Polycyclic aromatic compound, composition thereof and use thereof

Abstract

The present invention relates to a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer or isotopically labeled substance thereof, a pharmaceutical composition thereof, and the use thereof in the preparation of a drug for treating a disease associated with elevated plasma Lp(a) levels.

Description

Polyaromatic compounds, their compositions and uses

[0001] This application claims priority to the following Chinese applications: 202411903166.4 (filed December 20, 2024), 202510321637.9 (filed March 17, 2025), 202510815722.0 (filed June 17, 2025), 202511151612.5 (filed August 15, 2025), and 202511565806.X (filed October 29, 2025), all of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure relates to a polyaromatic ring compound that reduces Lp(a) levels, its pharmaceutically acceptable salt, stereoisomer or isotopic label, and pharmaceutical compositions thereof and their applications. Background Technology

[0003] Hyperlipidemia is a major risk factor for atherosclerosis and is closely related to cardiovascular disease, seriously threatening human health. In the human body, blood lipids must bind with apolipoproteins to form lipoproteins in order to dissolve in the blood and be transported to tissues for metabolism. Lipoproteins include: chylomicrons (CM), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein (Lp(a)).

[0004] Lp(a) readily deposits on blood vessel walls and can lead to the formation of atherosclerotic lesions through various mechanisms, its atherogenic effect being comparable to that of LDL-C. Furthermore, Lp(a) also has a thrombotic effect. Lp(a) is synthesized in the liver and secreted into the bloodstream, primarily depositing in vascular tissue and aortic valve leaflets. The lipid composition of Lp(a) is similar to that of LDL; however, Lp(a) contains a specific apolipoprotein, apo(a), which is bound to apo B100 disulfide bonds. Apo(a) is a highly glycosylated hydrophilic protein with structural polymorphism, accounting for 25%–40% of the total Lp(a) protein, and is key to Lp(a)'s role in causing atherosclerotic cardiovascular disease (ASCVD).

[0005] While some progress has been made in the development of drugs for treating cardiovascular diseases, it remains necessary to further develop cardiovascular drugs that meet clinical needs.

[0006] Invention Overview

[0007] One object of this disclosure is to provide a polyaromatic ring compound as shown in formula (I), its pharmaceutically acceptable salt, stereoisomer, or isotopic label. The compound has the effect of reducing Lp(a) levels.

[0008] According to one aspect of this disclosure, this disclosure provides compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers or isotopic labels,

[0009] in,

[0010] P is selected from aryl, heteroaryl, or heterocyclic groups, which are optionally substituted with R6, wherein the heteroaryl or heterocyclic group has one or more heteroatoms selected from N, O, and S, and at least one heteroatom is selected from N, the heteroaryl or heterocyclic group is optionally oxidized, and the aryl, heteroaryl, or heterocyclic group may have 1, 2, or 3 rings, and each ring in the heteroaryl or heterocyclic group may be, for example, a 3- to 7-membered ring;

[0011] R6 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy groups and halogens;

[0012] R1 and R2 are independently selected from hydrogen, halogen (e.g., F), and C, respectively. 1-6 Alkyl and C 1-6 Alkoxy group, wherein the alkyl group is optionally substituted with 1-3 F atoms;

[0013] R', R” and R”' are independently selected from hydrogen, C 1-6 Alkanes or C 3-6 Cycloalkanes;

[0014] X1 and X2 are independently selected from N and CH, respectively;

[0015] Y1, Y2, and Y3 are independently selected from -CH2-, -CO-, -SO2-, and -(CR4R), respectively. 4’ ) n O-、-(CR4R 4’ ) n N-、-CONHR 5 -, -CONH2-, -O-, -(CR4R) 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n O-、-(CR4R 4’ )n N-, -(CR4R 4’ ) n -、-(CR4R 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-; Both ends of the aforementioned groups can be connected to Z;

[0016] Wherein, K is selected from N or CH; Q is selected from nitrogen-containing heterocycles or saturated carbon rings, and is optionally C 1-6 Alkyl (e.g., C) 1-3 Alkyl groups or halogens (such as F) are substituted; or

[0017] Z is selected from Where W = CH or N; R y Selected from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Alkoxy group, wherein the alkyl group is optionally substituted with 1-3 F atoms;

[0018] A is selected from single bonds, -(CR4R) 4’ ) n -、-CO(CR4R 4’ ) n - and -SO2(CR4R 4’ ) n -;

[0019] 'a' represents the position where Z connects to Y1, Y2, and Y3;

[0020] R4,R 4’ Independently selected from hydrogen and C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0021] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0022] n is selected from 0, 1, or 2; or

[0023] The cycloalkyl or N-containing heterocyclic group as defined in Z (e.g., the cycloalkyl or N-containing heterocyclic group has 3-7 ring atoms), optionally surrounded by 0-5 R atoms. XGroup substitution, wherein the cycloalkyl or N-containing heterocyclic group optionally forms a cyclic ring with a 6-membered aryl or a 5-6-membered heteroaryl; the nitrogen-containing heterocyclic group optionally is oxidized; the nitrogen atom of the nitrogen-containing heterocyclic group optionally connects to Y1, Y2 or Y3; R x Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Alkyl group; when Z is substituted by two or more Rx groups, and Rx is C. 1-6 When alkyl, then two arbitrary R X The ring represented by Z forms a fused ring, bridged ring, or spirocyclic structure; the heteroatoms of the heterocyclic or heteroaryl group are selected from N, O, and S.

[0024] According to some embodiments of this disclosure, in formula (I), In this case, K is selected from N.

[0025] According to some embodiments of this disclosure, in formula (I), when Q is selected from a nitrogen-containing heterocycle, it is selected from a 3-7 member monocyclic ring or a bicyclic nitrogen-containing heterocycle composed of two 3-7 member rings; when Q is selected from a saturated carbide ring, it is selected from C 3-8 Cycloalkyl.

[0026] According to some embodiments of this disclosure, in formula (I), when Q is selected from a nitrogen-containing heterocycle, the nitrogen heteroatom therein is attached to A or one of Y1, Y2 and Y3.

[0027] According to some embodiments of this disclosure, in formula (I),

[0028] Z is selected from the following nitrogen-containing heterocycles: or

[0029] Z is selected from the following saturated carbon rings:

[0030] R x Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Alkoxy;

[0031] B = -O- or does not exist; C = -O-, -NR4-, -CH2O-, -CHNR4- or -SO2-;

[0032] m and n are independently selected from 0, 1, or 2;

[0033] m' and n' are independently selected from 0, 1, or 2.

[0034] According to some embodiments of this disclosure, in formula (I), when Z has a nitrogen-containing heterocycle, the nitrogen atom of the nitrogen-containing heterocycle is attached to one of Y1, Y2, and Y3, and one of Y1, Y2, and Y3 is selected from -CO-, -SO2-, and -CONHR. 5-, -CONH2-, -(CR4R 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-; or

[0035] The nitrogen atom of the nitrogen-containing heterocycle in Z is attached to A, and A is selected from -CO(CR4R) 4’ ) n -or-SO2(CR4R) 4’ ) n -

[0036] According to some embodiments of this disclosure, in formula (I), the nitrogen atom of the nitrogen-containing heterocycle in Z is attached to one of Y1, Y2, and Y3, and one of Y1, Y2, and Y3 is selected from -CO-, -SO2-, and -(CR4R). 4’ ) n CO- and -(CR4R) 4’ ) n SO2-.

[0037] According to some embodiments of this disclosure, K is selected from N, and when Z has a saturated carbon ring, A is selected from -CO(CR4R) 4’ ) n -or-SO2(CR4R) 4’ ) n -; or one of Y1, Y2, and Y3 connected to K is selected from -CO(CR4R) 4’ ) n -or-SO2(CR4R) 4’ ) n -

[0038] According to some embodiments of this disclosure, in formula (I), when P is selected from heteroaryl or heterocyclic group, it can be a nitrogen-containing 5-7 membered heteroaryl or 5-7 membered heterocyclic group; for example, P can be triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, pyrazolyl; the carbon ring atom of the above groups may be oxidized.

[0039] According to one aspect of this disclosure, this disclosure provides compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers or isotopic labels,

[0040] in,

[0041] P is selected from heteroaryl or heterocyclic groups, which are optionally substituted with R6, wherein the heteroaryl or heterocyclic group has one or more heteroatoms selected from N, O and S, and at least one N, and the heteroaryl or heterocyclic group is optionally oxidized to form a cyclic lactam;

[0042] Y1, Y2, and Y3 are independently selected from -CH2-, -CO-, -SO2-, and -(CR4R), respectively. 4’ ) n O-、-(CR4R 4’ ) n N-、-CONHR 5 -, -CONH2-, -O-, -(CR4R) 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n O-、-(CR4R 4’ ) n N-, -(CR4R 4’ ) n -、-(CR4R 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-;

[0043] Both ends of the groups defined above as Y1, Y2, and Y3 can be connected to Z;

[0044] or

[0045] P is selected from heteroaryl or heterocyclic groups, which are optionally substituted with R6, wherein the heteroaryl or heterocyclic group has one or more heteroatoms selected from N, O and S, and at least one N heteroatom is selected from N, and the N heteroatom is connected to Y3; the heteroaryl or heterocyclic group is optionally oxidized;

[0046] Y1 and Y2 are independently selected from -CH2-, -CO-, -SO2-, and -(CR4R) respectively. 4’ ) n O-、-(CR4R 4’ ) n N-、-CONHR 5 -, -CONH2-, -O-, -(CR4R) 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n O-、-(CR4R 4’ ) n N-, -(CR4R 4’ ) n -、-(CR4R 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-;

[0047] Y3 is selected from -CO-, -SO2-, and -CONHR. 5 -, -CONH2-, -(CR4R 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-;

[0048] The two ends of the groups defined above, Y1, Y2 and Y3, can be connected to Z;

[0049] Furthermore, in equation (I),

[0050] R6 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy groups and halogens;

[0051] R1 and R2 are independently selected from hydrogen, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy group, wherein the alkyl group is optionally substituted with 1-3 F atoms;

[0052] X1 and X2 are independently selected from N and CH, respectively;

[0053] R4,R 4’ Independently selected from hydrogen and C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0054] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0055] n is selected from 0, 1, or 2;

[0056]

[0057] 'a' represents the position connecting Y1, Y2, and Y3.

[0058] R5' is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0059] R',R” and R”' are selected from hydrogen, C 1-6 Alkanes or C 3-6 Cycloalkanes.

[0060] According to some embodiments of this disclosure, in formula (I), P can be selected from a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group containing an N heteroatom; for example, P is selected from triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, and pyrazolyl.

[0061] According to another aspect of this disclosure, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) of this disclosure or a pharmaceutically acceptable salt, stereoisomer, or isotopic label thereof.

[0062] According to another aspect of this disclosure, the disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or isotopic label thereof in the preparation of a medicament that reduces Lp(a) levels.

[0063] According to another aspect of this disclosure, the disclosure provides the use of compounds of formula (I) of this disclosure or pharmaceutically acceptable salts, stereoisomers or isotopic labels thereof in the preparation of medicaments for treating diseases with elevated Lp(a) plasma levels. Such diseases include, for example, cardiovascular diseases.

[0064] According to another aspect of this disclosure, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or isotopic label thereof for use in treatment.

[0065] According to another aspect of this disclosure, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or isotopic label thereof for use in reducing Lp(a) levels or treating diseases with elevated Lp(a) plasma levels.

[0066] According to another aspect of this disclosure, this disclosure provides a method for treating a disease with elevated Lp(a) plasma levels, comprising the step of administering a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or isotopic label thereof.

[0067] According to one embodiment of this disclosure, the diseases with elevated Lp(a) plasma levels described herein include, but are not limited to, cardiovascular diseases.

[0068] This disclosure also includes the following options:

[0069] 1. A compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, or isotopic label,

[0070] in,

[0071] P is selected from aryl, heteroaryl, or heterocyclic groups, which are optionally substituted with R6, wherein the heteroaryl or heterocyclic group has one or more heteroatoms selected from N, O, and S, and the heteroaryl or heterocyclic group is optionally oxidized;

[0072] R6 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy groups and halogens;

[0073] R1 and R2 are independently selected from hydrogen, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy group, wherein the alkyl group is optionally substituted with 1-3 F atoms;

[0074] X1 and X2 are independently selected from N and CH, respectively;

[0075] Y1, Y2, and Y3 are independently selected from -CH2-, -CO-, -SO2-, and -(CR4R), respectively.4’ ) n O-、-(CR4R 4’ ) n N-、-CONHR 5 -, -CONH2-, -O-, -(CR4R) 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n O-、-(CR4R 4’ ) n N-, -(CR4R 4’ ) n -、-(CR4R 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-; Both ends of the aforementioned groups can be connected to Z;

[0076] Wherein, K is selected from N or CH, and Q is selected from nitrogen-containing heterocycles that are substituted with halogens (such as F) (when K is selected from N, the nitrogen heteroatom in Q is attached to Y1, Y2 or Y3) or saturated carbon rings.

[0077] Where A = chemical bond (such as single bond), -(CR4R) 4’ ) n -、-CO(CR4R 4’ ) n -, -SO2(CR4R 4’ ) n -;-CO- or CR4R 4’ ;

[0078] n is selected from 0, 1, or 2;

[0079] R4,R 4’ Independently selected from hydrogen, heteroatoms, and C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0080] R5 is selected from hydrogen, C1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0081] R5' is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0082] 'a' represents the position connecting Y1, Y2, and Y3; or

[0083] The cycloalkyl or N-containing heterocyclic group defined in Z, optionally surrounded by 0-5 R groups, is used. X The group is substituted or forms a cyclic ring with a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring; and the two arbitrary R groups are substituted or form a cyclic ring with a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring. X The group can form a fused ring, bridged ring, or spiro ring structure with the ring represented by Z; the nitrogen-containing heterocyclic group is optionally oxidized; the nitrogen atom of the nitrogen-containing heterocyclic group is optionally attached to Y1, Y2, or Y3;

[0084] R x Selected from hydrogen, halogens (such as fluorine), C 1-6 Alkyl or C 1-6 alkoxy; or

[0085] Z is selected from Where W = CH or N; R y Selected from hydrogen, halogens, C 1-6 Alkyl, C 1- 6-alkoxy group, wherein the alkyl group is optionally substituted with 1-3 F atoms;

[0086] The heteroatom of the heterocyclic or heteroaryl group is selected from N, O, P, and S; and

[0087] R',R” and R”' are selected from hydrogen, C 1-6 Alkanes or C 3-6 Cycloalkanes.

[0088] 2. The compound according to Scheme 1, its pharmaceutically acceptable salt, stereoisomer, or isotope label, wherein, in formula (I), Y1, Y2, and Y3 are independently selected from -CH2-, -CO-, -SO2-, and -(CR4R) 4’ ) n O-、-(CR4R 4’ ) n N-、-CONHR 5 -, -CONH2-, -O-, -(CR4R) 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ )n O-、-(CR4R 4’ ) n N-, -(CR4R 4’ ) n -、-(CR4R 4’ ) n CONHR 5 -、-SO2NHR 5 -;

[0089] Wherein, K is selected from N or CH, and Q is selected from nitrogen-containing heterocycles (when K is selected from N, the nitrogen heteroatom in Q is connected to Y1, Y2 or Y3) or saturated carbon rings;

[0090] Where A = chemical bond (such as a single bond), -CO-, or CR4R 4’ .

[0091] 3. The compound according to Scheme 1, its pharmaceutically acceptable salt, stereoisomer, or isotopic label, wherein, in formula (I),

[0092] P is selected from aryl, heteroaryl, or heterocyclic groups, which are optionally substituted with R6, wherein the heteroaryl or heterocyclic group has one or more heteroatoms (e.g., N, O, and S), and the heteroaryl or heterocyclic group is optionally oxidized;

[0093] R1 and R2 are independently selected from hydrogen, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy group, wherein the alkyl group is optionally substituted with 1-3 F atoms;

[0094] X1 and X2 are independently selected from N and CH, respectively;

[0095] Y1, Y2, and Y3 are independently selected from -CH2-, -CO-, -SO2-, and -(CR4R), respectively. 4’ ) n O-、-(CR4R 4’ ) n N-、-CONHR 5 -, -CONH2- or -O-;

[0096] Wherein, Q is selected from nitrogen-containing heterocycles (for example, the nitrogen heteroatom in Q is connected to Y1, Y2 or Y3), saturated carbon rings, or

[0097] Or -CR5-;

[0098] Where A = chemical bond (such as single bond) or CR4R 4’ ;

[0099] n is selected from 0, 1, or 2;

[0100] R4,R 4’ Independently selected from hydrogen, heteroatoms, and C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0101] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy;

[0102] R6 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy groups and halogens;

[0103] Where Z represents a cycloalkyl group or an N-containing heterocycle, optionally surrounded by 0-5 R's. X The group is substituted or forms a cyclic ring with a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring; and the two arbitrary R groups are substituted or form a cyclic ring with a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring. X The group can form fused ring, bridged ring, or spiro ring structures with the ring represented by Z;

[0104] R x Selected from hydrogen, halogens (such as fluorine), C 1-6 Alkyl or C 1-6 Alkoxy;

[0105] 'a' represents the connection point between Y1, Y2, Y3, and Z;

[0106] The heteroatoms are selected from N, O, P, and S; and

[0107] R',R” and R”' are selected from hydrogen, C 1-6 Alkanes or C 3-6 Cycloalkanes.

[0108] 4. The compound according to any one of Schemes 1 to 3, its pharmaceutically acceptable salt, stereoisomer, or isotopic label, wherein, in formula (I), the nitrogen-containing heterocycle in Q is selected from a 3-7 membered monocyclic ring or a bicyclic nitrogen-containing heterocycle composed of two 3-7 membered rings (e.g., a bispiral ring or a bibridged ring, preferably one ring being a carbon ring and the other a nitrogen-containing heterocycle), and the saturated carbon ring is selected from C 3-8 Cycloalkyl; or Q is selected from 4-6 membered cycloalkyl groups and 4-6 membered nitrogen-containing heterocyclic groups.

[0109] 5. A compound according to any one of schemes 1 to 4, its pharmaceutically acceptable salt, stereoisomer, or isotopic label, wherein, in formula (I),

[0110] Z is selected from

[0111] B=-O-、CR4R 4’ Or it may not exist; C = -O-, -NR4-, -CH2O-, -CHNR4- or -SO2-.

[0112] m and n are independently selected from 0, 1, or 2;

[0113] m' and n' are independently selected from 0, 1, or 2.

[0114] 6. A compound according to any one of schemes 1 to 5, its pharmaceutically acceptable salt, stereoisomer, or isotopic label, wherein, in formula (I),

[0115] Z is selected from

[0116] 7. A compound according to any one of schemes 1 to 6, a pharmaceutically acceptable salt, stereoisomer or isotopic label thereof, wherein in formula (I), P is selected from aryl, heteroaryl or heterocyclic groups, which are optionally substituted with R6, wherein the heteroatom in the heteroaryl or heterocyclic group is selected from one or more N, O and S, and at least one N, and the heteroaryl or heterocyclic group is optionally oxidized.

[0117] 8. The compound according to any one of Schemes 1 to 7, its pharmaceutically acceptable salt, stereoisomer or isotope label, wherein in formula (I), P is selected from phenyl groups optionally substituted with halogen, 5-7-membered heteroaryl groups or 5-7-membered heterocyclic groups; preferably, P is selected from triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, 5-7-membered nitrogen-containing heterocyclic groups, wherein the carbon ring atoms of the above groups are optionally oxidized.

[0118] 9. A compound according to any one of schemes 1 to 8, its pharmaceutically acceptable salt, stereoisomer, or isotopic label, wherein in formula (I), Y1, Y2, and Y3 are independently selected from -CH2-, -CO-, -CH2CO-, -SO2-, -CH2SO2-, -CONH2-, or -(CR4R 4’ ) n O-;R4,R 4’ =H.

[0119] 10. A compound according to any one of schemes 1 to 9, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopic label thereof, wherein, in formula (I),

[0120] Wherein, Q is selected from a nitrogen-containing heterocycle, wherein the nitrogen atom of the nitrogen-containing heterocycle is attached to Y1, Y2, or Y3, and Y1, Y2, or Y3 is selected from -CO(CR4R) 4’ ) n-or-SO2(CR4R) 4’ ) n -;

[0121] A represents a chemical bond (such as a single bond), -(CR4R) 4’ ) n -、-CO(CR4R 4’ ) n -or-SO2(CR4R) 4’ ) n -;

[0122] n is selected from 0, 1, or 2;

[0123] R4,R 4’ It is independently selected from hydrogen.

[0124] 11. The compound according to Scheme 10, its pharmaceutically acceptable salt, stereoisomer or isotopic label, wherein Q is selected from 3-7 membered heterocycles or nitrogen-heterocyclic or nitrogen-bridged rings composed of two 3-7 membered rings.

[0125] 12. A compound according to any one of schemes 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer or an isotopic label thereof, wherein in formula (I), R5 is selected from hydrogen or C 1-6 Alkyl; or n and m are independently selected from 0, 1 or 2; or n' and m' are independently selected from 0 or 1.

[0126] 14. A pharmaceutical composition comprising the compound described in any one of schemes 1-13, a pharmaceutically acceptable salt thereof, a stereoisomer, or an isotopic label thereof.

[0127] 15. Use of any compound described in Schemes 1-13, its pharmaceutically acceptable salt, stereoisomer, or isotopic label in the preparation of a medicament for treating diseases associated with elevated Lp(a) plasma levels.

[0128] 16. According to the use described in Scheme 15, the disease is selected from cardiovascular diseases.

[0129] Invention Details

[0130] Exemplary implementations utilizing the principles of this application are described in detail below. A better understanding of the features and advantages of this application can be achieved by referring to the following description.

[0131] While preferred embodiments of this application are described herein, these embodiments are provided by way of example only. It should be understood that variations of the embodiments described herein can also be used to implement this application. Those skilled in the art will understand that various variations, changes, and substitutions may occur without departing from the scope of this application. It should be understood that the scope of protection of each aspect of this application is determined by the claims, and the methods and structures within the scope of these claims, as well as their equivalents, are all within the scope of these claims.

[0132] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0133] Some chemical terms

[0134] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety through reference.

[0135] It should be understood that the above summary and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of this application. In this application, unless otherwise specifically stated, the singular is used to include the plural. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the term “comprising” and other forms such as “including,” “containing,” and “contains” are non-limiting descriptions.

[0136] See references (including Carey and Sundberg, “Advanced Organic Chemistry 4”). THDefinitions of standard chemical terms can be found in ED. Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are those known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications may be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the descriptions in this application. The techniques and methods described herein are generally carried out in accordance with conventional methods well known in the art, based on the descriptions in the various summary and more specific literatures cited and discussed in this specification. In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds.

[0137] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0138] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation. For example, “optionally substituted alkyl” means “unsubstituted alkyl” (an alkyl group not substituted by a substituent) or “substituted alkyl” (an alkyl group substituted by a substituent).

[0139] The C1-C used in this article n Including C1-C2, C1-C3, ..., C1-C n For example, the term "C1-C6" alkyl refers to a moiety having 1-6 carbon atoms. Therefore, "C1-C6 alkyl" refers to an alkyl group having 1-6 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, etc. The term "alkyl" herein refers to an optionally substituted straight-chain or optionally substituted branched aliphatic hydrocarbon.

[0140] As used herein, “alkyl” includes alkyl groups combined with other groups, such as alkyl groups in alkoxy groups. The term “alkoxy” as used alone or in combination herein refers to an alkyl ether group (O-alkyl), and non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy, etc.

[0141] The term "alkenyl" as used alone or in combination herein refers to a monovalent hydrocarbon group of optional substituted straight or optional substituted branched form having one or more C=C double bonds. The double bonds in the alkenyl group may be in cis or trans conformations and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl.

[0142] The term "aryl / aromatic ring," used alone or in combination herein, refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20, such as 6 to 12 or 6 to 10 cyclic carbon atoms. It can be a fused aromatic ring or a non-fused aromatic ring. A fused aromatic ring comprises 2 to 4 rings, wherein the other independent ring fused with the aryl group can be an alicyclic, heterocyclic, aromatic, or heteroaromatic ring. The aryl group in this document includes monocyclic, bicyclic, tricyclic, or more cyclic aryl groups. Non-limiting examples of monocyclic aryl groups include monocyclic aryl groups with 6 to about 12, 6 to about 10, or 6 to about 8 cyclic carbon atoms, such as phenyl; bicyclic, tricyclic, or more cyclic aryl groups are, for example, naphthyl, phenanthryl, anthracene, or azulel. A non-fused aromatic ring is, for example, a bicyclic non-fused aromatic ring, such as biphenyl.

[0143] The term "heteroaryl / heteroaryl ring" as used alone or in combination herein refers to an arbitrary substituted monovalent heteroaryl group comprising about 5 to about 20, such as 5 to 12 or 5 to 10 skeletal cyclic atoms, wherein one or more (e.g., 1-4, 1-3, 1-2) of the cyclic atoms are heteroatoms, which are independently selected from, but not limited to, heteroatoms of oxygen, nitrogen, and sulfur. The ring of the group does not contain two adjacent O or S atoms. Heteroaryl groups include monocyclic or polycyclic heteroaryl groups (e.g., bicyclic, tricyclic, etc.). In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes an optionally substituted monovalent fused or non-fused heteroaryl group having at least one heteroatom. Fused heteroaryl groups may comprise 2-4 rings, wherein the other rings fused with the heteroaryl group may be alicyclic, heterocyclic, aromatic, or heteroaryl rings. Non-limiting embodiments of monocyclic heteroaryl groups include monocyclic heteroaryl groups with 5 to 12, 5 to 10, 5 to 7, or 6 cyclic skeletal atoms, for example, a non-limiting embodiment includes a pyridyl group. Fused heteroaryl groups include, for example, benzimidazolyl, quinolinyl, and acridinyl. Non-fused diheteroaryl groups include, for example, bipyridinyl. Other embodiments of heteroaryl groups include their oxides, such as pyridyl-N-oxide, etc.

[0144] The term "heterocycle" or "heterocyclic group" as used alone or in combination herein refers to a non-aromatic heterocycle, including heterocyclic alkyl (saturated heterocyclic groups) and heterocyclic alkenyl (unsaturated heterocyclic groups). One or more of the cyclic atoms (e.g., 1-4, 1-3, 1-2) are heteroatoms, such as oxygen, nitrogen, or sulfur atoms. Heterocyclic groups can include monocyclic heterocyclic groups (heterocyclic groups having one ring) or polycyclic heterocyclic groups (e.g., bicyclic heterocyclic groups (heterocyclic groups having two rings), tricyclic heterocyclic groups, etc.). Bicyclic heterocyclic groups can be spirocyclic or bridged rings. Heterocyclic groups can have 3 to about 20, such as 3 to about 10, 3 to about 8, 5 to about 8, or 5 to about 6 cyclic atoms. Heterocyclic groups also include heterocycles with one or more fused aromatic rings (i.e., sharing a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzodioxane, benzo-1,4-dioxane, phthalimide, and naphthalenedioximide. Heterocyclic groups with one or more fused aromatic rings can be linked to other groups via the aromatic or non-aromatic ring portions. Other groups can be linked to the heterocycle via heteroatoms or carbon atoms (i.e., the heterocycle is linked to the parent molecule or further substituted).

[0145] The term "cycloalkyl" as used alone or in combination herein refers to a saturated carbon ring. A cycloalkyl group can be monocyclic or polycyclic (e.g., having 2, 3, or 4 rings), can be spirocyclic or bridged, and can have 3 to 20 carbon atoms, for example, 3 to about 15 cyclic carbon atoms, 3 to about 10 cyclic carbon atoms, or 3 to 6 cyclic carbon atoms. Cycloalkyl groups also include rings having one or more aromatic rings fused together (i.e., sharing a common bond), such as benzopentane, hexane, etc. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0146] The term "fused ring" as used alone or in combination herein refers to a structure containing two or more rings linked together by sharing one or more atoms to form a fused system. The individual rings in a fused ring can be aromatic rings, aromatic heterocycles, heterocycles, or carbocyclic rings.

[0147] The term "substituted" means that one or more hydrogen atoms on a particular atom are replaced by a specified group. If the normal valence of the specified atom is not exceeded under the existing conditions, the result of the substitution is a stable compound.

[0148] Halogens include fluorine, chlorine, bromine, and iodine. A cyano group is represented by "-CN"; a hydroxyl group by "-OH"; a mercapto group by "-SH"; and an amino group by "-NH2".

[0149] As used alone or in combination herein, the terms "halogenated" or "halogen substituted" refer to the replacement of one or more hydrogen atoms in an optionally substituted group (such as an optionally substituted alkyl or alkoxy group) with fluorine, chlorine, bromine, iodine atoms, or combinations thereof. In some embodiments, two or more hydrogen atoms are replaced with the same halogen atom (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogen atoms that are not exactly the same (e.g., 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of halogenated alkyl groups include trifluoromethyl.

[0150] Oxo refers to the use of "=O" as a substituent.

[0151] The term "membered ring" refers to the number of skeleton atoms that make up the ring. For example, pyridine is a six-membered ring, and pyrrole is a five-membered ring.

[0152] As used herein, the term "isotope label" refers to the substitution of one or more atoms by an atom of a different atomic mass or mass number. Isotopes in the compounds listed in this application include H, C, N, and O, such as... 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O.

[0153] As used herein, the terms “subject,” “patient,” or “individual” refer to an individual suffering from a disease, symptom, or condition, including both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0154] As used herein, the term "treatment" and other similar synonyms include relieving, reducing, or improving symptoms of a disease or condition; inhibiting a disease or condition, such as preventing its progression; alleviating a disease or condition; improving a disease or condition; relieving symptoms caused by a disease or condition; or stopping symptoms of a disease or condition; preventing other symptoms; improving or preventing the underlying metabolic causes of symptoms; and, moreover, the term includes preventative purposes. The term also includes achieving therapeutic and / or preventative effects. A therapeutic effect refers to the cure or improvement of the underlying disease being treated. Furthermore, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect; for example, an improvement is observed in a patient even though they may still be affected by the underlying disease. In terms of preventative effects, the composition may be administered to patients at risk of developing a specific disease, or to patients exhibiting one or more physiological symptoms of a disease, even if no disease diagnosis has been made.

[0155] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to the amount of at least one active substance (such as the compounds of this application) that, when taken orally, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is the amount of a composition comprising the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0156] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral, duodenal, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa.

[0157] As used herein, the term "pharmaceutical acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of this application and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0158] As used herein, the term "pharmaceutical composition" refers to a mixture of the compound of this application with at least one pharmaceutically acceptable substance. The pharmaceutically acceptable substance includes, but is not limited to, a carrier. As used herein, the term "carrier" refers to a relatively non-toxic substance that facilitates the introduction of the compound of this application into cells or tissues.

[0159] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the bioavailability of the free acid and free base of the specified compound and has no adverse effects in biological or other respects. The compounds in this application also include pharmaceutically acceptable salts. A pharmaceutically acceptable salt is defined as a salt formed by converting a base group in a parent compound into its salt form. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts containing base groups such as amine (amino) groups. The pharmaceutically acceptable salts of this application can be synthesized from the parent compound by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system. Some suitable salts are listed in Remingtong's Pharmaceutical Scicences, 17. th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

[0160] Unless otherwise specified, the term "salt" in this application refers to acidic salts formed from organic / inorganic acids and basic salts formed from organic / inorganic bases. Additionally, when the basic functional group of a compound of the general formula is pyridine or imidazole (but not limited to pyridine or imidazole) and the acidic functional group is a carboxylic acid (but not limited to carboxylic acids), an zwitterion (internal salt) is formed, and internal salts are also included in the salts used in this application.

[0161] The stereoisomers described in this application include optical isomers. The compounds containing asymmetrically substituted carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. The compounds of this application also include tautomer forms. Tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton. Detailed Implementation

[0162] I. General Synthesis Method

[0163] All solvents and reagents were obtained from commercial sources and, unless otherwise specified, can be used without further purification. NMR spectra were obtained on a Bruker Neo400M spectrometer. Chemical shifts are expressed in ppm, and TMS was used as an internal standard for the deuterated reagent. LC-MS was performed on an Agilent 1260-6125B single quadrupole mass spectrometer using a Welch Biomate column (C18, 2.7µm, 4.6 x 50mm) and solvent A (…). Gradient elution was performed using a mixture of solvent A (0.05% FA) and solvent B (water and 0.05% FA). Detection wavelengths were 254 nm and 210 nm, respectively. Ionization was performed using ESI. Spectroscopic analysis was performed using Chemstation software. Analytical HPLC was performed on a Waters ARC system under acidic conditions on a YMC Pack Pro column (C18 S-3um, 12nm, 150*2.0mm) using solvent A (0.05% FA). Gradient elution with a mixture of solvents B (water and 0.05% FA) and D (water and 0.05% FA); or under alkaline conditions, elution with solvents C (water and 0.1% NH4OH) and D (water and 0.1% NH4OH) on an Agilent Poroshell HPH C18 column (2.7µm, 2.1 x 150 mm). Gradient elution was performed using a mixed solvent of 0.1% NH4OH. Detection wavelengths were 254 nm and 210 nm. Preparative HPLC was performed on a Waters AutoP system coupled to a single quadrupole mass spectrometer using a Welch C18 column (5 μm, 25 x 150 mm) and eluted with a mixed solvent of solvents A and B. Rapid column chromatography was performed on a Biotage Isolera Prime system using a Welch WelFlash Flash column (40–63 μm) and eluted with a mixed solvent as shown in the experimental procedure.

[0164] Preparation of intermediates A, B, C, D and E

[0165] Step 1: Preparation of (R)-3-(2-((S)-4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Int-A-1)

[0166] A solution of (R)-2-(1-(tert-butoxycarbonyl)pyrrolidine-3-ylacetic acid (20.00 g, 87.29 mmol) and triethylamine (22.07 g, 218.22 mmol) in tetrahydrofuran (200 mL) was stirred at 10 °C for 5 minutes. Neopentanoyl chloride (13.10 g, 109.11 mmol) was added to the above solution at 0 °C. The resulting mixture was then stirred for 15 minutes. Lithium chloride (4.58 g, 109.11 mmol) and (S)-4-benzyloxazolidine were slowly added to the above solution at 0 °C. A solution of 2-one (15.46 g, 87.29 mmol) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature for 24 hours under nitrogen protection. The mixture was then poured into 1 N hydrochloric acid (800 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 30% to 70%) to give a colorless oily liquid, Int-A-1 (21.00 g, 62.0%).

[0167] LC-MS[M+H-Boc] + =333.3

[0168] Step 2: Preparation of (R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Int-A-2)

[0169] At 0 °C, LiHMDS (1 M, 46.40 mL, 46.37 mmol) was added to a THF (100 mL) solution of Int-A-1 (15.00 g, 38.64 mmol). The resulting mixture was then stirred for 30 minutes. A tetrahydrofuran (70 mL) solution of 1-bromo-3-(bromomethyl)benzene (10.73 g, 43.28 mmol) was added to the above solution. The mixture was stirred overnight at room temperature under nitrogen protection. The reaction mixture was then poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a pale yellow oily liquid, Int-A-2 (20.00 g, 93.1%).

[0170] LC-MS[M+H] + =557.3

[0171] Step 3: Preparation of (S)-3-(3-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (Int-A-3)

[0172] At 0 °C, an aqueous solution (5 mL) of lithium hydroxide (0.52 g, 21.58 mmol) was slowly added to a tetrahydrofuran (70 mL) solution of Int-A-2 (8.00 g, 14.38 mmol) and hydrogen peroxide (0.88 M, 24.50 mL, 21.58 mmol). The mixture was stirred at room temperature for 4.5 hours under nitrogen protection. The mixture was then poured into an aqueous solution of sodium sulfite (150 mL) and extracted with methyl tert-butyl ether (50 mL). The inorganic layer was adjusted to pH approximately 3 by adding 5N hydrochloric acid and extracted with methyl tert-butyl ether (150 mL * 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a white solid, Int-A-3 (3.00 g, 52.5%).

[0173] LC-MS[M+H-56] + =342.0

[0174] Step 4: Preparation of (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Int-A-4)

[0175] To a solution of Int-A-3 (3.00 g, 7.55 mmol) in tetrahydrofuran (35 mL), O-tert-butyl-N,N'-diisopropylisourea (4.54 g, 22.66 mmol) was added. The mixture was stirred at 65 °C for 3 hours. At room temperature, O-tert-butyl-N,N'-diisopropylisourea (1.51 g, 7.55 mmol) was added to the mixture. Under nitrogen protection, the mixture was stirred overnight at 65 °C. After cooling to room temperature, the reaction mixture was filtered through a diatomaceous earth mat, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 10% to 20%) to give a white solid, Int-A-4 (1.80 g, 52.6%).

[0176] LC-MS[M+Na] + =476.2

[0177] Step 5: Preparation of (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Int-A)

[0178] Int-A-4 (4.00 g, 8.80 mmol), triethylsilane (3.45 mL, 26.41 mmol), triethylamine (3.60 mL, 26.41 mmol), and Pd(dppf)Cl2·DCM (0.719 g, 0.88 mmol) were mixed in anhydrous N,N-dimethylformamide (40 mL), and the mixture was degassed three times under a carbon monoxide atmosphere and stirred overnight at 80 °C. The resulting mixture was filtered through a diatomaceous earth mat, and the filtrate was diluted with ethyl acetate / water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily liquid Int-A (2.55 g, 71.8%).

[0179] Step 6: Preparation of (R)-3-((S)-1-(tert-butoxy)-3-(3-(hydroxymethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Int-B)

[0180] Sodium borohydride (90.7 mg, 0.53 mmol) was added to a tetrahydrofuran (16 mL) solution of Int-A (645.0 mg, 1.60 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was poured into a saturated aqueous solution of sodium bicarbonate (20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was concentrated to give a colorless oily liquid, Int-B (560.0 mg, 86.3%).

[0181] Step 7: Preparation of (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Int-C)

[0182] Under nitrogen protection at 0°C, carbon tetrabromide (687.0 mg, 2.07 mmol) and triphenylphosphine (543.0 mg, 2.07 mmol) were added to an anhydrous tetrahydrofuran (14 mL) solution of Int-B (560.0 mg, 1.60 mmol). The mixture was stirred overnight at room temperature. The organic solvent was removed under reduced pressure, and the crude product was purified by rapid column chromatography (eluent DCM 100%) to give a colorless oily liquid Int-C (400.0 mg, 61.7%).

[0183] Another synthetic route for intermediate B:

[0184] Step 1: Preparation of (3-(bromomethyl)phenyl)methanol (Int-B-1)

[0185] To a solution of toluene (1.5 L) in [3-(hydroxymethyl)phenyl]methanol (200 g, 1.45 mol), 200.0 mL of 48% HBr aqueous solution was added. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, poured into a saturated NaHCO3 aqueous solution, and extracted with ethyl acetate (500 mL * 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain Int-B-1 (300 g, crude product), which can be used directly in the next step.

[0186] Step 2: ((3-(bromomethyl)benzyl)oxy)(tert-butyl)dimethylsilane (Int-B-2)

[0187] Int-B-1 (200 g, 1 mol) was dissolved in DCM (2000 mL), and 2,6-dimethylpyridine (213.17 g, 2 mol) was added. Then, TBSOTf (394.42 g, 1.5 mol) was added dropwise at 0 °C. The reaction was then carried out under nitrogen protection at this temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into 2000 mL of water and extracted with DCM (500 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 0% to 10%) to give Int-B-2 as a colorless oil (301 g, 95.6%).

[0188] Step 3: Tert-butyl(R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (Int-B-3)

[0189] Int-A-1 (200 g, 514.86 mmol) was dissolved in THF (1000 mL), and LiHMDS (670.00 mL, 670.0 mmol) was added at -78 °C. The mixture was stirred for 1 hour under a nitrogen atmosphere. Subsequently, Int-B-2 (194 g, 617.8 mmol) was dissolved in THF (600 mL) and added dropwise to the reaction mixture. The reaction was stirred for 16 hours at 25 °C under nitrogen protection. When the reaction was complete (detected by thin-layer chromatography TLC), the reaction mixture was poured into water (1000 mL) and extracted with ethyl acetate (500 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0% to 50%) to give Int-B-3 as a colorless oil (209 g, 65.2%).

[0190] Step 4: (S)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)propionic acid (Int-B-4)

[0191] Int-B-3 (200 g, 370.87 mmol) and H₂O₂ (194 g, 30%, 1706 mmol) were dissolved in THF (2000 mL), and LiOH aqueous solution (14.21 g, 593.4 mmol, 500 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 4.5 h under nitrogen protection. The reaction solution was then quenched by adding Na₂SO₃ aqueous solution (233 g, 1854 mmol, 2000 mL). The pH was then adjusted to 5 by adding HCl (5N), and the mixture was extracted with ethyl acetate (500 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give Int-B-4 as a colorless oil (223.5 g, 100%), which was used directly as crude product in the next step.

[0192] Step 5: Tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(((tert-butyldimethylsilyl)oxymethyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (Int-B-5)

[0193] Int-B-4 (223 g, crude) was dissolved in dichloroethane (1500.00 mL), and O-tert-butyl-N,N'-diisopropylisourea (481 g, 2404.67 mmol) was added. The resulting solution was stirred at 80 °C for 16 hours under nitrogen protection. After cooling to room temperature, the suspension was filtered through a diatomaceous earth filter. The filter cake was washed with DCM, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 0% to 50%) to give Int-B-5 as a colorless oil (116 g, 60.4%, two steps).

[0194] Step 6: Tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(hydroxymethyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (Int-B)

[0195] Int-B-5 (116 g, 223.5 mmol) was dissolved in THF (1200.0 mL), and TBAF (894 mL, 894 mmol, 1 M) was added dropwise at 0 °C. The resulting solution was stirred at 20 °C for 2 hours. The mixture was then poured into ice water (500 mL) and extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 0% to 50%) to give a white solid Int-B (80 g, 88.4%).

[0196] Synthesis of intermediate D:

[0197] Step 1: 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzoic acid (Int-D)

[0198] Int-B (500 mg, 1.23 mmol) was dissolved in acetone (12 mL), and potassium permanganate (390 mg, 2.47 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with sodium sulfite (aqueous solution), and the mixture was adjusted to pH 2–3 with aqueous hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0% to 100% elution) to give Int-D (230 mg, 44.5%) as a colorless foam.

[0199] Synthesis of intermediate E:

[0200] Step 1: tert-butyl(R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-(benzyloxy)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (Int-E-1)

[0201] To a solution of Int-A-1 (36.0 g, 92.67 mmol) in tetrahydrofuran (360.0 mL), LiHMDS (112.0 mL, 112.0 mmol) was added at -78 °C. The mixture was stirred for 1 hour under a nitrogen atmosphere. 1-(bromomethyl)-3-anisolebenzene (28.77 g, 103.80 mmol) was dissolved in THF (50 mL) and added dropwise to the above solution. The reaction mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was poured into water (1000 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 0% to 50%) to give Int-E-1, a colorless oil (28.50 g, 52.68%).

[0202] Step 2: (S)-3-(3-(benzyloxy)phenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (Int-E-2)

[0203] Int-E-1 (13.7 g, 23.46 mmol) was dissolved in THF (150.0 mL), and H2O2 (13.3 g, 117 mmol) was added. A solution of LiOH (1.1 g, 46.92 mmol) dissolved in water (22 mL) was slowly added at 0 °C. The resulting mixture was stirred at 20 °C for 16 hours. After the reaction was complete, the mixture was poured into an aqueous solution of Na2SO3. The mixture was then acidified to pH 5 by adding HCl (3N), and extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the residue Int-E-2 (14.5 g, crude product), which could be used directly in the next reaction.

[0204] Step 3: Tert-butyl(R)-3-((S)-3-(3-(benzyloxy)phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (Int-E-3)

[0205] O-tert-butyl-N,N'-diisopropylisourea (13.5 g, 2.0 mmol) was added to a THF (35 mL) solution of Int-E-2 (14.5 g, crude). The resulting mixture was then stirred at 60 °C for 6 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 0% to 30%) to give Int-E-3 as a colorless oil (4.5 g, 39.9%, two-step yield).

[0206] Step 4: tert-Butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (Int-E)

[0207] Pd / C (0.45 g, 10%) was added to a MeOH solution of Int-E-3 (4500.0 mg, 9.34 mmol). The resulting mixture was stirred at 30 °C for 2 hours under a H2 atmosphere. Subsequently, the mixture was filtered through a layer of diatomaceous earth. The filtrate was concentrated to dryness. The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 0% to 100%) to give a white solid Int-E (3.5 g, 95.89%), which could be used directly in the next step.

[0208] General synthesis method:

[0209] GP1: Reductive amination reaction

[0210] The substrate amine (1 equivalent) and Int-A (1.1 equivalent per NH) were dissolved in methanol (0.1 M), and then acetic acid (4 equivalents) was added to the solution. The mixture was stirred at room temperature for half an hour. Sodium cyanoborohydride (1.15 equivalent per NH) was then added to the mixture. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was eluted by silica gel column chromatography to give the target reduced amination product.

[0211] GP2: Removal of tert-butyl and tert-butyloxycarbonyl groups

[0212] The substrate was placed in a suitable flask, and an excess of 1,4-dioxane hydrochloride solution or ethyl hydrochloride solution was added. The mixture was stirred overnight at room temperature, and a solid precipitated in the reaction system. The solvent was removed by vacuum distillation, and the residue was dissolved in water and prepared by high-performance liquid chromatography to obtain the target product.

[0213] II. Implementation Examples

[0214] Example 1: Preparation of Compound 01

[0215] Step 1: 3,3'-((2S, 2'S)-((((((1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)piperidin-4-yl)methyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(01-A)

[0216] The white solid 01-A (20.0 mg, 15.7%) was obtained by GP1 operation.

[0217] Step 2: (2S,2'S)-3,3'-bis(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)piperidin-4-yl)methyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (01)

[0218] The white solid O1 (9.1 mg, 15.7%) was obtained by GP2 operation.

[0219] Compound 01: MS (ESI) m / z: 808.4, [M+H] + ; 1 H NMR(400MHz,D2O)δ7.40–7.13(m,12H),4.39–4.09(m,6H),3.60–3.51(m,3H),3.40–3.26(m,5H),3.23–3.14(m,3H) ,3.05–2.87(m,8H),2.84–2.63(m,8H),2.58–2.42(m,3H),2.17–2.03(m,3H),1.86–1.61(m,6H),1.34–1.02(m,2H).

[0220] Example 2: Preparation of Compound O2

[0221] Step 1: (R)-3-((S)-1-(tert-butoxy)-3-(3-((R)-1-(3-(S)-3-(tert-butoxy)-2-(R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)pyrrolidine-3-yl)amino)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (02-A)

[0222] Acetic acid (0.66 mL) was added to a methanol (30 mL) solution of Int-A (2.56 g, 6.34 mmol) and (R)-pyrrolidine-3-amine (248.4 mg, 2.88 mmol), and the mixture was stirred for 30 min. Sodium cyanoborohydride (543.7 mg, 8.65 mmol) was added to the above solution, and the mixture was stirred under a nitrogen atmosphere for 16 h. The mixture was then poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with dichloromethane:methanol = 0% to 10%) to give a brown oily liquid, O2-A (1.74 g, 70.2%).

[0223] Step 2: 3,3'-((2S, 2'S)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)pyrrolidine-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(02-B)

[0224] To a methanol (8.1 mL) solution of 02-A (0.700 g, 0.813 mmol), acetic acid (0.19 mL) containing Int-A (394 mg, 0.975 mmol) was added, and the mixture was stirred for 30 minutes. Sodium cyanoborohydride (102 mg, 1.63 mmol) was added to the above solution, and the mixture was stirred under a nitrogen atmosphere for 16 hours. The mixture was then poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a white solid, 02-B (0.55 g, 54.2%).

[0225] Step 3: (2S, 2'S)-3,3'-(R)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)pyrrolidine-3-ylazadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-yl)propionic acid) hydrochloride (02)

[0226] Add 4 M 1,4-dioxane hydrochloride solution (4 mL) to a 50 mL flask containing O2-B (180 mg, 0.144 mmol), and then stir the mixture overnight at room temperature. Concentrate the solution to dryness. The residue was purified by preparative high-performance liquid chromatography to give a white solid O2 (67.8 mg, 48.9%).

[0227] Compound 02: MS (ESI) m / z: 780.4, [M+H] + ; 1 H NMR(400MHz,D2O)δ7.43–7.03(m,12H),4.39–4.16(m,7H),3.59–3.48(m,5H),3.45–3.31(m,5H), 3.24–3.13(m,3H),3.06–2.95(m,3H),2.94–2.39(m,14H),2.16–2.02(m,1H),1.75–1.61(m,3H).

[0228] Example 3: Preparation of Compound 03

[0229] Step 1: 3,3'-((2S, 2'S)-(S)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)pyrrolidine-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl))(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate))(03-A

[0230] The colorless oily liquid 03-A (423 mg, 29.2%) can be obtained by GP1 operation.

[0231] Step 2: (2S, 2'S)-3,3'-(S)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)pyrrolidine-3-ylazadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-yl)propionic acid) hydrochloride (03)

[0232] The white solid O3 (246.1 mg, 75.4%) was obtained by GP2 operation.

[0233] Compound 03: MS (ESI) m / z: 780.4, [M+H] + ; 1H NMR(400MHz,D2O)δ7.35–6.98(m,12H),4.36–4.15(m,7H),3.57–3.41(m,5H),3.41–3.27(m,5H),3.19–3.0 9(m,3H),3.01–2.92(m,3H),2.90–2.52(m,10H),2.51–2.35(m,4H),2.12–1.97(m,3H),1.71–1.56(m,3H).

[0234] Example 4: Preparation of Compound 04

[0235] Step 1: 3,3'-((2S, 2'S)-(((1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)azacyclobutane-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl))(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate))(04-A)

[0236] The colorless oily liquid 04-A (20.0 mg, 9.5%) can be obtained by GP1 operation.

[0237] Step 2: (2S, 2'S)-3,3'-(((1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azacyclobutane-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (04)

[0238] The white solid O4 (7.1 mg, 46.5%) was obtained by GP2 operation.

[0239] Compound 04: MS (ESI) m / z: 766.4, [M+H] + ; 1 H NMR(400MHz,D2O)δ7.29-7.12(m,12H),4.50-4.47(m,1H),4.35–3.75(m,10H),3.60–3.50(m,3H),3.36-3.34(m,3H) ,3.25-3.20(m,3H),3.10-3.03(m,3H),2.94–2.66(m,9H),2.52-2.49(m,3H),2.13-2.10(m,3H),1.83–1.58(m,3H).

[0240] Example 5: Preparation of Compound 05

[0241] Step 1: 3,3'-((2S, 2'S)-(((7-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-7-azaspiro[3.5]non-2-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester)(05-A)

[0242] The colorless oily liquid 05-A (40.0 mg, 28.7%) can be obtained by GP1 operation.

[0243] Step 2: (2S,2'S)-3,3'-((((7-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)-7-azaspiro[3.5]non-2-yl)azonyl)methylene)bis(3,1-phenyl))bis(2-((R)-pyrrolidine-3-yl)propionic acid)hydrochloride (05)

[0244] The white solid 05 (8.1 mg, 26.0%) was obtained by GP2 operation.

[0245] Compound 05: MS (ESI) m / z: 834.4, [M+H] + ; 1 H NMR(400MHz,D2O)δ7.34–7.03(m,12H),4.19–4.00(m,6H),3.89–3.76(m,1H),3.58–3.44(m,3H),3.38–3.08(m,8H),3.03–2.92(m,3H), 2.90–2.59(m,11H),2.54–2.38(m,3H),2.20–2.12(m,1H),2.11–2.01(m,3H),1.99–1.90(m,2H),1.89–1.80(m,2H),1.74–1.50(m,6H).

[0246] Example 6: Preparation of Compound 06

[0247] Step 1: (1R, 5S)-3-azabicyclo[3.1.0]hexane-6-amine hydrochloride (06-A)

[0248] Hydrochloric acid / ethyl acetate (2 mL) was added to a methanol (1 mL) solution of (1R,5S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (35.0 mg, 0.18 mmol), and the mixture was stirred at room temperature for 2 hours. The solution was concentrated to give a white solid 06-A (16.0 mg, 52.8%).

[0249] LC-MS[M+H] + =99.2

[0250] Step 2: 3,3'-((2S, 2S)-(((((1R, 5S)-3-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-3-azabicyclo[3.1.0]hexane-6-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester)(06-B)

[0251] The colorless oily liquid 06-B (43.0 mg, 38.8%) can be obtained by GP1 operation.

[0252] Step 3: (2S, 2S)-3,3'-(((((1R, 5S)-3-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)-3-azabicyclo[3.1.0]hexane-6-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (06)

[0253] The white solid O6 (8.1 mg, 24.4%) was obtained by GP2 operation.

[0254] Compound 06: MS (ESI) m / z: 792.4, [M+H] + ; 1 H NMR(400MHz,D2O)δ7.35–7.13(m,12H),4.42–4.06(m,7H),3.58–3.49(m,3H),3.39–3.32(m,4H),3.23–3.15(m,3H), 3.10–2.96(m,4H),2.96–2.55(m,11H),2.54–2.44(m,3H),2.15–2.05(m,3H),1.93–1.81(m,1H),1.74–1.61(m,4H).

[0255] Example 7: Preparation of Compound 07

[0256] Step 1: 3,3'-((2S, 2S)-((((1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)piperidin-4-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester))(07-A)

[0257] The colorless oily liquid 07-A (15.0 mg, 7.9%) can be obtained by GP1 operation.

[0258] Step 2: (2S, 2S)-3,3'-((((1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)piperidin-4-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid)hydrochloride (07)

[0259] The white solid 07 (4.6 mg, 39.3%) was obtained by GP2 operation.

[0260] Compound 07: MS (ESI) m / z: 794.4, [M+H] + ; 1 H NMR(400MHz,D2O)δ7.40–7.06(m,12H),4.30-4.15(m,5H),3.64–3.49(m,6H),3.36-3.33(m,3H),3.20-3.1 7(m,3H),3.10–2.62(m,15H),2.52-2.50(m,3H),2.45-2.35(m,2H),2.30-2.16(m,5H),1.75–1.62(m,3H).

[0261] Examples 8 and 9: Preparation of compounds 08 and 09

[0262] Step 1: (R)-3-((S)-1-(tert-butoxy)-3-(3-((methanesulfonyl)oxy)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (08-A)

[0263] At 0 °C, methanesulfonyl chloride (0.3 g, 2.4 mmol) was added to a solution of Int-B (500.0 mg, 1.2 mmol) and triethylamine (600.0 mg, 6.0 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at 0 °C for 2 hours. The mixture was purified by column chromatography (eluting with ethyl acetate:dichloromethane = 0% to 100%) to give a colorless oil, 08-A (380.0 mg, 68.1%).

[0264] Step 2: 3,3'-((2S,2'S)-di-tert-butyl-4-((methanesulfonyl)oxy)cyclohexyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(tert-butyl pyrrolidine-1-carboxylate))(08-B

[0265] Potassium carbonate (300.0 mg, 2.12 mmol) was added to a solution of 08-A (380.0 mg, 0.71 mmol) in N,N-dimethylformamide (5 mL). The mixture was then stirred at 60 °C for 16 hours under a nitrogen atmosphere. The mixture was then poured into water (50 mL) and extracted with ethyl acetate (*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 08-B (180.0 mg, 29.8%).

[0266] Step 3: 3,3',3'-((1S,1'S,1”S)-((tri(methylene))tri(phenyl-3,1-diyl))-tris(1-(2H-tetrazol-5-yl)ethane-2,1-diyl)-(3R,3'R,3”R)-tris(tert-butyl pyrrolidine-1-carboxylate))(08-C

[0267] At 0 °C, methanesulfonyl chloride (0.03 g, 0.33 mmol) was added to a solution of 08-B (180.0 mg, 0.21 mmol) and triethylamine (100.0 mg, 1.0 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 0 °C for 2 hours. The mixture was purified by column chromatography (eluting with ethyl acetate:dichloromethane = 0% to 100%) to give a colorless oily substance 08-C (120.0 mg, 56.1%).

[0268] Step 4: 3,3'-((2S, 2'S)-4-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenoxy)cyclohexyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(08-D1) and 3 ,3'-((2S, 2'S)-(1R, 4R)-4-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenoxy)cyclohexyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(08-D2)

[0269] Potassium carbonate (56.0 mg, 0.4 mmol) was added to a solution of 08-C (120.0 mg, 0.13 mmol) and Int-E (51.0 mg, 0.13 mmol) in N,N-dimethylformamide (1.5 mL). The mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. The mixture was then poured into water (50 mL) and extracted with ethyl acetate (*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give colorless oily 08-D1 (50.0 mg) and 08-D2 (30.0 mg).

[0270] Step 5: (2S, 2'S)-3,3'-(1S, 4S)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)cyclohexyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (08)

[0271] The white solid compound 08 (4.0 mg, 10.7%) was obtained by GP2 operation.

[0272] Compound 08: MS (ESI) m / z: [M+H] + 796.4; 1H NMR(400MHz,D2O)δ7.34–7.07(m,9H),6.88–6.70(m,3H),4.46–4.34(m,2H),4.33–4.2 3(m,1H),4.22–4.08(m,2H),3.61–3.47(m,3H),3.39–3.31(m,3H),3.24–3.13(m,4H), 3.05–2.95(m,3H),2.91–2.81(m,3H),2.80–2.72(m,3H),2.71–2.62(m,3H),2.55–2.4 3(m,3H),2.27–2.03(m,7H),1.93–1.78(m,2H),1.75–1.62(m,3H),1.43–1.25(m,2H).

[0273] Step 6: (2S,2'S)-3,3'-(1R,4R)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)cyclohexyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (09)

[0274] The white solid compound 09 (3.0 mg, 13.4%) was obtained by GP2 operation.

[0275] Compound 09: MS (ESI) m / z: [M+H] + 796.4; 1 H NMR(400MHz,D2O)δ7.38–7.06(m,9H),6.88–6.73(m,3H),4.45–4.34(m,2H),4.32–4.2 6(m,1H),4.22–4.07(m,2H),3.57–3.47(m,3H),3.38–3.30(m,3H),3.23–3.12(m,4H), 3.04–2.94(m,3H),2.89–2.80(m,3H),2.79–2.69(m,3H),2.68–2.58(m,3H),2.55–2.4 2(m,3H),2.27–2.03(m,7H),1.93–1.79(m,2H),1.75–1.61(m,3H),1.43–1.26(m,2H).

[0276] Example 10: Preparation of Compound 10

[0277] Step 1: 3,3'-((2S,2'S)-di-tert-butyl(1H-imidazol-2-yl)methyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)(10-A)

[0278] The brown oily liquid 10-A (490.0 mg, 99.0%) can be obtained by GP1 operation.

[0279] Step 2: 3,3'-((2S, 2'S)-(((1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-1H-imidazol-2-yl)methyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(10-B)

[0280] A mixture of 10-A (114.0 mg, 0.13 mmol), Int-C (61.2 mg, 0.013 mmol), and potassium carbonate (54.0 mg, 0.39 mmol) was stirred at 50 °C for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily compound 10-B (33.8 mg, 20.6%).

[0281] Step 3: (2S,2'S)-3,3'-bis(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)-1H-imidazol-2-yl)methyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (10)

[0282] The GP2 operation yielded a white, foamy solid compound 10 (14.2 mg, 54.4%).

[0283] Compound 10: MS (ESI) m / z: [M / 2+H] + 396.3; 1H NMR(400MHz,D2O)δ7.29–6.92(m,12H),6.78(d,J=7.6Hz,1H),6.66(s,1H),4.97(s,2H),3.74(s,2H),3.63–3.54(m,4H),3.43(dd,J= 11.7,7.9Hz,3H),3.34–3.24(m,3H),3.17–3.06(m,3H),2.92–2.82(m,3H),2.76–2.32(m,12H),2.08–1.96(m,3H),1.67–1.53(m,3H)

[0284] Example 11: Preparation of Compound 11

[0285] Step 1: 4,4-Difluoropyrrolidine-3-amine hydrochloride (11-A)

[0286] A solution of 4M hydrochloric acid in 1,4-dioxane (2.00 mL) was added to an ethanol (2.00 mL) solution of tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (100 mg, 0.16 mmol). The resulting solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was filtered to give a white solid 11-A (71 mg, 80.9%).

[0287] Step 2: 3,3'-((2S, 2'S)-(((1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-4,4-difluoropyrrolidine-3-ylazadiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(11-B)

[0288] To a solution of 11-A (71 mg, 0.36 mmol) in N,N-dimethylformamide (3.6 mL), Int-C (682 mg, 1.46 mmol) and potassium carbonate (302 mg, 2.18 mmol) were added. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by reverse-phase column chromatography (mobile phase: A: acetonitrile, B: aqueous solution of 0.1% formic acid) to give a colorless oily 11-B (86.0 mg, 18.4%).

[0289] Step 3: (2S, 2'S)-3,3'-(((1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)-4,4-difluoropyrrolidine-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (11)

[0290] Compound 11 (43.2 mg, 79.1%) was obtained by GP2 operation and was a white solid.

[0291] Compound 11: MS (ESI) m / z: [M / 2+H] + 408.8; 1 H NMR(400MHz,D2O)δ7.21(m,12H),4.30–4.20(m,2H),3.88–3.64(m,7H),3.57–3.27(m,8H),3.25–3.10(m,,3H),3. 09–2.92(m,,3H),2.91–2.71(m,6H),2.70–2.58(m,3H),2.56–2.35(m,3H),2.15–2.03(m,3H),1.75–1.60(m,3H).

[0292] Example 12: Preparation of Compound 12

[0293] Step 1: Di-tert-butyl 3,3'-((2S,2'S)-dioxopiperidin-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)(12-A)

[0294] A solution of (S)-5-aminopiperidin-2-one hydrochloride (33 mg, 0.22 mmol), Int-C (200 mg, 0.43 mmol), and potassium carbonate (209 mg, 1.51 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80 °C for 16 hours. The mixture was then poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily 12-A (80.0 mg, 40.9%).

[0295] Step 2: 3,3'-((2S, 2'S)-(R)-1-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-6-oxoperidin-3-yl)azadiyl)bis(methylene)bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(12-B)

[0296] At 0 °C, a 60% sodium hydride mineral oil mixture (8.0 mg, 0.20 mmol) was added to a solution of 12-A (50 mg, 0.056 mmol) in N,N-dimethylformamide (1 mL). The mixture was then stirred for 1 hour under a nitrogen atmosphere. Int-C (38 mg, 0.081 mmol) was added. The mixture was stirred for 5 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily 12-B (21.0 mg, 29.4%).

[0297] Step 3: (2S,2'S)-3,3'-dihydropyridine(S)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)-6-oxoperidin-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (12)

[0298] The white solid compound 12 (7.1 mg, 45.3%) was obtained by the GP2 operation.

[0299] Compound 12: MS (ESI) m / z: [M+H] + 808.4; 1 H NMR(400MHz,D2O)δ7.35–6.91(m,12H),4.52–4.37(m,2H),4.30–4.18(m,2H),4.16–4.01(m,2H),3.64–3.2 9(m,9H),3.23–3.12(m,3H),3.02–2.59(m,13H),2.55–2.38(m,4H),2.31–2.03(m,5H),1.79–1.59(m,3H).

[0300] Example 13: Preparation of Compound 13

[0301] Step 1: (R)-3-((S)-1-(tert-butoxy)-3-(3-((R)-3-(3-(S)-3-(tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)benzamido)pyrrolidine-1-yl)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolyl-1-carboxylic acid tert-butyl ester (13-A)

[0302] To a solution of Int-D (13 mg, 0.031 mmol) and 02-A (25 mg, 0.030 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (0.5 mL) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (18 mg, 0.050 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The mixture was then poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 13-A (18.0 mg, 47.5%).

[0303] Step 2: (S)-3-(3-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-((R)-1-(3-

[0304] ((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)pyrrolidine-3-yl)benzoylamino)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionate (13)

[0305] The white solid compound 13 (4.2 mg, 31.3%) was obtained by the GP2 operation.

[0306] Compound 13: MS (ESI) m / z: [M / 2+H] + 397.8; 1H NMR(400MHz,D2O)δ7.58–6.80(m,12H),4.56–4.43(m,2H),4.35–4.29(m,1H),4.24–4.13(m,1H),4.08–3.97(m,1H), 3.91–3.77(m,1H),3.56–2.38(m,28H),2.28–2.21(m,1H),2.14–1.93(m,3H),1.73–1.58(m,2H),1.45–1.25(m,1H).

[0307] Example 14: Preparation of Compound 14

[0308] Step 1: (R)-3-((S)-3-(3-((R)-3-((benzyloxy)carbonyl)amino)pyrrolidine-1-carbonyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-3-carboxylic acid tert-butyl ester (14-A)

[0309] N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) was added to a mixture of Int-D (230.0 mg, 0.55 mmol), (R)-pyrrolidine-3-ylcarbamate (121.0 mg, 0.55 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (250.0 mg, 0.66 mmol) in anhydrous N,N-dimethylformamide (5.4 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil of 14-A (268.0 mg, 78.6%).

[0310] Step 2: (R)-3-((S)-3-(3-((R)3-aminopyrrolidine-1-carbonyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (14-B)

[0311] The mixture of 14-A (268.0 mg, 0.43 mmol) in methanol (4.3 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered and concentrated to give 14-B (200.0 mg, 95.1%), which required no further purification.

[0312] Step 3: (R)-3-((S)-1-(tert-butoxy)-3-(3-((R)-1-(3-(S)-3-(tert-butoxy)-2-(R)-1-(tert-butyryl)pyrrolidine-3-yl)-3-oxopropyl)benzoyl)pyrrolyl-3-yl)amino)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (14-C)

[0313] The colorless oil 14-C (26.5 mg, 10.2%) can be obtained by GP1 operation.

[0314] Step 4: 3,3'-((2S, 2'S)-(R)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzoyl)pyrrolidine-3-yl)azacyclopentenyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate))(14-D

[0315] The colorless oily substance 14-D (21.0 mg, 63.3%) can be obtained by GP1 operation.

[0316] Step 5: (2S, 2'S)-3,3'-(R)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzoyl)pyrrolidine-3-ylazadiyl)bis(methylene))bis(3,1-phenylene)bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (14)

[0317] The white solid compound 14 (8.7 mg, 55.7%) was obtained by the GP2 operation.

[0318] Compound 14: MS (ESI) m / z: [M+H] + 794.4; 1 H NMR(400MHz,D2O)δ7.42–6.97(m,12H),4.56–4.47(m,2H),4.37–4.29(m,2H),4.22–3.59(m,4H),3.59–3.43(m,4H), 3.44–3.27(m,4H),3.22–3.12(m,3H),3.04–2.63(m,12H),2.54–2.33(m,4H),2.17–2.01(m,3H),1.77–1.58(m,3H).

[0319] Example 15: Preparation of Compound 15

[0320] Step 1: tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-5-chlorobenzyl)(R)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)pyrrolidine-3-yl)amino)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (15-A)

[0321] The synthesis of Int-F is carried out using the same method as the synthesis of Int-A.

[0322] The colorless oil 15-A (45.0 mg, 62.1%) can be obtained by GP1 operation from Int-F (25.0 mg, 0.06 mmol) and O2-A (50.0 mg, 0.06 mmol).

[0323] Step 2: (S)-3-(3-((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-5-chlorobenzyl)amino)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionate (15)

[0324] The white solid compound 15 (21.2 mg, 60.6%) was obtained by the GP2 operation.

[0325] Compound 15: MS (ESI) m / z: [M+H] + 814.4; 1 H NMR(400MHz,D2O)δ7.40–6.94(m,11H),4.40–4.17(m,6H),3.63–3.29(m,10H) ,3.23–3.13(m,3H),3.06–2.41(m,18H),2.15–2.03(m,3H),1.75–1.61(m,3H).

[0326] Example 16: Preparation of Compound 16

[0327] Step 1: 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-5-chlorobenzoic acid (Int-F-1)

[0328] Potassium permanganate (25.0 mg, 0.30 mmol) was added to a solution of Int-F (100.0 mg, 0.26 mmol) in acetone (3 mL). The mixture was stirred at 0 °C for 1 hour. The resulting mixture was then poured into water and extracted with ethyl acetate (*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by reversed-phase chromatography (acetonitrile / water, 0.5% formic acid, 0-60%) to give a colorless oily Int-F-1 (70.0 mg, 70.1%).

[0329] Step 2: tert-Butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((R)-3-(3-(S)-3-(tert-butoxy)-2-((R“-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-5-chlorobenzamido)pyrrolidine-1-yl)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolyl-1-carboxylate (16-A)

[0330] To a solution of Int-F-1 (70.0 mg, 0.16 mmol) and 02-A (130.0 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.3 mL) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (78.0 mg, 0.20 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The mixture was then poured into water and extracted with ethyl acetate (*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily 16-A (132.0 mg, 65.1%).

[0331] Step 3: (S)-3-(3-((S)-2-carboxy-2-(R-pyrrolidine-3-yl)ethyl)-N-((R)-1-(3-((S)-2-carboxy-2-yl)ethyl)

[0332] ((R)-pyrrolidine-3-yl)ethyl)benzyl)pyrrolidine-3-yl)-5-chlorobenzamide methyl)phenyl)-2-((R))-pyrrolidine-3-yl)propionate (16)

[0333] The white solid compound 16 (52.1 mg, 52.5%) was obtained by the GP2 operation.

[0334] Compound 16: MS (ESI) m / z: [M / 2+H]+ 414.8; 1 H NMR(400MHz,D2O)δ7.36–7.30(m,2H),7.29–7.18(m,5H),7.14–7.00(m,2H),6.95–6.75(m,2H), 4.58–4.53(m,1H),4.47–4.42(m,1H),4.33–4.28(m,1H),4.25–4.16(m,1H),4.07–3.79(m,2H), 3.55–3.45(m,3H),3.44–3.28(m,4H),3.25–3.02(m,6H),3.01–2.88(m,4H),2.85–2.70(m,5H), 2.66–2.41(m,6H),2.27–2.23(m,1H),2.13–1.97(m,3H),1.73–1.60(m,2H),1.45–1.29(m,1H).

[0335] Example 17: Preparation of Compound 17

[0336] Step 1: tert-butyl(R)-3-((S)-3-(3-(benzylthio)phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (17-A)

[0337] A mixture of Int-A-4 (500.0 mg, 1.10 mmol), benzyl mercaptan (0.13 mL, 1.11 mmol), DIPEA (0.21 mL, 1.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene (122.0 mg, 0.22 mmol), and tris(dibenzylacetone)palladium (100.8 mg, 0.11 mmol) in toluene (11.0 mL) was degassed three times under a nitrogen atmosphere, and the mixture was stirred overnight at 100 °C. The resulting mixture was filtered through a diatomaceous earth mat, and the filtrate was diluted with ethyl acetate / water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 0% to 100%) to obtain a colorless oil containing the title compound 17-A (475.0 mg, 86.7%).

[0338] Step 2: tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (17-B)

[0339] At 0 °C, 1,3-dichloro-5,5-dimethylhydantoin (296.1 mg, 1.50 mmol) was added in portions to a solution of 17-A (374.0 mg, 0.75 mmol) in an acetonitrile / acetic acid / water ratio of 40 / 1.5 / 1 (7.5 mL). The mixture was stirred at 0 °C for 20 minutes and then concentrated. The residue was dissolved in dichloromethane, and sodium bicarbonate (5% aqueous solution) was added at 0 °C. The mixture was stirred for 5 minutes, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give crude 17-B without further purification, which was used directly for the next step.

[0340] Step 3: tert-butyl(R)-3-((S)-3-(3-(((R)-3-(((benzyloxycarbonyl)amino)pyrrolidine-1-yl)sulfonyl)phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (17-C)

[0341] A solution of 17-B (356.0 mg, 0.75 mmol) and pyridine (0.04 mL, 0.49 mmol) in tetrahydrofuran (7.5 mL) was stirred at room temperature for 30 minutes, followed by the addition of (R)-pyrrolidine-3-ylcarbamate benzyl ester (165.4 mg, 0.75 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was boiled in water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give the title compound 17-C (114.0 mg, 23.1%, step 2) as a white solid.

[0342] Step 4: tert-butyl(R)-3-((S)-3-(3-(((R)-3-(((benzyloxycarbonyl)amino)pyrrolidine-1-yl)sulfonyl)phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (17-D)

[0343] A methanol solution (2.2 mL) containing 17-C (150.0 mg, 0.23 mmol) and 10% Pd / C (30.0 mg) was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered and concentrated to give 17-D (118 mg, 98.8%), which required no further purification.

[0344] Step 5: 3,3'-Di-tert-butyl(2S,2'S)-(R)-1-((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)pyrrolidine-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-ketopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)(17-E)

[0345] The colorless oily substance 17-E (118.0 mg, 40.3%) can be obtained from 17-D (118.0 mg, 0.23 mmol) and Int-A (200.0 mg, 0.50 mmol) via GP1 operation.

[0346] Step 6: (2S,2'S)-3,3'-Dibenzo(R)-1-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)pyrrolidine-3-ylazadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-yl)propionic acid) hydrochloride (17)

[0347] The white solid compound 17 (34.8 mg, 39.2%) was obtained by the GP2 operation.

[0348] Compound 17: MS (ESI) m / z: [M+H] + 830.3; 1 H NMR(400MHz,D2O)δ7.72–7.41(m,4H),7.34–7.19(m,4H),7.12–6.93(m,4H),4.25–4.06(m,4H),3.91–3.79(m,1H),3.65–3.4 5(m,5H),3.40–3.13(m,7H),3.07–2.64(m,13H),2.57–2.41(m,3H),2.36–2.22(m,2H),2.17–1.99(m,3H),1.76–1.58(m,3H).

[0349] Example 18: Preparation of Compound 18

[0350] Step 1: Dibenzyl 2,2-bis(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)malonate (18-A)

[0351] At 0 °C, 60% sodium hydride (132.2 mg, 3.30 mmol) was added to a solution of Int-C (1.00 g, 2.20 mmol) in N,N-dimethylformamide (3.0 mL). The mixture was then stirred for 1 hour under a nitrogen atmosphere. Dibenzyl malonate (284.0 mg, 1.00 mmol) was added. The mixture was stirred for 5 hours under a nitrogen atmosphere. The resulting mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 18-A (960.0 mg, 42.4%).

[0352] Step 2: 2,2-Bis(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)malonic acid (18-B)

[0353] A solution of 18-A (600.0 mg, 0.60 mmol) and 10% palladium on carbon (60.0 mg) in methanol (10.0 mL) was stirred at 50 °C for 2 hours under a hydrogen atmosphere. The mixture was then filtered and concentrated to obtain 18-B (505.0 mg), which was used directly in the next step.

[0354] Step 3: 2-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-3-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)propionic acid (18-C)

[0355] Lithium chloride (200.0 mg, 5.00 mmol) was added to a solution of 18-B (505.0 mg, 0.50 mmol) in dimethyl sulfoxide (5.0 mL). The mixture was then stirred at 130 °C for 1 hour under a nitrogen atmosphere. The mixture was purified by reversed-phase chromatography (eluting with acetonitrile:water / 0.5% hydrochloric acid = 0% to 100%) to give a colorless oily substance 18-C (265.0 mg, 56.0%).

[0356] Step 4: (R)-3-((S)-3-(3-(azidomethyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (18-D)

[0357] Sodium azide (42.0 mg, 0.27 mmol) was added to a solution of Int-C (200.0 mg, 0.18 mmol) in N,N-dimethylformamide (3.0 mL). The mixture was stirred at 65 °C for 2 hours. The mixture was then poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 18-D (125.0 mg, 68.0%).

[0358] Step 5: (R)-3-((S)-3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (18-E)

[0359] A methanol (3.0 mL) solution of 18-D (85.0 mg, 0.20 mmol) and 10% palladium on carbon (10.0 mg) was stirred for 1 hour at room temperature under a hydrogen atmosphere. The mixture was then filtered and concentrated to give 18-E (65.0 mg), which was used directly in the next step.

[0360] Step 6: Di-tert-butyl 3,3'-((2S, 2'S)-(2-((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)carbamoyl)propane-1,3-diyl)bis(3,1-phenylene)bis(3-(tert-butoxy)-3-ketopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate))(18-F

[0361] To a solution of 18-E (30.0 mg, 0.080 mmol) and 18-C (25.0 mg, 0.030 mmol) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.20 mL) and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (38.0 mg, 0.10 mmol) were added sequentially. The mixture was then stirred under a nitrogen atmosphere for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 18-F (25.0 mg, 68.4%).

[0362] Step 7: (2S, 2'S)-3,3'-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)carbamoyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (18)

[0363] The white solid compound 18 (15.2 mg, 86.1%) was obtained by GP2 operation.

[0364] Compound 18: MS (ESI) m / z: [M / 2+H] + 377.4; 1 H NMR(400MHz,D2O)δ7.20–7.12(m,2H),7.10–6.89(m,8H),6.62–6.53(m,1H),6.22–6.09(m,1H),3.91–3.77(m,2H),3.50–3.3 9(m,3H),3.37–3.28(m,3H),3.20–3.08(m,3H),3.02–2.55(m,17H),2.51–2.35(m,3H),2.14–1.97(m,3H),1.73–1.56(m,3H).

[0365] Example 19: Preparation of Compound 20

[0366] Step 1: 3,3'-((2S,2'S)-((2-(hydroxymethyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester)(20-A)

[0367] To a solution of 18-C (265.0 mg, 0.30 mmol) in tetrahydrofuran (3.0 mL), N,N'-carbonyldiimidazole (100.0 mg, 0.60 mmol) was added. The mixture was stirred at 25 °C for 2 hours. Sodium borohydride (23.0 mg, 0.80 mmol) was added. The mixture was stirred at 25 °C for 30 minutes. The resulting mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 20-A (120.0 mg, 46.1%).

[0368] Step 2: 3,3'-((2S,2'S)-((2-((((methanesulfonyl)oxy)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester)(20-B)

[0369] Triethylamine (0.30 mL) was added to a solution of 20-A (120.0 mg, 0.10 mmol) in dichloromethane (2.0 mL). Methanesulfonyl chloride (33.0 mg, 0.30 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 30 minutes under a nitrogen atmosphere. After direct concentration, the mixture was separated by column chromatography (dichloromethane:ethyl acetate = 0-50%) to obtain 20-B (115.0 mg, crude product).

[0370] Step 3: Di-tert-butyl 3,3'-((2S,2'S)-((2-((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenoxy)methyl)propane-1,3-diyl)bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester))(20-C

[0371] Cesium carbonate (35.0 mg, 0.10 mmol) was added to a solution of 20-B (35.0 mg, 0.010 mmol) and Int-E (15.0 mg, 0.01 mmol) in dichloromethane (1.0 mL) at room temperature. The mixture was stirred at 80 °C for 16 hours. The resulting mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 20-C (25.0 mg, 53.8%).

[0372] Step 4: Step 4: (2S,2'S)-3,3'-((2-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (20)

[0373] The white solid 20 (13.7 mg, 78.4%) was obtained by GP2 operation.

[0374] Compound 20: MS (ESI) m / z: [M+H] + 727.6; 1H NMR(400MHz,D2O)δ7.23–6.52(m,12H),3.65(s,2H),3.50–3.26(m,6H),3. 22–3.07(m,3H),2.96–2.37(m,19H),2.28–2.00(m,4H),1.76–1.53(m,3H).

[0375] Example 20: Preparation of Compound 21

[0376] Step 1: Di-tert-butyl 3,3'-((2S,2'S)-((2-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)piperolane-3-yl)-3-oxopropyl)benzyl)oxy)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(piperolane-1-carboxylic acid ester))(21-A

[0377] At 0 °C, a 60% sodium hydride mineral mixture (8.0 mg, 0.20 mmol) was added to a solution of Int-B (50.0 mg, 0.10 mmol) in N,N-dimethylformamide (2.0 mL). The mixture was then stirred for 1 hour under a nitrogen atmosphere. 20-B (35.0 mg, 0.050 mmol) was added. The mixture was stirred for 5 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 21-A (25.0 mg, crude).

[0378] Step 2: (2S,2'S)-3,3'-((2-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)oxy)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid)(21)

[0379] White solid 21 (1.4 mg, 4.2%, 2 steps) was obtained by GP2 operation.

[0380] Compound 21: MS (ESI) m / z: [M+H] + 741.6; 1H NMR(400MHz,D2O)δ7.35–6.79(m,12H),4.74–4.73(m,2H),3.50–3.10(m,11H) ,2.98–2.36(m,20H),2.27–2.20(m,1H),2.12–2.02(m,2H),1.75–1.57(m,3H).

[0381] 21: Preparation of Example 22

[0382] Step 1: 3,3'-((2S,2'S)-(R)-6-oxopiperidin-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(22-A)

[0383] A solution of (R)-5-aminopiperidin-2-one hydrochloride (40.0 mg, 0.30 mmol), Int-C (400.0 mg, 0.80 mmol), and potassium carbonate (409.0 mg, 3.00 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at 80 °C for 16 hours. The mixture was then poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 22-A (110.0 mg, 46.1%).

[0384] Step 2: Di-tert-butyl 3,3'-((2S,2'S)-(((((R)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-6-oxoperidin-3-yl)azadiyl)methylene)di(3,1-phenylene))di(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate))(22-B

[0385] At 0 °C, a 60% sodium hydride mineral oil mixture (8.0 mg, 0.20 mmol) was added to a solution of 22-A (110.0 mg, 0.10 mmol) in N,N-dimethylformamide (2.0 mL). The mixture was then stirred for 1 hour under a nitrogen atmosphere. Int-C (48.0 mg, 0.10 mmol) was added. The mixture was stirred for 5 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 22-B (73.0 mg, 50.1%).

[0386] Step 3: (2S,2'S)-3,3'-(((((R)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)-6-oxopiperidin-3-yl)azinyl)methylene)bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid)(22)

[0387] White solid 22 (50.9 mg, 93.3%) was obtained by GP2 operation.

[0388] Compound 22: MS (ESI) m / z: [M+H] + 808.4; 1 H NMR(400MHz,D2O)δ7.29-7.18(m,5H),7.13–6.92(m,7H),4.50–4.39(m,2H),4.30-4.18(m,2H),4.13–4.01(m,2H),3.68–3.59(m,1H), 3.56–3.46(m,4H),3.40–3.30(m,3H),3.23–3.09(m,3H),3.04–2.56(m,14H),2.55–2.37(m,4H),2.33–2.01(m,5H),1.76–1.58(m,3H).

[0389] 22: Preparation of Example 23

[0390] Step 1: Tert-butyl(R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-cyano-1-oxoprop-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (23-A)

[0391] At -78°C, a tetrahydrofuran solution of lithium bis-(trimethylsilyl)amine (1M, 18.0 mL, 18.0 mmol) was added to a tetrahydrofuran solution of Int-A-1 (5.00 g, 12.9 mmol). The resulting mixture was then stirred for 30 minutes. 2-Bromoacetonitrile (708.0 mg, 6.00 mmol) was added to the above solution. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was then poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 23-A (1.70 g, 30.8%).

[0392] Step 2: (S)-2-((R)-1-(tert-Butoxycarbonyl)pyrrolidine-3-yl)-3-cyanopropionic acid (23-B)

[0393] At 0 °C, an aqueous solution (5 mL) of lithium hydroxide (0.255 g, 6.00 mmol) was slowly added to a solution of 23-A (500 mg, 1.17 mmol) and hydrogen peroxide (120 mg, 3.60 mmol) in tetrahydrofuran (10 mL). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then poured into an aqueous solution of sodium sulfite and extracted with ethyl acetate. The aqueous phase was adjusted to pH 3 by adding hydrochloric acid (5 N) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 23-B (280.0 mg, crude), which was used directly in the next step.

[0394] Step 3: (R)-3-((S)-1-(tert-butoxy)-3-cyano-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (23-C)

[0395] N-(tert-butoxy(propyl-2-imideamino)methyl)propyl-2-amine (700.0 mg, 3.00 mmol) was added to a tetrahydrofuran (10 mL) solution of 23-B (280.0 mg, 1.00 mmol). The mixture was then stirred at 60 °C for 6 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 23-C (43.0 mg, 11.3%).

[0396] Step 4: (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (23-D)

[0397] Add 0.2 mL of aqueous hydroxylamine to a solution of 23-C (43.0 mg, 0.13 mmol) in dimethyl sulfoxide (1.0 mL). Stir the mixture at 50 °C for 6 hours. Purify the mixture by reversed-phase chromatography (eluting with acetonitrile:water / 0.1% hydrochloric acid = 0% to 100%) and freeze-dry to give a colorless oily 23-D-Int. (30.0 mg, crude product).

[0398] To a solution of 23-D-Int. (30.0 mg, crude) in tetrahydrofuran (3 mL), carbonyl diimidazole (30.0 mg, 0.19 mmol) was added. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (25.0 mg, 0.20 mmol) was added. The mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. The concentrated crude product was purified by reversed-phase chromatography (eluting with acetonitrile:water / 0.1% hydrochloric acid = 0% to 100%) to give a colorless oily 23-D (13.0 mg, 26.1%).

[0399] Step 5: 3,3'-((2S, 2'S)-(2-((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl))(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(23-E)

[0400] Cesium carbonate (30.0 mg, 0.092 mmol) was added to a solution of 23-D (13.0 mg, 0.034 mmol) and 20-B (25.0 mg, 0.026 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. The resulting solution was stirred at 80 °C for 16 hours, and the solid was removed by filtration. The resulting solution was purified by reversed-phase chromatography (eluting with acetonitrile:water / 0.1% hydrochloric acid = 0% to 100%), and the eluent was freeze-dried to give a colorless oily substance, 23-E (23.0 mg, 74.6%).

[0401] Step 6: (2S, 2'S)-3,3'-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (23)

[0402] The white solid 23 (8.5 mg, 53.0%) was obtained by GP2 operation.

[0403] Compound 23: MS (ESI) m / z: [M / 2+H] + 359.8; 1 H NMR(400MHz,D2O)δ7.31–7.25(m,2H),7.16–7.02(m,6H),3.67–3.52(m,4H),3.50–3.3 8(m,4H),3.32–3.20(m,3H),3.11–2.37(m,21H),2.27–2.03(m,3H),1.81–1.71(m,2H).

[0404] 23: Preparation of Example 24

[0405] Step 1: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic acid ethyl ester (24-A-1)

[0406] At 0 °C, 60% sodium hydroxide (4.57 g, 114.17 mmol) was added to a solution of ethyl 1H-pyrazole-4-carboxylate (10.0 g, 71.36 mmol) in tetrahydrofuran (170.0 mL). The mixture was then stirred under a nitrogen atmosphere for 0.5 h. Chloromethyltrimethylsilylethyl ether (15.16 mL) was added to the above system. The mixture was stirred to room temperature under a nitrogen atmosphere, poured into water, and extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 24-A-1 (16.3 g, 84.5%).

[0407] Step 2: (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)methanol(24-A-2)

[0408] A tetrahydrofuran solution (90.4 mmol, 90.4 mL) of lithium aluminum hydride was added to a tetrahydrofuran solution (180.0 mL) of 24-A-1 (16.3 g, 60.28 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. Water was added, followed by a 15% aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 1 hour, filtered, and the solid was washed with ethyl acetate. The combined organic solutions were rotary evaporated to give a colorless oily substance 24-A-2 (8.7 g, 63.2%).

[0409] Step 3: 4-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(24-A-3)

[0410] At 0 °C, carbon tetrachloride (11.98 g, 36.13 mmol) and triphenylphosphine (9.48 g, 36.13 mmol) were added to a solution of 24-A-2 (5.5 g, 24.08 mmol) in dichloromethane (36.0 mL). The mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil of 24-A-3 (4.4 g, 62.7%).

[0411] Step 4: (R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxo-3-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)propyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (24-B)

[0412] At -78°C, a solution of lithium bis-(trimethylsilyl)amine (1M, 7.7mL, 7.70mmol) was added to a solution of Int-A-1 (2.5g, 6.44mmol) in tetrahydrofuran (30mL). The mixture was then stirred for 1 hour under a nitrogen atmosphere. 24-A-3 (2.10g, 7.21mmol) was added. The reaction mixture was stirred for 16 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (50mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 24-B (1.65g, 42.9%).

[0413] Step 5: (S)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)propionic acid (24-C)

[0414] At 0 °C, hydrogen peroxide (796.6 mg, 3.6 mmol) was added to a tetrahydrofuran (11 mL) solution of 24-B (1.65 g, 2.76 mmol), followed by dropwise addition of an aqueous solution of lithium hydroxide (150.0 mg, 4.41 mmol) (2 mL). The mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was poured into water, the pH of the system was adjusted to 3, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 24-C (1.21 g, crude product), which was used directly in the next step.

[0415] Step 6: (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)propyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (24-D)

[0416] N-(tert-butoxy(propyl-2-imideamino)methyl)propyl-2-amine (4.44 g, 22.16 mmol) was added to a solution of 24-C (1.21 g, crude) in tetrahydrofuran (10 mL). The mixture was then stirred at 60 °C for 6 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 24-D (450.0 mg, 33.0%).

[0417] Step 7: (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(1H-pyrazol-4-yl)propyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (24-E)

[0418] To a solution of 24-D (100.0 mg, 0.20 mmol) in tetrahydrofuran (3.2 mL), 1.00 mL of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) was added. The mixture was stirred at room temperature for 2 hours under nitrogen protection. The resulting mixture was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 24-E (32.4 mg, 44.3%).

[0419] Step 8: 3,3'-((2S, 2'S)-(2-((4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-1H-pyrazole-1-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl))(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(24-F)

[0420] Cesium carbonate (4.2 mg, 0.13 mmol) was added to a solution of 20-B (60.0 mg, 0.07 mmol) and 24-E (31.2 mg, 0.09 mmol) in N,N-dimethylformamide (0.4 mL), and the mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 24-F (42.9 mg, 55.0%).

[0421] Step 9: (2S, 2'S)-3,3'-(2-((4-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-1H-pyrazole-1-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (24)

[0422] The white solid 24 (14.1 mg, 48.5%) was obtained by GP2 operation.

[0423] Compound 24: MS (ESI) m / z: [M / 2+H] + 350.8; 1 H NMR(400MHz,D2O)δ7.44–7.34(m,2H),7.20–7.10(m,2H),7.03–6.94(m,2H),6.93–6.85(m,4H),3.93(d,J=5.8Hz,2H),3.57–3. 45(m,3H),3.43–3.25(m,3H),3.23–3.08(m,3H),3.06–2.90(m,3H),2.85–2.25(m,17H),2.13–2.03(m,3H),1.74–1.58(m,3H).

[0424] 24: Preparation of Example 25

[0425] Step 1: 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (25-A-1)

[0426] To a stirred solution of 4-methylenepiperidin-1-carboxylic acid benzyl ester (10.0 g, 42.9 mmol) in chloroform (400 mL), m-chlorobenzoic acid (11.1 g, 64.4 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 30 minutes, then stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (50 mL) and washed successively with 10% sodium sulfite aqueous solution, 10% sodium bicarbonate aqueous solution, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography, eluting with ethyl acetate:petroleum ether = 0% to 20%, to give a brown oily substance 25-A-1 (9.36 g, 88.3%).

[0427] Step 2: 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (25-A-2)

[0428] Aluminum triisopropoxide (8.50 g, 41.6 mmol) was added to a xylene (380 mL) solution of 25-A-1 (9.36 g, 37.9 mmol). The resulting solution was stirred at 160 °C for 4 hours under a nitrogen atmosphere and then cooled to room temperature. Acetic acid (5 mL) was added to the mixture, and it was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography, eluting with ethyl acetate:petroleum ether = 0% to 30%, to give a brown oily substance 25-A-2 (1.23 g, 13.1%).

[0429] Step 3: 4-(bromomethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (25-A)

[0430] At 0 °C, triphenylphosphine (764 mg, 2.91 mmol) and carbon tetrabromide (966 mg, 2.91 mmol) were added to a solution of 25-A-2 (600 mg, 2.43 mmol) in dichloromethane (24 mL). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 4 hours. The mixture was then poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography, eluting with ethyl acetate:petroleum ether = 0% to 30%, to give a brown oily substance 25-A (180 mg, 23.9%).

[0431] Step 4: 4-((S)-3-((S)-4-benzyl-2-oxooxazolidine-3-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (25-B)

[0432] At -78°C, a solution of hexamethyldisilamide lithium (1M, 0.69mL, 0.69mmol) in tetrahydrofuran was added to a solution of Int-A-1 (225mg, 0.58mmol) in tetrahydrofuran (4mL). Then 25-A (225mg, 0.58mmol) was added. The mixture was slowly restored to room temperature under a nitrogen atmosphere and stirred for 16 hours. The resulting mixture was poured into water and extracted with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography, eluting with ethyl acetate:petroleum ether = 0% to 100%, to give a white solid 25-B (127mg, 35.4%).

[0433] Step 5: (S)-3-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (25-C)

[0434] Hydrogen peroxide (0.04 mL) and lithium hydroxide (12.9 mg, 0.31 mmol, dissolved in 0.3 mL water) were added to a tetrahydrofuran (2 mL) solution of 25-B (127 mg, 0.21 mmol). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was adjusted to pH 4 by adding 1 N hydrochloric acid and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 25-C (127 mg, crude product).

[0435] Step 6: 4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (25-D)

[0436] Add O-tert-butyl-N,N'-diisopropylisourea (222 mg, 1.11 mmol) to a solution of 25-C (127 mg, crude) in tetrahydrofuran (3 mL). Stir the resulting solution overnight at 65 °C under nitrogen atmosphere. After cooling to room temperature, pour the mixture into water and extract with ethyl acetate (10 mL x 3). Wash the combined organic layers with brine and dry to anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by column chromatography, eluting with ethyl acetate:petroleum ether = 0% to 50%, to give a white solid 25-D (50.0 mg, 35.1%).

[0437] Step 7: (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(piperidin-4-yl)propane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (25-E)

[0438] 10% palladium hydroxide / carbon (20.0 mg) was added to a solution of 25-D (50.0 mg, 0.097 mmol) in methanol (1 mL) and ethyl acetate (1 mL). The resulting solution was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction system was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to give a white solid 25-E (30.0 mg, 80.6%).

[0439] Step 8: 3,3'-((2S, 2S)-((2-(4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)piperidine-1-carbonyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester)(25-F)

[0440] To a solution of 25-E (30.0 mg, 0.078 mmol) in N,N-dimethylformamide (1.5 mL), 18-C (65.5 mg, 0.078 mmol) and diisopropylethylamine (30.4 mg, 0.24 mmol) were added, followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (35.8 mg, 0.094 mmol). The resulting solution was stirred at room temperature for 4 hours under a nitrogen atmosphere. The mixture was then poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography, eluting with ethyl acetate:petroleum ether = 0% to 50%, to give a white solid 25-F (28.0 mg, 29.7%).

[0441] Step 9: (2S, 2S)-3,3'-(2-(4-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)piperidine-1-carbonyl)propane-1,3-diacyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid)hydrochloric acid (25)

[0442] The white solid 25 (1.80 mg, 9.2%) was obtained by GP2 operation.

[0443] Compound 25: MS (ESI) m / z: 366.3, [M / 2+H] + ; 1 H NMR(400MHz,D2O)δ7.26(m,2H),7.16–6.98(m,6H),3.81–3.35(m,10H),3.34–3.18(m,3H),3.17–3.03(m,2H),3.01–2.64( m,11H),2.63–2.48(m,2H),2.47–2.03(m,7H),1.88–1.61(m,3H),1.60–1.06(m,4H),1.00–0.75(m,1H),0.65–0.35(m,1H).

[0444] 25: Preparation of Example 26

[0445] Step 1: (S)-4,4-difluoropyrrolidine-3-amine hydrochloride (26-A)

[0446] A solution of 4M hydrochloric acid in 1,4-dioxane (4.0 mL) was added to an ethanol (4.0 mL) solution of (S)-4-amino-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.45 mmol). The resulting solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was filtered to give a white solid 26-A (87.8 mg, 100%).

[0447] Step 2: 3,3'-((2S, 2'S)-((((S)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-4,4-difluoropyrrolidine-3-ylazadiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(26-B)

[0448] To a solution of 26-A (87.8 mg, 0.45 mmol) in N,N-dimethylformamide (4.5 mL), Int-C (848 mg, 1.80 mmol) and potassium carbonate (373 mg, 2.70 mmol) were added. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was quenched with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by reverse-phase column chromatography (mobile phase: A: acetonitrile, B: aqueous solution of 0.1% formic acid) to give a colorless oily substance 26-B (152 mg, 26.3%).

[0449] Step 3: (2S, 2'S)-3,3'-((((S)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)-4,4-difluoropyrrolidine-3-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (26)

[0450] The white solid 26 (42.4 mg, 35.9%) was obtained by GP2 operation.

[0451] Compound 26: MS (ESI) m / z: [M / 2+H] + 408.8; 1 H NMR(400MHz,D2O)δ7.24(m,4H),7.16–6.99(m,8H),4.25–4.20(m,3H),3.80–3.55(m,7H),3.53–3.42(m,3H),3.41–3.21(m,5H),3. 20–3.07(m,3H),3.00–2.89(m,3H),2.88–2.68(m,6H),2.66–2.37(m,3H),2.52–2.37(m,3H),2.14–1.98(m,3H),1.74–1.55(m,3H).

[0452] 26: Preparation of Example 27

[0453] Starting from (R)-4-amino-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester, a white solid 27 (42.4 mg) was obtained by similar procedures to those used in the synthesis of compound 26.

[0454] Compound 27: MS (ESI) m / z: [M / 2+H] + 408.8; 1H NMR(400MHz,D2O)δ7.27(m,7.5Hz,4H),7.19–7.03(m,8H),4.30–4.20(m,2H),3.92–3.59(m,7H),3.58–3.39(m,4H),3.39–3.27(m,4H) ,3.24–3.10(m,3H),3.10–2.93(m,3H),2.92–2.72(m,6H),2.72–2.61(m,3H),2.58–2.39(m,3H),2.18–2.00(m,3H),1.76–1.57(m,3H).

[0455] 27: Preparation of Example 28

[0456] Step 1: 3,3'-((2S, 2'S)-(2-((4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)piperidin-1-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene)bis(3-(tert-butoxy)-3-ketopropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(28-A)

[0457] Sodium carbonate (21.0 mg, 0.40 mmol) was added to a mixture of 25-E (25.0 mg, 0.065 mmol) and 20-B (59.0 mg, 0.65 mmol) in N,N-dimethylformamide (1.0 mL), and the resulting mixture was heated at 80 °C for 3 hours. The mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 28-A (30.0 mg, 39.0%).

[0458] Step 2: (2S, 2'S)-3,3'-(2-((4-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)piperidin-1-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (28)

[0459] The white solid 28 (10.0 mg, 45.8%) was obtained by GP2 operation.

[0460] Compound 28: MS (ESI) m / z: [M+H] + 717.4; 1H NMR(400MHz,D2O)δ7.28–7.19(m,2H),7.12–6.92(m,6H),3.58–3.50(m,2 H),3.46–3.29(m,6H),3.23–3.13(m,3H),3.04–2.80(m,8H),2.78–2.70( m,2H),2.69–2.62(m,2H),2.61–2.27(m,11H),2.15–1.97(m,3H),1.89(d ,J=14.1Hz,1H),1.76–1.56(m,5H),1.41–1.32(m,1H),1.32–1.19(m,2H).

[0461] 28: Preparation of Example 29

[0462] Step 1: (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-((2-oxopyrrolidone-1-yl)methyl)phenyl)prop-2-yl)pyrrolidone-1-carboxylic acid tert-butyl ester (29-A)

[0463] At 0 °C, 60% sodium hydride (200.0 mg, 5.00 mmol) was added to a solution of pyrrolidone (300.0 mg, 3.52 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred at 0 °C for 1 hour. Int-C (1.50 g, 3.20 mmol) dissolved in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at 0 °C for 3 hours. The mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The mixture was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 29-A (170.0 mg, 11.2%).

[0464] Step 2: 3,3',3”-(2S,2'S,2”S)-((2-oxopyrrolidine-1,3,3-triyl)tris(phenyl-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl)-(3R,3'R,3”R)-tris(pyrrolidine-1-carboxylate) (29-B)

[0465] At -78°C, a 1M sodium di(trimethylsilyl)aminotetrahydrofuran solution (0.5 mL, 0.50 mmol) was added to a 2 mL solution of 29-A (100 mg, 0.21 mmol). The mixture was then stirred for 1 hour under a nitrogen atmosphere. Int-C (250.0 mg, 0.53 mmol) was added to the above reaction system at -78°C, and the mixture was slowly restored to room temperature. The mixture was stirred for 16 hours under a nitrogen atmosphere, poured into water, and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil 29-B (40.0 mg, 25.9%).

[0466] Step 3: (2S, 2'S, 2”S)-3,3', 3”-((2-oxopyrrolidine-1,3,3-triyl)tris(methylene))tris(benzene-3,1-diyl))tri-(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (29)

[0467] The white solid 29 (27.9 mg, 94.7%) was obtained by GP2 operation.

[0468] Compound 29: MS (ESI) m / z: [M+H] + 780.4; 1 H NMR(400MHz,D2O)δ7.15–6.97(m,10H),6.62–6.43(m,2H),4.09–3.91(m,2H),3.52–3.42(m,3H),3.37–3.29(m,3H),3.20–3.1 2(m,3H),3.02–2.92(m,5H),2.82–2.58(m,11H),2.50–2.39(m,3H),2.20–2.01(m,5H),1.96–1.86(m,2H),1.72–1.59(m,3H).

[0469] 29: Preparation of Example 30

[0470] Step 1: (R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopent-4-en-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (30-A-1)

[0471] At -78°C, a 1M solution of lithium di(trimethylsilyl)aminotetrahydrofuran (18.5 mL, 18.5 mmol) was added to a 50 mL solution of Int-A-1 (5.0 g, 12.9 mmol). The mixture was then stirred for 1 hour under a nitrogen atmosphere. 3-Bromoprop-1-ene (3.1 g, 25.8 mmol) was added at -78°C. The mixture was stirred for 16 hours under a nitrogen atmosphere, poured into water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil, 30-A-1 (3.1 g, 59.6%).

[0472] Step 2: (S)-2-((R)-1-(tert-Butoxycarbonyl)pyrrolidine-3-yl)pent-4-enoic acid (30-A-2)

[0473] At 0 °C, hydrogen peroxide (1.6 g, 14.2 mmol) was added to a tetrahydrofuran (70 mL) solution of 30-A-1 (3.1 g, 7.23 mmol), followed by dropwise addition of an aqueous solution of lithium hydroxide monohydrate (1.0 g, 16.0 mmol) (5 mL). Under a nitrogen atmosphere, the mixture was stirred at 25 °C for 16 hours, then poured into water and the pH adjusted to 3. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 30-A-2 (3.5 g, crude), which was used directly in the next step.

[0474] Step 3: (R)-3-((S)-1-(tert-butoxy)-1-oxopent-4-en-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (30-A-3)

[0475] To a solution of 30-A-2 (3.5 g, crude) in tetrahydrofuran (35 mL), O-tert-butyl-N,N'-diisopropylisourea (3.5 g, 17.5 mmol) was added. The mixture was then stirred at 60 °C for 6 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 30-A-3 (800 mg, 33.7%).

[0476] Step 4: (3R)-3-((2S)-1-(tert-butoxy)-3-(ethylene-2-yl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (30-A-4)

[0477] To a methanol (3 mL) solution of 30-A-3 (800 mg, 2.46 mmol), sodium bicarbonate (400 mg, 4.76 mmol), dicyclohexylcarbodiimide (1.0 g, 4.85 mmol), and hydrogen peroxide (2 mL) were added sequentially. The mixture was stirred at 25 °C for 16 hours, then poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (eluting with acetonitrile:water / hydrochloric acid = 0% to 100%) to give a colorless oily substance 30-A-4 (300 mg, 35.7%).

[0478] Step 5: (3R)-3-((2S)-5-amino-1-(tert-butoxy)-4-hydroxy-1-oxopent-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (30-A-5)

[0479] A solution of 30-A-4 (300 mg, 0.88 mmol) in ammonia-methanol (3 mL) was stirred at 60 °C for 16 hours under a nitrogen atmosphere. The concentrated mixture was purified by preparative HPLC (eluting with acetonitrile:water / hydrochloric acid = 0% to 100%) to give a colorless oily substance 30-A-5 (130.0 mg, 41.2%).

[0480] Step 6: (3R)-3-((2S)-1-(tert-butoxy)-1-oxo-3-(2-oxooxazolidine-5-yl)propyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (30-A)

[0481] To a solution of 30-A-5 (130.0 mg, 0.36 mmol) in tetrahydrofuran (4 mL), 1,1′-carbonylimidazole (110.0 mg, 0.68 mmol) was added. The resulting solution was stirred at 25 °C for 16 hours. The concentrated mixture was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 30-A (40.0 mg, 28.9%).

[0482] Step 7: 3,3'-((2S, 2'S)-((2-((5-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-oxooxazolidine-3-yl,methyl)propane-1,3-diyl)bis(3,1-phenylene)bis(3-(tert-butoxy)-3-ketopropane-1,2-diyl)(3R, 3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)(30-B)

[0483] 60% sodium hydride (10.0 mg, 0.25 mmol) was added to a solution of 30-A (40.0 mg, 0.10 mmol) in 1 mL of N,N-dimethylformamide at 0 °C, and the mixture was stirred at 0 °C for 20 min. 20-B (80.0 mg, 0.089 mmol) was added to the system at 0 °C. The resulting solution was stirred at 80 °C for 16 hours and then allowed to return to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 30-B (25.0 mg, 23.4%).

[0484] Step 8: (2S, 2'S)-3,3'-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2-oxooxazolidine-3-ylmethyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (30)

[0485] The white solid 30 (3.9 mg, 20.0%) was obtained by GP2 operation.

[0486] Compound 30: MS (ESI) m / z: [M / 2+H] + 360.3; 1 H NMR (400MHz, D2O) δ7.28–6.93(m,8H),3.63–3.07(m,13H),3.06–2.20(m,21H),2.14–2.02(m,2H),1.98–1.87(m,1H),1.76–1.60(m,3H).

[0487] 30: Preparation of Example 31

[0488] Step 1: 3,3',3'-((2S,2'S,2”S)-((2,4-dioxo-1,3,8-triazaspiro[4.5]decane-1,3,8-trimethyl)tris(phenyl-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R,3'R)-tris(tert-butyl pyrrolidine-1-carboxylate)(31-A)

[0489] Cesium carbonate (30.0 mg, 0.092 mmol) was added to a solution of 1,3,8-triazaspiro[4.5]decane-2,4-dione (5.0 mg, 0.030 mmol) and Int-C (37.0 mg, 0.079 mmol) in N,N-dimethylformamide (1.0 mL), and the resulting mixture was heated at 90 °C for 16 hours. The mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily 31-A (18.0 mg, 45.1%).

[0490] Step 2: (2S, 2'S, 2”S)-3,3', 3'-((2,4-dioxo-1,3,8-triazaspiro[4.5]decane-1,3,8-trimethyl)tri(methylene))tri(benzene-3,1-dimethyl))tri-(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (31)

[0491] White solid 31 (1.6 mg, 12.2%) was obtained by GP2 operation.

[0492] Compound 31: MS (ESI) m / z: [M / 2+H] + 432.4; 1 H NMR(400MHz,D2O)δ7.42–6.88(m,12H),4.56–4.34(m,6H),3.54–3.38(m,5H),3.35–3.22(m,5H),3.18–3.08(m,3H),2.97–2. 88(m,3H),2.84–2.67(m,5H),2.64–2.53(m,3H),2.50–2.32(m,4H),2.12–1.97(m,4H),1.95–1.71(m,3H),1.69–1.54(m,3H).

[0493] 31: Preparation of Example 32

[0494] Step 1: Methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (32-A-1)

[0495] Arecoline hydrobromide (14 g, 90.21 mmol) was dissolved in 40 mL of water, and potassium carbonate was added to make the solution alkaline, which was then saturated with sodium chloride. The aqueous phase was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered, and then evaporated until a colorless oil was obtained. The oil was dissolved in 40 mL of toluene; the solution was cloudy. Sodium sulfate was added and the mixture was filtered, and the insoluble substances were washed with 26 mL of toluene. 1-Chloroethyl chloroformate (10.26 g, 71.81 mmol) was added to the organic solution. A precipitate formed, and the reaction mixture was heated under reflux in toluene for 12 hours. The precipitate was filtered off, and the organic phase was washed with 0.1 M hydrochloric acid aqueous solution; the aqueous phase was extracted once with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered, and then evaporated under reduced pressure. The residue was dissolved in 25 mL of methanol and then heated under reflux for 2 hours. The methanol was evaporated under reduced pressure to give a colorless oil 32-A-1 (5.9 g, crude product).

[0496] Step 2: 1-Benzyl-3-methyl 5-dihydropyridine-1,3(2H)-dicarboxylic acid (32-A-2)

[0497] At 0 °C, benzyl chloroformate (10.3 mL, 73.44 mmol) was added to a solution of 32-A-1 (5.9 g, crude) in anhydrous dichloromethane (150 mL), followed by triethylamine (40.1 mL, 195.9 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 32-A-2 (6.38 g, 25.7%, step 2).

[0498] Step 3: 5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (32-A-3)

[0499] At -78°C, a 1M tetrahydrofuran solution (51.2 mL) of diisobutylaluminum hydride was added to a solution of 32-A-2 (4.70 g, 17.07 mmol) in anhydrous dichloromethane (70 mL). The mixture was stirred at this temperature for 3 hours. Methanol was added at 0°C, followed by a saturated Rochelle salt solution (30 mL), forming a white slurry. After stirring for another 2 hours, the mixture was filtered; the filtrate was extracted with diethyl ether, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 32-A-3 (1.57 g, 37.1%).

[0500] Step 4: 5-(bromomethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (32-A)

[0501] At 0 °C, triphenylphosphine (2.00 g, 7.61 mmol) was added to a solution of 32-A-3 (1.57 g, 6.34 mmol) in anhydrous dichloromethane (16 mL), followed by carbon tetrabromide (2.52 g, 7.61 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily substance 32-A (1.41 g, 71.5%).

[0502] The synthesis of 32-E is similar to that of 25-E, starting from 32-A and Int-A-1.

[0503] The synthesis of 32 was similar to that of 25, starting from 32-E and 18-C, to give a white solid 32 (3.7 mg, 17.6%).

[0504] Compound 32: MS (ESI) m / z: [M+H] + 731.4; 1 H NMR(400MHz,D2O)δ7.32–6.96(m,8H),4.28–3.88(m,2H),3.66–3.57(m,2H),3.52 –3.37(m,5H),3.32–3.18(m,4H),3.13–3.03(m,2H),2.96–2.76(m,10H),2.64–2. 53(m,2H),2.52–2.30(m,2H),2.26–2.06(m,4H),1.85–1.66(m,3H),1.48–1.32(m ,2H),1.29–0.98(m,2H),0.96–0.74(m,2H),0.72–0.45(m,1H),0.32–0.00(m,1H).

[0505] 32: Preparation of Example 33

[0506] 33-C was synthesized according to the synthesis procedure of Int-A-4.

[0507] Step 4: (R)-3-((S)-1-(tert-butoxy)-1-oxopentyl-4-yn-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (33-D)

[0508] To a solution of 33-C (55.0 mg, 0.14 mmol) in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (0.2 mL, 0.21 mmol) was added. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil of 33-D (45.0 mg, 93.7%).

[0509] Step 5: Tert-butyl(3R)-3-((2S)-3-(3-(3-azido-2-(3-((R)-3-(tert-butoxy)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)propyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (33-E)

[0510] Sodium azide (21.7 mg, 0.33 mmol) was added to a solution of 20-B (0.1 g, 0.11 mmol) in 1.5 mL of N-methylpyrrolidone. The mixture was stirred at 60 °C for 3 hours under a nitrogen atmosphere. The mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil of 33-E (40.0 mg, 43.7%).

[0511] Step 6: Di-tert-butyl 3,3'-((2S, 2'S)-(2-((4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene)bis(3-(tert-butoxy)-3-carbonylpropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate))(33-F

[0512] To a solution of 33-E (40.0 mg, 0.04 mmol) and 33-D (40.0 mg, 0.25 mmol) in acetonitrile (1 mL), cuprous iodide (2.0 mg, 0.01 mmol) and N,N-diisopropylethylamine (13.0 mg, 0.10 mmol) were added. The resulting solution was stirred at 25 °C for 2 hours and then concentrated. The mixture was purified by column chromatography (ethyl acetate: petroleum ether = 0% to 100% elution) to give a colorless oily 33-F (65.0 mg, crude product).

[0513] Step 7: (2S, 2'S)-3,3'-(2-((4-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-1H-1,2,3-triazol-1-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (33)

[0514] The white solid 33 (22.2 mg, 48.0%) was obtained by GP2 operation.

[0515] Compound 33: MS (ESI) m / z: [M+H] + 701.3; 1 H NMR(400MHz,D2O)δ7.69(s,1H),7.42–7.29(m,2H),7.27–6.97(m,6H),4.37(s,2H),3.78–3.66(m,3H),3.54(t,3 H),3.41–3.31(m,3H),3.17(t,3H),3.07–2.82(m,9H),2.79–2.57(m,8H),2.38–2.18(m,3H),1.96–1.78(m,3H).

[0516] 33: Preparation of Example 34

[0517] Step 1: tert-butyl(R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxo-3-(2H-tetrazol-5-yl)propyl-2-yl)pyrrolidine-1-carboxylate (34-A)

[0518] At room temperature, trimethylsilane azide (540.0 mg, 4.68 mmol) and dibutyltin oxide (60.0 mg, 0.23 mmol) were added to a solution of 23-A (500.0 mg, 1.17 mmol) in toluene (3.0 mL). The mixture was then stirred at 110 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with acetonitrile:water / 0.5% hydrochloric acid = 0% to 100%) to give a white solid 34-A (300.0 mg, 54.5%).

[0519] Step 2: Di-tert-butyl 3,3'-((2S, 2'S)-(2-((5-((S)-3-(S)-4-benzyl-2-oxooxazolidine-3-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2H-tetrazole-2-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylate)(34-B)

[0520] At room temperature, cesium carbonate (100.0 mg, 0.7 mmol) and tetrabutylammonium iodide (62.0 mg, 0.17 mmol) were added to a solution of N-methylpyrrolidone (1 mL) containing 34-A (100.0 mg, 0.021 mmol) and 20-B (127.0 mg, 0.14 mmol). The resulting solution was stirred at 80 °C for 6 hours. The concentrated mixture was purified by preparative HPLC (eluting with acetonitrile:water / 0.5% hydrochloric acid = 0% to 100%) to give a colorless oily 34-B (70.0 mg, 39.9%).

[0521] Step 3: (2S, 2'S)-3,3'-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2H-tetrazole-2-yl)methyl)propane-1,3-diyl)bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-ylpropionic acid) hydrochloride (34)

[0522] White solid 34 (25 mg, 73.5%) was obtained by hydrolysis with lithium hydroxide / hydrogen peroxide and GP2 operation.

[0523] Compound 34: MS (ESI) m / z: [M+H] + 702.4; 1 H NMR(400MHz,D2O)δ6.99-6.85(m,8H),4.39(d,J=6.4Hz,2H),3.48(td,J=11.8,8.0Hz,3H),3.36-3 .25(m,3H),3.14(dt,J=11.6,5.7H,3H),3.05-2.39(m,20H),2.14–1.99(m,3H),1.73-1.57(m,3H).

[0524] 34: Preparation of Example 35

[0525] Step 1: Di-tert-butyl 3,3'-((2S, 2'S)-((2-formylpropane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate))(35-A

[0526] To a solution of 20-A (200.0 mg, 0.24 mmol) in dichloromethane (5 mL), Dys-Martin oxidant (163.0 mg, 0.73 mmol) and sodium bicarbonate (80.6 mg, 0.94 mmol) were added. The reaction mixture was stirred at 20 °C for 16 hours under nitrogen atmosphere. Water was added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give 35-A (160.0 mg, 80%) as a colorless oil.

[0527] Step 2: Di-tert-butyl 3,3'-((2S, 2'S)-((2-((Z)-(hydroxyimino)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate))(35-B

[0528] To a 5 mL ethanol solution of 35-A (160.0 mg, 0.19 mmol), N,N-diisopropylethylamine (101.2 mg, 0.78 mmol) and hydroxylamine hydrochloride (28.3 mg, 0.39 mmol) were added. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated. The crude product was purified by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oil of 35-B (130.0 mg, 80%).

[0529] Step 3: Di-tert-butyl 3,3'-((2S, 2'S)-((2-((E)-chloro(hydroxyimino)methyl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate))(35-C

[0530] N-chlorosuccinimide (8.2 mg, 0.05 mmol) was added to a solution of 35-B (30.0 mg, 0.03 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 20 °C for 2 hours. Water was added, and the aqueous layer was extracted with EA. The combined organic layers were dried over sodium sulfate and concentrated to obtain a crude product. Column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) yielded 35-C (29.8 mg, 95.7%) as a colorless oil.

[0531] Step 4: Di-tert-butyl 3,3'-((2S, 2'S)-(2-(5-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)isoxazo-3-yl)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-onepropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylate))(35-D

[0532] Sodium bicarbonate (6.2 mg, 0.07 mmol) and alkynyl compound 33-D (14 mg, 0.04 mmol) were added to a 1 mL solution of ethyl acetate (29.8 mg, 0.03 mmol) at 35°C. The mixture was stirred at 50°C for 2 hours. Water was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give a crude product. The crude product was obtained by column chromatography (eluting with ethyl acetate: petroleum ether = 0% to 100%) to give a colorless oily 35-D (10.2 mg, 25.1%).

[0533] Step 5: (2S, 2'S)-3,3'-((2-(5-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)isoxazo-3-yl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) hydrochloride (35)

[0534] The white solid 35 (2 mg, 29.1%) was obtained by GP2 operation.

[0535] Compound 35: MS (ESI) m / z: [M+H] + 687.6; 1H NMR(400MHz,D2O)δ7.08–7.04(m,2H),6.96–6.90(m,2H),6.87–6.81(m,4H),6.07(s,1H),3.45–3.2 5(m,6H),3.23–3.05(m,4H),3.02–2.80(m,7H),2.77–2.50(m,9H),2.40–2.28(m,3H),2.07–1.97(m 3H),1.68–1.53(m,3H).

[0536] 35: Preparation of Example 64

[0537] Step 1: 2,2-Bis(2-(benzyloxy)ethyl)-1,3-dioxane(64-A)

[0538] 2-[2-(2-hydroxyethyl)-1,3-dioxane-2-yl]ethanol (500.0 mg, 3.08 mmol) was dissolved in DMF (5.0 mL), and NaH (0.49 g, 9.16 mmol) was added at 0 °C. After 1 hour, BnBr (1.0 mL) was added to the above solution at 0 °C. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluent: EA / PE = 0-10%) to give 64-A, a colorless oil (800 mg, 75.8%).

[0539] Step 2: 1,5-bis(benzyloxy)pentan-3-one (64-B)

[0540] 64-A (800.0 mg, 2.34 mmol) was dissolved in acetone (20.00 mL), and p-toluenesulfonic acid monohydrate (0.04 g, 0.23 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: EA / PE = 0-10%) to give 64-B as a colorless oil (600 mg, 86.1%).

[0541] Step 3: 1,5-Di(benzyloxy)pentane-3-ol (64-C)

[0542] 64-B (600.0 mg, 2.01 mmol) was dissolved in THF (8.0 mL) and MeOH (2.0 mL), and NaBH4 (0.11 g, 3.02 mmol) was added in portions at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (eluent: EA / PE = 0-30%) to give 64-C, a colorless oily liquid (0.50 g, 82.8%).

[0543] Step 4: tert-Butyl(R)-3-((S)-3-(3-((1,5-di(benzyloxy)pentan-3-yl)oxy)phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (64-D)

[0544] 64-C (200.0 mg, 0.67 mmol) was dissolved in THF (3.0 mL), and Int-E (260.7 mg, 0.67 mmol), DIAD (200 mg, 1.01 mmol), and PPh3 (260 mg, 1.01 mmol) were added. The mixture was stirred at 50 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, water was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluent: EA / PE = 0-15%) to give 64-D as a white solid (140 mg, 42.6%).

[0545] Step 5: tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((1,5-dihydroxypentan-3-yl)oxy)phenyl)-1-oxopropionyl)pyrrolidine-1-carboxylic acid ester (106-E)

[0546] 64-D (140 mg) was dissolved in trifluoroethanol (5.00 mL), and 10% Pd / C (30 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a layer of diatomaceous earth, and the filtrate was concentrated to give crude product 64-E (85 mg). The crude product was used directly in the next reaction without purification.

[0547] Step 6: tert-Butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((1,5-dibromopent-3-yl)oxy)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (64-F)

[0548] 64-E (85 mg, 0.18 mmol) was dissolved in DCM (1.0 mL), and PPh3 (0.19 g, 0.72 mmol) and CBr4 (0.24 g, 0.72 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction mixture was concentrated and dried, the residue was purified by column chromatography (eluent: EA / PE = 0-15%) to give 64-F as a colorless oil (20 mg, 17.7%).

[0549] Step 7: 3,3'-((2S, 2'S)-((2-aminopropane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate))(64-H

[0550] To a 2 mL solution of toluene at 18°C ​​(100.0 mg, 0.12 mmol), diphenyl azidophosphate (65.0 mg, 0.24 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) were added. The mixture was stirred under nitrogen atmosphere for 2 hours. Benzyl alcohol (1 mL) and 4-dimethylaminopyridine (10 mg) were added. The mixture was stirred under nitrogen atmosphere for 16 hours. The reaction solution was concentrated and purified by reverse-phase column chromatography (eluting with acetonitrile:water = 0% to 100%) to give a colorless oil (70 mg).

[0551] A solution of the above-mentioned oily substance (70 mg, 0.07 mmol) and Pd / C (20.0 mg) in tetrahydrofuran (5 mL) was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was then filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (eluting with methanol:dichloromethane = 0% to 10%) to give a colorless oily 64-H (50.0 mg, 83.3%).

[0552] Step 8: Di-tert-butyl 3,3'-((2S,2'S)-((2-(4-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenoxy)piperidin-1-yl)propane-1,3-diyl)bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester))(64-G

[0553] 64-F (20.0 mg, 0.03 mmol) was dissolved in acetonitrile (1 mL), and 64-H (26.0 mg, 0.03 mmol), K₂CO₃ (0.01 g, 0.09 mmol), and NaI (3 mg, catalytic amount) were added. The resulting mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with H₂O and then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluent: EA / PE = 0-100%) to give 64-G as a white solid (20 mg, 49.0%).

[0554] Step 9: (2S,2'S)-3,3'-((2-(4-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)piperidin-1-yl)propane-1,3-diyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid)(64)

[0555] The white solid 64 (5.0 mg, 39.7%) was obtained by GP2 operation.

[0556] Compound 64: MS (ESI) m / z: [M+H] + 794.5; 1 H NMR(400MHz,D2O)δ7.26–6.63(m,12H),4.46–4.38(m,1H),3.88–3.74(m,1H),3.56–3.0 1(m,15H),3.00–2.53(m,14H),2.50–2.34(m,3H),2.29–1.74(m,7H),1.73–1.51(m,3H).

[0557] Following the synthetic methods for compounds 16 and 17, the following compounds were synthesized:

[0558] III. Biological Detection of Compounds

[0559] Test Example 1: SPR detection of the affinity of a compound for binding to Apo(a)

[0560] The affinity of small molecule compounds for Apo(a) protein was determined individually using a Biacore 8K (Cytiva, 29215379) system. Apo(a) protein was immobilized on a CM5 (Cytiva, 29149603) sensor chip via amine coupling, and the small molecule compounds flowed as analytes through the sensor chip surface. Serial dilutions of the small molecule compounds were prepared using single-cycle kinetics, ranging from 10 nM to 0.08 nM. The binding time was 90 seconds, and the dissociation time was 7200 seconds. The dissociation rate (kd) and binding constant (ka) were obtained using the Evaluation Biacore Insight software (1:1 binding mode). The equilibrium dissociation constant (KD) was calculated based on the ratio of kd to ka.

[0561] Test Example 2: Lp(a) Assembly Inhibition Screening ELISA Experiment

[0562] 1. Reagents, consumables, and instruments

[0563] 2. Experimental Procedure

[0564] 2.1 Cell culture medium passage

[0565] 1) Preheat the culture medium in a 37°C water bath.

[0566] 2) After digesting the cells with trypsin, add complete culture medium containing 10% fetal bovine serum to stop the digestion, and transfer the cell suspension to a new culture flask for culture.

[0567] 3) Incubate in a 37℃, 5% CO2 incubator.

[0568] 2.2 Preparation of HepG2 Conditional Culture Medium

[0569] 1) Digest and passage HepG2 cells, transfer an appropriate amount of cell suspension to a T175 culture flask to achieve a cell density of 80%.

[0570] 2) Culture for 48 hours and collect and filter the cell culture supernatant.

[0571] 3) Measure the APOB protein content in the supernatant using the APOB ELISA kit, label and aliquot, and store at -80℃ for later use.

[0572] 2.3 Lp(a) Assembly Experiment

[0573] 1) In a 96-well PCR plate, equal amounts of HepG2 culture supernatant, Apo(a) recombinant protein and the test compound were mixed and incubated at 37°C for 2 hours.

[0574] 2) Add 150mM 6-aminocaproic acid (EACA) to terminate the reaction. Add the reaction solution to the ELISA detection plate coated with ApoB-Capture antibody and incubate at room temperature for 2 hours.

[0575] 3) Wash the plate 4 times with detergent.

[0576] 4) Add Apo(a)-Detector antibody and incubate at room temperature for 1 hour.

[0577] 5) Wash the plate 4 times with detergent.

[0578] 6) Add HRP-labeled secondary antibody and incubate at room temperature for 1 hour.

[0579] 7) Wash the plate 4 times with detergent.

[0580] 8) Add the chromogenic substrate TMB solution and incubate at 37°C for 20-30 minutes.

[0581] 9) Add the reaction stop solution and measure the absorbance at 450 nm using an ELISA reader.

[0582] 10) Analyze the data and calculate IC50 using GraphPad Prism9 software. The OD value at a compound concentration of 0 (0.17% DMSO) corresponds to a 0% inhibition rate of Apo(a) and ApoB protein assembly; the OD value at a reference compound concentration of 3 nM corresponds to a 100% inhibition rate.

[0583] *The compound has solubility issues in DMSO; specific values ​​have not been obtained.

[0584] Test Example 3: Mouse Pharmacokinetic Test

[0585] 1. Experimental objective: Using C57BL / 6J mice as the research subjects, this study aims to detect the pharmacokinetic behavior of the small molecule compound of the present invention in mouse plasma, with administration routes including oral and intravenous administration.

[0586] 2. Detection instrument: LC-MS / MS (Waters ACQUITY I class PREMIER UPLC tandem with Sciex Triple Quad 7500)

[0587] 3. Experimental Design

[0588] 3.1 Experimental reagents: Small molecule compounds of this invention

[0589] 3.2 Experimental animals: C57BL / 6J mice, female, supplied by Shanghai Lingchang Experimental Animal Co., Ltd., with the animal production license number: SCXK(Shanghai)2023-0003

[0590] 3.3 Preparation of drug prescriptions:

[0591] Preparation of oral administration prescription: Dissolve the test compound in physiological saline at a concentration of 0.4 mg / mL. Shake well, ultrasonicate, and stir to obtain a colorless and clear solution.

[0592] Preparation of intravenous administration prescription: Dissolve the test compound in physiological saline at a concentration of 1 mg / mL. Shake well, ultrasonicate, and stir to obtain a colorless and clear solution.

[0593] 3.4 Animal drug administration:

[0594] Oral administration group: Prepare 3 C57 mice, female. After overnight fasting, administer the drug orally respectively, with a dose of 10 mg / kg and a dosing volume of 10 mL / kg.

[0595] Intravenous administration group: Prepare 3 C57 mice, female. After free diet, administer the drug orally respectively, with a dose of 2 mg / kg and a dosing volume of 5 mL / kg.

[0596] 3.5 Plasma sample collection: Before drug administration and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after drug administration, collect approximately 40 μL of mouse blood using the orbital blood collection method, collect it in an EDTA-K2 anticoagulant tube, and store it short-term on ice.

[0597] Centrifuge at 4000 RPM for 5 minutes at 4°C to separate the plasma, transfer the plasma to a new centrifuge tube for standby, and store it at -80°C.

[0598] 3.6 Plasma sample processing: Take 10 μL of plasma from C57BL / 6J female mice collected at each time point after drug administration, add 100 μL of 5% trichloroacetic acid aqueous solution to precipitate proteins. Vortex for 5 minutes, centrifuge at 3500 rpm for 10 minutes, transfer 50 μL of the supernatant to a 96-well plate, add 100 μL of dilution solution (25% MeOH containing 0.1% FA), vortex for 5 minutes, and perform LC / MS / MS injection analysis.

[0599] 3.7 Measurement results

[0600] Develop and validate the corresponding LC / MS / MS detection method, set the standard curve and QC samples, and measure the compound concentration in plasma samples.

[0601] 4. Experimental results:

[0602] Pharmacokinetic parameters were calculated using WinNonlin software, and the results are as follows:

[0603] Drug metabolism kinetic parameters in mice after oral administration

[0604] *Results are taken from patent WO2025103442

[0605] Drug metabolism kinetic parameters in mice after intravenous administration:

[0606] *Results are taken from patent WO2025103442

[0607] Test Example 4: Lp(a) Reduction Experiment in Humanized Mice

[0608] The in vivo Lp(a)-lowering activity of the compound was evaluated in a humanized Lp(a) transgenic mouse model. Humanized Lp(a) transgenic mice were obtained by mating mice expressing humanized apo(a) and apoB-100. Housing conditions: standard lighting, 20-25℃, humidity 40-70%, free access to water and food.

[0609] One day before the experiment, participants were grouped according to body weight and plasma Lp(a) concentration: test group and solvent control group.

[0610] The administration regimen involved oral administration of either the solvent (physiological saline, 10 ml / kg) or the test compound (physiological saline, 10 mg / kg, 10 ml / kg) once daily at 9:00 am for 3 consecutive days. Blood samples were collected at 5:00 pm to measure the rate of change in plasma Lp(a).

[0611] Plasma was collected from the cheek and added to a 1.5 ml centrifuge tube. The tube was centrifuged at 1600 rpm for 10 minutes at 4°C. The supernatant was aliquoted and stored at -80°C. The diluted Lp(a) concentration was measured using a double-antibody sandwich ELISA method. Anti-apoB-100 capture antibody, anti-apo(a) detection antibody, and anti-rabbit HRP secondary antibody were used. TMB was used for color development, and the reaction was terminated with 2M sulfuric acid. The OD450 was read using an Envision microplate reader, and the reduction rate for each group was calculated. Reduction rate (%) = (Lp(a) concentration before autologous administration - Lp(a) concentration after administration) / Lp(a) concentration before autologous administration × 100.

[0612] The results for some compounds are as follows, depending on the route of administration:

[0613] *Range of results from multiple experiments

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer or isotopically-labeled material thereof, in, P is selected from aryl, heteroaryl, or heterocyclic groups, which are optionally substituted with 0 to 4 R6 atoms, wherein the heteroaryl or heterocyclic group has one or more heteroatoms selected from N, O, and S, and at least one N atom, and the heteroaryl or heterocyclic group is optionally oxidized; R6is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy and halogen; R1, R2are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, said alkyl group being optionally substituted with 1-3 F atoms; R', R" and R'" are independently selected from hydrogen, C 1-6 alkane or C 3-6 cycloalkane; X1 and X2 are independently selected from N and CH, respectively; Y1, Y2, and Y3 are independently selected from -CH2-, -CO-, -SO2-, and -(CR4R), respectively. 4’ ) n O-、-(CR4R 4’ ) n N-、-CONHR 5 -, -CONH2-, -O-, -(CR4R) 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n O-、-(CR4R 4’ ) n N-, -(CR4R 4’ ) n -、-(CR4R 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-; Both ends of the aforementioned groups can be connected to Z; wherein K is selected from N or CH; Q is selected from a nitrogen containing heterocycle or a saturated carbocycle, optionally substituted with C 1-6 alkyl or halogen; or Z is selected from wherein W = CH or N; R y selected from hydrogen, halogen, C 1-6 alkyl, C 1- 6alkoxy, said alkyl being optionally substituted with 1-3 F atoms; A = single bond, -(CR4R) 4’ ) n -、-CO(CR4R 4’ ) n -, -SO2(CR4R 4’ ) n -; 'a' represents the position where Z connects to Y1, Y2, and Y3; R4, R 4’ are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy; R5is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy; n is selected from 0, 1, or 2; or The saturated carbocyclic or N-containing heterocyclic group defined in Z, optionally bound by 0-5 R groups, X Group substitution, wherein the cycloalkyl or N-containing heterocyclic group optionally forms a cyclic ring with a 6-membered aryl group or a 5-6-membered heteroaryl group; the nitrogen-containing heterocyclic group optionally is oxidized; the nitrogen atom of the nitrogen-containing heterocyclic group optionally connects to Y1, Y2 or Y3; R x Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Alkyl group; when Z is substituted by two or more Rx groups, and Rx is C. 1-6 When alkyl, then two arbitrary R X The ring represented by Z forms a fused ring, bridged ring, or spirocyclic structure; the heteroatoms of the heterocyclic or heteroaryl group are selected from N, O, and S.

2. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material of claim 1, wherein, In formula (I), wherein, K is selected from N when 3. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material thereof of any preceding claim, wherein, In formula (I), when Q is selected from a nitrogen-containing heterocycle, it is selected from a 3-7 membered monocyclic or bicyclic ring consisting of two 3-7 membered rings nitrogen-containing heterocycle; when Q is selected from a saturated carbocycle, it is selected from a C 3-8 cycloalkyl.

4. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material thereof of any preceding claim, wherein, In formula (I), Z is selected from the following nitrogen-containing heterocycles: or Z is selected from the following saturated carbocyclic rings: B = -O-, CR4R4- 4’ or nothing; C = -O-, -NR4-, -CH2O-, -CHNR4- or -SO2-; m and n are independently selected from 0, 1, or 2; m' and n' are independently selected from 0, 1, or 2; R x selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy.

5. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material of any one of claims 1 to 4, wherein, In formula (I), When Q in Z is selected from a nitrogen-containing heterocycle, the nitrogen atom of that nitrogen-containing heterocycle is attached to one of Y1, Y2, and Y3, and one of Y1, Y2, and Y3 is selected from -CO-, -SO2-, and -CONHR. 5 -, -CONH2-, -(CR4R 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-; or the nitrogen atom of the nitrogen containing heterocycle in Z is attached to A and A is selected from -CO(CR4R4)n- 4’ ) n - SO2(CR4R4)n- 4’ ) n - 6. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material of any one of claims 2-5, wherein, In formula (I), the nitrogen atom of the nitrogen-containing heterocycle in Z is attached to one of Y1, Y2and Y3, and the one of Y1, Y2and Y3is selected from -CO-, -SO2-, -(CR4R 4’ ) n -CO- and -(CR4R 4’ ) n SO2-.

7. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material of any one of claims 1 to 6, wherein, In formula (I), When Q in Z is selected from a nitrogen-containing heterocycle, the nitrogen atom of that nitrogen-containing heterocycle is attached to one of Y1, Y2, and Y3, and one of Y1, Y2, and Y3 is selected from -CO-, -SO2-, and -CONHR. 5 -, -CONH2-, -(CR4R 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-; and A is selected from -CO(CR4R 4’ ) n - SO2(CR4R 4’ ) n - 8. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material of any one of claims 1 to 7, wherein, In formula (I), when Q in Z is selected from nitrogen-containing heterocycles, it is oxidized and forms a cyclic lactam with nitrogen heteroatoms.

9. The compound according to claim 2, its pharmaceutically acceptable salt, stereoisomer, or isotopic label, wherein, In equation (I), where, When K is selected from N, at least one of Y1, Y2 and Y3 connected to K is selected from -CO-, -SO2-, or -CONHR. 5 -, -CONH2-, -(CR4R 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-.

10. The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, stereoisomer, or isotopic label, wherein, When Q in Z is selected from a saturated carbon ring, at least one of Y1, Y2, and Y3 connected to K is selected from -CO-, -SO2-, or -CONHR. 5 -, -CONH2-, -(CR4R 4’ ) n CO-, -(CR4R) 4’ ) n SO2-, -(CR4R) 4’ ) n SO2NR 5 -(CR4R) 4’ ) n CONHR 5 -、-SO2NHR 5 -、-(CR4R 4’ ) n NR 5 CO-, -(CR4R) 4’ ) n NR 5 SO2-.

11. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material thereof of any preceding claim, wherein, In formula (I), P is selected from nitrogen-containing 5-7 membered heteroaryl or 5-7 membered heterocyclic group; preferably, P is selected from triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, and the carbon ring atom of the above groups may be oxidized.

12. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer or isotopically-labeled material thereof, in, P is selected from heteroaryl or heterocyclic groups, which are optionally substituted with R6, wherein the heteroaryl or heterocyclic group has one or more heteroatoms selected from N, O and S, and at least one N, and the heteroaryl or heterocyclic group is optionally oxidized to form a cyclic lactam; Y1, Y2, Y3 separate independent selection -CH2-, -CO-, -SO2-, -(CR4R 4’ ) n O-,-(CR4R 4’ ) n N-, -CONHR 5 -, -CONH2-, -O-, -(CR4R 4’ ) n CO-, -(CR4R 4’ ) n SO2-, -(CR4R 4’ ) n SO2NR 5 ,-(CR4R 4’ ) n O-,-(CR4R 4’ ) n N-, -(CR4R 4’ ) n -,-(CR4R 4’ ) n CONHR 5 -, -SO2NHR 5 -,-(CR4R 4’ ) n NR 5 CO-, -(CR4R 4’ ) n NR 5 SO2-; Both ends of the groups defined above as Y1, Y2, and Y3 can be connected to Z; or P is selected from heteroaryl or heterocyclic groups, which are optionally substituted with R6, wherein the heteroaryl or heterocyclic group has one or more heteroatoms selected from N, O and S, and at least one N heteroatom is selected from N, and the N heteroatom is connected to Y3; the heteroaryl or heterocyclic group is optionally oxidized; Y1, Y2 separate independent selection -CH2-, -CO-, -SO2-, -(CR4R 4’ ) n O-,-(CR4R 4’ ) n N-, -CONHR 5 -, -CONH2-, -O-, -(CR4R 4’ ) n CO-, -(CR4R 4’ ) n SO2-, -(CR4R 4’ ) n SO2NR 5 ,-(CR4R 4’ ) n O-,-(CR4R 4’ ) n N-, -(CR4R 4’ ) n -,-(CR4R 4’ ) n CONHR 5 -, -SO2NHR 5 -,-(CR4R 4’ ) n NR 5 CO-, -(CR4R 4’ ) n NR 5 SO2-; Y3 is selected from -CO-, -SO2-, -CONHR 5 -, -CONH2-, -(CR4R 4’ ) n CO-, -(CR4R 4’ ) n SO2-, -(CR4R 4’ ) n SO2NR 5 、-(CR4R 4’ ) n CONHR 5 -, -SO2NHR 5 -, -(CR4R 4’ ) n NR 5 CO-, -(CR4R 4’ ) n NR 5 SO2-; The two ends of the groups defined above, Y1, Y2 and Y3, can be connected to Z; Furthermore, in equation (I), R6is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy and halogen; R1, R2are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, said alkyl group being optionally substituted with 1-3 F atoms; X1 and X2 are independently selected from N and CH, respectively; R4, R 4’ are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy; R5is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy; n is selected from 0, 1 or 2; 'a' represents the position connecting Y1, Y2, and Y3; R5' is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy; R', R" and R'" are selected from hydrogen, C 1-6 alkane or C 3-6 cycloalkane.

13. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material of claim 12, wherein, In formula (I), P is selected from 5-7 membered heteroaryl or 5-7 membered heterocyclic groups containing N heteroatoms; preferably, P is selected from triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, and pyrazolyl.

14. The compound, pharmaceutically acceptable salt, stereoisomer, or isotopically-labeled material of claim 1, wherein, The compound is selected from:

15. A pharmaceutical composition comprising the compound of any one of claims 1-14, a pharmaceutically acceptable salt thereof, a stereoisomer, or an isotopic label thereof.

16. Use of the compound of any one of claims 1-14, its pharmaceutically acceptable salt, stereoisomer or isotopic label in the preparation of a medicament for treating diseases associated with elevated Lp(a) plasma levels.

17. The use according to claim 16, wherein the disease is selected from cardiovascular diseases.

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