylene-, -C(O)-, -C 1~3 alkylene-C(O)-, -OC 1~3 alkylene-C(O)-, -NH-C 1~3 alkylene-C(O)-, -S-C 1~3 alkylene-C(O)-, -O-C 1~3 alkylene-C(O)-C 1~3 alkylene-, -C 1~3 alkylene-O-C 1~3 alkylene-, -NH-C 1~3 alkylene-, -S-C 1~3 alkylene-, -C1~3 Alkylene-NH-C(O)-,-C 1~3 The alkylenes selected are -OC(O)-, -NH-C(O)-, -OC(O)-, and -SC(O)-.

[0198] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are linked independently, -CD2-, and -C. 1~3 Alkylene-,-OC 1~3 Alkylene-, -C(O)-, -C 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-,-NH-C 1~3 Alkylene-C(O)-, -SC 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-C 1~3 Selected from alkylene.

[0199] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are each independently of -C 1~3 Alkylene-,-OC 1~3 Alkylene-,-C 1~3 Alkylene-C(O)-,-OC 1~3 It is selected from alkylene -C(O)-, -NH-C(O)-, and -OC(O)-.

[0200] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are one or more -CD2-, -C, each independently. 1~2 Alkylene-,-OC 1~3 Alkylene-, -C(O)-, -C 1~2 Alkylene-C(O)-,-OC1~2 alkylene-C(O)-, -NH-C 1~2 alkylene-C(O)-, -S-C 1~2 alkylene-C(O)-, -O-C 1~2 alkylene-C(O)-C 1~2 alkylene-, -C 1~2 alkylene-O-C 1~2 alkylene-, -NH-C 1~2 alkylene-, -S-C 1~2 alkylene-, -C 1~2 alkylene-NH-C(O)-, -C 1~2 selected from alkylene-O-C(O)-, -NH-C(O)-, -O-C(O)-, -S-C(O)-.

[0201] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 is one or more independent bonds, -CD2-, -C 1~2 alkylene-, -OC 1~2 alkylene-, -C(O)-, -C 1~2 alkylene-C(O)-, -OC 1~2 alkylene-C(O)-, -NH-C 1~2 alkylene-C(O)-, -S-C 1~2 alkylene-C(O)-, -O-C 1~2 alkylene-C(O)-C 1~2 selected from alkylene-.

[0202] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z<​​​​​​​​​They are selected from among them.

[0204] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are, independently, a methylene group and an ethylene group,

[0205] [ka] They are selected from among them.

[0206] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are, independently, a methylene group and an ethylene group,

[0207] [ka] Selected from, * This represents the connection point with A.

[0208] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are, independently, a methylene group, an ethylene group, and -CD2,

[0209] [ka] Selected from, * This represents the connection point with A.

[0210] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 Each is independently selected from the methylene group and -CD2, and Z 11These are methylene group, ethylene group, -CD2,

[0211] [ka] Selected from, and Z 21 These are methylene group, ethylene group, -CD2,

[0212] [ka] Selected from, and Z 31 teeth,

[0213] [ka] Selected from, and more preferably Z 31 teeth

[0214] [ka] Selected from, * This represents the connection point with A.

[0215] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 Each is independently selected from the methylene group and -CD2, and Z 11 These are methylene group, ethylene group, -CD2,

[0216] [ka] Selected from, and Z 21 These are methylene group, ethylene group, -CD2,

[0217] [ka] Selected from, and Z 31 teeth,

[0218] [ka] Selected from, * This represents the connection point with A.

[0219] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 These are, independently, a methylene group and an ethylene group,

[0220] [ka] They are selected from among them.

[0221] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 Each of these is independently selected from -CD2 and a methylene group, and a methylene group is preferred.

[0222] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 These are independently selected from -CD2, a methylene group, and an ethylene group.

[0223] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 Both are -CD2, a methylene group, and a methylene group is preferred.

[0224] In one embodiment of the present invention, Z 11 -CD2, -C 1~3 Alkylene-,-OC 1~3 Alkilen - Selected from, -C 1~3 It is preferably an alkylene group, preferably a -CD2 group, a methylene group, an ethylene group, a methyleneoxy group, or an ethyleneoxy group, and more preferably a methylene group.

[0225] In one embodiment of the present invention, Z 21 is, -OC 1~3 Alkylene-,-NH-C 1~3 Alkylene-, -SC 1~3 Alkylene-,-Se-C 1~3 Alkylene-,-C 1~2 Alkylene-OC 1~3 Alkilen - Selected from, -OC 1~3 Alkylene-,-NH-C 1~2 Alkylene-, -SC 1~2 Alkylene-,-C 1~2 Alkylene-OC 1~3 It is preferable that it be alkylene-

[0226] In one embodiment of the present invention, Z 31 is -C(O)-, -C 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-,-NH-C 1~3 Alkylene-C(O)-, -SC 1~3 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-C 1~3 Alkylene-,-C 1~3 Alkylene-NH-C(O)-,-C 1~3 Alkylene-OC(O)-,-NH-C(O)-,-OC(O)-,-SC(O)-,-C 1~3 Selected from alkylene -C(S)-, -C(O)-, -C 1~2 Alkylene-C(O)-,-OC 1~2 It is preferable that the alkylene is -C(O)-, -NH-C(O)-, -OC(O)-, -SC(O)-, and -C 1~2 Alkylene-C(O)-,-OC 1~2 It is preferably alkylene-C(O)-, -NH-C(O)-, -OC(O)-, and -SC(O)-, and preferably -CH2C(O)-.

[0227] In one embodiment of the present invention, Z 11 It is independently -OC 1~3 Alkyl-,-NH-C 1~3 alkyl-, -SC1~3 Alkyl-, -Se-C 1~3 Alkyl-, -C 1~3 Alkyl-OC 1~3 Selected from alkyl-, and Z 21 These are all independently -OC 1~3 Alkyl-,-NH-C 1~3 alkyl-, -SC 1~3 Alkyl-, -Se-C 1~3 Alkyl-, -C 1~3 Alkyl-OC 1~3 Selected from alkyl-.

[0228] In one embodiment of the present invention, Z 21 is, -OC 1~3 Alkylene-,-NH-C 1~3 Alkylene-, -SC 1~3 Alkylene-,-Se-C 1~3 Alkylene-,-C 1~2 Alkylene-OC 1~3 Selected from Alkilen, and Z 31 is -C(O)-, -C 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-,-NH-C 1~3 Alkylene-C(O)-, -SC 1~3 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-C 1~3 Alkyl-, -C 1~3 Alkylene-NH-C(O)-,-C 1~3 Alkylene-OC(O)-,-NH-C(O)-,-OC(O)-,-SC(O)-,-C 1~3 Selected from alkylene-C(S)-

[0229] In one embodiment of the present invention, Z 11 -CD2, -C 1~3 Alkylene-,-OC 1~3 Selected from Alkilen, and Z 21 is, -OC 1~3 Alkylene-,-NH-C 1~3 Alkylene-, -SC 1~3 Alkylene-,-Se-C1~3 Alkylene-,-C 1~2 Alkylene-OC 1~3 Selected from Alkilen, and Z 31 is -C(O)-, -C 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-,-NH-C 1~3 Alkylene-C(O)-, -SC 1~3 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-C 1~3 Alkylene-,-C 1~3 Alkylene-NH-C(O)-,-C 1~3 Alkylene-OC(O)-,-NH-C(O)-,-OC(O)-,-SC(O)-,-C 1~3 Selected from alkylene-C(S)-. In one embodiment of the present invention, Z 11 -CD2, -C 1~3 Alkylene-,-OC 1~3 Selected from Alkilen, and Z 21 is, -OC 1~3 Alkylene-,-NH-C 1~3 Alkylene-, -SC 1~3 Alkylene-,-Se-C 1~3 Alkylene-,-C 1~2 Alkylene-OC 1~3 Selected from Alkilen, and Z 31 is -C(O)-, -C 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-,-NH-C 1~3 Alkylene-C(O)-, -SC 1~3 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-C 1~3 Alkylene-,-C 1~3 Alkylene-NH-C(O)-,-C 1~3 Alkylene-OC(O)-,-NH-C(O)-,-OC(O)-,-SC(O)-,-C 1~3 Selected from alkylene-C(S)-

[0230] In one embodiment of the present invention, Z 11is -C 1~3 Alkylene-,-OC 1~3 Selected from Alkilen, and Z 21 is, -OC 1~3 Alkylene-,-NH-C 1~3 Alkylene-, -SC 1~3 Alkylene-,-Se-C 1~3 Alkylene-,-C 1~2 Alkylene-OC 1~3 Selected from Alkilen, and Z 31 is -C(O)-, -C 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-,-NH-C 1~3 Alkylene-C(O)-, -SC 1~3 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-C 1~3 Alkylene-,-C 1~3 Alkylene-NH-C(O)-,-C 1~3 Alkylene-OC(O)-,-NH-C(O)-,-OC(O)-,-SC(O)-,-C 1~3 Selected from alkylene-C(S)-. In one embodiment of the present invention, Z 11 -CD2, -C 1~3 Alkylene-,-OC 1~3 Alkilen * And, Z 21 is, -OC 1~3 Alkilen * , -NH-C 1~3 Alkilen * , -SC 1~3 Alkilen * , -Se-C 1~3 Alkilen * , -C 1~2 Alkylene-OC 1~3 Alkilen * Selected from, and Z 31 is -C(O)-, -C 1~3 Alkylene-C(O)- * ,-OC 1~3 Alkylene-C(O)- * , -NH-C 1~3 Alkylene-C(O)- *, -SC 1~3 Alkylene-C(O)- * ,-OC 1~2 Alkylene-C(O)-C 1~3 Alkilen * , -C 1~3 Alkylene-NH-C(O)- * , -C 1~3 Alkylene-OC(O)- * , -NH-C(O)- * , -OC(O)- * , -SC(O)- * , -C 1~3 Alkylene-C(S)- * Selected from, * This represents the connection point with A.

[0231] In one embodiment of the present invention, Z11 is -C 1~3 Alkylene-,-OC 1~3 Alkilen * And, Z 21 is, -OC 1~3 Alkilen * , -NH-C 1~3 Alkilen * , -SC 1~3 Alkilen * , -Se-C 1~3 Alkilen * , -C 1~2 Alkylene-OC 1~3 Alkilen * Selected from, and Z 31 is -C(O)-, -C 1~3 Alkylene-C(O)- * ,-OC 1~3 Alkylene-C(O)- * , -NH-C 1~3 Alkylene-C(O)- * , -SC 1~3 Alkylene-C(O)- * ,-OC 1~2 Alkylene-C(O)-C 1~3 Alkilen * , -C 1~3 Alkylene-NH-C(O)- * , -C 1~3 Alkylene-OC(O)-* , -NH-C(O)- * , -OC(O)- * , -SC(O)- * , -C 1~3 Alkylene-C(S)- * Selected from, * This represents the connection point with A.

[0232] In one embodiment of the present invention, Z 11 -CD2-, -C 1~2 Alkylene-,-OC 1~2 Alkilen * And, Z 21 is, -OC 1~2 Alkilen * , -NH-C 1~2 Alkilen * , -SC 1~2 Alkilen * , -Se-C 1~2 Alkilen * -CH2-OC 1~2 Alkilen * Selected from, and Z 31 is -C(O)-, -C 1~2 Alkylene-C(O)- * ,-OC 1~2 Alkylene-C(O)- * , -NH-C 1~2 Alkylene-C(O)- * , -SC 1~2 Alkylene-C(O)- * , -C 1~2 Alkylene-NH-C(O)- * , -C 1~2 Alkylene-OC(O)- * , -NH-C(O)- * , -OC(O)- * , -SC(O)- * , -C 1~2 Alkylene-C(S)- * Selected from, and more preferably Z 31 is -C 1~2 Alkylene-C(O)- * ,-OC 1~2 Alkylene-C(O)- * , -NH-C1~2 Alkylene-C(O)- * , -SC 1~2 Alkylene-C(O)- * , -C 1~2 Alkylene-NH-C(O)- * , -C 1~2 Alkylene-OC(O)- * -CH2NH-C(O)- * , -NH-C(O)- * , -OC(O)- * , -SC(O)- * , -C 1~2 Alkylene-C(S)- * Selected from, and more preferably Z31 is -C 1~2 Alkylene-C(O)- * -OCH2-C(O)- * -CH2-OC(O)- * , -NH-C(O)- * , -OC(O)- * , -SC(O)- * Selected from, and more preferably Z 31 is -CH2C(O)- * Selected from, * This represents the connection point with A.

[0233] In one embodiment of the present invention, L1 and L2 are one or more independently

[0234] [ka]

[0235] [ka] Selected from, * This represents the connection point with A.

[0236] In one embodiment of the present invention, L1 and L2 are one or more independently

[0237] [ka] Selected from, * This represents the connection with N (i.e., A).

[0238] In one embodiment of the present invention, L3 is

[0239] [ka]

[0240] [ka] Selected from, * This represents the connection point with A.

[0241] In one embodiment of the present invention, L1, L2, and L3 are one or more independently

[0242] [ka] Selected from, * This represents the connection point with N (i.e., A).

[0243] In one embodiment of the present invention, R is H,

[0244] [ka]

[0245] [ka]

[0246] [ka] Selected from, * This represents the connection point with A.

[0247] In one embodiment of the present invention, R is H,

[0248] [ka]

[0249] [ka]

[0250] [ka] Selected from, * This represents the connection point with A.

[0251] In one aspect of the present invention, compounds represented by the following formulas (I'-1), (I'-2), and (I'-3) are provided, or pharmaceutically acceptable salts of said compounds.

[0252] [ka]

[0253] However, A, L1, L2, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 31 , R 32 , R 41 , R 42 , R 50 , R 51 h1, h2, h3, and h4 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4).

[0254] In one embodiment of the compounds represented by the above formulas (I'-1), (I'-2), and (I'-3), R is a group containing L3, and Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0255] The present invention further provides a compound represented by the following formula (II) or a pharmaceutically acceptable salt of said compound,

[0256] [ka] However, L1 and L2 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4). R' is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 12-membered heteroaryl group, C 1~6 Selected from alkyl groups, the C 1~3 The alkylene group consists of one or more independently derived elements: deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1~3They may be substituted with substituents selected from alkyl groups, and the aryl group, heteroaryl group may be independently one or more deuterium, halogen, -CN, C 1~3 Alkoxy group, C 1~3 The C does not necessarily have to be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl group, one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0257] In one embodiment of the present invention, R' is H, -C 1~3 Alkylene-C 6~10 Aryl group, -C 1~3 Alkylene-5 to 10-membered heteroaryl group, C 1~6 Selected from alkyl groups, the C 1~3 The alkylene group may be substituted with one or more substituents independently selected from deuterium, halogen, oxo group, -CN, -OH, and -NH2, and the aryl group and heteroaryl group may be substituted with one or more substituents independently selected from deuterium, halogen, -CN, methoxy group, and C 1~3 The C may be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl groups are one or more independently of deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. L1 is

[0258] [ka] And, * This represents the connection point with N. L2 is

[0259] [ka] And, * This represents the connection point with N. Rings W1 and W2 each independently contain one or more C 6~12 Selected from aryl groups and 5-12 membered heteroaryl groups, the aryl group and heteroaryl group are each independently composed of one or more deuterium, halogen, -CN, and C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups. Z 11 , Z 12 , Z 21 , Z 22 These are each independently of -C 1~3 Alkylene-,-C 1~3 The alkylene group and oxyalkylene group may be selected from oxyalkylene, and each of these substituents may be independently substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, methyl group, and methoxy group.

[0260] In one embodiment of the present invention, R' is H, -C 1~3 Alkylene-phenyl group, -methylene-5-6 membered heteroaryl group, C 1~6 Selected from alkyl groups, the methylene group, C 1~3 Alkylene group, one or more independently of a halogen, oxo group, -CN, -OH, -NH2, C 1~3 The phenyl group and heteroaryl group may be substituted with substituents selected from alkyl groups, and each of the phenyl group and heteroaryl group may be independently one or more halogens, -CN, and C 1~3 Alkoxy group, C 1~3 The C does not necessarily have to be substituted with a substituent selected from aminoalkyl groups. 1~6 Alkyl group, one or more halogens, oxo group, carboxyl group, -CN, -OH, -NH2, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0261] In one embodiment of the present invention, R' is H, a methylene-phenyl group, an ethylene-phenyl group, a methylene-pyridyl group, and C 1~6 Selected from alkyl groups, the phenyl group and pyridyl group are each independently one or more halogen, -CN, methoxy group,

[0262] [ka] The C may be substituted with a substituent selected from the above. 1~6 The alkyl group may be substituted with one or more substituents independently selected from a carboxyl group and -NH2.

[0263] In one embodiment of the present invention, R' is H,

[0264] [ka] They are selected from among them.

[0265] In one embodiment of the present invention, rings W1 and W2 may each be independently selected from a phenyl group and a 5- to 12-membered heteroaryl group, and may be substituted with the phenyl group, the heteroaryl group, and one or more substituents independently selected from a halogen and -CN.

[0266] In one embodiment of the present invention, rings W1 and W2 are each independently selected from one or more phenyl groups and 8-10 membered bicyclic heteroaryl groups, and may be substituted with the phenyl group, the bicyclic heteroaryl group, and one or more substituents independently selected from halogens and -CN, and the heteroatoms in the bicyclic heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is one or two.

[0267] In one embodiment of the present invention, rings W1 and W2 are independently

[0268] [ka] They are selected from among them.

[0269] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 These are each independently of -C 1~3 Alkylene-,-C 1~3 The alkylene group and the oxyalkylene group may be selected from oxyalkylene groups, and each of these substituents may be independently substituted with one or more substituents selected from deuterium and oxo groups.

[0270] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 These are, independently, a methylene group and an ethylene group,

[0271] [ka] They are selected from among them.

[0272] In one embodiment of the present invention, L1 and L2 are independent of each other.

[0273] [ka] Selected from, * This represents the connection point with N.

[0274] The present invention further provides compounds represented by the following formulas (II-A), (II-B), (II-C), (II-A'), (II-B'), (II-C'), or pharmaceutically acceptable salts of said compounds.

[0275] [ka] However, W1, W2, and R' are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), or (II). The present invention further provides a compound represented by the following formula (III) or a pharmaceutically acceptable salt of said compound,

[0276] [ka] However, A, L1, L2, and L3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4).

[0277] In one embodiment of the compound represented by formula (III) above, L1, L2, and L3 are Z 11 , Z 21 and Z 31 It is a group that includes Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0278] The present invention further provides a compound represented by the following formula (III-1) or a pharmaceutically acceptable salt of said compound,

[0279] [ka] However, W1, W2, W3, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 This is as described for compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), or formula (III).

[0280] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 These are independently selected from a methylene group and an ethylene group, Z 11 , Z 21 , Z 31 These are joined independently, -C 1~4 Alkylene-,-C 1~6 Oxyalkylene-(for example, -C 1~4 Oxyalkylene-), -C 1~4 Thioalkylene-,-C 1~4 Azaalkilene-,-C 1~4 Selected from selenoalkylene, the alkylene group, oxyalkylene group, thioalkylene group, azaalkylene group, and selenoalkylene group are Z 41 It may be substituted with one or more substituents selected from Z 41 These are independently deuterium, halogens (e.g., fluorine, chlorine), oxo groups, thio groups, -CN, -OH, -NH2, and C 1~3Alkyl alkyl group, C 1~3 Haloalkyl group, C 1~3 Alkoxy group, C 1~3 Selected from haloalkoxy groups, or any two Z groups 41 along with the atoms linked to them, C 3~6 A cycloalkyl group or a 3-6 membered heterocyclic group (e.g., an oxetanyl group) is formed, and the heteroatom in the heterocyclic group is O, N, or S, and the number of heteroatoms is 1. Rings W1, W2, and W3 are each independently selected from a phenyl group and a 5-6 membered monocyclic heteroaryl group, and the phenyl group and heteroaryl group are each independently selected from one or more deuterium, halogen, -CN, -OH, -NH2, -CHO, and C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 The heteroaryl group may be substituted with substituents selected from alkyl groups, and the heteroatoms in the heteroaryl group are O, N, or S, and the number of heteroatoms is one or two.

[0281] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 These are all methylene groups.

[0282] In one embodiment of the present invention, the compound is given Z 11 , Z 21 and Z 31 If both exist simultaneously, Z 11 , Z 21 and Z 31 The combinations defined include two or three heteroatoms or heteroatomic groups, and the heteroatoms or heteroatomic groups are selected from -O-, -S-, -NH-, and -CO-. In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a phenyl group and a thienyl group, and the phenyl group and thienyl group are each independently selected from one or more deuterium, halogen, -CN, -OH, -NH2, -CHO, and C 1~3 Alkyl alkyl group, C 1~3Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 It may be substituted with substituents selected from alkyl groups.

[0283] In one embodiment of the present invention, rings W1, W2, and W3 are each independently

[0284] [ka] The above group may be selected from and each of the above groups may be independently substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methoxy group, and ethoxy group.

[0285] In one embodiment of the compound represented by the above formula (III-1), Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0286] The present invention further provides a compound represented by the following formula (III-2) or a pharmaceutically acceptable salt of said compound,

[0287] [ka] However, W1, W2, W3, Z 11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 , R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 31 , R 32 , R 33 This is as described for the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), or formula (III-1).

[0288] In one embodiment of the present invention, Z 31 The heteroatoms or heteroatomic groups within it contain -CO- or -C(S)-.

[0289] In one embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 44 , R 45 , R 46 , R 47 , R 48 , R49 , R 31 , R 32 , R 33 It is selected from hydrogen or deuterium.

[0290] In one embodiment of the compound represented by formula (III-2) above, Z 11 , Z 21 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 , Z 21 and Z 31 There are two distinct pairs of them, or Z 11 , Z 21 and Z 31 Two of the groups in which there are no double bonds are the same, and these two identical groups include -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 , Z 21 and Z 31 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0291] The present invention further provides compounds represented by the following formulas (III-1-1) and (III-2-1), or pharmaceutically acceptable salts of said compounds.

[0292] [ka] However, W1, W2, W3, Z11 , Z 12 , Z 21 , Z 22 , Z 31 , Z 32 , R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 31 , R 32 , R 33 This is as described for compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), or formula (III-1) or formula (III-2).

[0293] The present invention further provides compounds represented by the following formula (III-A) or pharmaceutically acceptable salts of said compounds,

[0294] [ka] However, L3 is as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), or formula (III-1).

[0295] In one embodiment of the present invention, L3 is -C 1~6 Alkylene-,-C 2~6 Alkynylene-,-methylene-phenyl-phenyl-methylene-,-methylene-6-membered heteroaryl-6-membered heteroaryl-methylene- (e.g.,-methylene-pyridyl-pyridyl-methylene-),

[0296] [ka] The alkylene group, methylene group, and alkynylene group may be substituted with one or more substituents independently selected from halogens, oxo groups, -CN, -OH, and -NH2, and the aryl group and heteroaryl group do not need to be substituted with one or more substituents independently selected from halogens, -CN, C1-3 alkyl groups, and C1-3 alkoxy groups. * This represents the connection point with N.

[0297] In one embodiment of the present invention, ring W3 is selected from a phenyl group, a naphthyl group, an 8-10 membered bicyclic heteroaryl group, and a C8-10 bicyclic cycloalkyl group, and the phenyl group, naphthyl group, heteroaryl group, and cycloalkyl group are each independently one or more halogens, -CN, and C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0298] In one embodiment of the present invention, ring W3 is selected from a phenyl group, a naphthyl group, a 5-membered / 5-membered condensed heteroaryl group, a 5-membered / 6-membered condensed heteroaryl group, a 6-membered / 5-membered condensed heteroaryl group, a 6-membered / 6-membered condensed heteroaryl group, a 4-membered / 6-membered spirocycloalkyl group, and the phenyl group, naphthyl group, condensed heteroaryl group, and spirocycloalkyl group may each be independently substituted with one or more substituents selected from fluorine, chlorine, bromine, methyl group, ethyl group, methoxy group, and ethoxy group.

[0299] In one embodiment of the present invention, W3 is

[0300] [ka] They are selected from among them.

[0301] In one embodiment of the present invention, Z 31 , Z 32 These are each independently of -C 1~3 Alkylene-,-C 1~3Oxyalkylene-,-C 1~3 Thioalkylene-,-C 1~3 Selected from azaalkylene, preferably Z 31 , Z 32 These are each independently of -C 1~2 Alkylene-,-C 1~2 Oxyalkylene-,-C 1~2 Thioalkylene-,-C 1~2 Azaalkylene is selected from azaalkylene groups, however, the alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be substituted with one or more substituents independently selected from deuterium and oxo groups.

[0302] In one embodiment of the present invention, Z 31 , Z 32 These are -CD2- and -C, respectively, independently. 1~2 Alkylene-,-OC 1~2 Alkylene-, -C(O)-, -C 1~2 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-,-NH-C 1~2 Alkylene-C(O)-, -SC 1~2 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-C 1~2 Selected from alkylene.

[0303] In one embodiment of the present invention, Z 31 , Z 32 These are each independently of -C 1~3 Alkylene-,-C 1~3 The alkylene group and oxyalkylene group may be selected from oxyalkylene, and each of these substituents may be independently substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, methyl group, and methoxy group.

[0304] In one embodiment of the present invention, Z 31 , Z 32 These are each independently of -C 1~3The alkylene group is selected from alkylene groups, and the alkylene group may be substituted with one or more substituents independently selected from deuterium and oxo groups.

[0305] In one embodiment of the present invention, Z 31 , Z 32 Each of these independently comprises one or more methylene groups, ethylene groups, -CD2-,

[0306] [ka] They are selected from among them.

[0307] In one embodiment of the present invention, L3 is

[0308] [ka] Selected from, * This represents the connection point with N.

[0309] The present invention further provides compounds represented by the following formula (III-A') or pharmaceutically acceptable salts of said compounds,

[0310] [ka] However, L3 is as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), or formula (III-A).

[0311] The present invention further provides compounds represented by the following formula (III-B) or pharmaceutically acceptable salts of said compounds,

[0312] [ka] However, L1 and L2 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), or formula (III-1).

[0313] In one embodiment of the present invention, L1 is

[0314] [ka] And, * This represents the connection point with N.

[0315] In one embodiment of the present invention, L2 is

[0316] [ka] And, * This represents the connection point with N.

[0317] In one embodiment of the present invention, rings W1 and W2 are independently C 6~12 Selected from aryl groups and 5-12 membered heteroaryl groups, the aryl group and heteroaryl group are each independently composed of one or more deuterium, halogen, -CN, and C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0318] In one embodiment of the present invention, rings W1 and W2 are independently selected from phenyl groups, and C 8~12 The phenyl group, aryl group, and heteroaryl group may be selected from an aryl group and a 7- to 12-membered heteroaryl group, and each of these may be independently substituted with one or more substituents selected from a halogen, -CN, methyl group, and methoxy group.

[0319] In one embodiment of the present invention, rings W1 and W2 are each independently selected from a phenyl group, a naphthyl group, and an 8-10 membered bicyclic heteroaryl group, and the phenyl group, naphthyl group, and heteroaryl group are each independently selected from one or more halogens, -CN, and C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0320] In one embodiment of the present invention, rings W1 and W2 are each independently selected from a phenyl group, a naphthyl group, a 5-membered / 5-membered condensed heteroaryl group, a 5-membered / 6-membered condensed heteroaryl group, a 6-membered / 5-membered condensed heteroaryl group, and a 6-membered / 6-membered condensed heteroaryl group may be substituted with one or more substituents independently selected from fluorine, chlorine, bromine, -CN, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0321] In one embodiment of the present invention, rings W1 and W2 are independently

[0322] [ka] They are selected from among them.

[0323] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 These are each independently of -C 1~3 Alkylene-,-C 1~3 Oxyalkylene-,-C 1~3 Thioalkylene-,-C 1~3 The alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be selected from azaalkylene, and each alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be independently substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, methyl group, and methoxy group.

[0324] In one embodiment of the present invention, Z 11 , Z12 , Z 21 , Z 22 These are each independently of -C 1~3 Alkylene-,-C 1~3 The alkylene group and oxyalkylene group may be selected from oxyalkylene, and each of these substituents may be independently substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, methyl group, and methoxy group.

[0325] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 These are each independently of -C 1~2 Alkylene-,-C 1~2 Oxyalkylene-,-C 1~2 Thioalkylene-,-C 1~2 The alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be selected from azaalkylene, and each alkylene group, oxyalkylene group, thioalkylene group, and azaalkylene group may be independently substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, methyl group, and methoxy group.

[0326] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 It is selected from one or more methylene groups, each independently.

[0327] In one preferred embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 Each of them independently has a methylene group,

[0328] [ka] They are selected from among them.

[0329] In particular, L1 and L2 are Z 11 and Z 21It is a group that includes Z 11 and Z 21 In this group, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, preferably, the double bond is, for example, a double bond between C and O in -C(O)-, and more preferably, Z 11 and Z 21 None of them are methylene groups, or Z 11 and Z 21 The double bond-free group in the group is -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 and Z 21 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0330] In one embodiment of the present invention, L1 and L2 are independent of each other.

[0331] [ka] Selected from, * This represents the connection point with N.

[0332] The present invention further provides compounds of the following formulas (III-B'), (III-B'-1)', or pharmaceutically acceptable salts of said compounds.

[0333] [ka] However, L1 and L2 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), or formula (III-B).

[0334] In particular, L1 and L2 are Z 11 and Z 21 It is a group that includes Z 11 and Z 21 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 21 None of them are methylene groups, or Z 11 and Z 21 The double bond-free group in the group is -O-, -NH-, -S- or -Se-, preferably -O-, and more preferably Z 11 and Z 21 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0335] The present invention further provides compounds represented by the following formula (III-C) or pharmaceutically acceptable salts of said compounds,

[0336] [ka] However, W1, W2, and W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), or formula (III-1).

[0337] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from phenyl groups, naphthyl groups, 8-10 membered bicyclic heteroaryl groups, and 5-6 membered monocyclic heteroaryl groups, and the phenyl groups, naphthyl groups, and heteroaryl groups are each independently one or more halogens, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0338] In one embodiment of the present invention, rings W1, W2, and W3 are each independently

[0339] [ka] They are selected from among them.

[0340] The present invention further provides a compound represented by the following formula (III-C') or a pharmaceutically acceptable salt of said compound,

[0341] [ka] However, W1, W2, and W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), or formula (III-C).

[0342] The present invention further provides compounds represented by the following formula (III-D) or pharmaceutically acceptable salts of said compounds,

[0343] [ka] However, W1, W2, and W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), or formula (III-1).

[0344] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a phenyl group, a naphthyl group, and an 8-10 membered bicyclic heteroaryl group, and the phenyl group, naphthyl group, and heteroaryl group are each independently one or more halogens, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0345] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a phenyl group and a 9-10 membered bicyclic heteroaryl group, the heteroatoms in the heteroaryl group are each independently selected from O or N, the number of heteroatoms is one or two, and the phenyl group and the heteroaryl group may be substituted with one or more substituents each independently selected from fluorine, chlorine, a methyl group, and a methoxy group.

[0346] In one embodiment of the present invention, rings W1, W2, and W3 are each independently

[0347] [ka] They are selected from among them.

[0348] The present invention further provides compounds represented by the following formula (III-D') or pharmaceutically acceptable salts of said compounds,

[0349] [ka] However, W1, W2, and W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), or formula (III-D).

[0350] The present invention further provides compounds represented by the following formula (III-E) or pharmaceutically acceptable salts of said compounds,

[0351] [ka] However, W1, W2, and W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), or formula (III-1).

[0352] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a phenyl group, a naphthyl group, and an 8-10 membered bicyclic heteroaryl group, and the phenyl group, naphthyl group, and heteroaryl group are each independently one or more halogens, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0353] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from a 9-membered bicyclic heteroaryl group, and the heteroatoms in the heteroaryl group are independently selected from O or N, with the number of heteroatoms being one or two.

[0354] In one embodiment of the present invention, rings W1, W2, and W3 are each independently

[0355] [ka] They are selected from among them.

[0356] The present invention further provides compounds represented by the following formula (III-E') or pharmaceutically acceptable salts of said compounds,

[0357] [ka] However, W1, W2, and W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), or formula (III-E).

[0358] The present invention further provides a compound represented by the following formula (IV) or a pharmaceutically acceptable salt of said compound,

[0359] [ka] However, R3, R4, R9, R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 Each of these is independently selected from H and deuterium, and R3, R4, R9, R 10 , R 13 ~R 26 At least one of them is deuterium.

[0360] The present invention further provides a compound represented by the following formula (A) or a pharmaceutically acceptable salt of said compound,

[0361] [ka] However, R3, R4, R9, R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R25 , R 26 Each of these is independently selected from H and deuterium, and R3, R4, R9, R 10 , R 13 ~R 26 At least one of them is deuterium, R A , R B , R C These are hydrogen and C, respectively, independently. 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 1~6 Alkoxy group, -C 1~3 Alkylene group OC 1~6 Alkyl alkyl group, -C 1~3 Alkylene-OC(O)-C 1~6 Selected from alkyl groups, the alkyl group, alkenyl group, alkoxy group, alkylene group is one or more independently of deuterium, halogen, -OH, -NH2, -CN, oxo group, C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with substituents selected from alkoxy groups.

[0362] In one embodiment of the present invention, R A , R B , R C Each of them is independently C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, -C 1~2 Alkylene-OC 1~4 Alkyl alkyl group, -C 1~2 Alkylene-OC(O)-C 1~4 Selected from alkyl groups, the alkyl group, C 1~6 The alkoxy group and alkylene group may each be independently substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, -OH, -NH2, -CN, oxo group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, and isopropoxy group.

[0363] In one embodiment of the present invention, R A , R B , R C Each of them is independently C1~3 Alkyl,-methylene-OC 1~4 Alkyl alkyl, -methylene-OC(O)-C 1~3 The alkyl group is selected from alkyl groups, and the methylene group and alkyl group may be substituted with one or more substituents independently selected from methyl, ethyl, n-propyl, and isopropyl groups.

[0364] In one embodiment of the present invention, R A , R B , R C These are independently selected from a methyl group, an ethyl group, and -CH2-OC(O)-CH(CH3)2.

[0365] The present invention further provides compounds represented by the following formulas (B), (B-1), (C), (C-1), (D), and (D-1), or pharmaceutically acceptable salts of said compounds.

[0366] [ka] However, Z 11 , Z 21 , Z 31 , R 31 , R 32 , R 33 h1, h2, h3, h4, h5, h6 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), or formula (III-B), respectively, X, X2 are independently selected from O, CH2, NH, S, Se, X1 is independently selected from O, S, n, n1, n3 are independently 0 or 1, n2 is independently 0, 1, 2, or 3, Z 12 , Z 22 , Z 32 Each is independently selected from a methylene group, an ethylene group, and -CD2-, or selected from a methylene group and an ethylene group. Rings W1, W2, and W3 are each independently selected from a phenyl group and a 5-6 membered monocyclic heteroaryl group, and the phenyl group and heteroaryl group are each independently selected from one or more deuterium, halogen, -CN, -OH, -NH2, -CHO, and C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 The heteroaryl group may be substituted with substituents selected from alkyl groups, and the heteroatoms in the heteroaryl group are O, N, or S, and the number of heteroatoms is one or two.

[0367] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 It is selected from one or more methylene groups and -CD2- groups, each independently.

[0368] In one embodiment of the present invention, Z 11 It is -CD2-.

[0369] In one embodiment of the present invention, Z 11 -C is independent 1~3 Alkylene-,-OC 1~3 Alkylene-, -NH-C1~3Alkylene-, -SC 1~3 Alkylene-,-Se-C 1~3 Alkylene-,-C 1~2 Alkylene-OC 1~3 Selected from alkylenes, preferably Z 11 -C is independent 1~3 Alkylene-,-OC 1~3 Selected from alkylenes, preferably Z 11 The group is independently selected from a methylene group, an ethylene group, a methyleneoxy group, and an ethyleneoxy group, preferably Z 11 The group is independently selected from a methylene group and a -CD2- group, preferably Z 11 These are independently selected from the methylene group.

[0370] In one embodiment of the present invention, Z 21 It is -CD2-.

[0371] In one embodiment of the present invention, Z 21 -C is independent 1~3 Alkylene-,-OC 1~3 Alkylene-,-NH-C 1~3 Alkylene-, -SC 1~3 Alkylene-,-Se-C 1~3 Alkylene-,-C 1~2 Alkylene-OC 1~3 Selected from alkylenes, preferably -OC 1~3 Alkylene-,-NH-C 1~2 Alkylene-, -SC 1~2 Alkylene-,-C 1~2 Alkylene-OC 1~3 It is alkylene-

[0372] In one embodiment of the present invention, Z 31 These are independently -C(O)- and -C 1~3 Alkylene-C(O)-,-OC 1~3 Alkylene-C(O)-,-NH-C 1~3 Alkylene-C(O)-, -SC 1~3 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-C 1~3 Alkylene-,-C 1~3 Alkylene-NH-C(O)-,-C 1~3 Alkylene-OC(O)-,-NH-C(O)-,-OC(O)-,-SC(O)-,-C 1~3 Selected from alkylene-C(S)-, preferably -C(O)-, -C 1~2 Alkylene-C(O)-,-OC 1~2 These are alkylenes -C(O)-, -NH-C(O)-, -OC(O)-, and -SC(O)-.

[0373] In one embodiment of the present invention, Z 12 , Z 22 , Z 32 These are all methylene groups.

[0374] In one embodiment of the present invention, X2 is selected from O, NH, and S, and preferably X2 is O.

[0375] In one embodiment of the present invention, n2 is 0 or 1, n3 is 0, and X2 is CH2.

[0376] In one embodiment of the present invention, n2 is 2 or 3, n3 is 0, and X2 is O, NH, or S; or n2 is 1 or 2, n3 is 1, and X2 is O, NH, or S; more preferably, n2 is 2 or 3, n3 is 0, and X2 is O; or n2 is 2, n3 is 1, and X2 is O.

[0377] In one embodiment of the present invention, n2 is 2, n3 is 0, and X2 is O, NH, or S, preferably n2 is 2, n3 is 0, and X2 is O.

[0378] In one embodiment of the present invention, the sum of n2 and n3 is 3 or less (specifically, 0, 1, 2, or 3), preferably the sum of n2 and n3 is 2 or less (specifically, 0, 1, or 2), and preferably the sum of n2 and n3 is 1 or 2 (i.e., n2 is 2 and n3 is 0, or n2 is 1 and n3 is 1, or n2 is 0 and n3 is 2).

[0379] In one embodiment of the present invention, X1 is O.

[0380] In one embodiment of the present invention, X is CH2.

[0381] In one embodiment of the present invention, X is selected from O, CH2, NH, and S, n is 1 and n1 is 0, or X is O or CH2, n is 1 and n1 is 1.

[0382] In one embodiment of the present invention, X1 is O, X is selected from O, CH2, NH, and S, n is 1 and n1 is 0, or X1 is O, X is O or CH2, n is 1 and n1 is 1, more preferably X1 is O, X is selected from O and CH2, n is 1 and n1 is 0, or X1 is O, X is O or CH2, n is 1 and n1 is 1, more preferably X1 is O, X is selected from CH2, n is 1 and n1 is 0.

[0383] In one embodiment of the present invention, the sum of n and n1 is 0, 1, or 2, preferably the sum of n and n1 is 1 or 2 (i.e., n is 1 and n1 is 0, or n is 0 and n1 is 1, or n is 1 and n1 is 1, or n is 0 and n1 is 2, or n is 2 and n1 is 0), preferably the sum of n and n1 is 1 (i.e., n is 1 and n1 is 0, or n is 0 and n1 is 1).

[0384] In particular, in equations (B) and (B-1) above, Z 11 and Z 21 All of these groups do not contain a double bond, and the double bond is, for example, a double bond between C and O in -C(O)-, or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 21 It is the same as or different from Z 11 and Z 21 Among them, at least one is a group containing -O-, -NH-, -S-, or -Se-, preferably a group containing -O-, for example, * -CH2O-, * It is -CH2CH2O-, * is a terminal connected to N, and more preferably Z 11 , Z 21 and * -C(X1)-(CH2) n1 -(X) n-The molecular weights are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0385] In particular, in equations (B) and (B-1) above, Z 12 , Z 22 , Z 32 It is selected from one or more methylene groups and -CD2- groups, each independently.

[0386] Z 11 , Z 21 These are -CD2- and -C, respectively, independently. 1~3 Alkylene-(preferably, -C) 1~2 Alkylene-), -OC 1~3 Alkilen * (preferably, -OC) 1~2 Alkilen * ), -SC 1~3 Alkilen * , -NHC 1~3 Alkilen * , -Se-C 1~3 Alkilen * -CH2-OC 1~2 Alkilen * Selected from, * This is the connection point with N, X1 is O or S, X is selected from O, CH2, NH, S, n is 1, n1 is 0, or X1 is O or S, X is O or CH2, n is 1, n1 is 1, or X1 is O or S, n is 0, n1 is 0.

[0387] In particular, in equations (B) and (B-1) above, Z 12 , Z 22 , Z 32 It is selected from one or more methylene groups and -CD2- groups, each independently.

[0388] Z 11 These are independently -CD2-, -CH2-, -CH2CH2-, and -OCH2- * ,-OCH2CH2- * Selected from, * This is the connection point with N, Z 21 It is independently -OCH2CH2- * ,-CH2OCH2CH2- * ,-OCH2CH2CH2- * Selected from, * This is the connection point with N, X1 is O, X is selected from O, CH2, NH, and S, n is 1, and n1 is 0, or X1 is O, X is O or CH2, n is 1, and n1 is 1.

[0389] In particular, in equations (B) and (B-1) above, Z 12 , Z 22 , Z 32 Each is independently selected from the methylene group and -CD2-, Z 11 , Z 21 These are one or more -CD2-, -C, each independently. 1~3 Alkylene-(preferably, -C) 1~2 Alkylene-), -OC 1~3 Alkilen * (preferably, -OC) 1~2 Alkilen * ), -SC 1~3 Alkilen * , -NHC 1~3 Alkilen * , -Se-C 1~3 Alkilen * -CH2-OC 1~2 Alkilen * Selected from, *is the bond with N, X1 is O or S, X is selected from O, CH2, NH, S, the sum of n and n1 is 0, 1, 2, and more preferably Z 21 It is independently -OCH2CH2- * ,-CH2OCH2CH2- * ,-OCH2CH2CH2- * Selected from, * The bond with N is, more preferably, X1 is O, X is selected from O, CH2, NH, and S, and the sum of n and n1 is 1 or 2.

[0390] In particular, in equations (C) and (C-1) above, Z 11 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 31 The groups in the group that do not contain a double bond are * -(CH2) n2 -X2-(CH2) n3 -( * (is the terminal connected to N) is the same as or different from, and more preferably Z 11 ,-(CH2) n2 -X2-(CH2) n3 - and Z31 are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0391] In particular, in equations (C) and (C-1) above, Z 12 , Z 22, Z 32 It is selected from one or more methylene groups and -CD2- groups, each independently. Z 11 These are independently -CD2- and -C 1~3 Alkylene-(preferably, -C) 1~2 Alkylene-), -OC 1~3 Alkilen * (preferably, -OC) 1~2 Alkilen * ), -SC 1~2 Alkilen * , -NHC 1~2 Alkilen * , -Se-C 1~2 Alkilen * -CH2-OC 1~2 Alkilen * Selected from, * This is the connection point with N, Z 31 These are independently -C(O)- and -C1~3 alkylene-C(O)- * ,-OC 1~2 Alkylene-C(O)- * -NHCH2-C(O)- * -SCH2-C(O)- * -CH2-NHC(O)- * , -C 1~2 Alkylene-OC(O)- * , -NH-C(O)- * , -OC(O)- * , -SC(O)- * , -C 1~2 Alkylene-C(S)- * Selected from, * This is the connection point with N, n2 is 2 or 3, n3 is 0, and X2 is O, NH, or S, or n2 is 1 or 2, n3 is 1, and X2 is O, NH, or S, or n2 is 0 or 1, n3 is 0, and X2 is CH2.

[0392] In particular, in equations (C) and (C-1) above, Z 12 , Z 22 , Z 32It is selected from one or more methylene groups and -CD2- groups, each independently. Z 11 These are independently -CD2-, -CH2-, -CH2CH2-, and -OCH2- * ,-OCH2CH2- * Selected from, * This is the connection point with N, Z 31 These are independently -C(O)- and -CH2CH2C(O)- * -CH2C(O)- * -OCH2C(O)- * , -NHC(O)- * , -OC(O)- * , -SC(O)- * Selected from, * This is the connection point with N, n2 is 2 or 3, n3 is 0, and X2 is 0, or n2 is 1 or 2, n3 is 1, and X2 is 0, or n2 is 0 or 1, n3 is 0, and X2 is CH2.

[0393] In particular, in equations (C) and (C-1) above, Z 12 , Z 22 , Z 32 Each of the following groups is independently selected from methylene groups, -CD2-, and Z 11 These are independently -CD2- and -C 1~3 Alkylene-(preferably, -C) 1~2 Alkylene-), -OC 1~3 Alkilen * (preferably, -OC) 1~2 Alkilen * ), -SC 1~2 Alkilen * , -NHC 1~2 Alkilen * , -Se-C 1~2 Alkilen * -CH2-OC 1~2 Alkilen * , Z 31 These are independently -C(O)- and -C 1~3 Alkylene-C(O)- * ,-OC 1~2Alkylene-C(O)- * -NHCH2-C(O)- * -SCH2-C(O)- * -CH2-NHC(O)- * , -C 1~2 Alkylene-OC(O)- * , -NH-C(O)- * , -OC(O)- * , -SC(O)- * , -C 1~2 Alkylene-C(S)- * Selected from, * This is the connection with N, and more preferably Z 11 These are independently -CD2-, -CH2-, -CH2CH2-, and -OCH2CH2- * Selected from, * This is the connection with N, and more preferably Z 31 It is independently -CH2CH2C(O)- * -CH2C(O)- * -OCH2C(O)- * , -NHC(O)- * , -OC(O)- * , -SC(O)- * Selected from, * The bond with N is, more preferably X2 is O, NH, S, Se, and the sum of n2 and n3 is 1, 2, or 3, and more preferably X2 is O, and the sum of n2 and n3 is 2 or 3.

[0394] In particular, in equations (D) and (D-1) above, Z 11 is a group that does not contain a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 teeth * -(CH2) n2 -X2-(CH2) n3 -( * (is the terminal connected to N) is the same as or different from, and more preferably Z 11 -C(X1)-(CH2) n1 -(X) n -and-(CH2)n2 -X2-(CH2) n3 -The molecular weights are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0395] In particular, in equations (D) and (D-1) above, Z 12 , Z 22 , Z 32 It is selected from one or more methylene groups and -CD2- groups, each independently. Z 11 These are independently -CD2- and -C 1~2 Alkylene-,-OC 1~2 Alkilen * , -SC 1~2 Alkilen * , -NHC 1~2 Alkilen * , -Se-C 1~2 Alkilen * -CH2-OC 1~2 Alkilen * Selected from, * This is the connection point with N, n2 is 2 or 3, n3 is 0, and X2 is O, NH, or S, or n2 is 1 or 2, n3 is 1, and X2 is O, NH, or S, or n2 is 0 or 1, n3 is 0, and X2 is CH2, X1 is O or S, X is selected from O, CH2, NH, S, n is 1, n1 is 0, or X1 is O or S, X is O or CH2, n is 1, n1 is 1.

[0396] In particular, in equations (D) and (D-1) above, Z12 , Z 22 , Z 32 It is selected from one or more methylene groups and -CD2- groups, each independently. Z 11 These are independently -CD2-, -CH2-, -CH2CH2-, and -OCH2- * ,-OCH2CH2- * Selected from, * This is the connection point with N, n2 is 2 or 3, n3 is 0, X2 is 0, or n2 is 1 or 2, n3 is 1, X2 is 0, or n2 is 0 or 1, n3 is 0, X2 is CH2, X1 is O, X is selected from O, CH2, NH, and S, n is 1, and n1 is 0, or X1 is O, X is O or CH2, n is 1, and n1 is 1.

[0397] In particular, in equations (D) and (D-1) above, Z 12 , Z 22 , Z 32 It is selected from one or more methylene groups and -CD2- groups, each independently. Z 11 These are independently -CD2-, -CH2-, -CH2CH2-, and -OCH2CH2- * Selected from, * This is the connection point with N, n2 is 2 or 3, n3 is 0, and X2 is O, or n2 is 2, n3 is 1, and X2 is O. X1 is O, X is selected from O, CH2, NH, and S, n is 1, and n1 is 0.

[0398] In particular, in equations (D) and (D-1) above, Z 12 , Z 22 , Z 32 Each is independently selected from the methylene group and -CD2-, Z 11 These are independently -CD2- and -C 1~2 Alkylene-,-OC 1~2 Alkilen * , -SC 1~2 Alkilen *, -NHC 1~2 Alkilen * , -Se-C 1~2 Alkilen * -CH2-OC 1~2 Alkilen * Selected from, * is the bond with N, X2 is O, NH, S, Se, the sum of n2 and n3 is 1, 2, 3, X1 is O or S, X is selected from O, CH2, NH, S, the sum of n and n1 is 0, 1, 2, and more preferably Z 11 These are independently -CD2-, -CH2-, -CH2CH2-, and -OCH2CH2- * Selected from, * The bond with N is, more preferably, X2 is O, the sum of n2 and n3 is 2 or 3, X1 is O, X is selected from O, CH2, NH, and S, and the sum of n and n1 is 1 or 2.

[0399] In one embodiment of the present invention, rings W1, W2, and W3 may each be substituted independently:

[0400] [ka] Selected from, and "may be substituted" means unsubstituted, or one or more independently of deuterium, halogen, -CN, -OH, -NH2, -CHO, C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 This means that the alkyl group is substituted with a substituent selected from the alkyl group.

[0401] In one embodiment of the present invention, rings W1, W2, and W3 may each be substituted independently:

[0402] [ka] Selected from, and "may be substituted" means either unsubstituted or substituted by one or more substituents independently selected from deuterium, fluorine, chlorine, bromine, methyl group, ethyl group, methoxy group, and ethoxy group.

[0403] The present invention further provides compounds represented by the following formulas (B-2), (B-3), (C-2), (C-3), (D-2), and (D-3), or pharmaceutically acceptable salts of said compounds.

[0404] [ka] However, Z in equations (B-2) and (B-3) 11 , Z 21 , Z 12 , Z 22 , Z 32 X, X1, n, n1, rings W1, W2, W3 are as described in formula (B), and Z in formulas (C-2) and (C-3) 11 , Z 31 , Z 12 , Z 22 , Z 32 X2, n2, n3, rings W1, W2, W3 are as described in formula (C) compound, and Z in formulas (D-2) and (D-3) 11 , Z 12 , Z 22 , Z 32 X, X1, X2, n, n1, n2, n3, and rings W1, W2, and W3 are as described in compound (D).

[0405] In particular, in equations (B-2) and (B-3) above, Z 11 and Z 21 All of these groups do not contain a double bond, and the double bond is, for example, a double bond between C and O in -C(O)-, or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 21 It is the same as or different from Z 11 and Z 21Among them, at least one is a group containing -O-, -NH-, -S-, or -Se-, preferably a group containing -O-, for example, * -CH2O-, * It is -CH2CH2O-, * is a terminal connected to N, and more preferably Z 11 , Z 21 and * -C(X1)-(CH2) n1 -(X) n -The molecular weights are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0406] In particular, in equations (C-2) and (C-3) above, Z 11 and Z 31 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 31 The groups in the group that do not contain a double bond are * -(CH2) n2 -X2-(CH2) n3 -( * (is the terminal connected to N) is the same as or different from, and more preferably Z 11 ,-(CH2) n2 -X2-(CH2) n3- and Z31 are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0407] In particular, in equations (D-2) and (D-3) above, Z 11 is a group that does not contain a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 teeth * -(CH2) n2 -X2-(CH2) n3 -( * (is the terminal connected to N) is the same as or different from, and more preferably Z 11 -C(X1)-(CH2) n1 -(X) n -and-(CH2) n2 -X2-(CH2) n3 -The molecular weights are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0408] The present invention further provides compounds represented by the following formulas (E), (E-1), and (F), or pharmaceutically acceptable salts of said compounds.

[0409] [ka] However, L1 and L2 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), formula (III-B), formula (B), formula (C), or formula (D), and X is O, CH2, NH, and R a Deuterium, halogen, -CN, -OH, -NH2, -CHO, C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 It is an alkyl group, where n1 is 0 or 1, m is 0 or 1, and n is 0 or 1, R 23 , R 24 It is selected from one or more atoms, each independently chosen from H and deuterium.

[0410] In particular, in equations (E) and (E-1) above, L1 and L2 are Z 11 and Z 21 It is a group that includes, and Z 11 and Z 21 All of these are groups that do not contain a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 21 It is the same as or different from Z 11 and Z 21 At least one of them * -C(O)-(CH2) n1 -(X) n -( * (is a terminal group linked to N), and more preferably Z 11 , Z21 and -C(O)-(CH2) n1 -(X) n -The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0411] In particular, in equation (F) above, L1 and L2 are Z 11 and Z 21 It is a group that includes, and Z 11 and Z 21 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 21 Those that do not contain double bonds * -(CH2)2-O-( * (is the terminal connected to N) is the same as or different from, and more preferably Z 11 and Z 21 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0412] In one embodiment of the present invention, R a These are fluorine, chlorine, methyl group, ethyl group, methoxy group, and ethoxy group, preferably R a It is fluorine.

[0413] In one embodiment of the present invention, m is 1.

[0414] In one embodiment of the present invention, X is CH2.

[0415] In one embodiment of the present invention, X is selected from O, CH2, NH, and S, n is 1 and n1 is 0, or X is O or CH2, n is 1 and n1 is 1.

[0416] In one embodiment of the present invention, the sum of n and n1 is 0, 1, or 2, preferably the sum of n and n1 is 1 or 2 (i.e., n is 1 and n1 is 0, or n is 0 and n1 is 1, or n is 1 and n1 is 1, or n is 0 and n1 is 2, or n is 2 and n1 is 0), preferably the sum of n and n1 is 1 (i.e., n is 1 and n1 is 0, or n is 0 and n1 is 1).

[0417] In particular, in equations (E), (E-1), and (F) above, R a The group is fluorine, chlorine, methyl group, ethyl group, methoxy group, or ethoxy group, m is 1, X is selected from O, CH2, NH, and S, and the sum of n and n1 is 0, 1, or 2.

[0418] More preferably, R a is fluorine or a methoxy group, m is 1, X is selected from O, CH2, NH, and S, and the sum of n and n1 is 1 or 2.

[0419] In one embodiment of the present invention, L1 is

[0420] [ka] And L2 is

[0421] [ka] And, * The symbol represents the bond with N, and rings W1 and W2 are independent of each other.

[0422] [ka] Selected from, the phenyl group is one or more halogens, each independently C 1~3 It may be substituted with substituents selected from alkoxy groups (fluorine and methoxy groups are preferred).

[0423] In one embodiment of the present invention, Z 11 , Z 12 , Z 21 , Z 22 These are each independently of -C 1~2 Alkylene-,-OC 1~3 Alkylene-,-NH-C 1~2 Alkylene-, -SC 1~2 Alkylene-,-C 1~2 Alkylene-OC 1~2 Alkylene-,-C 1~2 Alkylene-C(O)-,-OC 1~2 Alkylene-C(O)-, -C 1~2 Alkylene-NH-C(O)-,-C 1~2 Alkylene-OC(O)-,-NH-C(O)-,-NH-C 1~2 It is selected from alkylenes -C(O)-, -OC(O)-, and -SC(O)-.

[0424] In one embodiment of the present invention, Z 11 , Z 12 , Z 21, Z 22 These are, independently, a methylene group and an ethylene group,

[0425] [ka] They are selected from among them.

[0426] In one embodiment of the present invention, L1 and L2 are independent of each other.

[0427] [ka] Selected from, * This represents the connection point with N.

[0428] The present invention further provides compounds represented by the following formulas (E-2), (E-3), (E-4), (F-1), and (F-2), or pharmaceutically acceptable salts of said compounds.

[0429] [ka] Here, L1, L2, X, m, n, n1, R in equations (E-2), (E-3), and (E-4) are a This is as described for the compounds of formula (E) and formula (E-1), and R in formula (E-4). 23 , R 24 The values ​​of L1 and L2 in formulas (F-1) and (F-2) are as described in formula (F).

[0430] In particular, in equations (E-2), (E-3), and (E-4) described above, L1 and L2 are Z 11 and Z 21 It is a group that includes, and Z 11 and Z 21All of these are groups that do not contain a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 21 It is the same as or different from Z 11 and Z 21 At least one of them * -C(O)-(CH2) n1 -(X) n -( * (is a terminal group linked to N), and more preferably Z 11 , Z 21 and -C(O)-(CH2) n1 -(X) n -The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0431] In particular, in equations (F-1) and (F-2) described above, L1 and L2 are Z 11 and Z 21 It is a group that includes, and Z 11 and Z 21 Among these, there is only one group containing a double bond, and the double bond is, for example, a double bond between C and O in -C(O)- or a double bond between C and S in -C(S)-, and more preferably Z 11 and Z 21 Those that do not contain double bonds * -(CH2)2-O-( *(is the terminal connected to N) is the same as or different from, and more preferably Z 11 and Z 21 The molecular weights of each are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0432] The present invention further provides a compound represented by the following formula (G) or a pharmaceutically acceptable salt of said compound,

[0433] [ka] However, X, X1, X2, n, n1, n2, n3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), formula (III-B), formula (B), formula (C), or formula (D), m is independently 0 or 1, n4 is 0, 1, 2, or 3, X3 is O, S, CH2, NH, or X3 is O, S, CH2, NH, CD2, R a Deuterium, halogen, -CN, -OH, -NH2, -CHO, C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 It is an alkyl group.

[0434] In one embodiment of the present invention, R aThe group is fluorine, chlorine, methyl group, ethyl group, methoxy group, or ethoxy group, with fluorine and methoxy group being preferred.

[0435] In one embodiment of the present invention, m is 1.

[0436] In one embodiment of the present invention, n4 is 0, 1, or 2, preferably 0 or 1, and more preferably 0.

[0437] In one embodiment of the present invention, X3 is O, CH2, or X3 is O, CH2, CD2.

[0438] In one embodiment of the present invention, X3 is O and n4 is 2, or X3 is CH2 and n4 is 0 or 1, or X3 is CH2, CD2 and n4 is 0 or 1, and more preferably X3 is CH2, CD2 and n4 is 0.

[0439] In particular, in equation (G) above, R a The group is fluorine, chlorine, methyl group, ethyl group, methoxy group, or ethoxy group, m is 1, X2 is O, NH, S, or Se, the sum of n2 and n3 is 1, 2, or 3, X1 is O or S, X is selected from O, CH2, NH, or S, and the sum of n and n1 is 0, 1, or 2. X3 is O and n4 is 2, or X3 is CH2, CD2 and n4 is 0 or 1.

[0440] More preferably, R a is fluorine, chlorine, or methoxy group, m is 1, X2 is O, the sum of n2 and n3 is 2 or 3, X1 is O, X is selected from O, CH2, NH, and S, and the sum of n and n1 is 1 or 2. X3 is O and n4 is 2, or X3 is CH2, CD2 and n4 is 0 or 1.

[0441] In particular, in equation (G) above, R a These are fluorine, chlorine, methyl group, ethyl group, methoxy group, and ethoxy group, and m is 1. X3 is O and n4 is 2, or X3 is CH2, CD2 and n4 is 0 or 1. n2 is 2 or 3, n3 is 0, and X2 is O, NH, or S, or n2 is 1 or 2, n3 is 1, and X2 is O, NH, or S, or n2 is 0 or 1, n3 is 0, and X2 is CH2, X1 is O or S, X is selected from O, CH2, NH, S, n is 1, n1 is 0, or X1 is O or S, X is O or CH2, n is 1, n1 is 1.

[0442] In particular, in equation (G) above, R a The groups are fluorine, chlorine, and methoxy, and m is 1. X3 is O and n4 is 2, or X3 is CH2, CD2 and n4 is 0 or 1. n2 is 2 or 3, n3 is 0, X2 is 0, or n2 is 1 or 2, n3 is 1, X2 is 0, or n2 is 0 or 1, n3 is 0, X2 is CH2, X1 is O, X is selected from O, CH2, NH, and S, n is 1, and n1 is 0, or X1 is O, X is O or CH2, n is 1, and n1 is 1.

[0443] The present invention further provides compounds represented by the following formulas (G-1) and (G-2), or pharmaceutically acceptable salts of said compounds.

[0444] [ka] However, X, X1, X2, X3, n, n1, n2, n3, n4, m, R a This is as described in compound (G).

[0445] The present invention further provides compounds represented by the following formulas (G-3) and (G-4), or pharmaceutically acceptable salts of said compounds,

[0446] [ka] However, X, X1, X2, X3, n, n1, n2, n3, n4, m, R a This is as described in the compound of formula (G), and R 19 , R 20 , R 21 , R 22 , R 23 , R 24 Each of these is independently selected from H or deuterium.

[0447] In particular, in equations (G), (G-1), (G-2), (G-3), and (G-4) mentioned above, * -(CH2) n4 -X3-, * -(CH2) n2 -X2-(CH2) n3 -, and * -C(X1)-(CH2) n1 -(X) n -( * The atoms (where is the terminal linked to N) are the same or different from each other, and their molecular weights are independently 14.0 to 107.1, preferably 14.0 to 60, preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60, and more preferably Z 11 , Z 21 and Z 31 The selected group is -CH2-, -CD2-, -CH2CH2-, -CD2CH2-, -C(O)-, -CH2C(O)-, -NHC(O)-, -OC(O)-, -CH2CH2O-, -OCH2C(O)-, -CH2OC(O)-, -CH2CH2CH2O-, and -SC(O)-.

[0448] The present invention further provides a compound represented by the following formula (H) or a pharmaceutically acceptable salt of said compound,

[0449] [ka] However, X, X1, X2, n, n1, n2, n3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), formula (III), formula (III-1), formula (III-B), formula (B), formula (C), formula (D), or formula (G), m is independently 0 or 1, n5 is 1, 2, 3, or 4, and RA is deuterium, halogen, -CN, -OH, -NH2, -CHO, C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -N(C 1~3 Alkyl)2,-NH(C 1~3 Alkyl), -C(O)C 1~3 Selected from alkyl groups.

[0450] In one embodiment of the present invention, R a These are fluorine, chlorine, methyl group, ethyl group, methoxy group, and ethoxy group, preferably R a These are fluorine and methoxy groups.

[0451] In one embodiment of the present invention, m is 1.

[0452] In one embodiment of the present invention, n5 is 1, 2, or 3, preferably 1 or 2, and more preferably 1.

[0453] The present invention further provides compounds represented by the following formulas (H-1) and (H-2), or pharmaceutically acceptable salts of said compounds.

[0454] [ka] However, X, X1, X2, n, n1, n2, n3, n5, m, R a This is as described in formula (H) compound.

[0455] The present invention further provides compounds represented by the following formulas (H-3) and (H-4), or pharmaceutically acceptable salts of said compounds.

[0456] [ka] However, X, X1, X2, n, n1, n2, n3, n5, m, R a This is as described in formula (H) compound, and R 13 , R 14 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 Each of these is independently selected from either H or deuterium.

[0457] The present invention further provides compounds having the structures represented by formula (Dc), formula (Df), formula (Dg), and formula (Dh), or pharmaceutically acceptable salts of said compounds.

[0458] [ka] However, Z 11 , Z 12 , Z 22 , Z 32 X, X1, X2, n, n1, n2, n3, rings W1, W2, W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), and formula (D), and Pg 1 Pg 2 These are protecting groups. Preferably, Pg 1 The group is independently selected from the t-butyl group, methyl group, and benzyl group, and Pg 2 The group is independently selected from t-butoxycarbonyl group (Boc), 9-fluorenylmethoxycarbonyl group (FMOC), and benzyloxycarbonyl group (Cbz), with Boc being preferred.

[0459] Based on common sense in this field, the above preferred conditions can be arbitrarily combined to obtain each preferred embodiment of the present invention.

[0460] In one embodiment of the present invention, the compound of the present invention or a pharmaceutically acceptable salt of the said compound is selected from the following:

[0461] Table 1-1

[0462] Table 1-2

[0463] Table 1-3

[0464] Table 1-4

[0465] Table 1-5

[0466] Table 1-6

[0467] Table 1-7

[0468] Table 1-8

[0469] Table 1-9

[0470] Table 1-10

[0471] Table 1-11

[0472] Table 1-12

[0473] Table 1-13

[0474] Table 1-14

[0475] Table 1-15

[0476] Table 1-16

[0477] Table 1-17

[0478] Table 1-18

[0479] Table 1-19

[0480] Table 1-20

[0481] Table 1-21

[0482] Table 1-22

[0483] Table 1-23

[0484] Table 1-24

[0485] Table 1-25

[0486] Table 1-26

[0487] Table 1-27

[0488] Table 1-28

[0489] Table 1-29

[0490] Table 1-30

[0491] Table 1-31

[0492] [Table 1-32]

[0493] In one embodiment of the present invention, the compound of the present invention or a pharmaceutically acceptable salt of the said compound is selected from the following:

[0494] [Table 2-1]

[0495] [Table 2-2]

[0496] [Table 2-3]

[0497] [Table 2-4]

[0498] [Table 2-5]

[0499] [Table 2-6]

[0500] [Table 2-7]

[0501] [Table 2-8]

[0502] Table 2-9

[0503] Table 2-10

[0504] Table 2-11

[0505] Table 2-12

[0506] Table 2-13

[0507] Table 2-14

[0508] Table 2-15

[0509] Table 2-16

[0510] Table 2-17

[0511] Table 2-18

[0512] [Table 2-19]

[0513] [Table 2-20]

[0514] In one embodiment of the present invention, the compound is 3-(3-(2-((3-(2-carboxyl-2-(pyrrolidine-3-yl)ethyl)benzyl)(2-(3-(2-carboxyl-2-(pyrrolidine-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-(pyrrolidine-3-yl)propionic acid or a pharmaceutically acceptable salt of the compound:

[0515] [ka]

[0516] In one embodiment of the present invention, the compound is 3-(3-(2-((3-(2-carboxyl-2-(pyrrolidine-3-yl)ethyl)benzyl)(2-(3-(2-carboxyl-2-(pyrrolidine-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-(pyrrolidine-3-yl)propionic acid or a pharmaceutically acceptable salt of the compound has stereoisomer form:

[0517] [ka]

[0518] In one embodiment of the present invention, the compound is (S)-3-(3-(2-((3-((S)-2-carboxyl-2-(pyrrolidine-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxyl-2-(pyrrolidine-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-(pyrrolidine-3-yl)propionic acid or a pharmaceutically acceptable salt of the compound:

[0519] [ka]

[0520] In one embodiment of the present invention, the compound is (S)-3-(3-(2-((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid or a pharmaceutically acceptable salt of the compound:

[0521] [ka]

[0522] In one embodiment of the present invention, the compound is (S)-3-(3-(2-((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid or a deuterated derivative of the compound or a pharmaceutically acceptable salt of the compound:

[0523] [ka]

[0524] In one embodiment of the present invention, the compound is (2S,2'S)-3,3'-(((((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)acetyl)azandiyl)bis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) or a deuterated derivative of the compound or a pharmaceutically acceptable salt of the compound:

[0525] [ka]

[0526] In one embodiment of the present invention, the compound is (S)-3-(3-(2-((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)carbonyl)amino)ethoxy)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid, or a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the compound:

[0527] [ka]

[0528] In one embodiment of the present invention, the compound of the present invention or a pharmaceutically acceptable salt of the said compound is selected from the following:

[0529] [ka] however, * This is the connection point with N.

[0530] [Table 3-1]

[0531] [Table 3-2]

[0532] The present invention relates to the preparation of formulas (I), (I-1-P1), (I-1-P2), (I-1-P3), (I-1-P4), (I-2), (I-3), (I'-1), (I'-2), (I'-3), (II), (II-A), (II-A'), (II-B), (II-B'), (II-C), (II-C'), (III), (III-1), (III-2), (III-1-1), (III-2-1), (III-A), (III-A'), (III-B), (III-B'), (III-B'-1), (III-C), (III-C'), (III-D), (III-D'), and (I II-E), Formula (III-E'), Formula (IV), Formula (A), Formula (B), Formula (B-1), Formula (C), Formula (C-1), Formula (D), Formula (D-1), Formula (B-2), Formula (B-3), Formula (C-2), Formula (C-3), Formula (D-2), Formula (D-3), Formula (E), Formula (F), Formula (E-1), Formula (E-2), Formula (E-3), Formula (E-4) The present invention further provides methods for obtaining compounds represented by formulas (F-1), (F-2), (G), (G-1), (G-2), (G-3), (G-4), (H), (H-1), (H-2), (H-3), (H-4), (Dc), (Df), (Dg), and (Dh), or pharmaceutically acceptable salts of said compounds.

[0533] The compounds of the above general formula can be prepared by various methods, including, but not limited to, the following methods.

[0534] Appearance 1:

[0535] [ka]

[0536] However, Y1 and Y2 are one or more halogens (e.g., fluorine, chlorine, bromine), preferably bromine; Y is independently a halogen (e.g., fluorine, chlorine, bromine) or an oxo group (an oxo group refers to =O in -C(O)H), preferably bromine or an oxo group (an oxo group refers to =O in -C(O)H); the definition of R' is as described in the formula (II) compound; and W1, W2, and W3 are as described in the formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4) compounds. Under the action of a base, compound (a) and compound (b) react at room temperature for 16 hours to obtain compound (c). Compound (c) undergoes hydrolysis of its chiral auxiliary under basic conditions of hydrogen peroxide, followed by esterification to obtain intermediate (d). Intercalation of carbon at atmospheric pressure yields intermediate (e). Reduction with DIBAL-H yields intermediate (f). Reductive amination of intermediate (f) in a tetrahydrofuran solution of ammonia yields intermediate (g). Further reductive amination of intermediate (i) or substitution reactions are carried out to obtain intermediate (i). Deprotection under acidic conditions yields compound (II-A'). Substitution or reductive amination of intermediate (g) and intermediate (f) yields intermediate (j). Deprotection under acidic conditions yields compound (III-C').

[0537] Appearance 2:

[0538] [ka]

[0539] Y3 is independently a halogen (e.g., fluorine, chlorine, bromine) or an oxo group (where oxo refers to =O in -C(O)H), preferably bromine or an oxo group (where oxo refers to =O in -C(O)H), and L3 is as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4).

[0540] Compound (k) is synthesized under the conditions of patent CN114008021A, and compound (m) is obtained by reductive amination or substitution reaction of compound (k) and compound (l), and then deprotected under acidic conditions to obtain the compound of formula (III-A').

[0541] Appearance 3:

[0542] [ka]

[0543] However, W1, W2, and W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), and formula (I-1-P4). Compound (p) is reduced and aminated with a tetrahydrofuran solution of ammonia to obtain compound (q), and compound (q) and compound (s) are further reduced and aminated to obtain intermediate (t). Intermediate (t) is then deprotected under acidic conditions to obtain the compound of formula (III-D').

[0544] Appearance 4:

[0545] [ka]

[0546] However, Z 11 , Z 12 , Z 22 , Z 32 X, X1, X2, n, n1, n2, n3, rings W1, W2, W3 are as described in the compounds of formula (I), formula (I-1-P1), formula (I-1-P2), formula (I-1-P3), formula (I-1-P4), and formula (D), and Pg 1 Pg 2 These are protecting groups. Preferably, Pg 1 Each is independently selected from the t-butyl group, methyl group, and benzyl group, and Pg 2Each of these groups is independently selected from t-butoxycarbonyl group (Boc), 9-fluorenylmethoxycarbonyl group (FMOC), and benzyloxycarbonyl group (Cbz), with Boc being preferred.

[0547] The present invention further provides pharmaceutical compositions comprising a compound according to the present invention or a pharmaceutically acceptable salt of said compound.

[0548] The present invention further provides pharmaceutical compositions comprising the compound according to the present invention or a pharmaceutically acceptable salt of the said compound and a pharmaceutically acceptable auxiliary material.

[0549] In the above-mentioned pharmaceutical composition, the compound according to the present invention or a pharmaceutically acceptable salt of said compound accounts for 0.1 to 99.9% by weight of the pharmaceutical composition, for example, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight, 99% by weight, 99.5% by weight, or any combination of any two of the above point values, with the remainder being a pharmaceutically acceptable auxiliary material.

[0550] In some embodiments of the present invention, the pharmaceutical composition is an inhibitor of Lp(a) assembly.

[0551] In some embodiments of the present invention, the pharmaceutical composition is used as a drug for treating cardiovascular disease (CVD).

[0552] The administration of the compounds shown in the present invention or pharmaceutically acceptable salts thereof can be carried out by providing any acceptable method of administration of a drug of similar use, in pure form or in the form of a suitable pharmaceutical composition. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable auxiliary materials. The pharmaceutical compositions of the present invention can be prepared as solid, semi-solid, liquid, or gas formulations. Generally, the pharmaceutical compositions can be prepared using conventional excipients in the pharmaceutical field and conventional preparation methods.

[0553] The present invention further provides the use of the compound according to the present invention or a pharmaceutically acceptable salt of said compound in the preparation of agents for the prevention and / or treatment of cardiovascular disease (CVD).

[0554] One embodiment of the present invention provides for the use of a compound shown in the present invention or a pharmaceutically acceptable salt of said compound in the preparation of a drug for preventing and / or treating a disease or condition associated with an elevated Lp(a) plasma level.

[0555] In one embodiment of the present invention, the disease or condition associated with an increase in Lp(a) plasma level is a cardiovascular disease (CVD), and the cardiovascular disease (CVD) includes, but is not limited to, atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases. The ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0556] The term "elevated Lp(a) plasma level" means that the plasma level is above normal. In humans, "elevated Lp(a) plasma level" means a plasma level of approximately 30 mg / dL or higher.

[0557] In one embodiment of the present invention, in humans, "elevated Lp(a) plasma level" refers to a plasma level of approximately 50 mg / dL or higher. The compounds described in this paper can be used in therapies to reduce Lp(a) plasma levels.

[0558] The present invention further provides the use of the compound according to the present invention or a pharmaceutically acceptable salt of said compound in the preparation of agents for preventing and / or treating diseases mediated by Lp(a).

[0559] Furthermore, in the use of the present invention, the disease mediated by Lp(a) is cardiovascular disease (CVD).

[0560] Furthermore, in the use of the present invention, the cardiovascular disease (CVD) is atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, atrial fibrillation-related diseases, and the ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0561] The present invention further provides a method for preventing and / or treating cardiovascular disease, comprising administering to a patient a therapeutically effective amount of a compound shown in the present invention or a pharmaceutically acceptable salt of said compound or a pharmaceutical composition according to the present invention.

[0562] One embodiment of the present invention provides a method for preventing and / or treating a disease or condition associated with elevated Lp(a) plasma levels, comprising administering to a patient a therapeutically effective amount of a compound shown in the present invention or a pharmaceutically acceptable salt of said compound or a pharmaceutical composition according to the present invention. In one embodiment of the present invention, the disease or condition associated with elevated Lp(a) plasma levels is a cardiovascular disease (CVD), which includes, but is not limited to, atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases. ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0563] The present invention further provides a method for preventing and / or treating a disease mediated by Lp(a), comprising administering to a patient a therapeutically effective amount of a compound shown in the present invention or a pharmaceutically acceptable salt of said compound or a pharmaceutical composition according to the present invention, preferably the disease mediated by Lp(a) is a cardiovascular disease (CVD), said cardiovascular disease (CVD) includes atherosclerotic cardiovascular disease (ASCVD), coronary stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, atrial fibrillation-related diseases, said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, ischemic stroke-related diseases.

[0564] Furthermore, in use or methods according to the present invention, the compounds shown in the present invention or pharmaceutically acceptable salts thereof may be administered in combination with other compounds for treating or preventing diseases mediated by Lp(a), such as cardiovascular diseases (CVD).

[0565] The present invention further provides compounds according to the present invention, or pharmaceutically acceptable salts of said compounds, or pharmaceutical compositions according to the present invention for preventing and / or treating cardiovascular diseases.

[0566] The present invention further provides the use of the indicated compounds or pharmaceutically acceptable salts of said compounds or pharmaceutical compositions according to the present invention as pharmaceuticals.

[0567] The present invention provides the use of a indicated compound or a pharmaceutically acceptable salt of said compound or a pharmaceutical composition according to the present invention in the prevention and / or treatment of cardiovascular disease. The present invention provides the use of a indicated compound or a pharmaceutically acceptable salt of said compound or a pharmaceutical composition according to the present invention in the prevention and / or treatment of diseases or conditions associated with elevated Lp(a) plasma levels. In one embodiment of the present invention, the disease or condition associated with elevated Lp(a) plasma levels is a cardiovascular disease (CVD), which includes, but is not limited to, atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases. ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0568] The present invention further provides the use of the indicated compounds or pharmaceutically acceptable salts of said compounds or pharmaceutical compositions according to the present invention in the prevention and / or treatment of Lp(a)-mediated diseases, preferably said Lp(a)-mediated diseases being cardiovascular diseases (CVD), more preferably said cardiovascular diseases (CVD) being atherosclerotic cardiovascular diseases (ASCVD), coronary stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, atrial fibrillation-related diseases, and said ASCVD being peripheral vascular diseases, peripheral artery-related diseases, coronary heart diseases, ischemic stroke, ischemic stroke-related diseases.

[0569] One embodiment of the present invention provides a compound or a pharmaceutically acceptable salt of the compound or a pharmaceutical composition according to the present invention for preventing and / or treating a disease or condition associated with elevated Lp(a) plasma levels. In one embodiment of the present invention, the disease or condition associated with elevated Lp(a) plasma levels is a cardiovascular disease (CVD), which includes, but is not limited to, atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases. ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0570] In a further embodiment, the present application provides compounds or pharmaceutically acceptable salts of such compounds or pharmaceutical compositions according to the present invention for preventing and / or treating diseases mediated by Lp(a), wherein the diseases mediated by Lp(a) are preferably cardiovascular diseases (CVD), and more preferably, the cardiovascular diseases (CVD) are atherosclerotic cardiovascular diseases (ASCVD), coronary stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, atrial fibrillation-related diseases, and the ASCVD includes peripheral vascular diseases, peripheral artery-related diseases, coronary heart diseases, ischemic stroke, and ischemic stroke-related diseases.

[0571] The present invention provides for the use of the compounds shown in this invention, or pharmaceutically acceptable salts thereof, in combination with other compounds for the prevention and / or treatment of cardiovascular disease, in the preparation of agents for the prevention and / or treatment of cardiovascular disease.

[0572] In one embodiment of the present invention, the cardiovascular disease is a disease or condition associated with an increase in Lp(a) plasma levels.

[0573] In one embodiment of the present invention, the disease or condition associated with the elevation of the Lp(a) plasma level is a cardiovascular disease (CVD), and the cardiovascular disease (CVD) includes, but is not limited to, atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases. The ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0574] The present invention provides for the prevention and / or treatment of cardiovascular diseases by using a compound shown in the present invention or a pharmaceutically acceptable salt of said compound in combination with other compounds. Furthermore, said other compounds are used to prevent and / or treat cardiovascular diseases. Furthermore, said cardiovascular diseases are diseases or conditions associated with elevated Lp(a) plasma levels. Furthermore, said diseases or conditions associated with elevated Lp(a) plasma levels include, but are not limited to, atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases. ASCVD includes peripheral vascular diseases, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0575] The compounds shown in this invention or pharmaceutically acceptable salts thereof are administered together with the treatment method. In some embodiments, the treatment method may be, but is not limited to, Lp(a) plasma replacement therapy. The drugs or therapies may be administered co-administered or concurrently. The drugs or therapies may be administered sequentially or later.

[0576] The present invention further provides pharmaceutical compositions, or pharmaceutically acceptable salts of said compounds, and other compounds for treating or preventing diseases mediated by Lp(a), preferably such that the diseases mediated by Lp(a) are, for example, cardiovascular diseases (CVD).

[0577] When the compound of the present invention or a pharmaceutically acceptable salt of said compound is administered in combination with other agents for treating cardiovascular disease (CVD), the compound of the present invention or its medicinal salt can provide a more effective treatment for cardiovascular-related diseases.

[0578] definition The terms “optional,” “optional,” “preferably,” or “optional” mean that the events or circumstances described later may occur but do not need to occur, and the descriptions include both cases where such events or circumstances occur and cases where such events or circumstances do not occur.

[0579] In "may be substituted by one or more substituents independently selected from...", "multiple" means 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 1, 2, 3, or 4, and more preferably 1 or 2.

[0580] When describing molecular weight using "approximately," "approximately" refers to rounding to the nearest whole number.

[0581] Unless otherwise specified, the term "alkyl group" refers to a monovalent saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1~10 Alkyl), more preferably containing 1 to 8 carbon atoms (C 1~8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C 1~6 Alkyl), for example, "C 1~6The term "alkyl group" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, s-butyl group, n-pentyl group, neopentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, n-heptyl group, n-octyl group, etc.

[0582] Unless otherwise specified, the term "alkylene group" refers to a monovalent saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1~10 alkylene group), more preferably containing 1 to 8 carbon atoms (C 1~8 alkylene group), even more preferably containing 1 to 6 carbon atoms (i.e., C 1~6 alkylene group). For example, the term "C<X 1~6 alkylene group" means that the group is an alkylene group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methylene group, ethylene group, n-propylene group, n-pentylene group, n-hexylene group, <00X7891><00X7892><00X7893><00X7894>

Chemical formula

[0585] Unless otherwise specified, the term "alkynyl group" refers to an unsaturated aliphatic hydrocarbon group having at least one triple bond in a straight or branched chain composed of carbon atoms and hydrogen atoms. An alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2~10 Alkynyl group), more preferably containing 2 to 8 carbon atoms (C 2~8 Alkynyl group), more preferably containing 2 to 6 carbon atoms (i.e., C 2~6 Alkynyl group), containing 2 to 5 carbon atoms (i.e., C 2~5 Alkynyl group), containing 2 to 4 carbon atoms (i.e., C 2~4 Alkynyl group), containing 2-3 carbon atoms (i.e., C 2~3 An alkynyl group) contains two carbon atoms (i.e., a C2 alkynyl group), for example, "C 2~6 An "alkynyl group" means that the group is an alkynyl group and has between 2 and 6 carbon atoms on its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-exclusive examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl groups.

[0586] Unless otherwise specified, the term "cycloalkyl group" refers to a monocyclic, bicyclic, or polycyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3 to 14 carbon atoms (i.e., C 3~14 Cycloalkyl), preferably containing 4 to 14 carbon atoms (i.e., C 4~14 Cycloalkyl), preferably containing 5 to 14 carbon atoms (i.e., C 5~14 Cycloalkyl), more preferably containing 6 to 14 carbon atoms (C 6~14 Cycloalkyl), more preferably containing 6 to 12 carbon atoms (C 6~12 (Cycloalkyl). Examples include, but are not limited to, cyclohexyl groups and spiro[3.5]nonyl groups.

[0587] Unless otherwise specified, the term "oxaalkyl group" refers to an alkyl residue in which one or more carbon atoms (and associated hydrogen atoms) are substituted with oxygen, such as "alkoxy group" or "alkoxyalkyl group." For example, the C3 oxyalkylene group is -OC 1~3 This includes alkoxy groups, -CH2OCH2CH3, -CH2CH2OCH3, etc. Examples include methoxy groups, ethoxy groups, propoxy groups, methoxypropyl groups, etc. The term oxaalkyl group is understood in this field [see Nomenclature and Index of Chemicals for Chemical Extraction, published by the American Chemical Society, not limited to 196, 127(a)], that is, it refers to compounds in which the oxygen is bonded to an adjacent atom by a single bond (forming an ether bond), and does not refer to the double bond oxygen found in carbonyl groups. The terms "thioalkyl group" and "selenoalkyl group" are similar to "oxaalkyl group". The term "azaalkyl group" refers to the atomic groups "NH" and "-N(C) 1~3 This refers to alkyl groups containing "-", for example, the C3 azaalkylene group includes cases such as -NHCH2CH2CH3, -CH2NHCH2CH3, -CH2CH2NHCH3, and -CH2CH2N(CH3)CH3.

[0588] "Alkoxy group" means an -O-alkyl group, and the definition of alkyl group is the same as above, that is, it contains 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms (specifically, 1, 2, 3, 4, 5, or 6). Typical examples include, but are not limited to, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, 1-methylpropoxy group, 2-methylpropoxy group, t-butoxy group, pentoxy group, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropoxy group, 1-ethylpropoxy group, etc.

[0589] Unless otherwise specified, the terms "halogen" or "halogenation" refer to F, Cl, Br, and I.

[0590] Unless otherwise specified, the term “heterocyclic” or “heterocyclic group” refers to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituents, which have a non-aromatic structure and contain 3 to 20 ring atoms, where 1, 2, 3 or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, they contain 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. There are preferably 1 to 4 heteroatoms, and more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, and pyranyl groups. Bicyclic or polycyclic heterocyclic groups include heterocyclic groups of spiro rings, fused rings, and bridging rings.

[0591] Unless otherwise specified, the term "aryl group" refers to monocyclic, bicyclic, and tricyclic aromatic carbocyclic systems containing 6 to 16 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably containing 6 to 10 carbon atoms. The term "aryl group" can be used interchangeably with the term "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, or pyrenyl groups.

[0592] Unless otherwise specified, the term "heteroaryl group" refers to an aromatic monocyclic, bicyclic, or polycyclic system containing a 5-16 membered structure, or a 5-14 membered structure, a 5-12 membered structure, a 5-10 membered structure, a 5-8 membered structure, or a 5-6 membered structure, where one, two, three or more ring atoms are heteroatoms, and the remaining atoms are carbon, with the heteroatoms independently selected from O, N, or S, and preferably the number of heteroatoms being one, two, or three. A polycyclic heteroaryl group is a condensed heteroaryl group. Examples of heteroaryl groups include furanyl group, thienyl group, oxazolyl group, thiazolyl group, isoxazolyl group, oxadiazolyl group, thiadiazolyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyridyl group, pyrazinyl group, pyridadinyl group, thiodiazolyl group, triazinyl group, phthalazinyl group, quinolinyl group, isoquinolinyl group, pteridinyl group, prinyl group, indolyl group, isoindolyl group, indazolyl group, benzofuranyl group, and benzothienyl group. This includes, but is not limited to, benzopyridyl groups, benzopyridyl groups, benzopyradinyl groups, benzimidazolyl groups, benzophthalazinyl groups, pyrrolo[2,3-b]pyridyl groups, imidazo[1,2-a]pyridyl groups, pyrazolo[1,5-a]pyridyl groups, pyrazolo[1,5-a]pyridyl groups, imidazo[1,2-b]pyridazinyl groups, [1,2,4]triazolo[4,3-b]pyridazinyl groups, [1,2,4]triazolo[1,5-a]pyridyl groups, and [1,2,4]triazolo[1,5-a]pyridyl groups.

[0593] Unless otherwise specified, the term "condensed heteroaryl group" refers to an aromatic ring system formed by two or more cyclic structures sharing two adjacent atoms with each other, wherein each ring in the condensed heteroaryl group is an unsaturated aromatic ring and may contain 5 to 20 ring atoms, preferably 6 to 14 ring atoms, more preferably 7 to 10 ring atoms, and among them 1 to 4 ring heteroatoms, preferably 1 to 3 (i.e., 1, 2, or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O, and S. Condensed heteroaryl groups include bicyclic, tricyclic, tetracyclic, or polycyclic condensed heteroaryl groups, preferably bicyclic, tricyclic, or tetracyclic condensed heteroaryl groups, more preferably bicyclic or tricyclic condensed heteroaryl groups. Exemplary examples of condensed heteroaryl groups are:

[0594] [ka] This includes (but is not limited to) the following.

[0595] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within the bounds of reasonable medical judgment, does not cause excessive toxicity, irritation, or allergic reactions when applied to the tissues of mammals, particularly humans, and that has a reasonable benefit / risk ratio. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in their respective fields. The salt may be prepared in situ during the final separation and purification period of the compound of the present invention, or it may be prepared alone by reacting a free base or free acid with a suitable reagent.

[0596] Unless otherwise specified, the compounds and pharmaceutically acceptable salts of the present invention further include their "stereoisomers." The term "stereoisomer" refers to a compound having the same chemical structure but with different arrangements of atoms or groups in space. Stereoiomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atrop isomers, etc. Any mixture of stereoisomers obtained can be separated into pure or essentially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. The compounds and pharmaceutically acceptable salts described herein may contain one or more chiral (i.e., asymmetric) centers. Where a structure or chemical name in this specification does not represent chirality, the structure or name is intended to include any single stereoisomer corresponding to the structure or name (i.e., any single chiral isomer) and any mixture of stereoisomers (e.g., a racemate). In some embodiments, a single stereoisomer is obtained by separating it from a mixture of isomers (e.g., a racemate) by, for example, using chiral dromatography separation. In other embodiments, a single stereoisomer is obtained by, for example, direct synthesis from chiral starting materials.

[0597] Certain enantiomers of the compounds of the present invention may be more active than other enantiomers of the same compound. In one embodiment, the compound or a pharmaceutically acceptable salt thereof has a single enantiomer excess (%ee) of ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%. On the other hand, the single enantiomer exists with an enantiomer excess (%ee) of ≥99%.

[0598] Certain diastereomers of the compounds of the present invention may be more active than other diastereomers of the same compound. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a single diastereomer having a diastereomer excess (%de) of ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%. Alternatively, the diastereomer excess (%de) of a single diastereomer is ≥99%.

[0599] Unless otherwise specified, the compounds and pharmaceutically acceptable salts of the present invention further include their “tautomers.” The term “tautomer” refers to structural isomers that can be interconverted by low energy barriers having different energies. When tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include interconversions that occur by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur by rearrangement of several bonding electrons.

[0600] Unless otherwise specified, the compounds and pharmaceutically acceptable salts of the present invention further include their “isotope derivatives.” The term “isotope derivative” means that the compounds of the present invention may exist in an isotope-labeled or isotope-rich form, and that they contain one or more atoms whose atomic weight or mass number differs from the atomic weight or mass number of the largest amount of atom found in nature. The isotopes may be radioactive or non-radioactive. The isotopes commonly used as isotope labels are hydrogen isotopes. 2 H and 3 H, carbon isotope 13 C and 14 C, chlorine isotope 35 Cl and 37 Cl, fluorine isotope 18 F, iodine isotope 123 I and 125 I, Nitrogen Isotopes 13 N and 15 N, oxygen isotope 15 O, 17O, 18 O, and sulfur isotopes 35 It is S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, 3 H and 13 C is more widely used because it is easy to label and detect. Several heavier isotopes, such as deuterium ( 2 Substitution of H) enhances metabolic stability, extends the half-life, and reduces the dose, thereby providing a therapeutic advantage. Isotope-labeled compounds are generally synthesized from labeled initiators using known synthetic techniques to complete the synthesis of unlabeled compounds. All compounds in which one atom in the compound of the present invention is substituted with one or more of its isotopes (for example, one or more carbon atoms in the compound of formula (I) are carbon isotopes) 11 C or 13 It is C, or one or more hydrogen atoms are isotopes 2 H or 3 All of the above (H) are included in this paper.

[0601] Unless otherwise specified, the compounds and pharmaceutically acceptable salts of the present invention further include their “solvates” or “solubilized products.” The terms “solvate” and “solubilized product” mean the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). Such physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solubilized product can be separated. The solvent molecules in the solubilized product may be arranged regularly and / or irregularly. The solubilized product may contain stoichiometric or non-stoichiometric solvent molecules. "Solvates include solvent compounds that are separable from the solution phase. Exemplary solvent compounds include, but are not limited to, hydrates, ethanol dihydrates, methanol dihydrates, and isopropyl alcohol dihydrates. Solvention methods are known in the art. The term "hydrate" refers to a substance formed by water molecules bonding to cations or anions in a compound by coordination bonds or covalent bonds, or by water ions not directly bonding to cations or anions, but existing in fixed positions on a solid lattice in a certain proportion."

[0602] Unless otherwise specified, the compounds and pharmaceutically acceptable salts of the present invention further include their “prodrugs.” The term “prodrug” refers to a drug that is converted to a parent drug in the body. Prodrugs are usually useful and can improve several established, unnecessarily physical or biological properties. Physical properties are usually related to the solubility (too high or too low lipid or water solubility) or stability, while problematic biological properties include properties that are metabolized too quickly or properties that have poor bioavailability, which may themselves be related to physicochemical properties. For example, they may be bioavailable by oral administration, whereas the parent drug is not. The solubility of the prodrug in a pharmaceutical composition is also improved compared to the parent drug. One example of a prodrug may be any compound of the present invention administered as an ester ("prodrug") to facilitate transmembrane transfer, where water solubility is detrimental to mobility but beneficial once inside the cell, and is subsequently metabolized and hydrolyzed to a carboxylic acid, i.e., the active entity. Another example of a prodrug is a short peptide (polyamino acid) bound to an acid group, in which the peptide is metabolized to reveal the active site.

[0603] The term "oxo group" refers to a double bond formed when two hydrogen atoms at the same substitution site are substituted by the same oxygen atom.

[0604] The term "thio group" refers to the formation of a double bond when two hydrogen atoms at the same substitution site are substituted by the same sulfur atom.

[0605] The term "therapeutic dose" refers to the amount of compound or combination of compounds that provides the desired clinical or therapeutic benefit to the subject being treated. The therapeutic dose can be determined by the prescribing physician in accordance with normal practice, depending on factors such as the general circumstances of the subject being treated (e.g., weight, age, and sex), the severity of the disease, the specific compound administered, the dosing plan, and the use of concomitant medications. For example, a pharmaceutical composition may be administered in a dose appropriate to the disease being treated (or prevented), for example, at least one compound at a dose of about 0.5 μg to about 50 mg / kg of body weight of the subject, preferably at a dose of about 10 μg to about 100 mg / kg of body weight / day.

[0606] The term "pharmaceutically acceptable auxiliary material" refers to a carrier that does not cause obvious irritation to the living body and does not negate the biological activity and properties of the administered compound. Any commonly used pharmaceutically acceptable carrier can be used, and its selection depends on factors such as the specific administration mode, the effect on the solubility and stability of the carrier, and the properties of the dosage form, and is a matter of general skill for those skilled in the art. Examples of such pharmaceutically acceptable auxiliary materials include, but are not limited to, common diluents, excipients, fillers, adhesives, wetting agents, disintegrants, lubricants, colorants, fragrances, absorption enhancers, surfactants, and adsorbent carriers in the pharmaceutical field.

[0607] Unless otherwise specified, the term “treatment” includes any treatment for a patient’s disease, illness, or condition, including (a) inhibiting the symptoms of the disease, illness, or condition, i.e., preventing their development; (b) alleviating the symptoms of the disease, illness, or condition, i.e., eliminating the disease or symptoms; or (c) improving or eliminating one or more symptoms of the disease, illness, or condition or associated with the disease.

[0608] The following abbreviations are used in the preparation examples, examples, and other parts of this paper.

[0609] THF: Tetrahydrofuran, Dioxane: 1,4-dioxane, FA: Formic acid, PE: Petroleum ether, EA: Ethyl acetate, DCM: Dichloromethane, TFA: Trifluoroacetic acid, XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0610] The beneficial effects of the present invention are one or more of the following:

[0611] This invention provides a new direction for the development of drugs that reduce plasma Lp(a) levels by designing a novel compound with an innovative structure. In vitro activity studies have shown that the compound of this invention has a strong inhibitory effect on Lp(a) synthesis, possesses good pharmacokinetic properties, and safety evaluation studies have shown that the compound of this invention has excellent safety. In vivo efficacy studies in mice have shown that the compound of this invention can significantly reduce serum Lp(a) levels, making it a promising compound for treating Lp(a)-mediated diseases. Furthermore, this invention has studied a specific synthesis method that is simple in process, easy to operate, and advantageous for large-scale industrial production and application. [Modes for carrying out the invention]

[0612] The present invention will be further described below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not explicitly stated generally follow ordinary conditions or conditions suggested by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those well known to those skilled in the art. Furthermore, any similar or equivalent methods and materials described herein are applicable to the methods of the present invention. Preferred methods and materials shown herein are illustrative only.

[0613] The compound structures of the present invention were determined by nuclear magnetic resonance spectroscopy (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The instrument used for NMR measurements was a Bruker 400 MHz and / or Varian 400 MHz; the instrument used for LC-MS was an Agilent 1260 Infinity II-6120 / 6125MSD; and the instrument used for HPLC was a Waters UPCC (CA-352).

[0614] The starting materials used in the embodiments of this invention are known, commercially available, or can be synthesized by methods known in the art.

[0615] The present invention provides a method for preparing the aforementioned compound. The aforementioned compound can be prepared by the following steps.

[0616] Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediates 1-5):

[0617] [ka]

[0618] Step 1: Synthesis of (R)-3-(2-((S)-4-benzyl-2-oxoxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate t-butyl (intermediate 1-1): Triethylamine (11.03 g, 109.04 mmol, 2.5 eq) was added to a solution of 2-[(3R)-1-t-butoxycarbonylpyrrolidine-3-yl]acetic acid (10 g, 43.62 mmol, 1 eq) in tetrahydrofuran (150 mL) maintained at 10°C. After 5 minutes, pivaloyl chloride (6.57 g, 54.52 mmol, 1.25 eq) was added. After 15 minutes, lithium chloride (2.31 g, 54.52 mmol, 1.25 eq) and (4S)-4-benzyloxazolidine-2-one (7.73 g, 43.62 mmol, 1 eq) in tetrahydrofuran (50 mL) were added, and the mixture was heated to room temperature and stirred for 24 hours. After 24 hours, 1 N aqueous HCl solution (50 mL) was added to separate the organic phase from the aqueous phase. The organic phase was washed with 1N sodium hydroxide aqueous solution (50 mL) and saturated NaCl aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the solution was concentrated under vacuum. Separation and purification were performed by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 5:1, volume ratio) to obtain the target compound (15 g). LCMS(ESI)[M+H] + = 332.7. 1 1H NMR (400MHz, CDCl3)δ 7.38-7.27(m,3H),7.23-7.17(m,2H),4.68(ddd,J=10.8,7.2,3.2Hz,1H),4.26 -4.16(m,2H),3.68(dd,J=10.8,7.2Hz,1H),3.48(ddd,J=11.6,8.4,3.6Hz,1H), 3.37-3.23(m,2H),3.12-2.94(m,3H),2.78(dd,J=13.2,9.6Hz,1H),2.67(dt,J =14.8,7.2Hz,1H),2.17-2.06(m,1H),1.63-1.55(m,1H),1.46(d,J=4.4Hz,9H).

[0619] Step 2: Synthesis of (R)-3-((S)-1-((S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediate 1-2): Under nitrogen gas protection, a solution of bis(trimethylsilyl)aminolithium (1M in THF, 30.1 mL, 30.1 mmol, 1 eq) was added dropwise to a solution of (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidine-3-yl]-2-oxo-ethyl]pyrrolidine-1-carboxylate t-butyl (12 g, 30.89 mmol, 1 eq) in tetrahydrofuran (100 mL) at 0°C. After stirring the mixture at 0°C for 30 minutes, a solution of 1-bromo-3-(bromomethyl)benzene (8.49 g, 33.98 mmol, 1.1 eq) in tetrahydrofuran (20 mL) was slowly added, and the reaction mixture was slowly raised to room temperature and stirred overnight. The reaction mixture was cooled in an ice bath, saturated aqueous solution of ammonium chloride was added, water was added to the mixture and extracted with ethyl acetate, and then the organic layer was washed with saturated aqueous solution of sodium chloride. The organic matter was dried over anhydrous sodium sulfate, filtered, and vacuum concentrated to obtain the target compound (17 g). LC-MS(ESI)[Mt-butyl+H] + = 501.1.

[0620] Step 3: Synthesis of (S)-3-(3-bromophenyl)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (intermediate 1-3): A solution of hydrogen peroxide (0.88 M in water, 3.4 mL, 32.3 mmol, 1.5 eq) was added all at once to a solution of (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidine-3-yl]-1-[(3-bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate t-butyl (12 g, 21.53 mmol, 1 eq) in tetrahydrofuran (120 mL). The mixture was cooled in an ice bath / water bath, and a solution of lithium hydroxide monohydrate (0.77 g, 32.3 mmol, 1.5 eq) in water (10 mL) was added. The reaction temperature was raised to room temperature and the mixture was stirred for 2.5 hours. The reaction mixture was cooled to 0°C, an aqueous solution of sodium bisulfite (4.1g) (20mL) was added, and an aqueous solution of sodium hydroxide (5N) was added to adjust the pH of the reaction mixture to be greater than 12. Then, water and methyl t-butyl ether were added to separate the layers. The aqueous layer was extracted with methyl t-butyl ether, the organic matter was combined and extracted with water, and then this aqueous extract was added to the main aqueous solution. The aqueous solution was stirred with methyl t-butyl ether (100mL), the mixture was cooled to 0°C, hydrochloric acid (5N) was added to adjust the pH of the solution to 3, the layers were separated, the organic layer was washed with a mixture of water and saturated sodium chloride aqueous solution, the organic matter was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (5.5g). LCMS(ESI)[Mt-butyl+H] + = 341.6.

[0621] Step 4: Synthesis of (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediates 1-4): (S)-3-(3-bromophenyl)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (5.5 g, 13.81 mmol, 1 eq) was dissolved in 2-methyltetrahydrofuran (80 mL), and under nitrogen gas protection, ot-butyl-N,N'-diisopropylisourea (13.83 g, 69.05 mmol, 5 eq) was added. The mixture was heated to 65°C and stirred for 16 hours. Insoluble matter was filtered off, the filter cake was washed with methyl t-butyl ether, the filtrate was concentrated, and the mixture was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (5 g). LCMS(ESI)[M-2×t-butyl+H] + = 343.6.

[0622] Step 5: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediates 1-5): A solution of (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (3 g, 6.6 mmol, 1 eq) in toluene (25 mL) was added to a pressurized vessel. Then, palladium(II) acetate (148.22 mg, 0.66 mmol, 0.1 eq), butyldi-1-adamantylphosphine (355.07 mg, 0.99 mmol, 0.15 eq), and N,N,N',N'-tetramethylethylenediamine (1.15 g, 9.9 mmol, 1.5 eq) were added, and the mixture was stirred at 100°C for 16 hours under a synthesis gas (CO / H2=1:1) atmosphere at 2 MPa. The insoluble matter was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and the target compound (3g) was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 5:1). LC-MS (ESI) [M-Boc] + = 303.8. 1H NMR(400MHz,CDCl3)δ 9.99(s,1H),7.72(dd,J=8.6,4.5Hz,2H),7.44(dd,J=8.5,4.4Hz,2H),3.6 6(dd,J=10.3,7.7Hz,1H),3.50(t,J=8.6Hz,1H),3.26(td,J=10.4,6.9Hz, 1H),3.06-2.83(m,3H),2.56-2.48(m,1H),2.40(dd,J=16.5,7.1Hz,1H),2 .01-1.90(m,1H),1.68(dt,J=22.3,10.2Hz,1H),1.47(s,9H),1.26(s,5H).

[0623] Synthesis of 3,3'-((2S,2'S)-((azandiylbis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (intermediates 1-6):

[0624] [ka]

[0625] (R)-3-((S)-1-(t-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.6 g, 3.97 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), and methanol solution of ammonia (0.62 mL, 4.36 mmol, 1.1 eq, 7 N) was added. The mixture was stirred at room temperature for 0.5 hours, and sodium borohydride (0.49 g, 7.93 mmol, 2 eq) was added. The mixture was stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, dichloromethane:methanol = 30:1) to obtain the target compound (400 mg). LCMS(ESI)[M+H] + = 793.3.

[0626] Preparation of Intermediate 2

[0627] [ka]

[0628] Step 1: Synthesis of methyl 1-benzofuran-5-carboxylate: In a strengthening vessel, 5-bromo-1-benzofuran (20.00 g, 101.51 mmol, 1 eq), palladium acetate (2.28 g, 10.15 mmol, 0.1 eq), and triethylamine (2.05 g, 203.02 mmol, 2 eq) were added to a mixed solvent of dimethyl sulfoxide (100 mL) and methanol (100 mL). CO gas was passed through to increase the pressure to 20 atmospheres, and the mixture was heated to 80°C in an oil bath and reacted for 18 hours. Water was added to the reaction, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and separated by a positive phase separation column (petroleum ether:ethyl acetate = 10:1) to obtain the target compound (6.00 g). 1 HNMR(400MHz,CD3OD)δ 8.35(d,J=1.6Hz,1H),8.01(dd,J=8.8,1.6Hz,1H),7.87(d,J=2.4Hz,1H),7.58(d,J=8.8Hz,1H),7.00-6.89(m,1H),3.94(s,3H).

[0629] Step 2: Synthesis of methyl 2,3-dibromo-2,3-dihydro-1-benzofuran-5-carboxylate: Methyl 1-benzofuran-5-carboxylate (6.00 g, 34.06 mmol, 1 eq) was added to a solution of anhydrous dichloromethane (60 mL), and then liquid bromine (6.53 g, 40.87 mmol, 1.2 eq) was slowly added dropwise, and the reaction was carried out for 2 hours under nitrogen gas protection at 0°C. The reaction mixture was slowly added dropwise to a solution of sodium sulfite, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude target compound (11.44 g, crude product). The crude product was used directly in the next reaction without purification. 1H NMR(400MHz,CD3OD)δ 8.14(s,1H),8.00(dd,J=8.4,1.6Hz,1H),7.15(s,1H),7.06(d,J=8.4Hz,1H),5.97(s,1H),3.82(d,J=3.6Hz,3H).

[0630] Step 3: Synthesis of 3-bromo-1-benzofuran-5-carboxylic acid: 2,3-Dibromo-2,3-dihydro-1-benzofuran-5-carboxylate methyl (11.00 g, 32.74 mmol, 1 eq) was dissolved in ethanol, and potassium hydroxide solution in ethanol (2.0 eq, 15%) was added. The mixture was reacted at 80°C for 2 hours. The pH of the reaction mixture was adjusted to 2-3 with hydrochloric acid (2M) solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (10.00 g, crude product). The crude product was used directly in the next reaction without purification.

[0631] Step 4: Synthesis of (3-bromo-1-benzofuran-5-yl)methanol: 3-Bromo-1-benzofuran-5-carboxylic acid (10.00 g, 41.49 mmol, 1.0 eq) was dissolved in tetrahydrofuran, and a solution of borane in tetrahydrofuran (860 mg, 62.23 mmol, 1.5 eq) was added at 0°C. The mixture was reacted at 0°C for 2 hours. Methanol was slowly added dropwise under low temperature conditions to quench the mixture, and then the solution was concentrated to obtain the target compound (10.00 g, crude product). The crude product was used directly in the next reaction without purification. LCMS(ESI)[M-OH] + = 209.2.

[0632] Step 5: Synthesis of 3-bromo-5-(bromomethyl)-1-benzofuran: (3-bromo-1-benzofuran-5-yl)methanol (10.00 g, 37.44 mmol, 1 eq) was dissolved in dichloromethane (100 mL), and tribromophosphoran (11.15 g, 41.18 mmol, 1.1 eq) was slowly added dropwise at 0°C, and the reaction was allowed to proceed for 2 hours at 0°C. The reaction mixture was slowly added to water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to concentrate and obtain the crude product of the target compound (10.10 g). The crude product was used directly in the next reaction without purification.

[0633] Step 6: Synthesis of 3-{1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-3-(3-bromo-1-benzofuran-5-yl)-1-oxopropan-2-yl}pyrrolidine-1-carboxylate t-butyl: 3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylate t-butyl (10.25 g, 26.38 mmol, 1 eq) was dissolved in tetrahydrofuran (100 mL), and bis(trimethylsilyl)aminolithium (5.30 g, 31.65 mmol, 1.2 eq) was slowly added dropwise at -78 °C and the mixture was allowed to react for 1 hour. 3-bromo-5-(bromomethyl)-1-benzofuran (9.00 g, 26.38 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL) and slowly added dropwise to the reaction mixture. The reaction was slowly raised to room temperature and stirred for 12 hours. The reaction mixture was added to saturated ammonium chloride, extracted with ethyl acetate, combined with the organic phase, washed with saturated sodium chloride, dried over sodium sulfate, and filtered to concentrate and obtain the target compound (12.00 g). The crude product was used directly in the next reaction without purification: LC-MS(ESI)[M+Na] + = 619.0.

[0634] Step 7: Synthesis of 3-(3-bromo-1-benzofuran-5-yl)-2-{1-[(t-butoxy)carbonyl]pyrrolidine-3-yl}propionic acid: 3-{1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-3-(3-bromo-1-benzofuran-5-yl)-1-oxopropan-2-yl}pyrrolidine-1-carboxylate t-butyl (11.00 g, 18.41 mmol, 1 eq) was dissolved in tetrahydrofuran (300 mL), and lithium hydroxide (440 mg, 18.41 mmol, 1 eq) was dissolved in water (100 mL) and hydrogen peroxide solution (11 mL). These were added to the reaction mixture at 0°C and reacted at room temperature for 2 hours. Sodium sulfite solution was added to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, and filtered to concentrate and obtain the target compound (5.50 g). The crude product was used directly in the next reaction without purification. LCMS(ESI)[M-Boc+H] + =339.0.

[0635] Step 8: Synthesis of 3-[3-(3-bromo-1-benzofuran-5-yl)-1-(t-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate t-butyl: 3-(3-bromo-1-benzofuran-5-yl)-2-{1-[(t-butoxy)carbonyl]pyrrolidine-3-yl}propionic acid (5.50 g, 12.55 mmol, 1.0 eq) and Ot-butyl-N,N'-diisopropylisourea (7.54 g, 37.64 mmol, 3.0 eq) were dissolved in 2-methyltetrahydrofuran (50 mL), heated to 80°C, and reacted for 3 hours. Ethyl acetate and water were added for extraction, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, stirred, and purified through a column to obtain the target compound (2.50 g). LCMS(ESI)[M+Na] + = 516.2, 518.2.

[0636] Step 9: Synthesis of 3-[1-(t-butoxy)-3-(3-formyl-1-benzofuran-5-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate t-butyl: In a high-pressure reaction vessel, 3-[3-(3-bromo-1-benzofuran-5-yl)-1-(t-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate t-butyl (1.5 g, 3.03 mmol, 1.0 eq), palladium acetate (68 mg, 0.30 mmol, 0.1 eq), [2-(dimethylamino)ethyl]dimethylamine (704 mg, 6.06 mmol, 2.0 eq), and bis(adamantan-1-yl)(butyl)phosphine (217 mg, 0.61 mmol, 0.2 eq) were added to toluene (15 mL), and the mixture was aerated with H2 / CO (volume ratio: 1 / 1) to a pressure of 1.3 MPa and reacted at 100°C for 18 hours. The reaction was extracted with ethyl acetate and water, washed with saturated sodium chloride solution, dried over sodium sulfate, and separated into two phases (Silica gel, petroleum ether:ethyl acetate = 6:1, volume ratio) to obtain the target compound (700 mg). 1 H NMR(400MHz,CDCl3)δ 10.09(s,1H),8.18(d,J=4.1Hz,1H),7.94(d,J=6.0Hz,1H),7.38(d,J=8.5Hz,1H),7.15(t,J=7.2Hz,1H),3.71-3.34(m,2H),3.23-3.13( m,1H),3.02-2.77(m,3H),2.45(d,J=8.6Hz,1H),2.39-2.28(m,1H),1.92-1.84(m,1H),1.57(d,J=13.9Hz,1H),1.40(s,9H),1.21(s,9H).

[0637] Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediate 3-5)

[0638] [ka]

[0639] Synthesis of (R)-3-((S)-1-((S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromo-5-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediate 3-1): Referring to the method for intermediates 1-2, the target product (21.9 g) was synthesized using 1-bromo-3-(bromomethyl)-5-fluorobenzene as a starting material. LCMS(ESI)[Mt-butyl+H] + = 521.2.

[0640] Synthesis of (S)-3-(3-bromo-5-fluorophenyl)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (intermediate 3-2): The target product (8.8 g) was obtained by synthesis following the method for intermediates 1-3. LCMS(ESI)[Mt-butyl+H] + = 359.9.

[0641] Synthesis of (R)-3-((S)-3-(3-bromo-5-fluorophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediate 3-3): Following the method for intermediates 1-4, the target product (6.1 g) was synthesized. LCMS(ESI)[M-2×t-butyl+H] + = 359.9.

[0642] Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-fluoro-5-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediates 3-4): A three-necked flask was taken, and (R)-3-((S)-3-(3-bromo-5-fluorophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (5.6 g) was dissolved in 1,4-dioxane (45 mL). Potassium vinyltrifluoroborate (8 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (922 mg), and triethylamine (3.6 g) were added in sequence, water (15 mL) was added, and the mixture was heated to 75°C under nitrogen gas protection and stirred for 5 hours. Complete reaction was detected by liquid chromatography-mass spectrometry. Insoluble matter was filtered through diatomaceous earth, the filter cake was washed with an appropriate amount of ethyl acetate, and the filtrate was concentrated. Separation and purification by high-performance chromatography (Silica gel, PE:EA = 10:1, volume ratio) was performed to obtain the target compound (4.4 g). LCMS(ESI)[M-2×t-butyl+H] + = 308.3.

[0643] Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (intermediate 3-5): A three-necked flask was taken, and (R)-3-((S)-1-(t-butoxy)-3-(3-fluoro-5-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (4.4 g, 10.53 mmol, 1 eq) was dissolved in tetrahydrofuran (44 mL), water (12 mL) was added, and after protecting with nitrogen gas, potassium osmate (388 mg, 1.05 mmol, 0.1 eq) and sodium periodate (6.76 g, 31.59 mmol, 3 eq) were added in order under ice bath, and the mixture was heated to room temperature and stirred for 3 hours. The insoluble matter was filtered, the filtrate was poured into water, then ethyl acetate was added for extraction, the organic phase was combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by high-performance chromatography (Silica gel, PE:EA = 10:1, volume ratio) to obtain the target compound (2.7 g). LCMS(ESI)[M-2×t-butyl+H] + =310.0. 1H NMR(400MHz,DMSO-d6)δ 9.97(d,J=1.5Hz,1H),7.63(s,1H),7.46(d,J=9.8Hz,1H),3.52(q,J=10.5Hz,1H),3.42-3.34(m,1H),3.24-3.09(m,1H),3.02(t,J=10 .0Hz,1H),2.83(q,J=13.9Hz,2H),2.59(d,J=8.9Hz,1H),2.30(s,1H),1.91-1.76(m,1H),1.68-1.49(m,1H),1.40(s,9H),1.21(s,9H).

[0644] Synthesis of (3R)-3-[(2S)-1-(t-butoxy)-3-(5-formylpyridyl-3-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate t-butyl (intermediate 4-1):

[0645] [ka]

[0646] Referring to the method for intermediates 1-5, 1-bromo-3-(bromomethyl)benzene was replaced with 3-bromo-5-bromomethylpyridine, and the target compound (320 mg) was synthesized. LCMS(ESI)[M+H] + = 405.2. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.95(d,J=1.8Hz,1H),8.71(d,J=1.9Hz,1H),8.09(s,1H),3.59-3.47(m,2H),3.21-3.12(m,1H),3.05(t,J=10.0Hz,1H),2. 96-2.88(m,1H),2.87-2.79(m,1H),2.65-2.56(m,1H),2.39-2.27(m, 1H), 1.90-1.81 (m, 1H), 1.64-1.54 (m, 1H), 1.40 (s, 9H), 1.19 (s, 9H).

[0647] Example 1 (Compound 5) Preparation of (2S,2'S)-3,3'-(((((S)-5-amino-5-carboxylpentyl)azandiyl)bis(methylene))bis(5-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0648] [ka]

[0649] Step 1: Synthesis of N6,N6-bis(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-5-fluorobenzyl)-N2-(t-butoxycarbonyl)-L-lysine: (R)-3-((S)-1-(t-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (376 mg, 0.893 mmol, 2.2 eq) and (t-butoxycarbonyl)-L-lysine (100 mg, 0.406 mmol, 1.0 eq) were dissolved in tetrahydrofuran (2 mL), and sodium borohydride (64 mg, 1.02 mmol, 2.5 eq) and one drop of acetic acid were added. The reaction mixture was stirred overnight at room temperature. Saturated ammonium chloride solution and dichloromethane were added. The organic phase solvent was rotated dry and separated and purified by high-performance chromatography (Silica gel, DCM:MeOH = 15:1, volume ratio) to obtain the target compound (89 mg). LCMS(ESI)[M+H] + = 1057.9.

[0650] Step 2: Synthesis of (2S,2'S)-3,3'-(((((S)-5-amino-5-carboxylpentyl)azandiyl)bis(methylene))bis(5-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): N 6 ,N 6-Bis(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-5-fluorobenzyl)-N2-(t-butoxycarbonyl)-L-lysine (89 mg, 0.084 mmol, 1.0 eq) was dissolved in 1,4-dioxane (0.2 mL), and 4 M HCl (1,4-dioxane) solution (0.2 mL) was added. The reaction mixture was stirred overnight at room temperature, and after monitoring for complete reaction by LC-MS, the solvent was rotated dry and separated and purified by preparative HPLC (C 18 A 10 mmol / L aqueous / acetonitrile solution of NH4HCO3 was used to obtain the target compound (9.8 mg). LC-MS (ESI) [M+H] + = 645.4. 1 H NMR(400MHz,D2O)δ 6.97-6.86(m,6H),3.78(s,4H),3.64-3.57(m,1H),3.51-3.42(m,2H),3.40-3.31(m,2H),3.23-3.13(m,2H),2.97-2.87( m,2H),2.77-2.68(m,4H),2.66-2.53(m,2H),2.45-2.33(m,4H),2.10-2.00(m,2H),1.81-1.53(m,6H),1.32-1.17(m,2H).

[0651] Example 2 (Compound 6) Preparation of (2S,2'S)-3,3'-(((((5-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzofuran-3-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0652] [ka]

[0653] Step 1: Synthesis of 3,3'-((2S,2'S)-(((((5-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)benzofuran-3-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): 3,3'-((2S,2'S)-((azandiylbis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (50 mg, 0.063 mmol, 1.0 eq) and (R)-3-((S)-1-(t-butoxy)-3-(3-formylbenzofuran-5-yl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate t-butyl (33 mg, 0.076 mmol, 1.2 eq) were dissolved in tetrahydrofuran (0.2 mL), and sodium borohydride (6 mg, 0.095 mmol, 1.5 eq) and one drop of acetic acid were added. The reaction mixture was stirred overnight at room temperature. A saturated ammonium chloride solution and dichloromethane were added. The organic phase solvent was rotated dry and separated and purified by high-performance chromatography (Silica gel, DCM:MeOH = 15:1, volume ratio) to obtain the target compound (45 mg).

[0654] Step 2: Synthesis of (2S,2'S)-3,3'-(((((5-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzofuran-3-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): Dissolve 3,3'-((2S,2'S)-(((((5-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)benzofuran-3-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl)(t-butoxycarbonyl) (45 mg, 0.037 mmol, 1.0 eq) in 1,4-dioxane (0.2 mL), add 4 M HCl (1,4-dioxane) solution (0.2 mL), stir the reaction mixture overnight at room temperature, swiftly dry the solvent, separate and purify by preparative HPLC (C 18 A 10 mmol / L aqueous / acetonitrile solution of NH4HCO3 was used to obtain the target compound (13 mg). LC-MS (ESI) [M+H] + = 751.5. 1 H NMR(400MHz,D2O)δ 7.45(s,1H),7.30(d,J=8.4Hz,1H),7.18(t,J=7.5Hz,2H),7.06(d,J=9.1Hz,4H),7.01(d,J=11.7Hz,4H),3.53-3.44(m,3H),3.32 -3.18(m,7H),3.12-3.05(m,3H),2.83-2.67(m,7H),2.65-2.54(m,3H),2.38-2.27(m,7H),2.03-1.96(m,3H),1.68-1.60(m,3H).

[0655] Example 3 (Compound 12) Preparation of (2S,2'S)-3,3'-((((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)-5-fluorobenzoyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0656] [ka]

[0657] Step 1: Synthesis of 3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-5-fluorobenzoic acid: (R)-3-((S)-1-(t-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (50 mg), sodium hydroxide (8 mg), and potassium permanganate (30 mg) were dissolved in acetonitrile (0.5 mL) and water (0.5 mL). The reaction mixture was stirred overnight at 60°C. Water and dichloromethane were added. The organic phase solvent was rotated dry and separated and purified by high-performance chromatography (Silica gel, DCM:MeOH = 30:1, volume ratio) to obtain the target compound (15 mg). LCMS(ESI)[M-Boc+H] + =338.49.

[0658] Step 2: Synthesis of 3,3'-((2S,2'S)-((((3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-5-fluorobenzoyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate di-t-butyl): 3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-5-fluorobenzoic acid (15 mg) was dissolved in N,N-dimethylformylamine (0.3 mL), and 3,3'-((2S,2'S)-((azandiylbis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (27 mg), O-(7-azabenzotriazolyl-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (15 mg) and N,N-diisopropylethylamine (14 mg) were added. The reaction mixture was stirred overnight at room temperature. Water and ethyl acetate were added. The organic phase solvent was rotated dry and separated and purified by high-performance chromatography (Silica gel, DCM:MeOH = 30:1, volume ratio) to obtain the target compound (20 mg). LC-MS (ESI) [M-Boc+H] + = 1111.92.

[0659] Step 3: Synthesis of (2S,2'S)-3,3'-((((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)-5-fluorobenzoyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid: 3,3'-((2S,2'S)-((((3-((S) -3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-5-fluorobenzoyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) Dissolve 3,3'-((2S,2'S)-((((3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-5-fluorobenzoyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (115 mg) in 1,4-dioxane (0.2 mL), add 4 M HCl (1,4-dioxane) solution (0.2 mL), stir the reaction mixture overnight at room temperature, rotate dry the solvent, separate and purify by preparative HPLC, and (C 18 A 10 mmol / L aqueous / acetonitrile solution of NH4HCO3 was used to obtain the target compound (39.9 mg). LC-MS (ESI) [M+H] + = 743.65. 1 H NMR(400MHz,D2O)δ 7.30-7.18(m,2H),7.16-6.93(m,7H),6.92-6.81(m,2H),4.60(s,2H),4.41(s,2H),3.42-3.23(m,6 H),3.20-3.06(m,3H),2.88-2.60(m,9H),2.45-2.24(m,6H),2.11-1.93(m,3H),1.75-1.53(m,3H).

[0660] Example 4 (Compound 47) Preparation of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid):

[0661] [ka]

[0662] Step 1: Synthesis of 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-1-(t-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid t-butyl (R)-3-((S)-1-(t-butoxy)-3-(3-formylbenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid t-butyl (600 mg, 1.38 mmol, 1 eq) was dissolved in isopropyl alcohol (6 mL), and methanol solution of ammonia (1.0 eq, 7.0 M) and sodium triacetoborohydride (436 mg, 2.10 mmol, 1.5 eq) were added. The mixture was reacted at 25 °C for 16 hours. The reaction mixture was concentrated and separated by silica gel column chromatography (Silica gel, petroleum ether / ethyl acetate = 1 / 1, volume ratio) to obtain the target compound (30 mg). LCMS(ESI)[M+H] + = 1322.6.

[0663] Step 2: Synthesis of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl) (35 mg, 0.03 mmol, 1 eq) was dissolved in a solution of dioxane hydrogen chloride (1 mL, 4 M) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, water was added, and then freeze-dried to obtain the target compound (15.88 mg). LC-MS(ESI)[M+H] + = 831.4. 1H NMR(400MHz,CD3OD)δ 8.10(s,3H),7.56-7.47(m,6H),7.27(d,J=8.4Hz,3H),4.64(s,6H),3.52-3.35(m,6H),3.26-3. 19(m,3H),3.08-2.93(m,12H),2.52(d,J=7.6Hz,3H),2.16(d,J=7.2Hz,3H),1.91-1.73(m,3H).

[0664] Example 5 (Compound 89) Preparation of (2S,2'S)-3,3'-((((3-fluoro-5-methoxyphenylethyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0665] [ka]

[0666] Step 1: Synthesis of (E)-1-(2-ethoxyvinyl)-3-fluoro-5-methoxybenzene: Under nitrogen gas protection, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (1.14 g), cesium carbonate (29.32 g), 1,4-dioxane (180 mL), and water (30 mL) were added to a three-necked flask. 3-fluoro-5-bromoanizole (6.15 g) and (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (6.54 g) were added in sequence. The reaction mixture was heated to 100°C and allowed to react for 3 hours. After the reaction was complete, the reaction mixture was quenched with saturated saline solution and extracted with ethyl acetate. After combining the organic phases, the mixture was washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (Silica gel, petroleum ether:ethyl acetate = 3:1, volume ratio) to obtain the target compound (3.60 g).

[0667] Step 2: Synthesis of 2-(3-fluoro-5-methoxyphenyl)acetaldehyde: (E)-1-(2-ethoxyvinyl)-3-fluoro-5-methoxybenzene (500 mg) was dissolved in HCl / Dioxane (5 mL) and stirred at room temperature for 16 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 10:1, volume ratio) to obtain the target compound (150 mg). LCMS(ESI)[M+H] + = 169.07.

[0668] Step 3: Synthesis of 3,3'-((2S,2'S)-((((3-fluoro-5-methoxyphenylethyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): 47 mg of 2-(3-fluoro-5-methoxyphenyl)acetaldehyde was dissolved in 5 mL of methanol. At room temperature, 200 mg of 3,3'-((2S,2'S)-((azandiylbis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (3R,3'R) and 2 drops of acetic acid were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 5:1, volume ratio) to obtain the target compound (120 mg). LC-MS(ESI)[M+H] + =944.89.

[0669] Step 4: Synthesis of (2S,2'S)-3,3'-((((3-fluoro-5-methoxyphenylethyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3'-((2S,2'S)-((((3-fluoro-5-methoxyphenylethyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl)(t-butoxycarbonyl) (120 mg) was dissolved in HCl / Dioxane (5 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly concentrated and separated and purified by preparative HPLC (C18, 0.1% FA water / acetonitrile solution) to obtain the target compound (47.46 mg). LCMS(ESI)[M+H] + = 632.4.

[0670] Example 6 (Compound 62) Preparation of (2S,2'S)-3,3'-((((3-fluoro-5-methoxybenzyl)azandiyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0671] [ka]

[0672] Step 1: Synthesis of 2-{[(3-fluoro-5-methoxyphenyl)methyl](2-hydroxyethyl)amino}ethane-1-ol: 2-[(2-hydroxyethyl)amino]ethane-1-ol (2.00 g) was added to a solution of dichloromethane (30 mL), and at 25°C, 3-fluoro-5-methoxyphenyl-1-formaldehyde (4.00 g) and sodium triacetoborohydride (12.00 g) were added. The reaction was allowed to proceed at 25°C for 2 hours, and the reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was extracted with dichloromethane and water, and the organic phase was rotate-dried. After purification (through a reverse column: acetonitrile / water = 10%), the target compound (4.00 g) was obtained. LCMS(ESI)[M+H] + = 244.2.

[0673] Step 2: Synthesis of [bis(2-chloroethyl)][(3-fluoro-5-methoxyphenyl)methyl]amine: 1.50 g of 2-{[(3-fluoro-5-methoxyphenyl)methyl](2-hydroxyethyl)amino}ethane-1-ol was added to 15 mL of dichlorosulfoxide and reacted overnight at 70°C. After detecting the compound by LC-MS, the dichlorosulfoxide was rotated dry, beaten with ethyl acetate, and extracted with aqueous ammonium chloride solution. The target compound (1.8 g, crude product) was obtained without further purification and used directly in the next reaction without further purification.

[0674] Step 3: Synthesis of 3,3'-((2S,2'S)-((((3-fluoro-5-methoxybenzyl)azandiyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-1-(t-butoxy)-3-(1H-indole-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (0.5 g) was added to N,N-dimethylformylamine (5 mL), and at room temperature, [bis(2-chloroethyl)][(3-fluoro-5-methoxyphenyl)methyl]amine (338 mg) and cesium carbonate (1.2 g) were added. The reaction mixture was allowed to react overnight at 100 °C under nitrogen gas protection, detected by LC-MS, saturated brine was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the organic phase was rotate-dried and washed with (pure ethyl acetate) through a positive-phase column to obtain the target compound (190 mg). LC-MS (ESI) [M+H] + = 1036.6.

[0675] Step 4: Synthesis of (2S,2'S)-3,3'-((((3-fluoro-5-methoxybenzyl)azandiyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3'-((2S,2'S)-((((3-fluoro-5-methoxybenzyl)azandiyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (140 mg) was added to TFA (2 mL), stirred at 25°C for 0.5 hours, and the product signal was detected by LC-MS. The reaction mixture was then rotated dry, dissolved in acetonitrile, and separated and purified by preparative HPLC (FA) to obtain the target compound (13.6 mg). LC-MS (ESI) [M+H] + = 725.04. 1 H NMR(400MHz,MeOD-d4)δ 8.42(s,1H),7.42(d,J=8.0Hz,2H),7.11(d,J=3.2Hz,2H),6.91(d,J=7.2Hz,2H),6.87-6.84(m, 2H),6.45-6.43(m,3H),6.29(t,J=2.8Hz,2H),4.07(d,J=6.2Hz,4H),3.63(d,J=3.2Hz,3H),3.59 (s,2H),3.21-3.18(m,4H),3.13-3.03(m,6H),2.99-2.92(m,2H),2.87(s,2H),2.78-2.66(m,2H ),2.60-2.54(m,2H),2.38-2.30(m,2H),2.01(d,J=24.0Hz,2H),1.85-1.76(m,1H),1.56(s,1H).

[0676] Example 7 (Compound 95) Preparation of (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)acetyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0677] [ka]

[0678] Step 1: Synthesis of (3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)boric acid: (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.9g, 4.18mmol, 1eq), (dihydroxyboryl)boric acid (562.29mg, 6.27mmol, 1.5eq), potassium acetate (1230.7mg, 12.54mmol, 3eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (199.27mg, 0.42mmol, 0.1eq), and X-Phos Pd G2 (164 mg, 0.21 mmol, 0.05 eq) was added to EtOH (20 mL), purged three times with nitrogen gas, and reacted at 90°C for 16 hours. The presence of the product was detected by LC-MS, ethyl acetate (20 mL) was added to the reaction system, filtered through diatomaceous earth, and the filtrate was rotary-dried to obtain the target compound (2.0 g). The crude product was used directly in the next step without further purification. LC-MS [M-2×t-butyl+H] + = 308.2.

[0679] Step 2: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)boric acid (2000 mg, 4.77 mmol, 1 eq) was dissolved in THF (20 mL), hydrogen peroxide solution (8 mL, 235.2 mmol, 49.31 eq) was added, and the mixture was reacted at 20 °C for 16 hours. The presence of the product was detected by LC-MS, saturated sodium bisulfite solution (20 mL) and ethyl acetate (20 mL) were added, and the mixture was extracted by liquid-liquid extraction. The organic phase was dried over sodium sulfate, rotated dry, and separated and purified by high-performance chromatography (Silica gel, PE:Ã=4:1, volume ratio) to obtain the target compound (800 mg). LC-MS(ESI)[M+H] + = 392.2.

[0680] Step 3: Synthesis of (R)-3-((S)-3-(3-(2-(benzyloxy)-2-oxoethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (2.0 g, 5.11 mmol, 1 eq), benzyl 2-bromoacetate (2.34 g, 10.22 mmol, 2 eq), and dipotassium carbonate (2.12 g, 15.33 mmol, 3 eq) were added to acetonitrile (50 mL) and reacted at 90°C for 16 hours. The presence of a product was detected by LC-MS, and the product was separated and purified by high-performance chromatography (Silica gel, PE:SiO=5:1, volume ratio) to obtain the target compound (2.5 g). LC-MS(ESI)[M+Na] + = 561.9.

[0681] Step 4: Synthesis of 2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)acetic acid: (R)-3-((S)-3-(3-(2-(benzyloxy)-2-oxoethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (2.5 g, 4.63 mmol, 1 eq) was dissolved in methanol (50 mL), palladium carbon (300 mg, 10% content) was added, the mixture was purged three times with hydrogen gas, stirred at room temperature for 16 hours, and after detecting completion of the reaction by LC-MS, the mixture was filtered and the filtrate was rotate-dried to obtain the target compound (1.5 g). LC-MS(ESI)[M+Na] + = 472.2.

[0682] Step 5: Synthesis of 3,3'-((2S,2'S)-((((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)acetyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): 3,3'-((2S,2'S)-((Azandiylbis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (88.1 mg, 0.11 mmol, 1 eq), 2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)acetic acid (50 mg, 0.11 mmol, 1 eq), O-(7-azaben Zotriazolyl-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (41.83 mg, 0.11 mmol, 1 eq) and N,N-diisopropylethylamine (43.12 mg, 0.33 mmol, 3 eq) were dissolved in N,N-dimethylformylamine (3 mL), stirred at room temperature, and reacted for 16 hours. After detecting completion of the reaction by LC-MS, the reaction solvent was rotated dry and purified on a thin-layer silica gel plate (DCM:MeOH = 20:1, volume ratio) to obtain the target compound (100 mg). LC-MS (ESI) [M+Na] + = 1245.8.

[0683] Step 6: Synthesis of (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)acetyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid)(t-butoxycarbonyl): 3,3'-((2S,2'S)-((((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)acetyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (100 mg, 0.08 mmol, 1 eq) was added to hydrochloric acid-dioxane (2 mL, 4.0 M), reacted at room temperature for 6 hours, filtered, and the filtered cake was washed with dioxane to obtain the target compound (46 mg). LCMS(ESI)[M+H] + = 755.2. 1 H NMR(400MHz,CD3OD)δ 7.34-7.20(m,5H),7.18-7.10(m,4H),6.92-6.85(m,2H),6.7-6.75(m,1H),4.92(s,2H),4.61(s,4H),3.57-3.40(m,6H) ),3.34-3.21(m,3H),2.99-2.81(m,11H),2.78-2.72(m,3H),2.56-2.49(m,3H),2.29-2.15(m,3H),1.87-1.81(m,3H).

[0684] Example 8 (Compound 96) Preparation of (S)-3-(3-(2-((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)amino)2-oxoethyl)phenyl)2-((R)-pyrrolidine-3-yl)propionic acid:

[0685] [ka]

[0686] Step 1: Preparation of (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl: A single-necked flask was taken, and (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.5 g, 3.30 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL). Then, 1,1-bis(diphenylphosphine)ferrocenedichloropalladium dichloromethane complex (II) (270.0 mg, 0.33 mmol, 0.1 eq), bis(pinacorato)diborone (1.26 g, 4.95 mmol, 1.5 eq), and potassium acetate (972 mg, 9.9 mmol, 3 eq) were added, and the mixture was stirred at 90°C for 16 hours under nitrogen gas protection. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:SiO=2:1) ​​to obtain the target compound (1.2g). LCMS(ESI)[M-Boc+H] + = 402.2.

[0687] Step 2: Preparation of (R)-3-((S)-1-(t-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: A single-necked flask was taken, and the product obtained in Step 1 (1.2 g, 2.39 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL). Then, hydrogen peroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:SiO=1:1) to obtain the target compound (800.0 mg). LCMS(ESI)[M-2x tert-butyl+H] + =280.0.

[0688] Step 3: Preparation of (R)-3-((S)-1-(t-butoxy)-3-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: A single-necked flask was taken, and the product obtained in step 2 (500.0 mg, 1.28 mmol, 1.0 eq) was dissolved in N,N-dimethylformylamine (5 mL). Then, 2-(2-bromoethyl)isoindoline-1,3-dione (647.7 mg, 2.56 mmol, 2 eq) and potassium carbonate (530.7 mg, 3.83 mmol, 3 eq) were added, and the mixture was stirred at 90°C for 2 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:₹=1:1) to obtain the target compound (280 mg). LCMS(ESI)[M+H] + = 565.3.

[0689] Step 4: Preparation of (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: A single-necked flask was taken, and the product obtained in step 3 (280.0 mg, 0.5 mmol, 1.0 eq) was dissolved in ethanol (10 mL). Then, hydrazine hydrate (124 mg, 2.50 mmol, 5.0 eq) was added, and the mixture was reacted at 90°C for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:₹=1:5) to obtain the target compound (160 mg). LCMS(ESI)[M+H] + = 435.3.

[0690] Step 5: Preparation of (R)-3-((S)-1-(t-butoxy)-3-(3-(((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)ethyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: A single-necked flask was taken, and the product obtained in step 4 (160 mg, 0.37 mmol, 1.0 eq) was dissolved in methanol (10 mL). Then, (R)-3-((S)-1-(t-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (178.1 mg, 0.44 mmol, 1.2 eq) was added, followed by sodium borohydride cyanohydride (23.2 mg, 0.37 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:HCl=1:5) to obtain the target compound (233 mg). LCMS(ESI)[M+H] + = 822.6.

[0691] Step 6: Preparation of (R)-3-((S)-3-(3-allylphenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: Take a single-necked flask and dissolve (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (7.0 g, 15.4 mmol, 1.0 eq) in 1,4-dioxane (20 mL) and water (4 mL). Then add 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxolane (5.2 g, 30.8 mmol, 2 eq), potassium phosphate (9.8 g, 46.2 mmol, 3 eq), and 1,1-bis(diphenylphosphine)ferrocenedichloropalladium dichloromethane complex (II) (1.25 g, 1.54 mmol, 0.1 eq). The mixture was stirred at 90°C for 16 hours under nitrogen gas protection. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:ÃO=2:1) ​​to obtain the target compound (5.0 g). LCMS[M-2×t-butyl+H] + =304.1.

[0692] Step 7: Preparation of 2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)acetic acid: A single-necked flask was taken, and the product obtained in step 6 (6.0 g, 14.4 mmol, 1.0 eq) was dissolved in 1,4-dioxane (100 mL). Then, sodium periodate (12.3 g, 57.75 mmol, 4 eq) and potassium osmate dihydrate (532.0 mg, 1.44 mmol, 0.1 eq) were added, and the mixture was stirred at room temperature for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:SiO=1:1) to obtain the target compound (500 mg). LCMS(ESI)[M+H] + = 434.2.

[0693] Step 8: Preparation of (R)-3-((S)-1-(t-butoxy)-3-(3-((N-(2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)ethyl)-2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)acetamide)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: A single-necked flask was taken, and the product obtained in step 5 (70 mg, 0.0852 mmol, 1.0 eq) was dissolved in DMF (5 mL). Then, the product obtained in step 7 (44.3 mg, 0.102 mmol, 1.2 eq), O-(7-azabenzotriazolyl-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (64.7 mg, 0.17 mmol, 2.0 eq) and N,N-diisopropylethylamine (33.0 mg, 0.25 mmol, 3.0 eq) were added. The mixture was stirred at room temperature for 16 hours, and complete reaction was detected by liquid chromatography-mass spectrometry. The reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, PE:HCl=1:8) to obtain the target compound (70 mg). LCMS(ESI)[M+H] + = 1237.9.

[0694] Step 9: Preparation of (S)-3-(3-(2-((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid: A single-necked flask was taken, and the product obtained in step 8 (70.0 mg, 0.056 mmol) was dissolved in hydrochloric acid-dioxane (2 mL) and stirred at room temperature for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by preparative chromatography to obtain the target compound (27.2 mg). LC-MS(ESI)[M+H] + = 769.4. 1H NMR(400MHz, Deuterium Oxide)δ 7.20(dq,J=30.0,7.5Hz,3H),7.11-6.86(m,6H),6.81(s,1H),6.69-6.59(m,2H),4.59(d,J=4 .6Hz,2H),4.10(t,J=5.0Hz,1H),4.00(d,J=5.2Hz,1H),3.88(s,1H),3.79(d,J=5.2Hz,1H),3. 69(d,J=5.2Hz,2H),3.29(dtt,J=13.1,9.3,4.6Hz,6H),3.12(dd,J=11.9,7.9Hz,3H),2.87-2 .58(m,8H),2.54-2.48(m,1H),2.41-2.23(m,6H),2.01(s,3H),1.63(dt,J=22.4,11.3Hz,3H).

[0695] Example 9 (Compound 8) Preparation of 3,3'-(((((4-(2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzofuran-2-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0696] [ka]

[0697] Step 1: Synthesis of methyl 3-hydroxy-2-iodobenzoate: Methyl 2-amino-3-hydroxybenzoate (25 g, 149.65 mmol, 1 eq) was dissolved in aqueous sulfuric acid (1000 mL, 1.0 M), cooled to 0°C, and an aqueous solution of sodium nitrite (11.25 g, 163.0 mmol, 1.08 eq) (100 mL) was added. The mixture was stirred at 25°C for 20 minutes, and an aqueous solution of potassium iodide (111.7 g, 672.9 mmol, 4.5 eq) (100 mL) was added. The mixture was stirred at 70°C for 1.5 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted and separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 5:1) to obtain the target compound (20.0 g). LCMS(ESI)[M+H] + = 278.9.

[0698] Step 2: Synthesis of methyl 2-hydroxymethylbenzofuran-4-carboxylate: The product obtained in Step 1 (20.0 g, 71.94 mmol, 1.0 eq) was dissolved in N,N-dimethylformylamine (200 mL), and cuprous iodide (1.37 g, 7.19 mmol, 0.1 eq), bistriphenylphosphine dichloropalladium (5 g, 7.19 mmol, 0.1 eq), triethylamine (21.86 g, 214.55 mmol, 3.0 eq), and propynyl alcohol (6.1 g, 108.81 mmol, 1.5 eq) were added. The mixture was stirred at 75°C for 16 hours under nitrogen gas protection. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (11 g). LCMS(ESI)[M+H] + = 207.4.

[0699] Step 3: Synthesis of 2-(((t-butyldiphenylsilyl)oxy)methyl)benzofuran-4-carboxylate methyl: The product obtained in Step 2 (11.0 g, 53.38 mmol, 1.0 eq) was dissolved in dichloromethane (80 mL), imidazole (4.5 g, 66.09 mmol, 1.5 eq) and t-butyldiphenylchlorosilane (13.0 g, 47.30 mmol, 0.8 eq) were added, and the mixture was stirred at 25°C for 16 hours. After detecting complete reaction by LC-MS, the mixture was filtered, the filtrate was directly rotate-dried, and the compound was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (12.2 g). LC-MS(ESI)[M+Na] + = 467.4.

[0700] Step 4: Synthesis of (2-(((t-butyldiphenylsilyl)oxy)methyl)benzofuran-4-yl)methanol: The product obtained in Step 3 (12.2 g, 27.47 mmol, 1 eq) was dissolved in tetrahydrofuran (100 mL), lithium borohydride (1.79 g, 82.41 mmol, 3.0 eq) was added at 0°C, and the mixture was stirred at 25°C for 16 hours. After detecting complete reaction by LC-MS, water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and stirred. The mixture was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the target compound (7.64 g). LC-MS(ESI)[M+Na] + = 439.4.

[0701] Step 5: Synthesis of ((4-(bromomethyl)benzofuran-2-yl)methoxy)(t-butyl)diphenylsilane: The product obtained in Step 4 (2.0 g, 4.81 mmol, 1.0 eq) was added to dichloromethane (20 mL), phosphorus tribromide (1.95 g, 7.21 mmol, 1.5 eq) was added at 0°C, and the mixture was stirred for 2 hours. After detecting that the reaction was complete by TLC, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 100:1) to obtain the target compound (1.42 g).

[0702] Step 6: Synthesis of (R)-3-(2-(t-butoxy)-2-oxoethyl)pyrrolidine-1-carboxylate t-butyl: (R)-2-(1-(t-butoxycarbonyl)pyrrolidine-3-yl)acetic acid (25.0 g, 109.11 mmol, 1.0 eq) was dissolved in dichloromethane (200 mL), and at 25 °C, N,N'-dicyclohexylcarbodiimide (22.5 g, 109.11 mmol, 1.0 eq), t-butanol (24.25 mL, 327.33 mmol, 3.0 eq), and 4-dimethylaminopyridine (13.3 g, 109.11 mmol, 1.0 eq) were added. After the additions were complete, the mixture was stirred for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, water and ethyl acetate were added, and the mixture was extracted by liquid-liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This product was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (24.0 g).

[0703] Step 7: Synthesis of (3R)-3-(1-(t-butoxy)-3-(2-(((t-butyldiphenylsilyl)oxy)methyl)benzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: The product obtained in Step 6 (905 mg) was dissolved in tetrahydrofuran (10 mL), lithium bistrimethylsilylamide (4.8 mL) was slowly added dropwise at 0°C, and the mixture was stirred at 0°C for 30 minutes. The product from Step 5 (1.42 geq) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise to the aforementioned reaction mixture, and the mixture was stirred at 25°C for 3 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the target compound (1.67 g). LCMS(ESI)[M+H] + = 684.2.

[0704] Step 8: Synthesis of (3R)-3-(1-(t-butoxy)-3-(2-(hydroxymethyl)benzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (3R)-3-(1-(t-butoxy)-3-(2-(((t-butyldiphenylsilyl)oxy)methyl)benzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.67 g, 2.44 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (3.18 g, 12.2 mmol, 5.0 eq) was added at 25 °C. The mixture was stirred at room temperature for 2 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the mixture was filtered, and the organic phase was rotate-dried to obtain the target compound (1.8 g). LCMS(ESI)[M+Na] + = 468.4.

[0705] Step 9: Synthesis of (3R)-3-(1-(t-butoxy)-3-(2-formylbenzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: The product obtained in Step 8 (1.8 g, 4.04 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and manganese dioxide (1.75 g, 20.2 mmol, 5.0 eq) was added at 25 °C. The reaction mixture was stirred at 60 °C for 2 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the mixture was filtered, the organic phase was concentrated, and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 5:1) to obtain the target compound (894 mg). LC-MS(ESI)[M+Na] + = 476.4.

[0706] Step 10: Synthesis of 3,3'-((((((4-(3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)benzofuran-2-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): The product obtained in Step 9 (100 mg, 0.23 mmol, 1.0 eq) was dissolved in methanol (5 mL), and at 25°C, 3,3'-(((azandiylbis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (197.8 mg, 0.25 mmol, 1.1 eq) was added, and the mixture was stirred at 25°C for 30 minutes. Then sodium triacetoborohydride (146.2 mg, 0.69 mmol, 3.0 eq) was added, and the reaction was continued for 2 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, water was added and ethyl acetate was added. Extraction and liquid-liquid separation were performed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified on a silica gel plate (petroleum ether:ethyl acetate = 1:1) to obtain the target compound (65 mg). LCMS(ESI)[M+H] + = 1220.1.

[0707] Step 11: Synthesis of 3,3'-(((((4-(2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzofuran-2-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): The product obtained in Step 10 (65 mg) was dissolved in hydrochloric acid / 1,4-dioxane (1 mL) and stirred at 25°C for 2 hours. After detecting complete reaction by LC-MS, the mixture was concentrated to obtain the crude product and the Prep-HPLC target compound (4 mg). LC-MS (ESI) [M+H] + = 751.5. 1 H NMR(400MHz,MeOD-d4)δ 7.36-7.30(m,3H),7.26-7.21(m,4H),7.18-7.09(m,4H),6.85(s,1H),3.81-3.71(m,2H),3.67-3.60(m,4H),3.2 6-2.96(m,14H),2.81-2.64(m,5H),2.51-2.42(m,2H),2.42-2.30(m,3H),2.10-2.01(m,3H),1.84-1.57(m,3H).

[0708] Example 10 (Compound 11) Preparation of (2S,2'S)-3,3'-(((((6-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzo[b]thiophen-2-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0709] [ka]

[0710] Step 1: Synthesis of 3,3'-((2S,2'S)-(((((6-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)benzo[b]thiophen-2-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-1-(t-butoxy)-3-(2-formylbenzo[b]thiophen-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (86.7 mg, 0.189 mmol, 1.5 eq) was dissolved in methanol (5 mL), and 3,3'-((2S,2'S)-((azandiylbis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropan-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (100 mg, 0.126 mmol, 1.0 eq) and sodium borohydride cyanohydride (15.84 mg, 0.252 mmol, 2.0 eq) were added at room temperature. The mixture was stirred for 36 hours at room temperature. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (90 mg). LCMS(ESI)[M+H] + = 1235.8.

[0711] Step 2: Synthesis of (2S,2'S)-3,3'-(((((6-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzo[b]thiophen-2-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3'-((2S,2'S)-(((((6-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)benzo[b]thiophen-2-yl)methyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (90 mg, 0.07 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by preparative chromatography to obtain the target compound (32.96 mg). LCMS(ESI)[M+H] + = 767.4. 1 H NMR(400MHz, Deuterium Oxide)δ 7.78(d,J=8.2Hz,1H),7.70(s,1H),7.43(s,1H),7.30(dd,J=18.7,7.5Hz,5H),7.17(d,J=7. 6Hz,2H),7.12(s,2H),4.59(s,2H),4.35(s,4H),3.56(ddd,J=16.4,11.8,7.9Hz,3H),3.43- 3.34(m,3H),3.27-3.16(m,3H),3.08-2.90(m,5H),2.86-2.69(m,5H),2.64(td,J=9.6,5.0H z,2H),2.51(dq,J=17.4,8.7Hz,3H),2.18-2.04(m,3H),1.72(ddd,J=18.5,13.0,9.2Hz,3H).

[0712] Example 11 (Compound 49) Preparation of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid):

[0713] [ka]

[0714] Step 1: Synthesis of 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl): 3,3'-((2S,2'S)-((azandiylbis(methylene))bis(benzo[b]thiophene-3,5-diyl))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (40 mg, 0.04 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and then (R)-3-((S)-1-(t-butoxy)-3-(3-formylbenzo[b]thiophene-5-yl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate t-butyl (22.36 mg, 0.05 mmol, 1.1 eq) and sodium borohydride cyanohydride (2.74 mg, 0.04 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 16 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (40 mg). LCMS(ESI)[M+H] + = 1347.1.

[0715] Step 2: Synthesis of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl) (40 mg, 0.03 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by preparative chromatography to obtain the target compound (22.36 mg). LCMS(ESI)[M+H] + = 879.0. 1 H NMR(400MHz, Deuterium Oxide)δ 8.08-8.00(m,3H),7.92(d,J=8.3Hz,3H),7.23(dd,J=8.4,1.5Hz,3H),6.47(s,3 H),4.86(d,J=13.7Hz,3H),4.75(s,3H),3.37(ddd,J=12.0,10.0,5.6Hz,6H),3.2 1-3.13(m,3H),2.91(t,J=11.0Hz,3H),2.53(ddd,J=44.9,11.3,5.5Hz,6H),2.4 2-2.24(m,6H),2.05(dtd,J=13.6,7.0,3.3Hz,3H),1.65(dq,J=13.2,9.7Hz,3H).

[0716] Example 12 (Compound 65) Preparation of (2S,2'S,2”S)-3,3',3”-((nitrilotris(ethane-2,1-diyl))tris(phenyl-3,1-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid):

[0717] [ka]

[0718] Step 1: Synthesis of (R)-3-((S)-3-(3-allylphenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1500 mg, 3.3 mmol, 1.0 eq) is dissolved in 1,4-dioxane (20 mL), then 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxolane (1.11 g, 6.6 mmol, 2 eq) and potassium phosphate (2.1 g, 9.9 mmol, 3 eq) are added, and then water (4 mL) is added. The mixture was stirred at 90°C for 16 hours under nitrogen gas protection. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the target compound (900 mg). LCMS(ESI)[M+H] + = 416.3.

[0719] Step 2: Synthesis of (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-3-(3-allylphenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (900 mg, 2.17 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), sodium periodate (1.85 g, 8.66 mmol, 4 eq) and potassium osmate dihydrate (80 mg, 0.22 mmol, 0.1 eq) were added, and the mixture was stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate c=1:1) to obtain the target compound (600 mg). LCMS(ESI)[M+H] + = 418.3.

[0720] Step 3: Synthesis of 3,3'-((2S,2'S)-((Azandiylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl (400 mg, 0.96 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonia / methanol (16.31 mg, 0.96 mmol, 1.0 eq), 2 drops of acetic acid, and sodium borohydride cyanohydride (71 mg, 1.15 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (100 mg). LCMS(ESI)[M+H] + = 820.6.

[0721] Step 4: Synthesis of 3,3',3”-((2S,2'S,2”S)-((nitrilotris(ethane-2,1-diyl))tris(phenyl-3,1-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl): 3,3'-((2S,2'S)-((azandiylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (100 mg, 0.12 mmol, 1.0 eq) was dissolved in methanol (5 mL), and (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl (51 mg, 0.12 mmol, 1.0 eq), 2 drops of acetic acid, and sodium borohydride cyanohydride (7.5 mg, 0.12 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 16 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (80 mg). LCMS(ESI)[M+H] + = 1221.9.

[0722] Step 5: Synthesis of (2S,2'S,2”S)-3,3',3”-((nitrilotris(ethane-2,1-diyl))tris(phenyl-3,1-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3',3”-((2S,2'S,2”S)-((nitrilotris(ethane-2,1-diyl))tris(phenyl-3,1-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl) (80 mg) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by preparative chromatography to obtain the target compound (9.7 mg). LCMS(ESI)[M+H] + = 753.7. 1H NMR(400MHz, Deuterium Oxide)δ 7.21(t,J=7.5Hz,3H),7.09-6.99(m,9H),3.40-3.30(m,6H),3.14(ddd,J=11.7,9.9,7.3Hz,4H),2.96(d,J=7.5Hz,4H),2.85(dd,J=11.7 ,9.2Hz,4H),2.78(d,J=9.1Hz,7H),2.72-2.64(m,5H),2.39(dq,J=14.9,9.1,6.8Hz,6H),2.04(td,J=6.5,3.6Hz,3H),1.71-1.63(m,3H).

[0723] Example 13 (Compound 67) Preparation of (2S,2'S,2”S)-3,3',3”-((nitrilotris(ethane-2,1-diyl))tris(benzofuran-3,5-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid):

[0724] [ka]

[0725] Step 1: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-((E)-2-(hydroxyimino)ethyl)benzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(2-oxoethyl)benzofuran-5-yl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl (120 mg, 0.26 mmol, 1.0 eq) was dissolved in ethanol (10 mL), hydroxyamine hydrochloride (37 mg, 0.52 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 16 hours. After detecting that the reaction was complete by LC-MS, the reaction mixture was filtered, the filtrate was concentrated, and the compound was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (100 mg). LC-MS (ESI) [M+H] + = 473.2.

[0726] Step 2: Synthesis of (R)-3-((S)-3-(3-(2-aminoethyl)benzofuran-5-yl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-((E)-2-(hydroxyimino)ethyl)benzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (100 mg, 0.21 mmol, 1.0 eq) was dissolved in methanol (10 mL), palladium carbon (10 mg) was added, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 16 hours. After detecting that the reaction was complete by LC-MS, the reaction mixture was filtered and rotated dry, and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (70 mg). LC-MS(ESI)[M+H] + = 459.2.

[0727] Step 3: Synthesis of 3,3',3”-((2S,2'S,2”S)-((nitrilotris(ethane-2,1-diyl))tris(benzofuran-3,5-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-3-(3-(2-aminoethyl)benzofuran-5-yl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (100 mg, 0.22 mmol, 1.0 eq) was dissolved in methanol (10 mL), and (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(2-oxoethyl)benzofuran-5-yl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl (200 mg, 0.44 mmol, 2.0 eq) and sodium borohydride cyanohydride (27 mg, 0.44 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was cooled and concentrated, then separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the target compound (100 mg).

[0728] Step 4: Synthesis of (2S,2'S,2”S)-3,3',3”-((nitrilotris(ethane-2,1-diyl))tris(benzofuran-3,5-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3',3”-((2S,2'S,2”S)-((nitrilotris(ethane-2,1-diyl))tris(benzofuran-3,5-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl) (100 mg, 0.07 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (4 mL) and stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by preparative chromatography to obtain the target compound (6.58 mg). LCMS(ESI)[M+H] + = 873.2. 1H NMR(400MHz, Deuterium Oxide)δ 7.26-7.14(m,6H),6.94(s,6H),3.17(d,J=33.2Hz,4H),2.95(d,J=26.8Hz,5H),2.61 (d,J=51.5Hz,22H),2.41-2.10(m,7H),1.73(dd,J=101.8,31.7Hz,3H),1.08(s,1H).

[0729] Example 14 (Compound 71) Preparation of (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0730] [ka]

[0731] Step 1: Synthesis of (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.5 g) was dissolved in 1,4-dioxane (20 mL), bis(pinacolato)diborone (1.75 g), 1,1-bis(diphenylphosphine)ferocenedichloropalladium(II) (241.4 mg), and potassium acetate (972 mg) were added, water (4 mL) was added, and the mixture was stirred at 90°C for 16 hours under nitrogen gas protection. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the target compound (1.2 g). LCMS(ESI)[M+H-Boc] + = 402.2.

[0732] Step 2: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl (1200 mg) was dissolved in tetrahydrofuran (20 mL), hydrogen peroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the target compound (800 mg). LCMS(ESI)[M-2×t-butyl] + =280.

[0733] Step 3: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (500 mg) was dissolved in N,N-dimethylformylamine (5 mL), and 2-(2-bromoethyl)isoindoline-1,3-dione (649 mg) and potassium carbonate (530 mg) were added. The mixture was stirred at 90°C for 2 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the target compound (280 mg). LCMS(ESI)[M+H] + = 565.3.

[0734] Step 4: Synthesis of (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (280 mg) was dissolved in ethanol (10 mL), hydrazine hydrate (124 mg) was added, and the mixture was stirred at 90°C for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:5) to obtain the target compound (160 mg). LCMS(ESI)[M+H] + = 435.3.

[0735] Step 5: Synthesis of 3,3'-((2S,2'S)-((((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)ethyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (80 mg) was dissolved in methanol (10 mL), and (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl (154 mg) and sodium borohydride cyanohydride (23 mg) were added. The mixture was stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (100 mg). LCMS(ESI)[M+H] + = 1237.9.

[0736] Step 6: Synthesis of (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3'-((2S,2'S)-((((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)ethyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (100 mg) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by preparative chromatography to obtain the target compound (27.9 mg). LCMS(ESI)[M+H] + = 769.5. 1H NMR(400MHz, Deuterium Oxide)δ 7.24-7.09(m,4H),7.00(q,J=8.0Hz,5H),6.82(d,J=7.4Hz,1H),6.73(d,J=8.3Hz,2H),4.17-4.06(m,2H),3.39-3.28(m,6H),3.17-3 .03(m,5H),2.90(d,J=9.4Hz,3H),2.86-2.58(m,14H),2.37(td,J=17.0,15.4,6.6Hz,6H),2.02(s,3H),1.66(dd,J=14.2,6.5Hz,3H).

[0737] Example 15 (Compound 80) Preparation of (2S,2S)-3,3'-((2,2'-((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)azandiyl)bis(acetyl))bis(3,1-phenylene))bis(2((R)-pyrrolidine-3-yl)propionic acid):

[0738] [ka]

[0739] Step 1: Synthesis of (3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)boric acid: (3R)-3-[(2S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate t-butyl (1900 mg, 4.18 mmol, 1 eq), (dihydroxyboryl)boric acid (562.29 mg, 6.27 mmol, 1.5 eq), potassium acetate (1230.7 mg, 12.54 mmol, 3 eq), dicyclohexyl[2',4',6'-tris(propyl-2-yl)-[1,1'-bife Nyl-2-ylphosphine (199.27 mg, 0.42 mmol, 0.1 eq) and XPhosPdG2 (164 mg, 0.21 mmol, 0.05 eq) were added to ethanol (20 mL), the reaction mixture was purged three times with nitrogen gas, stirred at 90°C for 16 hours, and liquid chromatography-mass spectrometry was used to detect that the reaction was complete. Ethyl acetate was then added, filtered through diatomaceous earth, and the filtrate was rotary-dried to obtain the target compound (2000 mg), which was used directly in the next step.

[0740] Step 2: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: {3-[(2S)-3-(t-butoxy)-2-[(3R)-1-[(t-butoxy)carbonyl]pyrrolidine-3-yl]-3-oxypropyl]phenyl}boric acid (2000 mg, 4.77 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL), hydrogen peroxide (8 mL) was added, and the mixture was stirred at 20°C for 16 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, saturated sodium bisulfite solution and ethyl acetate were added, and the mixture was extracted by liquid-liquid extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the target compound (800 mg). LCMS(ESI)[M+H] + = 392.2.

[0741] Step 3: Synthesis of (R)-3-((S)-3-(3-(2-(((benzyloxy)carbonyl)amino)ethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (3R)-3-[(2S)-1-(t-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate t-butyl (2 g, 5.11 mmol, 1 eq), benzyl (2-bromoethyl)carbamate (2.64 g, 10.22 mmol, 2 eq), and potassium carbonate (2.12 g, 15.33 mmol, 3 eq) were added to acetonitrile (50 mL), stirred at 90°C for 16 hours, and liquid chromatography-mass spectrometry was used to detect complete reaction. The reaction mixture was then purified by direct column chromatography (petroleum ether / ethyl acetate = 7:1) to obtain the target compound (3 g). LCMS(ESI)[M+H] + = 569.0.

[0742] Step 4: Synthesis of (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-3-(3-(2-(((benzyloxy)carbonyl)amino)ethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (3 g, 5.27 mmol, 1 eq) was dissolved in methanol (50 mL), palladium (300 mg, 10%) was added, the mixture was purged three times with hydrogen gas, and stirred at 25 °C for 16 hours. After detecting completion of the reaction by LC-MS, the reaction mixture was filtered, and the filtrate was concentrated to obtain the target compound (2 g). LC-MS (ESI) [M+H] + = 435.4.

[0743] Step 5: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-(2-chloroacetyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-(methoxycarbonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (700 mg, 1.614 mmol, 1 eq) is dissolved in anhydrous tetrahydrofuran (10 mL), cooled to -78°C, diisopropylaminolithium (1.0 M, 2.42 mL, 2.42 mmol, 1.5 eq) is added, and the mixture is stirred at -78°C for 1 hour. Domethanum (854.03 mg, 4.84 mmol, 3 eq) was added, and the mixture was stirred at -78°C for 2 hours. After detecting that the reaction was complete by LC-MS, saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. Extraction and liquid-liquid separation were performed, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the target compound (100 mg). LC-MS(ESI)[M+H-Boc] + = 352.4.

[0744] Step 6: Synthesis of 3,3'-((2S,2'S)-((2,2'-((2-((3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)ethyl)azandiyl)bis(acetyl))bis(3,1-phenylene))bis(1-(t-butoxy)-1-oxopropane-3,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (192.2 mg, 0.44 mmol, 2 eq) and (R)-3-((S)-1-(t-butoxy)-3-(3-(2-chloroacetyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (100 mg, 0.22 mmol, 1 eq) were dissolved in acetonitrile (3 mL), anhydrous potassium carbonate (91.1 mg, 0.66 mmol, 3 eq) was added, and the mixture was stirred at 60°C for 2 hours. After detecting complete reaction by LC-MS, the reaction mixture was directly concentrated and purified on a silica gel plate (petroleum ether:ethyl acetate = 1:1) to obtain the target compound (50 mg). LC-MS (ESI) [M+H] + = 1265.3.

[0745] Step 7: Synthesis of (2S,2S)-3,3'-((2,2'-((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)azandiyl)bis(acetyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): Under ice bath conditions, 3,3'-((2S,2'S)-((2,2'-((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)ethyl)azandiyl)bis(acetyl))bis(3,1-phenylene))bis(1-(t-butoxy)-1-oxopropane-3,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (50 mg, 0.04 mmol, 1 eq) was added to hydrochloric acid / 1,4-dioxane (2 mL, 4.0 M), stirred at 25°C for 6 hours, and after detecting completion of the reaction by LC-MS, the reaction mixture was directly concentrated to obtain the crude product, which was purified by Prep-HPLC to obtain the target compound (6 mg). LCMS(ESI)[MH] -= 795.6. 1H NMR(400MHz,DMSO)δ7.90(s,2H),7.81(d,J=8.0Hz,2H),7.63(d,J=7.6Hz,2H),7.53(d,J=8.0Hz,2H),7.10(t,J=8.0Hz,1H),6.76(d,J=7.6Hz) ,1H),6.53-6.45(m,2H),5.34(s,3H),4.46(s,2H),3.92(s,2H),3.34- 2.69(m,25H),2.41-2.32(m,3H),2.03-1.95(m,3H),1.69-1.62(m,3H).

[0746] Example 16 (Compound 81) Preparation of (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)acetyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0747] [ka]

[0748] Step 1: Synthesis of 3,3'-((2S,2'S)-((Azandiylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-3-(3-(2-aminoethyl)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (100 mg) was dissolved in methanol (10 mL), and (R)-3-((S)-1-(t-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propyl-2-yl)pyrrolidine-1-carboxylate t-butyl (100 mg) and sodium borohydride cyanohydride (15 mg) were added. The mixture was stirred at room temperature for 16 hours. After detecting that the reaction was complete by liquid chromatography-mass spectrometry, the reaction mixture was cooled and concentrated, and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the target compound (100 mg). LCMS(ESI)[M+H] + = 820.6.

[0749] Step 2: Synthesis of 3,3'-((2S,2'S)-((((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)acetyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): 3,3'-((2S,2'S)-((Azandiylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (100 mg), 2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)acetic acid (82 mg), O-(7-azabenzotriazolyl-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (93 mg) and diisopropylethylamine (47 mg) were added, and the mixture was stirred at room temperature for 16 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was diluted with water, extracted with ethyl acetate, the organic phase was dried and filtered, concentrated to obtain the crude product, and separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 1:8) to obtain the target compound (70 mg). LCMS(ESI)[M+H-Boc] + = 1152.0.

[0750] Step 3: Synthesis of (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)acetyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3'-((2S,2'S)-((((2-(3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenoxy)acetyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (70 mg) was dissolved in hydrochloric acid / 1,4-dioxane (4 mL) and stirred at room temperature for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the reaction mixture was directly concentrated and separated and purified by preparative chromatography to obtain the target compound (13.41 mg). LCMS(ESI)[M+H] + = 783.1. 1 H NMR(400MHz, Deuterium Oxide)δ 7.21(td,J=7.7,2.0Hz,2H),7.14-6.99(m,7H),6.80(d,J=7.6Hz,1H),6.57(t,J=2. 1Hz,1H),6.08(dd,J=8.2,2.6Hz,1H),4.14-4.04(m,2H),3.63-3.55(m,2H),3.41-3. 26(m,7H),3.14(dddd,J=25.2,23.0,11.2,4.0Hz,4H),2.87-2.63(m,12H),2.60-2. 54(m,1H),2.43-2.25(m,6H),2.10-1.98(m,3H),1.66(td,J=12.8,11.1,7.5Hz,3H).

[0751] Example 17 (Compound 90) Preparation of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene-d2))tris(phenyl-3,1-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid):

[0752] [ka]

[0753] Step 1: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-(hydroxymethyl-d2)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-(methoxycarbonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.2 g, 2.77 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (14.4 mL) and deuterated methanol (4.2 mL). Under nitrogen gas protection, sodium borohydride deuteride (695.19 mg, 16.61 mmol, 6 eq) was added in batches, and the mixture was stirred at 70°C for 3 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the mixture was cooled to room temperature, heavy water (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified on a silica gel plate (petroleum ether / ethyl acetate = 2:1) to obtain the target compound (600 mg). LCMS(ESI)[M+Na] + = 430.2.

[0754] Step 2: Synthesis of (R)-3-((S)-3-(3-(bromomethyl-d2)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-(hydroxymethyl-d2)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (600 mg, 1.47 mmol, 1 eq) was dissolved in dichloromethane (5 mL), cooled to 0°C, and triphenylphosphine (1158.47 mg, 4.42 mmol, 3 eq) and N-bromosuccinimide (786.09 mg, 4.42 mmol, 3 eq) were added. The mixture was stirred at room temperature for 2 hours, and after detecting that the reaction was complete by liquid chromatography-mass spectrometry, water and dichloromethane were added. Extraction and liquid-liquid separation were performed, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. This was purified on a silica gel plate (petroleum ether / ethyl acetate = 3:1) to obtain the target compound (400 mg). LCMS(ESI)[M+Na] + = 492.7.

[0755] Step 3: Synthesis of 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene-d2))tris(phenyl-3,1-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-3-(3-(aminomethyl-d2)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (30 mg, 0.07 mmol, 1 eq), (R)-3-((S)-3-(3-(bromomethyl-d2)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (69.43 mg, 0.15 mmol, 2 eq) and potassium carbonate (30.6 mg, 0.22 mmol, 3 eq) were added to acetonitrile (1 mL), the reaction was heated to 60°C and stirred for 4 hours, and completion of the reaction was detected by liquid chromatography-mass spectrometry. The reaction mixture was filtered, and the filtrate was purified directly on a silica gel plate (petroleum ether / ethyl acetate = 3:1) to obtain the target compound (55 mg), which was then analyzed by LC-MS (ESI) [M+H]. + = 1185.8.

[0756] Step 4: Synthesis of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene-d2))tris(phenyl-3,1-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene-d2))tris(phenyl-3,1-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl) (50 mg, 0.04 mmol, 1 eq) was added to hydrochloric acid / 1,4-dioxane (3.0 mL, 4 M), stirred at 25°C for 2 hours, and liquid chromatography-mass spectrometry detected that the reaction was complete. The reaction mixture was then filtered, and the filtered cake was freeze-dried with acetonitrile and water to obtain the target compound (25.84 mg), with LCMS(ESI)[MH]-=715.5. 1 H NMR(400MHz,D2O)δ 7.38-7.27(m,6H),7.1-7.11(m,6H),3.61-3.51(m,3H),3.38-3.33(m,3H),3.28-3.16(m,3H),3.07-2.98(m,3H), 2.91-2.87(m,3H),2.84-2.74(m,3H),2.68-2.58(m,3H),2.53-2.47(m,3H),2.15-2.09(m,3H),1.78-1.65(m,3H).

[0757] Example 18 (Compound 91) Preparation of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene))tris(phenyl-3,1-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid-3,3-d2):

[0758] [ka]

[0759] Step 1: Synthesis of (R)-3-((S)-1-((S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromophenyl)-1-oxopropan-2-yl-3,3-d2)pyrrolidine-1-carboxylate t-butyl: Under ice bath and nitrogen gas protection, a solution of bis(trimethylsilyl)aminolithium (7.08 mL, 7.08 mmol, 1.1 eq, 1.0 M) was added dropwise to a solution of (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidine-3-yl]-2-oxo-ethyl]pyrrolidine-1-carboxylate t-butyl (2.5 g, 6.44 mmol, 1 eq) in tetrahydrofuran (30 mL). The mixture was stirred at 0°C for 30 minutes, and a solution of 1-bromo-3-(chloromethyl-d2)benzene (1.47 g, 7.08 mmol, 1.1 eq) in tetrahydrofuran (2 mL) was slowly added dropwise. After the addition was complete, the reaction temperature was slowly raised to room temperature and the mixture was stirred for 16 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was cooled in an ice bath, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then purified by column chromatography to obtain the target product (3.1 g). LCMS(ESI)[M+Ht-butyl] + = 503.2.

[0760] Step 2: Synthesis of (S)-3-(3-bromophenyl)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)propionic acid-3,3-d2: Hydrogen peroxide solution (275 mg, 8.1 mmol, 1.5 eq) was added to a solution of (R)-3-((S)-1-((S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromophenyl)-1-oxopropan-2-yl-3,3-d2)pyrrolidine-1-carboxylate t-butyl (3 g, 5.28 mmol, 1 eq) in tetrahydrofuran (120 mL), cooled in an ice bath, and an aqueous solution of lithium hydroxide (192 mg, 8.1 mmol, 1.5 eq) (10 mL) was added. The mixture was stirred at 25°C for 2.5 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the reaction mixture was cooled to 0°C, and aqueous solutions of sodium bisulfite (1 g) (5 mL) and sodium hydroxide (5 N) were added to adjust the pH of the reaction mixture to greater than 12. Water and methyl t-butyl ether were added, and the mixture was extracted by liquid-liquid extraction. The organic phase was discarded, and hydrochloric acid solution (5 N) was added to the aqueous phase to bring the pH to 3. Extraction was performed with methyl t-butyl ether, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (1.8 g). LCMS(ESI)[M+H-Boc] + = 300.20.

[0761] Step 3: Synthesis of (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl-3,3-d2)pyrrolidine-1-carboxylate t-butyl: (S)-3-(3-bromophenyl)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)propionic acid-3,3-d2 (1.8 g, 4.5 mmol, 1 eq) was dissolved in 2-methyltetrahydrofuran (50 mL), and ot-butyl-N,N'-diisopropylisourea (4.5 g, 22.5 mmol, 5 eq) was added. The mixture was heated to 65°C under nitrogen gas protection and stirred for 16 hours. After detecting the completeness of the reaction by liquid chromatography-mass spectrometry, the insoluble matter was filtered off, the filter cake was washed with methyl t-butyl ether, and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (0.6 g). LCMS(ESI)[M+H-2×t-butyl]+ =344.16.

[0762] Step 4: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl-3,3-d2)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-3-(3-bromophenyl)-1-(t-butoxy)-1-oxopropan-2-yl-3,3-d2)pyrrolidine-1-carboxylate t-butyl (0.6 g, 1.31 mmol, 1 eq) was dissolved in N,N-dimethylformylamine (4 mL), and palladium acetate (59 mg, 0.26 mmol, 0.2 eq), 1,4-bis(diphenylphosphine)butane (112 mg, 0.26 mmol, 0.2 eq), N-formylsaccharin (691 mg, 3.296 mmol, 2.5 eq), sodium carbonate (418 mg, 3.94 mmol, 3 eq), and triethylsilane (305 mg, 2.63 mmol, 2 eq) were added. The mixture was heated to 75°C under nitrogen gas protection and stirred for 16 hours. After detecting complete reaction by liquid chromatography-mass spectrometry, the insoluble material was filtered, the filter cake was washed with methyl t-butyl ether, the filtrate was concentrated, and the product was separated and purified by high-performance chromatography (Silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target product (165 mg). LCMS(ESI)[M+H-Boc] + = 306.35.

[0763] Step 5: Synthesis of 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene))tris(phenyl-3,1-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl-1,1-d2))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-1-(t-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl-3,3-d2)pyrrolidine-1-carboxylate t-butyl (160 mg, 0.39 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and ammonia was added in methanol (0.018 mL, 0.13 mmol, 0.33 eq, 7.0 M), sodium borohydride (61 mg, 0.97 mmol, 2.5 eq), and one drop of acetic acid. The mixture was stirred overnight at room temperature, and after detecting complete reaction by liquid chromatography-mass spectrometry, saturated ammonium chloride solution was added to quench the reaction. Ethyl acetate and water were added, and the mixture was extracted by liquid-liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography to obtain the product (40 mg). LCMS(ESI)[M+H] + = 1186.02.

[0764] Step 6: Synthesis of (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene))tris(phenyl-3,1-diyl))tris(2-((R)-pyrrolidine-3-yl)propionic acid-3,3-d2): 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene))tris(phenyl-3,1-diyl))tris(3-(t-butoxy)-3-oxopropane-1,2-diyl-1,1-d2))(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate t-butyl) (30 mg, 0.03 mmol, 1 eq) was dissolved in 1 mL of 1,4-dioxane, hydrochloric acid / 1,4-dioxane (1 mL, 4.0 M) was added, and the mixture was stirred overnight at room temperature. The complete reaction was monitored by liquid chromatography-mass spectrometry. The solvent was rotated dry and separated and purified by Prep-HPLC. 18 10 mmol / LNH4HCO3in water (MeCN) was used to obtain the target compound (4.5 mg). LC-MS (ESI) [M+H] + = 717.63. 1H NMR(400MHz, Deuterium Oxide)δ 8.37(s,2H),7.40-7.25(m,6H),7.24-7.09(m,6H),4.19(s,6H),3.56-3.43(m,3H),3.40-3.29(m,3 H),3.26-3.13(m,3H),3.00-2.87(m,3H),2.49-2.30(m,6H),2.15-1.97(m,3H),1.75-1.59(m,3H).

[0765] Example 19 (Compound 93) Preparation of (2S,2'S)-3,3'-((((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azandiyl)bis(methylene-d2))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid):

[0766] [ka]

[0767] Step 1: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-(hydroxymethyl-d2)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-(methoxycarbonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.2 g, 2.77 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (14.4 mL) and deuterated methanol (4.2 mL). Under nitrogen gas protection, sodium borohydride deuteride (695.19 mg, 16.61 mmol, 6 eq) was added in batches, and the mixture was stirred at 70°C for 3 hours. When the reaction was confirmed to be complete by liquid chromatography-mass spectrometry, the reaction mixture was cooled to room temperature, heavy water (5 mL) was added, and the mixture was stirred for 10 minutes. Water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the target compound (600 mg). LCMS(ESI)[M+Na] + = 430.2.

[0768] Step 2: Synthesis of (R)-3-((S)-3-(3-(bromomethyl-d2)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: (R)-3-((S)-1-(t-butoxy)-3-(3-(hydroxymethyl-d2)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (600 mg, 1.47 mmol, 1 eq) was dissolved in dichloromethane (5 mL), cooled to 0°C, and triphenylphosphine (1158.47 mg, 4.42 mmol, 3 eq) and N-bromosuccinimide (786.09 mg, 4.42 mmol, 3 eq) were added under an ice bath. The mixture was stirred at room temperature for 2 hours, and after detecting that the reaction was complete by LC-MS, water and dichloromethane were added. Extraction and liquid-liquid separation were performed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the target compound (400 mg). LC-MS(ESI)[M+Na] + = 491.7.

[0769] Step 3: Synthesis of 3,3'-((2S,2'S)-((((3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)benzyl)azandiyl)bis(methylene-d2))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl): (R)-3-((S)-3-(3-(aminomethyl)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (40 mg, 0.1 mmol, 1 eq), (R)-3-((S)-3-(3-(bromomethyl-d2)phenyl)-1-(t-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (93.03 mg, 0.2 mmol, 2 eq), and potassium carbonate (41 mg, 0.3 mmol, 3 eq) were added to acetonitrile (1 mL). The reaction mixture was stirred at 60°C for 4 hours. After detecting complete reaction by LC-MS, the reaction mixture was filtered to obtain the crude product, which was purified on a large silica gel plate (petroleum ether / ethyl acetate = 3:1) to obtain the target compound (60 mg). LC-MS (ESI) [M + Na] + = 1205.6.

[0770] Step 4: Synthesis of (2S,2'S)-3,3'-((((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azandiyl)bis(methylene-d2))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid): 3,3'-((2S,2'S)-((((3-((S)-3-(t-butoxy)-2-((R)-1-(t-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)benzyl)azandiyl)bis(methylene-d2))bis(3,1-phenylene))bis(3-(t-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate t-butyl) (70 mg, 0.06 mmol, 1 eq) was added to hydrochloric acid / 1,4-dioxane (3 mL, 4.0 M), stirred at 25°C for 2 hours, and after detecting completion of the reaction by LC-MS, the reaction mixture was filtered and lyophilized with acetonitrile and water to obtain the target compound (41.67 mg). LC-MS(ESI)[M+H] + =715.2.1HNMR(400MHZ,D2O)δ 7.41-7.26(m,6H),7.15-7.11(m,6H),4.25-421(m,2H),3.59-353(m,3H)3.39-3.34(m,3H),3.27-3.17(m,3H),3 .08-2.98(m,3H),2.92-2.87(m,3H),2.85-2.64(m,6H),2.53-2.48(m,3H),2.21-2.02(m,3H),1.78-1.63(m,3H).

[0771] Example 20 (Compound 94) Preparation of (2S,2'S)-3,3'-(((((3-((S)-2-carboxyl-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)methyl-d2)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride:

[0772] [ka]

[0773] Step 1: Synthesis of (R)-3-((S)-1-(t-butoxy)-3-(3-cyanophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl: Oxalyl chloride (365 mg) was added to acetonitrile (10 mL), and the reaction mixture was cooled to 0°C under nitrogen gas protection. N,N-dimethylformylamine (262 mg) was added to the reaction mixture and stirred for 40 minutes. (R)-3-((S)-1-(t-butoxy)-3-(3-carbamoylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (1.0 g) was added in a solution of N,N-dimethylformylamine (10 mL) and stirred for 3 hours. Complete reaction was detected by TLC. Triethylamine (1 mL) was added, and the reaction mixture was rotate-dried to obtain the crude product. The product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the target compound (500 mg). LCMS(ESI)[M+Na] + = 423.2.

[0774] Step 2: Synthe...

Claims

1. The following compounds: Or a pharmaceutically acceptable salt of the compound.

2. The following compounds: The compound according to claim 1.

3. The following compounds: A pharmaceutically acceptable salt of the compound according to claim 1, which is a pharmaceutically acceptable salt of the compound according to claim 1.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable auxiliary material.

5. The pharmaceutical composition according to claim 4 for preventing and / or treating a disease or condition associated with elevated Lp(a) plasma levels.

6. The pharmaceutical composition according to claim 5, wherein the disease or condition associated with the elevation of the Lp(a) plasma level is a cardiovascular disease (CVD).

7. The pharmaceutical composition according to claim 6, wherein the cardiovascular disease (CVD) is selected from the group consisting of atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, aortic valve stenosis, heart failure, and atrial fibrillation.

8. The pharmaceutical composition according to claim 7, wherein the atherosclerotic cardiovascular disease (ASCVD) is selected from the group consisting of peripheral vascular disease, coronary heart disease, and ischemic stroke.

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