Cyclic peptide for capturing interleukin-1β

Abstract

This provides additional non-surgical treatments beyond standard cholesterol-lowering medications to slow the progression of atherosclerosis and reduce the risk of MACE. [Solution] The present invention provides a compound or a pharmaceutically acceptable salt thereof that can capture IL-1β and is expected to be useful as a therapeutic agent for treating cardiovascular disease and inflammatory disorders. The present disclosure also relates to pharmaceutical compositions comprising the compounds disclosed herein or a pharmaceutically acceptable salt thereof, methods for use in the treatment and prevention of cardiovascular disease and inflammatory disorders, and methods for preparing pharmaceuticals for this purpose.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on U.S. Provisional Patent Application No. 63 / 598,56, filed on November 14, 2023. U.S. Provisional Patent Application No. 7 and U.S. Provisional Patent Application No. 63 / 717,339, filed on November 7, 2024. They assert their interests, and these contents in their entirety are incorporated herein by reference.

[0002] Reference to electronically submitted sequence listings Electronic sequence listing (25836-WO-PCT_SL.xml; size: 2,104,813) The content of the byte (created on October 31, 2024) is incorporated herein by reference in its entirety. To be absorbed.

[0003] field This disclosure relates to a certain cyclic peptide that captures interleukin-1β (IL-1β), and Pharmaceutical compositions containing peptides such as, and IL-1β, including atherosclerosis. To treat or suppress one or more cardiovascular disease conditions that may benefit from capturing them. The method of using the compound for the purpose of doing or improving. [Background technology]

[0004] Atherosclerosis is characterized by the accumulation of cholesterol plaque on the inner walls of arteries. It is a disease of the arteries characterized by atherosclerosis. The progression of atherosclerosis is due to hardening or narrowing of the arteries. This can lead to an increased risk of plaque rupture. These ruptures can cause cholesterol microclusters. And other substances may be released into the bloodstream, potentially leading to blockage of blood flow to the brain, heart, or other organs. These are known medically as major adverse cardiovascular events (MACEs).

[0005] High cholesterol is a risk factor for the onset and progression of atherosclerotic cardiovascular disease (ASCVD). Terror, high blood pressure, high saturated fat diet, smoking, obesity, diabetes, lack of exercise, and inflammation One indicator is an elevated level of C-reactive protein (CRP), which is a key marker.

[0006] The first line of treatment to prevent the progression of ASCVD is a healthy diet and exercise. However, compliance is generally insufficient. Pharmacological treatment of ASCVD involves statins, Cholesterol absorption inhibitors and low-density lipoprotein (LDL) receptor inhibitors, etc. The focus has been primarily on cholesterol-lowering drugs. These drugs address the accumulation of fatty acid deposits. It is very effective in reducing and improving arterial health. AS is a disease that does not improve. Other medications prescribed for CVD include those that prevent platelet aggregation in narrowed arteries. Blood thinners such as aspirin, and blood to reduce the risk and severity of heart attacks. It contains blood pressure-lowering drugs. Surgery for more aggressive intervention in advanced cases of ASCVD. The available options include angioplasty, stent placement, endarterectomy (surgical removal of plaque), and This includes bypass surgery.

[0007] Cholesterol-lowering drugs are an important standard for slowing the progression of atherosclerosis. Although it has been useful as a treatment, clinical data shows that it is not effective in the progression of untreated ASCVD. This supports the further important role of inflammation. Biomarkers of inflammation, such as CRP, It is associated with an increased risk of cardiovascular events, regardless of resterol levels. (Kanakinuma) The Anti-inflammatory Thrombosis Outcome Trial (CANTOS) shows that in the absence of concomitant lipid reduction, vasculitis This is the first clinical trial to show that reducing the symptoms lowers the incidence of cardiovascular events. [translate] N Engl J Med 2017;377:1119-1131. Kanakinuma B is an anti-interleukin-1β ( approved for clinical use in rheumatic disorders) IL-1β is a human monoclonal antibody. IL-1β induces IL-6, and then... Elevated high-sensitivity C-reactive protein (hsCRP), a more downstream inflammatory biomarker. It is a pro-inflammatory cytokine that causes inflammation. Therefore, CANTOS targets IL-1β. This treatment is complementary and potentially additive to standard treatments that lower LDL. This provides proof of concept that it may be possible to reduce the rate of MACE in certain patients. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] Standard treatments to slow the progression of atherosclerosis and reduce the risk of MACE. Additional non-surgical treatment approaches beyond cholesterol-lowering drugs are needed. Furthermore, patients suffering from inflammatory disorders have the same cytokines as canakinumab. They may benefit from orally administered agents that block IL-1β. [Means for solving the problem]

[0009] This disclosure relates to reducing inflammation by binding to IL-1β cytokines and IL-1 receptors. Certain cyclic peptides prevent engagement with the body and lead to the inhibition of downstream pro-inflammatory signaling. These cyclic peptides provide cytoplasm for the treatment of cardiovascular disease and inflammatory disorders. It may be a beneficial pharmaceutically active compound. In one embodiment, the present disclosure relates to a compound of formula (I). [ka]

[0010] and pharmaceutically acceptable salts thereof are provided.

[0011] The compound captures IL-1β, thereby promoting downstream inflammation that may be associated with cardiovascular disorders. It may affect progressive signaling pathways. Therefore, in another embodiment, this disclosure may affect A cardiovascular disorder comprising administering a therapeutically effective dose of the compound of this disclosure to a subject in need thereof. The invention provides a method for treating harm (e.g., atherosclerosis or vasculitis). In some embodiments, administration includes oral administration of the compound.

[0012] This disclosure further relates to the compounds of this disclosure and pharmaceutically acceptable carriers for the compounds of this disclosure. The present invention provides a process for preparing a pharmaceutical composition containing [a specific substance]. [Brief explanation of the drawing]

[0013] [Figure 1-1] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-2] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-3] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-4] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-5] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-6] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-7] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-8] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-9] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-10] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-11] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-12] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-13] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-14] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-15] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-16] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-17] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-18] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-19] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-20] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-21] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-22] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-23] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-24]The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-25] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-26] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-27] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-28] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-29] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-30] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-31] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-32] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-33] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-34] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-35] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-36] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-37] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-38] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-39] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-40]The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-41] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-42] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-43] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-44] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-45] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-46] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-47] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-48] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-49] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-50] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-51] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-52] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-53] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-54] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-55] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-56]The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-57] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-58] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-59] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-60] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-61] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-62] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-63] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-64] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-65] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Figure 1-66] The amino acid sequences of sequence numbers 1-465 and their associated properties are described below. [Modes for carrying out the invention]

[0014] Compounds of the Disclosure In one embodiment, the present disclosure relates to a compound having the structural formula (I) shown above (wherein, R 1 teeth, (i)R 1a -C(O)N(H)-CH2CH2-O-, R 1a teeth, (a) C1-C3 alkyl or (b)(CH3)3N-CH2CH2-M- (wherein M is -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH 2CH2- 、 or -O-CH2CH2-O-CH2CH2-), (ii)(CH3)3N-CH2CH2-O-, (iii)C 1 (wherein C 1 is: (a) phenyl or 5- to 6-membered monocyclic heteroaryl which contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, 5- to 6-membered monocyclic heteroar yl, (b) 5- to 6-membered heterocycloalkyl which is saturated and contains 1 or 2 heteroatoms selected from the group consisting of N, O and S, 5- to 6-membered heterocycloalkyl (wherein C 1 is unsubstituted or substituted by 1 to 3 R substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 flu oroalkyl, carboxy, C1-C3 alkoxy, C2-C3 acyl and C1-C3 alkoxymethyl, R C1 substituted with ), (iii)(CH3)3N-CH2CH2-O-, or (iv) a group

Chemical Formula

[0015] In another embodiment, the present disclosure relates to compound formula (I) (In the formula, C 1 It is phenyl, R 2 It is indolyl or naphthyl, C 6 phenyl, indolyl, pyridyl, pyridadinyl or bicyclo[1.1.1 ] It is pentanyl, C 9 The material is phenyl or pyrimidinyl.

[0016] In another embodiment, the disclosure is R 1 However, CH3-C(O)N(H)-CH2CH2-O - Provides a compound of formula (I) which is 4-fluorophenyl.

[0017] In another embodiment, the present disclosure relates to a compound of formula (I) (wherein R 1 (CH3)3N-C H2CH2-M-J, where M is CH2-, -CH2CH2CH2-, -O-CH2CH It provides 2-, or -O-CH2CH2-O-CH2CH2-.

[0018] In another embodiment, the present disclosure provides that R 1 is C 1 a compound of formula (I).

[0019] In another embodiment, the present disclosure provides that A 2 is H, fluoro, chloro or methyl, the compound of formula ( I) is provided.

[0020] In another embodiment, the present disclosure provides a compound of formula (I), wherein R 2 is unsubstituted or is substituted naphthyl or indolyl.

[0021] In another embodiment, the present disclosure provides that R 3 is -(CH2) m a compound of formula (I) which is CO2H is provided.

[0022] In another embodiment, the present disclosure provides a compound of formula (I) wherein the subscript m is 1.

[0023] In another embodiment, the present disclosure provides that R 4 and R 5 are methyl, a compound of formula (I) is provided.

[0024] In another embodiment, the present disclosure provides a compound of formula (I), wherein, X 1 and X 2 is C(H), and A 1 is carboxy.

[0025] In another embodiment, the present disclosure provides a compound of formula (I) wherein, (i) substituted or unsubstituted 5- to 6-membered monocyclic aryl or heteroaryl, wherein the 5- to 6-membered monocyclic heteroaryl contains 1 to 2 N atoms, 5- to 6-membered monocyclic ary l or heteroaryl, or (ii) substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl having 1 to 2 N atoms, which is a 9- to 10-membered bicyclic heteroaryl).

[0026] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 6 is indolyl.

[0027] In another embodiment, the present disclosure provides a compound of formula (I), wherein R 7 is H.

[0028] In another embodiment, the present disclosure provides a compound of formula (I), wherein R 8 is -H, -OH, -N H2, (CH3)3N-(CH2)5-C(O)-, or (CH3)3N-CH2CH 2-O-CH2CH2-O-CH2CH2-C(O)-).

[0029] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 8 is H or -NH2 .

[0030] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 9 is substituted at the 4-position of the depicted pyrrolidinyl ring .

[0031] In another embodiment, the present disclosure provides a compound of formula (I) wherein C 9 is substituted or unsubstituted phenyl or pyrimidinyl .

[0032] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 9 is -CH2-(4-fluorophenyl) or pyrim idin-5-yl.

[0033] In another embodiment, the present disclosure provides a compound of formula (I), wherein R 1 CH3-C(O)N(H)-CH2CH2-O- or 4-fluorophenyl And, R 2 These are unsubstituted or substituted naphthyl or indolyl, R 3 is, -(CH2) m CO2H R 4 and R 5 It is methyl, X 1 and X 2 is C(H), A 1 It is a carboxyl, A 2 H is, R 6 teeth, (i) Substituted or unsubstituted 5-6 member monocyclic aryl or heteroaryl, , a 5-6 member monocyclic heteroaryl containing 1-2 N atoms, 5-6 member monocyclic heteroaryl or heteroaryl, (ii) A substituted or unsubstituted 9-10 member bicyclic heteroaryl, 1-2 It is a 9-10 member bicyclic heteroaryl containing a nitrogen atom, R 7 H is, R 8 is H or -NH2, R 9 It is substituted at position 4 of the pyrrolidinyl ring as shown in the diagram.

[0034] In one embodiment of this disclosure, the present disclosure provides a compound of formula (I), wherein, R 6 It is an indolyl, R 9 This is -CH2-(4-fluorinated) which is substituted at the 4-position of the pyrrolidinyl ring as shown in the diagram. It is lophenyl) or pyrimidine-5-yl, The subscript 'm' is 1.

[0035] In some embodiments, the compound of formula (I) has formula (IA). [ka]

[0036] (In the formula, R 1 teeth, (i)R 1a -C(O)N(H)-CH2CH2-O-, R 1a teeth, (a) Methyl, or (b) Is it (CH3)3N-CH2CH2-O-CH2CH2-? (ii)(CH3)3N-CH2CH2-O-, or (iii) 4-carboxyphenyl, R 2 is, [ka] or [ka]

[0037] And, R 2a is halo or methyl, The subscript x is either 0 or 1. R 3 It is -CH2CO2H or -CH2-tetrazolyl, R 4 and R 5 Is it methyl? Alternatively, R 4 and R 5 Together with the atoms to which they are attached, they form piperidinyl Forming a ring, R D is 4-carboxyphenyl or hydroxy, R 6 teeth, [ka] [ka] or [ka]

[0038] It is a base selected from, R 7 is H or methyl, R 8 is -H, -NH2, or -OH, C 9 teeth, [ka] or [ka]

[0039] (It is a base selected from the others.)

[0040] In other embodiments, the compound of formula (I) has formula (IB): [ka]

[0041] (In the formula, R 1 teeth, (i)R 1a -C(O)N(H)-CH2CH2-O- (In the formula, R 1a teeth, (a) C1-C3 alkyl, or (b) Selected from (CH3)3N-CH2CH2-M- During the ceremony, M is -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2CH2 -,or -O-CH2CH2-O-CH2CH2-), or (ii)C 1 (In the formula, C 1 It is phenyl or a 5-6 member monocyclic aryl or heterozygous compound. A reel in which a 5-6 member monocyclic heteroaryl is independent of the group consisting of N, O, and S. A 5-6 member monocyclic aryl or heteroaryl compound containing 1-2 selected heteroatoms. It is a ru, C 1 It is either unsubstituted or halo, C1-C3 alkyl, or C1-C3 fluoroalkyl. Independently from the group consisting of carboxyl, carboxyl, C1-C3 alkoxy, and C2-C3 acyl 1 to 3 R selected C1 (substituted with substituents) R 2 teeth, (i) Naphthyl, or (ii) A bicyclic heteroaryl with 9 to 10 members, and a bicyclic heteroaryl with 9 to 10 members The compound contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S. (In the formula, R 2 is either unsubstituted or 1~ selected independently from the group consisting of halos 2 R 2a (substituted with substituents), R 3 is, -(CH2) m CO2H, -(CH2) m CO2NH2, -(CH2) m CO 2N(CH3)2, or -(CH2) m -It is tetrazolyl, R 4 It is a C1-C3 alkyl group, R 5 is H or C1-C3 alkyl, Alternatively, R 4 and R 5 These, together with the atoms to which they are attached, pyrrolidin Forming a piperidinyl or azepinyl ring, X 1 and X 2 These are independently C(H) or N, A 1 This is -CO2H or -N(H)SO2CH3, A 2 is H, halo, or C1-C3 alkyl; R 6 is, -(CH2) n NH2, -(CH2) n N(H)CH3, -(CH2) n OH ,-(CH2) n OCH3, -(CH2) n N(H)CH2CH2O(CH2CH2-O) q -CH2CH2N(C H3)3, or -C 6 And, C 6 teeth, (i) 5-6 member monocyclic aryl or heteroaryl, and 5-6 member monocyclic hetero The aryl group consists of 1-2 heteroatoms independently selected from the group consisting of N, O, and S. Includes 5-6 membered monocyclic aryl or heteroaryl compounds. (ii) A bicyclic aryl or heteroaryl with 9 to 10 members, wherein the bicyclic aryl has 9 to 10 members. A cyclic heteroaryl is independently selected from the group consisting of N, O, and S. A 9-10 membered bicyclic aryl or heteroaryl containing a telogen atom, or (iii) A monocyclic or bicyclic cycloalkyl with 3 to 8 members, C 6 It is either unsubstituted or halo, amino, hydroxy, carboxy, C1-C3 Independently from the group consisting of alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy 1 to 3 R's are selected. C6 Substituting with a substituent; R 7is H or C1-C4 alkyl, R 8 These are -H, -OH, -NH2, (CH3)3N-(CH2) r -C(O)-, also teeth (CH3)3N-CH2CH2-O-(CH2CH2-O) s -CH2CH2-C(O )- and, R 9 is -C 9 or -CH2-C 9 And, C 9 is a phenyl or a 5-6 member monocyclic heteroaryl, and is a 5-6 member monocyclic heteroaryl. A loaryl group consists of 1-2 heteroatoms independently selected from the group consisting of N, O, and S. It is a 5-6 member monocyclic heteroaryl, C 9 It is either unsubstituted or halo, amino, hydroxy, C1-C3 alkyl, C Independently from the group consisting of 1-C3 fluoroalkyl, C1-C3 alkoxy, and phenyl 1 to 3 R selected C9 Substituting with substituents, The subscript m is either 1 or 2. The subscript n is 1, 2, or 3. The subscript q is either 1 or 2. The subscript r is 3, 4, 5, or 6. The subscript 's' is either 1 or 2; Having, or The pharmaceutically acceptable salt.

[0042] In certain embodiments, the present disclosure is selected from the group consisting of Sequence IDs 1 to 465 shown in Figure 1. A compound of formula (I) is provided, which is selected. In a particular embodiment, the compound is shown in Figure 1. Selected from the group consisting of sequence numbers 1 to 103.

[0043] In certain embodiments, the present disclosure relates to a compound of formula (I), wherein the compound is as follows (each And, sequence numbers 1, 2, 78, 80, 82, 92, 94, 95, 98, 99, 100, 10 Select from the group consisting of 1, 102, 215, 216, 217, and 218: [ka] TIFF2026148581000013.tif156142TIFF2026148581000014.tif156141TIFF2026148581000015.tif155142TIFF2026148581000016.tif230143TIFF2026148581000017.tif156141TIFF2026148581000018.tif156139TIFF2026148581000019.tif161142 and [ka] .

[0044] While not bound by any particular theory, the applicant believes that the compounds of the disclosure are interloyal It captures Kin-1β and prevents signal transduction via the IL-1 receptor, and therefore downstream It is thought that the compound reduces IL-6 and CRP, which are stimulants. Therefore, the compound is AS Treating the inflammatory components of cardiovascular diseases such as CVD and heart failure with preserved ejection fraction (HFpEF) It may be useful for treating hidradenitis suppurativa (acne reversal), inflammatory bowel disease, and It may be useful in treating inflammatory disorders such as osteoarthritis.

[0045] definition Unless otherwise defined, all technical and scientific terms used herein are defined in this text. It has the same meaning as that generally understood by those skilled in the art to which the invention pertains.

[0046] When used through this disclosure, the terms "compounds of this disclosure," "compounds of the present invention," and The terms “compounds disclosed herein” are used interchangeably with the disclosed cyclic peptides and It is understood that this includes the compound of formula (I). References to the compound of formula (I) in this specification are, Each compound of formulas (IA) and (IB), as well as all embodiments and classes thereof It includes. Compounds of formula (I) can form salts that are included within the scope of this disclosure. References to the compounds of this disclosure (or compounds of formula (I)) in this specification are as follows: To the extent that it includes a reference to the salt, as used herein, "(one or more) The term "salt" refers to acidic salts formed with inorganic and / or organic acids, as well as inorganic and It shows a basic salt formed by a and / or organic base. Furthermore, the compound of formula (I) is one of these This includes, but is not limited to, a basic moiety such as an amino group, pyrrolidine, or imidazole, and While not limited to these, if it includes both the acidic part, such as a carboxylic acid, then the zwitterion ("internal") A salt may be formed, and the term "(one or more) salt" as used herein It is included. In one embodiment, the salt is pharmaceutically acceptable (i.e., non-toxic and raw). It is a physically acceptable salt. In another embodiment, the salt is a pharmaceutically acceptable salt. It is outside. A salt of the compound of formula (I) is, for example, when the compound of formula (I) is subjected to an equal or equal amount of acid. Alternatively, the reaction is carried out with a base in a medium such as a medium that precipitates salts, or in an aqueous medium, followed by freezing. It can be formed by drying.

[0047] "Acyl" means alkyl-C(O)- group, and alkyl is defined as follows: Yes, it exists. The bond to the parent group is via the carbon atom of the carbonyl group.

[0048] "Alkyl" and other groups having the prefix "alky," such as alkoxy, are shown. A carbon chain containing a certain number of carbon atoms, which may be linear, branched, or a combination thereof. It means that, for example, C1-C6 alkyl groups have 1 (i.e., methyl) to 6 carbon atoms. This refers to an alkyl group having (i.e., hexyl). In certain embodiments, a linear alkyl group A kill group has 1 to 6 carbon atoms, and a branched alkyl group has 3 to 7 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and sec. -and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc. It can be done.

[0049] "Alkoxy" and "alkyl-O-" are used interchangeably, with alkyl linked to oxygen. It refers to the lu group.

[0050] "Amino" refers to the H2N- group. The bond to the parent group is via a nitrogen atom.

[0051] "Amino acids" refer to naturally occurring α-amino acids and their stereoisomers, as well as This refers to unnatural amino acids (such as β-amino acids and substituted amino acids) and their stereoisomers. In the sequence of the peptide (compound) shown in this disclosure, the amino acid residues are These have their traditional meanings. Therefore, "G" is glycine and "W" is tryptophthol. It is "A", and "A" is alanine, "S" is serine, and so on. "d" is opposite sex The body is specified by adding "d" before a single-letter code or amino acid name. Please understand. For example, dA is a d isomer of L-alanine. Ami is not included in the above. The no-acid residues have the definitions shown in the table in the Examples section below.

[0052] As used herein, "aryl" refers to a monocyclic 6-membered or bicyclic 10-membered ring system. Furthermore, at least one ring is aromatic, and all ring atoms are carbon.

[0053] A "biring ring system" refers to two joined rings. The rings may be fused, that is, two rings They may share adjacent atoms, or they may form a "spiro ring," i.e., a single atom. You may share it.

[0054] "Carboxylate" refers to the HO2C- group. The bond to the parent group is the carbonyl component. It is mediated by elementary atoms.

[0055] "Cycloalkyl" means saturated cyclic hydrocarbon radical. In certain embodiments, Cycloalkyl groups have 3 to 12 carbon atoms and form a carbon ring of 1 to 3 carbon atoms. The ring is, They may be condensed, or they may be in a "spirocyclic" form, that is, they may share only a single atom. Also, "bridging," that is, sharing three or more atoms, with two bridgehead atoms. However, they may be connected by a bridge containing at least one atom. Examples of R-alkyl compounds include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl Examples include syl, cycloheptyl, adamantyl, and bicyclo[1.1.1]pentanyl. It can be done.

[0056] "Fluoroalkyl" includes monosubstituted and polyfluorosubstituted alkyl groups, and maximum fluorophosphate groups. This includes luoro-substituted alkyl groups. For example, fluoromethyl, 1,1-difluoroethyl, It contains trifluoromethyl or 1,1,1,2,2-pentafluorobutyl.

[0057] Unless otherwise specified, "halogen" or "halo" refers to fluorine (fluoro) and chlorine (chlorine). It contains halo, bromine, and iodine. In one embodiment, halo is fluorine It is either chloro(-F) or chloro(-Cl).

[0058] "Heterocycloalkyl" or "heterocyclyl" is a ring atom consisting of approximately 3 to 10 ring atoms. Each ring contains approximately 5 to 10 ring atoms, and one or more atoms in the ring system may also be present individually. The combination is a non-aromatic monocyclic compound, which is an element other than carbon, such as nitrogen, oxygen, or sulfur. This refers to a biring or triring ring system. The rings in biring and triring rings may be condensed. or "Spirocyclic," that is, it may share only a single atom, or "Bridged," that is, it may share three or more atoms, and two bridgehead atoms , linked by a bridge containing at least one atom. Adjacent oxygen atoms in the ring system B and / or sulfur atoms are absent. In some embodiments, heterocycloalkyls are It contains approximately 5 to 6 ring atoms. The prefix aza, o before the root name of heterocycloalkyl xa or thia each have at least one nitrogen, oxygen, or sulfur atom as a ring atom. It means that it exists. In some embodiments, the nitrogen of a heterocycloalkyl or The sulfur atom, if necessary, forms the corresponding N-oxide, S-oxide, or S,S-oxide. It can be oxidized to side. A non-limiting example of a suitable monocyclic heterocycloalkyl ring is pi Peridyl, pyrrolidinil, piperazinil, morpholinil, thiomorpholinil, thiazolidinil Nyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydro Examples include dorothiophenyl.

[0059] "Heteroaryl" refers to one or more atoms in a ring, or (one or more) heteroatoms. This refers to aromatic monocyclic, bicyclic, and tricyclic ring structures in which the element is not carbon. Heteroatoms are Typically, these are O, S, or N atoms. Examples of heteroaromatic groups include pyridinyl. Pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl Examples include indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl. .

[0060] Any variable (for example, R C1 ) is any component or formula (I) or in this specification If a general formula appears more than once in other formulas, the definition of that formula in each occurrence is the same as that of all other formulas. This is independent of the current definition. The combination of substituents and / or variables is as follows: A combination is only acceptable if it results in a stable compound. Selecting a compound from this disclosure is... Those skilled in the art can use various substituents, for example, R C9 However, the connectivity and stability of the chemical structure They will recognize that choices should be made according to the principles of knowledge. They will not explicitly state otherwise. Unless otherwise stated, substitution by a specified substituent is such that such ring substitution is chemical Any atom in the ring (e.g., aryl, hetero) is acceptable as long as it results in a stable compound. Acceptable for aryl rings or saturated heteroaryl rings. "Stable" compounds are: It can be prepared and isolated while maintaining its structure and properties, or as specified herein. This enables the use of the compound for the purposes described (e.g., therapeutic or prophylactic administration to the subject). It is a compound that can be maintained in an essentially unchanged state for a sufficient period of time.

[0061] The term "substituted" is considered to include multiple degrees of substitution by the specified substituent. If multiple substituent portions are disclosed or claimed, the substituted compound is disclosed or claimed. One or more of the claimed substituent portions are independently substituted, either individually or in combination. It is possible. To be independently substituted means that even if the substituents are the same, they are different. It also means good.

[0062] Unless otherwise explicitly shown or described, structural formulas that have "floating" bonds are shown. The variable is allowed on any available carbon atom within the ring to which the variable is bonded. The part is described as "may be replaced" in formula (I) or any embodiment thereof. If so, it means that formula (I) or its embodiments have substituents described on that part ( Compounds containing (or multiple substituents) and substituents (or multiple substituents) described on the part thereof This means that compounds that do not contain the substituents are also included.

[0063] The dashed lines used in this specification [ka]

[0064] This indicates the bonding site with the rest of the compound.

[0065] Some of the compounds described herein are hydrogen heterogeneous with one or more double bond shifts. They may exist as tautomers having a bond site. For example, ketones and their enol forms. The state is a keto-enol tautomer. Individual tautomers and mixtures thereof are This is included in the compounds disclosed herein.

[0066] In the compounds of this disclosure, atoms may exhibit their natural isotopic abundances, or original One or more of the children have the same atomic number, but their atomic mass or mass number is mainly found in nature. It may be artificially enriched with specific isotopes having different atomic masses or mass numbers. The disclosure described herein and claimed herein relates to the compounds and embodiments thereof. This means including all appropriate isotopic variations. For example, different isotopic forms of hydrogen (H) The state is protium ( 1 H) and deuterium ( 2 H (also known as D in this specification) is included. Protium is the primary hydrogen isotope found in nature. It can be used to enrich deuterium. This may result in specific therapeutic benefits (e.g., increased in vivo half-life or reduced required dose). Compounds that can be obtained or that are useful as standards for characterizing biological samples The isotope-enriched compounds of this disclosure can be obtained by conventional techniques well known to those skilled in the art, or Using appropriate isotope enrichment reagents and / or intermediates, the schemes and examples described herein can be performed as follows: It can be prepared using a process similar to that described, without the need for excessive experimentation. Cut.

[0067] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable non-toxic base or This refers to a salt prepared from an acid. The compounds of this disclosure are acidic (or may be anionic). If it has a functional group, its corresponding salt is pharmaceutically acceptable, including inorganic and organic bases. They can be conveniently prepared from non-toxic bases. Suitable examples of inorganic cations include: Li + na + , and K + Alkali metal ions such as Ca2 + , and Mg2 + etc. Alkaline earth metal cations, as well as Al 3+ and Zn + Other cations such as However, it is not limited to these. Suitable examples of organic cations include the ammonium ion ( Nawachi, NH4 + This includes, but is not limited to, substituted ammonium ions. Examples of suitable substituted ammonium ions include methylamine, ethylamine, and diethylamine. The compounds of this disclosure are derived from triethylamine and ethylenediamine. If it is basic, its corresponding salt may be pharmaceutically acceptable, including inorganic and organic acids. They can be conveniently prepared from non-toxic acids. Examples of such acid addition salts include halogens. Hydrogen acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid), formic acid, acetic acid, capric acid, and It contains salts formed from citric acid, such as acetate, formate, caprate, and chloride salts. Salts containing sodium salts are typical for use with the compounds of this disclosure. In some embodiments, a salt of the compound of the disclosure is subjected to anion exchange, for example, trifluoroacetic acid. Formed by exchanges well known to those skilled in the art, such as replacing ions with chloride ions. It is possible.

[0068] Furthermore, the compounds of this disclosure exist in amorphous and / or crystalline forms. This is also true, and therefore all amorphous and crystalline forms of compounds of formula (I), including the example. Furthermore, those mixtures are intended to be included within the scope of this disclosure. Some of these compounds are dissolved in water (i.e., hydrates) or acetic acid or acetonitrile, etc. However, it can form solvates with general organic solvents, not limited to these. Solvates and hydrates like these, especially pharmaceutically acceptable solvates and hydrates, are also included. These are included within the scope of this disclosure, along with non-solvated and anhydrous forms.

[0069] Any pharmaceutical of the compounds disclosed herein that results in in vivo conversion to compounds within the scope of this disclosure Prodrug modifications that are generally acceptable are also within the scope of this disclosure.

[0070] The present disclosure is also described in the following examples, and the compounds of the present disclosure can be obtained therefrom. This invention relates to a method for preparing the compound of formula (I).

[0071] "Treatment" and "to treat" mean slowing the progression of the disease or disorder described herein. This refers to all processes that may be interrupted, suppressed, controlled, or stopped. These terms must be used. This does not necessarily mean the complete elimination of all disease or disorder symptoms.

[0072] As used herein, “prevent” or “prevent” refers to the disease or disorder described herein. To reduce the likelihood of contracting harm, or the severity of the disease or disorder described herein. This refers to reducing [something].

[0073] The terms "therapeutic effective (or effective) dose" and "amount effective for treatment" or "effective dose" Similar explanations, such as those mentioned above, are requested by researchers, veterinarians, physicians, or other clinicians. The amount of the compound of this disclosure that induces a biological or medical response in a plant, system, animal or human is not considered to be the amount of the compound of this disclosure that induces a biological or medical response in a plant, system, animal or human. It is intended to taste. In a preferred embodiment, the term “therapeutic effective dose” is used for human This means the amount of the compound of this disclosure that alleviates at least one clinical symptom in a patient. The term "(or effective) dose" and similar descriptions such as "a dose effective for prevention" are used by researchers. To be prevented in tissues, systems, animals or humans by a veterinarian, physician or other clinician. This disclosure relates to preventing or reducing the risk of biological or medical events that require such action. It is intended to indicate the quantity of the mixture.

[0074] Dosage of compounds in this disclosure The medication regimens utilizing the compounds disclosed herein may vary depending on the patient's type, species, age, weight, sex, and The symptoms, the severity of the condition being treated, the efficacy of the compound selected for administration, the route of administration, Furthermore, the selection is made according to various factors, including the patient's renal and hepatic function. Consideration is given to the treatment that is effective or preventive in preventing, counteracting, or stopping the progression of the condition. For the purpose of determining the effective dosage, this is well within the understanding of those skilled in the art. A specific daily dose is: For example, a therapeutically effective dose for treating an oncological condition, and for example, a prophylactic dose for preventing an oncological condition. It is understood that both can be effective doses.

[0075] While individual needs vary, determining the optimal range of effective amounts of the compounds disclosed herein is a skill of the art. Within the scope of the procedure. Curative or preventive treatment of conditions and disorders identified herein. For administration to humans in the present invention, for example, a typical dose of the compound disclosed herein is about 0.0 The dose may range from 5 mg / kg / day to approximately 50 mg / kg / day. In some embodiments, the patient is given The dosage ranges from approximately 5 mg / day to approximately 120 mg / day, for example, 10 mg / day, 20 mg / day, 30 mg / day. / day, 40mg / day, 50mg / day, 60mg / day, 70mg / day, 80mg / day, mg A certain compound of the present disclosure is administered at a dose of 90 mg / day or 100 mg / day. In terms of administration, patients receive approximately 0.2 mg / kg to approximately 5 mg / kg, for example, 0.5 mg / kg. g, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, or 1.5 mg / kg g of the compound of this disclosure is administered. Such a dose may be administered as a single dose, Alternatively, the dose may be divided into multiple doses.

[0076] Pharmaceutical composition The compounds of this disclosure and their pharmaceutically acceptable salts are pharmaceutically acceptable in themselves and in relation to each other. Administered to animals, preferably mammals, in particular humans, either in mixture or in the form of a pharmaceutical composition. It is possible. The terms "subject" or "patient" are used for the prevention or treatment of a medical condition. The activator is used in animals, preferably mammals, particularly humans. Administration includes both self-administration and administration to patients by others. The target group is those with a pre-existing disease or You may need or desire treatment for a medical condition, or you may have a disease. Or, preventive measures are needed to prevent or reduce the risk of developing a medical condition. Or, as desired. When used herein, treatment of existing conditions or Those who "need" preventive measures are determined by a medical professional's assessment of the need and other factors. It encompasses both the patient's wishes regarding the treatment.

[0077] Therefore, this disclosure also relates to the compounds of this disclosure and their pharmaceutical use. Scientifically acceptable salts, their use to modulate the activity of the cytokine IL-1β, In particular, their use in the treatment and prevention of diseases or disorders described later, and these To provide their use for preparing pharmaceuticals for the purpose of [specific purpose]. In certain embodiments The compounds of this disclosure and their pharmaceutically acceptable salts capture IL-1β.

[0078] Furthermore, this disclosure provides an effective amount of at least one compound of this disclosure and / or a pharmaceutically acceptable salt thereof, further comprising a conventionally pharmaceutically acceptable carrier, In other words, a medical device containing one or more pharmaceutically acceptable carriers and / or additives To provide a pharmaceutical composition.

[0079] Therefore, this disclosure includes, for example, an effective amount of the compound of this disclosure as an active ingredient and / or It contains a pharmaceutically acceptable salt thereof, and further contains a conventionally pharmaceutically acceptable carrier. Compounds for use as pharmaceutical compositions and their pharmaceutically acceptable salts, as well as subsequent Compounds in the treatment or prevention of the diseases or disorders described below, such as atherosclerosis. and / or the use of pharmaceutically acceptable salts thereof, as well as pharmaceuticals for these purposes. It provides their use for preparing products.

[0080] The pharmaceutical compositions disclosed herein include, for example, pills, tablets, lacquered tablets, sugar-coated tablets, granules, and hard tablets. and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions It can be administered orally in the form of a suspension, or, for example, rectally in the form of a suppository. It can be administered parenterally, for example, by injection or intramuscularly. It can also be done in the form of a solution for injection.

[0081] Other suitable forms of administration include, for example, transdermal or topical administration, such as ointments, tinctures, and sprays. -or in the form of a percutaneous treatment system, or for example, microcapsules, implants or It is in rod form. The preferred dosage form depends, for example, on the disease being treated and its severity. ru.

[0082] This disclosure also provides a pharmaceutical composition comprising a compound of formula (I). The compound of formula (I) is It can be used in combination with any suitable pharmaceutical carrier or excipient. The drug composition comprises one or more compounds of formula (I) in a therapeutically effective amount and pharmaceutically acceptable A certain pharmaceutical product comprising (one or more) excipients and / or (one or more) carriers. The composition is suitable for the mode of administration. In certain embodiments, a pharmaceutically acceptable carrier is water or It could be a buffer solution.

[0083] Excipients contained in pharmaceutical compositions serve different purposes, for example, depending on the properties and mode of administration of the drug. It has. Examples of commonly used excipients include, but are not limited to, physiological saline and buffer. Physiological saline, dextrose, sterile water for injection, glycerol, ethanol and combinations thereof Compounds, stabilizers, solubilizers and surfactants, buffers and preservatives, isotonic agents, fillers, lubricants Augmentants (e.g., talc or silica), and fats, e.g., vegetable stearin, stearic acid Magnesium or stearic acid), emulsifiers, suspending agents or viscous agents, inert diluents, fillers Agents (e.g., cellulose, dicalcium phosphate, vegetable oil, lactose, sucrose, glycerides) Lucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate Um), disintegrants (e.g., cross-linked polyvinylpyrrolidone, sodium starch glycolate, Cross-linked carboxymethylcellulose sodium), binder (e.g., starch, gelatin, ce Lurose, methylcellulose or microcrystalline cellulose, hydroxypropylcellulose, etc. Which modified cellulose, sugars such as sucrose and lactose, or xylitol, sorbitol Sugar alcohols such as vitol or maltitol, polyvinylpyrrolidone and poly (Tylene glycol), wetting agents, antibacterial agents, chelating agents, coatings (e.g., cellulose fiber) Film coating, synthetic polymer, shellac, corn protein zein or Other polysaccharides and gelatin), preservatives (vitamin A, vitamin E, vitamin C, palm oil) Retinyl tinate, as well as selenium, cysteine, methionine, citric acid and sodium citrate. (including thorium, and synthetic preservatives containing methylparaben and propylparaben), Examples include sweeteners, fragrances, flavorings, colorings, absorption enhancers, administration aids, and combinations thereof. It can be done.

[0084] The carrier improves and / or extends the delivery of the active ingredient to the target in the context of the pharmaceutical composition. These are compounds and substances. The carrier uses controlled release technology to release the drug into the target. It may help to prolong vivo activity or delay drug release. The carrier is Furthermore, it may reduce drug metabolism in the target and / or reduce drug toxicity. The body uses this to target the delivery of drugs to specific cells or tissues in a target. It can also be done this way. Common carriers (both hydrophilic and hydrophobic carriers) include fat emulsions and lipids. PEGylated phospholipids, PEGylated liposomes, and cyclic RGD peptides via PEG spacers PEGylated liposomes, liposomes and lipospheres coated with microscopy Fair (including those made from biodegradable polymers or albumin), polymer matrix Biocompatible polymers, protein-DNA complexes, protein conjugates, The aforementioned carrier includes red blood cells, vesicles, nanoparticles, and side chains for hydrocarbon stapling. The cell membrane permeability of the compound of formula (I) can also be increased using the present disclosure. In addition to their use in compositions, carriers can be used in vitro (e.g., for delivery to cultured cells). In compositions for (for) and / or for other uses such as in vivo research use. It can also be used.

[0085] Pharmaceutical compositions suitable for oral administration may be available in individual units such as capsules or tablets, or as powders or It is available as granules, as a solution in aqueous or non-aqueous liquids, as a syrup or suspension, and as food-grade food. It may be provided as a foam or whip, or as an emulsion. Tablets or Suitable excipients for hard gelatin capsules include lactose, corn starch, or other excipients. It contains derivatives of stearic acid or its salts. Suitable for use with soft gelatin capsules. Excipients include, for example, vegetable oils, waxes, fats, and semi-solid or liquid polyols. Excipients that may be used for the preparation of solutions and syrups include, for example, water, polyoxide. It contains sugars and other ingredients. For the preparation of the suspension, use an oil, such as vegetable oil, to make a water-in-oil mixture. Alternatively, an oil-in-water suspension can be provided. Excipients that promote absorption from the gastrointestinal tract, for example It may include permeation enhancers such as sodium caprate. In certain situations, delay Release preparations may be advantageous for delivering the compounds of this disclosure in a delayed release or controlled release manner. Compositions that can achieve this can also be prepared. Long-term retention in the stomach is due to degradation by enzymes present in the stomach. Because this can cause problems, enteric coating is used so that the active substance is released lower down in the gastrointestinal tract. The resulting capsules can also be prepared by standard techniques well known to those skilled in the art.

[0086] Pharmaceutical compositions suitable for transdermal administration remain in close contact with the recipient's epidermis for extended periods. It may be provided as an individual patch intended for a specific purpose. For example, the active ingredient is Pharm It is generally described in aceutical Research, 3(6):318 (1986). As described, it can be delivered from the patch by iontophoresis.

[0087] Pharmaceutical compositions suitable for topical administration include ointments, creams, suspensions, lotions, powders, and solutions. It can be formulated as a paste, gel, spray, aerosol, or oil. If used, the active ingredient is used with either a paraffin-based ointment base or a water-miscible ointment base. It may be used. Alternatively, the active ingredient may be a water-in-oil cream base or an oil-in-water cream base. It may be formulated into a cream containing the agent. A pharmaceutical composition suitable for topical administration to the eye contains active This includes eye drops in which the ingredients are dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration include lozenges, troches, and mouthwashes.

[0088] Pharmaceutical compositions suitable for rectal administration may be provided as suppositories or enemas.

[0089] Pharmaceutical compositions adapted for nasal administration, in which the carrier is solid, are administered by taking snuff, It is administered by rapid inhalation through the nasal passages from a powder container held close to the nose. It includes, for example, a coarse powder having a particle size in the range of 20 to 500 microns. The carrier is liquid. Yes, compositions suitable for administration as a nasal spray or nasal solution include active ingredients It contains an aqueous solution or an oil solution.

[0090] Pharmaceutical compositions suitable for administration by inhalation include various types of quantitatively pressurized aerosols and nebulizers. This includes particulate dust or mist that may be generated by an izzer or blower.

[0091] Pharmaceutical compositions suitable for vaginal administration, pessaries, tampons, creams, gels, pastes, and more. It may be provided as a foam or spray formulation.

[0092] Pharmaceutical compositions suitable for parenteral administration include antioxidants, buffers, bacteriostatic agents, and formulations. Aqueous and non-aqueous sterile injections that may contain a solute that is substantially isotonic with the recipient's blood. The solution, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners, are included. Excipients that may be used in injectable solutions include, for example, water for injection, alcohol, and polio. Examples include glycerin and vegetable oil. The composition is available in unit dose or multi-dose containers. For example, they may be supplied in sealed ampoules and vials, and immediately before use, a sterile liquid carrier For example, freeze-dried (lyophilized) products that only require the addition of water or saline solution for injection. ) May be stored in this state. Immediate injection solutions and suspensions may be in the form of sterile powder, granules and tablets. The following can be prepared: Pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, and sweeteners. Colorants, odorants, salts (the substances of this disclosure themselves are provided in the form of pharmaceutically acceptable salts) They may contain buffering agents, coating agents, or antioxidants. They are also disclosed in this disclosure. In addition to the compound, it may contain a therapeutic activator.

[0093] Method of using the compound disclosed herein This application relates to contacting cells with the compounds of the present disclosure or pharmaceutically acceptable salts thereof. This provides a method for IL-1-mediated cell signaling, including IL-1-mediated cell signaling. Inhibition of IL-6 signaling leads to the development of downstream biomarkers IL-6 and CRP (e.g., hsCRP). This can be evaluated by detecting a decrease in the bell.

[0094] This application also relates to the compounds of the present disclosure (or pharmaceutically acceptable salts thereof) or similar compounds. Using a pharmaceutical composition containing such compounds, symptoms including those involving IL-1β are treated. This provides a method for treating a wide range of disease conditions.

[0095] In some embodiments, the present disclosure relates to a method for treating cardiovascular disease, wherein the therapeutically effective dose Compounds of the present disclosure (or pharmaceutically acceptable salts thereof) or containing such compounds This includes administering one of the aforementioned pharmaceutical compositions to a subject requiring such treatment. A method is provided. In some embodiments, cardiovascular disease is vascular inflammation. In the embodiment, the cardiovascular disease is atherosclerosis. In some embodiments, the heart The vascular disease is heart failure with preserved ejection fraction (HFpEF). In other embodiments, cardiovascular disease This is heart failure with reduced ejection fraction (HFrEF).

[0096] In some embodiments, the present disclosure relates to a method for treating chronic kidney disease, wherein the therapeutically effective dose Compounds of the present disclosure (or pharmaceutically acceptable salts thereof) or containing such compounds This includes administering one of the aforementioned pharmaceutical compositions to a subject requiring such treatment. Provide a method.

[0097] In some embodiments, the present disclosure relates to a method for treating an inflammatory disorder, wherein the therapeutically effective dose Compounds of the present disclosure (or pharmaceutically acceptable salts thereof) or containing such compounds This includes administering one of the aforementioned pharmaceutical compositions to a subject requiring such treatment. A method is provided. In a particular embodiment, the inflammatory disorder is hidradenitis suppurativa (acne reversal), inflammation. A group consisting of venereal intestinal disease, arthritis, and non-alcoholic steatohepatitis (NASH) was selected. ru.

[0098] In some embodiments, the inflammatory disorder is hidradenitis suppurativa (acne suppurativa).

[0099] In certain embodiments, the inflammatory disorder is inflammatory bowel disease, such as Crohn's disease or ulcerative colitis. It's enteritis.

[0100] In some embodiments, the inflammatory disorder is arthritis, for example, osteoarthritis, rheumatoid arthritis. It is either psoriatic arthritis or gouty arthritis.

[0101] In other embodiments, the inflammatory disorder is non-alcoholic steatohepatitis (NASH).

[0102] Combination therapy One or more additional pharmacological activators may be administered in combination with the compounds of this disclosure. One or more additional activators are prodrugs that are converted into a pharmaceutically active form after administration. However, this is intended to mean one or more pharmaceutical activators that are active in the body, Unlike the compounds of formula (I), these also contain free acids, free bases, and drugs of the additional activators. This includes scientifically acceptable salts. Generally, but not limited to, antihypertensive agents, lipid-modifying compounds, etc. Any anti-atherosclerotic agents, anti-diabetic agents and / or anti-obesity agents, including anti-inflammatory agents. One or more appropriate additional activators in a single-dose formulation (fixed-dose drug combination) The compounds disclosed herein may be used in any combination, or simultaneously administered with the activator. This is a single or more separate formulation that enables sequential administration (combined administration of different activators). It can be administered to elephants.

[0103] Examples of additional activators that may be used in the treatment of cardiovascular diseases include, but are not limited to, these. The following are examples of angiotensin-converting enzyme inhibitors (e.g., alacepril, Benazepril, Captopril, Seronapril, Cilazapril, Delapril, Enalapril Enalaprilat, Fosinopril, Imidapril, Lysinopril, Mobertipril, Perindopril, quinapril, ramipril, spirapril, temocapril, or tolando Lapril), angiotensin II receptor antagonist (e.g., losartan, in other words) COZAAR (registered trademark), valsartan (including in combination with sacubitril), cande Used in combination with sartan, olmesartan, telmisartan, and hydrochlorothiazide. These drugs (such as HYZAAR®); sGC activators (for example, riosigma) (ato and beliciguat), PCSK9 inhibitors (e.g., evolocumab, alirocumab, (Disclosed in MK-0616 and International Publication No. 2019 / 246349), Neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), ald Steroid antagonists, aldosterone synthase inhibitors, renin inhibitors, endothelin Receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, th Dalabil and vardenafil), vasodilators, calcium channel blockers (e.g., Amlodipine, nifedipine, verapamil, diltiazem, garopamil, nidipine, ni (Modipine and nicardipine), potassium channel activators (e.g., nicorandil, pi) Nasidil, chromacarim, minoxidil, aprilcarim, loprazolam), diuretics (examples) For example, hydrochlorothiazide); sympathetic nerve blockers, β-adrenergic blockers (for example, pro Planolol, atenolol, bisoprolol, carvedilol, metoprolol or Metoprolol tartrate; alpha-adrenergic blockers (e.g., doxazosin, prazosin) (e.g., α-methyldopa), central α-adrenergic agonists, peripheral vasodilators (e.g., hydra) Radins; lipid-lowering agents (for example, simvastatin, an HMG-CoA reductase inhibitor) N and lovastatin (ZOCOR® and MEVACOR®, respectively) (Target) A lactone-type prodrug that is marketed commercially and functions as an inhibitor after administration. ), as well as atorvastatin (calciulo marketed as LIPITOR®) (Calcium salt), rosuvastatin (calcium salt sold under the registered trademark CRESTOR) , pravastatin (sodium salt, marketed as PRAVACHOL®), Fluvastatin (sodium salt, marketed as LESCOL®), Cryvas Dihydroxy ring-opening acid type HMG-CoA reductase inhibitors such as tatin and pitavastatin Pharmacologically acceptable salts of harmful agents; cholesterol absorption inhibitors, e.g., ezetimibe (ZET) IA(registered trademark)) is used with other optional HMG-CoA reductase inhibitors as described above. In combination with lipid-lowering agents, especially simvastatin (VYTORIN®) In combination with, or in combination with atorvastatin calcium; niacin (immediate Concomitant use with a release-type or controlled-release-type HMG-CoA reductase inhibitor and / or an HMG-CoA reductase inhibitor; Niacin receptor agonists (e.g., acipimox and acifuran), as well as na Iacin receptor partial agonists; metabolic regulators (insulin and insulin mimetic agents (for example) (For example, insulin degludec, insulin glargine, insulin lispro), dipeptidyl Lupeptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin) , omaligliptin, linagliptin and vildagliptin); insulin sensitizers, e.g. For example, (i) PPARγ agonists glitazone (e.g., pioglitazone, mitoglitazone) (PPARs) and other PPARs For example, (1) PPARα / γ double agonists (e.g., Tigritazar, Murag (2) Ritazar, Allegritazar, Sodergritazar, and Nabegritazar; (2) PPARα agonists, for example, fenofibrosin derivatives (e.g., gemfibrozil, (clofibrate, cyprofibrate, fenofibrate, and bezafibrate) (3) Selective PPARγ modulator (SPPARγM), (e.g., International Publication No. 0) Issue No. 2 / 060388, International Publication No. 02 / 08188, International Publication No. 2004 / 01986 Issue 9, International Publication No. 2004 / 020409, International Publication No. 2004 / 020408, (4)P (ii) PARγ partial agonists; (ii) biguanides (e.g., metformin and its pharmacopoeias) Salts that are generally acceptable, especially metformin hydrochloride, as well as Glumetza®, F Sustained-release formulations such as ortamet(trademark), GlucophageXR(trademark); and (iii) Protein tyrosine phosphatase 1B (PTP-1B) inhibitors; insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, etc.) Insulin degludec, insulin glargine, insulin lispro, and each Inhaled preparations of leptin and leptin derivatives and their agonists; amylin and amylin analogs (e.g., pramylintide); sulfonylurea and nonsulfonylurea Basic insulin secretagogues (e.g., tolbutamide, glibenclamide, glipizide, Glimepiride, mitiglinide, meglitinide, nateglinide and repaglinide); α- Glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol); Lucagon receptor antagonists; GLP-1, GLP-1 analogs, derivatives, and mimics. Which incretin mimetic; as well as GLP-1 receptor agonists (e.g., dulaglutin Semaglutide, Albiglutide, Exenatide, Liraglutide, Lixisenatide, etc. Bisopoglutide, including its nasal spray, transdermal, and once-weekly formulations; bile acids Scavengers (e.g., cholestiran, cholestimide, cholestiverm hydrochloride, cholestipol, Cholestyramine, and dialkylaminoalkyl derivatives of cross-linked dextran; CoA: Cholesterol acyltransferase inhibitors (e.g., abasimib); anti Obesity compounds; drugs intended for use in inflammatory conditions (e.g., aspirin); nonsteroidal antisteroids. Non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase -2 (COX-2) inhibitors; and selective cyclooxygenase-2 (COX-2) inhibitors. Harmful agents; glucokinase activators (GKA); 11β-hydroxysteroid dehydrogenase 1 Inhibitors of the type (e.g., those disclosed in U.S. Patent No. 6,730,690), fluc Inhibitors of tose 1,6-bisphosphatase (e.g., U.S. Patent No. 6,054,587) , No. 6,110,903, No. 6,284,748, No. 6,399,782 and (Disclosed in Patent Nos. 6,489,476); Acetyl-CoA carboxylase 1 This is an inhibitor of ACC1 or ACC2, as well as AMP-activated protein kinase ( AMPK activator; other agonists of G protein-coupled receptors, (i) GPR-109 (ii) GPR-119, and (iii) GPR-40, SSTR3 antagonist (For example, as disclosed in International Publication No. 2009 / 001836), Neuromedic U receptor agonists (for example, disclosed in International Publication No. 2009 / 042053) substances; but not limited to these, neuromedin S (NMS); SCD regulators; GPR -105 Antagonists (for example, disclosed in International Publication No. 2009 / 000087) (e.g., empagliflozin, dapagliflozin, canagly) Flozin, ertugliflozin, remogliflozin, tofogliflozin and iplug Liflozin; Acyl coenzyme A: Diacylglycerol acyltransferase 1 Inhibitors of DGAT-1 and DGAT-2; inhibitors of fatty acid synthase; acyl Coenzyme A: Monoacylglycerol acyltransferase 1 and 2 (MGAT-1) Inhibitors of MGAT-2; agonists of the TGR5 receptor (GPBAR1, BG37) Also known as GPCR19, GPR131, and M-BAR; ileal bile acid tran Receptor inhibitors; PACAP, PACAP mimetic, and PACAP receptor 3 agonists Protein tyrosine phosphatase 1B (PTP-1B) inhibitor; IL-1β antibody (For example, gevokizumab and canakinumab), as well as bromocriptine mesylate and its immediate-release formulation; or, if chemically possible, the free acid form of the above activator, free Treatment of the conditions or disorders mentioned above, including base forms and pharmaceutically acceptable salt forms. Concomitant use with other drugs that are beneficial for the same purpose.

[0104] Examples of additional activators that may be used in the treatment of inflammatory disorders include steroids and These include nonsteroidal anti-inflammatory drugs, glucocorticoids, and therapeutic hormones. , but not limited to, treatment of hidradenitis suppurativa (and acne vulgaris) in certain embodiments. In this context, additional activators include antibiotics, injectable steroids, therapeutic hormones, and TNF inhibitors. (For example, infliximab, adalimumab, etanercept, golimumab, certoliz Mab), analgesics (e.g., codeine, hydrocodone, morphine, pregabalin, gabapentin) Chin, intralesional triamcinolone, corticosteroids, naproxen, ketoprofen, These may be diclofenac, ibuprofen, or acetaminophen. In other embodiments, In the treatment of inflammatory bowel disease, additional activators include methotrexate, TNF inhibitors, and Oral sphingosine 1-phosphate receptor modulators (e.g., fingolimod, siponimo) (e.g., ozanimod, ponesimod) or selective JAK inhibitors (e.g., tofacitinib, b) It may be licitinib or upadacitinib. In some embodiments, it is used to treat osteoarthritis. In this configuration, the additional activator may be an analgesic (examples listed above). In other embodiments, In the treatment of gouty arthritis, additional activators include corcitin and nonsteroidal anti-inflammatory drugs. Alternatively, it may be a glucocorticoid.

[0105] [Examples] Method for preparing the compounds of this disclosure The compounds described herein can be used with appropriate materials in the following schemes and examples. It can be prepared according to the following procedure, which is further illustrated by the following specific examples. This also includes methods for testing such compounds in cell assays. However, However, the compounds shown in the examples are construed to form the sole genus considered to be the present disclosure. It shouldn't be done.

[0106] The examples further illustrate the details of the preparation of the compounds of this disclosure. Those skilled in the art will know the following preparation procedure. These compounds can be easily prepared using known variations of the conditions and processes. They will understand. For example, in some cases, the order in which the steps of the reaction scheme are carried out. The order has been altered to facilitate the reaction or to avoid undesirable reaction products. The starting materials and intermediates of the final compound can be purchased or prepared using known procedures. or otherwise illustrated. Examples are provided for further illustration purposes only. This disclosure is not intended to limit the scope of this information.

[0107] NMR data were obtained in CDCl3, DMSO-d6, or methanol-d4 at 300°C. Acquired using MHz or 400MHz instruments, the chemical shift is identified by a tetramethylsilane label. The report was based on the standard. Resonance signals are reported using the following abbreviation: s = singlet , d=doublet, t=triplet, q=quartet, dd=doublet of doublets, m=multiplet or unequal Overlap of valence resonances. The coupling constant (J) is reported in Hertz (Hz).

[0108] Throughout the synthesis schemes and examples, unless otherwise indicated, abbreviations and acronyms are used below. It can be used in this sense. [Table 1] TIFF2026148581000023.tif237153TIFF2026148581000024.tif234152TIFF20261485810 00025.tif234152TIFF2026148581000026.tif233152TIFF2026148581000027.tif239156

[0109] The following examples are illustrative and should not be construed as further limitations. The contents of the drawings and all references, patents and published patents cited throughout this application The application is expressly incorporated herein by reference.

[0110] Intermediate synthesis: Synthesis Scheme 1 [ka]

[0111] AEFC4acidNMe3 [ka]

[0112] (S)-4-((2-(4-(2-((((9H-fluorene-9-yl)methoxy) Carbonyl)amino)-2-carboxyethyl)phenoxy)ethyl)amino)-N,N N-trimethyl-4-oxobutan-1-aminium 2,2,2-trifluoroaceta te Step 1: EtOH (60 mL) contains tert-butyl 4-bromobutanoate (3 g, 1 3.45 mmol) and trimethylamine hydrochloride (10.28 g, 108 mmol) NaHCO3 (12.44 g, 148 mmol) was added to the stirred solution at room temperature. The mixture was stirred at 50°C for 16 hours. The mixture was cooled to room temperature, and the solid was filtered off. The filtrate was then subjected to reduced pressure. The mixture was concentrated under pressure, and the residue was suspended in DCM (30 mL). The solid was filtered off, and the filtrate was concentrated under reduced pressure. And, 4-(tert-butoxy)-N,N,N-trimethyl-4-oxobutane-1- Aminium (2g, 7.91 mmol, yield 58.8%) was obtained as a colorless oil. C1 1H 24 NO2 + [M] + MS ESI calculated value and measured value for 202.18. 20.

[0113] Step 2: 4-(tert-butoxy)-N,N,N-trimethyl-4-oxobutane- Stir in 1-aminium (2g, 9.89 mmol) with 4N HCl dioxane (50mL). The solution was stirred at 25°C for 2 hours. The solvent was concentrated under reduced pressure, and 3-carboxy-N,N,N was added. -Trimethylpropane-1-aminium chloride (1.3g, 8.89 mmol, yield 9 0% was obtained as an off-white solid. C7H 16 NO2 + [M-Cl] + MS E SI calculated value: 146.12, measured value: 146.15.

[0114] Step 3: tert-butyl(S)-3-(4-(2-aminoethoxy)phen in DMF (Lu)-2-((tert-butoxycarbonyl)amino)propanoate (5g, 13. In a 14 mmol) stirred solution, add 3-carboxy-N,N,N-trimethylpropane-1- Aminium chloride (5.76g, 39.4mmol) and DIEA (8.49g, 6 5.7 mmol) was added at room temperature. The solution was stirred at 0°C for 10 minutes. HATU(6.0 (0g, 15.77 mmol) was added to the solution and the solution was stirred at 0°C for 2 hours. The solution was then prepared as follows: Purified by RP-flash under the following conditions, C 18 Using a column (330g), 1% in 5 minutes. ~1%, then 1%~40% in 25 minutes, using MeCN (0.05% TFA) in water, (S)-4 -((2-(4-(3-(tert-butoxy)-2-((tert-butoxycarbony (Lu)amino)-3-oxopropyl)phenoxy)ethyl)amino)-N,N,N-tri Methyl-4-oxobutane-1-aminium was obtained as an off-white solid. 27 H 46 N3O6[M-CF3COO] + MS ESI calculated value: 508.34, measured value: 508 .twenty five.

[0115] Process 4: (S)-4-((2-(4-(3-(tert-butoxy)-2-((ter t-Butoxycarbonyl)amino)-3-oxopropyl)phenoxy)ethyl)amino )-N,N,N-trimethyl-4-oxobutane-1-aminium-2,2,2-triflu A stirred solution of oloacetate (6.4g, 10.29 mmol) in DCM (80mL) is prepared. TFA (120 mL) was added at room temperature. The solution was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure. Concentrated, (S)-4-((2-(4-(2-amino-2-carboxyethyl)phenoxy C(ethyl)amino)-N,N,N-trimethyl-4-oxobutan-1-aminium2 ,2,2-trifluoroacetate (4.7g, 10.10 mmol, yield 98%) yellow It was obtained as a colored oily substance. 18 H 30 N3O4[M-CF3COO] + MS ESI calculation Value 352.22, measured value 352.10.

[0116] Step 5: In THF (60 mL) and water (60 mL) (S)-4-((2-(4-(2 -amino-2-carboxyethyl)phenoxy)ethyl)amino)-N,N,N-trimeth Chil-4-oxobutane-1-aminium 2,2,2-trifluoroacetate (6.4 A mixture of (g, 13.75 mmol) contains NaHCO3 (5.78 g, 68.7 mmol) And Fmoc-OSu (4.64 g, 13.75 mmol) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The pH of the reaction mixture was adjusted to 3 with 1N HCl. The mixture was concentrated under reduced pressure. The residue was purified by RP-flush under the following conditions, and C 18 Using a column (330g), 1% to 1% was added in 5 minutes, and 1% to 50% in 30 minutes, and MeCN in water ( Using 0.05% TFA, (S)-4-((2-(4-(2-((((9H-Fluorine (-9-yl)methoxy)carbonyl)amino)-2-carboxyethyl)phenoxy) Ethyl)amino)-N,N,N-trimethyl-4-oxobutane-1-aminium-2,2 ,2-trifluoroacetate (4.7434g, 6.55 mmol, yield 47.7%) It was obtained as a pale yellow semi-solid. 33 H 40N3O6[M-CF3COO] + MS ES Calculated value: 574.29, measured value: 574.15. 1 1H NMR (300 MHz, CD3O) D)δ 7.76-7.74(m,2H),7.59-7.56(m,2H),7.40 -7.35(m,2H),7.31-7.26(m,2H),7.16-7.14(m, 2H),6.84-6.81(m,2H),4.38-4.12(m,4H),3.98 -3.95(m,2H),3.52(t,J=5.4 Hz,2H),3.32-3.2 4(m,2H),3.13-3.03(m,10H),2.91-2.85(m,1H) ,2.30(t,J=6.9 Hz,2H),2.05-1.99(m,2H). Synthesis Scheme 2 [ka]

[0117] AEFC6acidNMe3 [ka]

[0118] (S)-6-((2-(4-(2-((((9H-fluorene-9-yl)methoxy) Carbonyl)amino)-2-carboxyethyl)phenoxy)ethyl)amino)-N,N N-trimethyl-6-oxohexane-1-aminium trifluoroacetate Step 1: 6-(dimethylamino)hexanoic acid (2g, 12.56) in DCM (20mL) To the stirred mixture of mmol, add N,N-dimethylformamide (0.092 g, 1) at 25°C. Add 0.256 mmol) and then add oxalyl dichloride (4.7) in DCM (10 mL). A solution of 8 g (37.7 mmol) was added at 0°C. The resulting mixture was stirred at 30°C for 1 hour. Mixed. The reaction mixture was concentrated under reduced pressure to obtain crude 6-(dimethylamino)hexanoyl Lorid (2.232 g, 12.56 mmol, 100% yield) was obtained as a yellow oily substance. This was dissolved in DCM (7 mL). TEA (5.78 g, 57.1 mmol) and DC M (7mL) contains 6-(dimethylamino)hexanoyl chloride (2.232g, 12.5 A 6 mmol solution is added to tert-butyl(S)-3-(4-(2) in DCM (13 mL). -aminoethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)pro It was added to a stirred mixture of panoate (4.34 g, 11.42 mmol) at 0°C. The mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure. The residue was scanned using silica gel column chromatography. Purified by matrixing, and eluted with 0-30% MeOH (1% NH4OH) in DCM. The fraction containing the product was collected and evaporated in a vacuum, and tert-butyl(S)-2-(( tert-butoxycarbonyl)amino)-3-(4-(2-(6-(dimethylamino) Hexaneamide (ethoxy)phenyl)propanoate (1.7g, 3.26mmol, A yield of 29% was obtained as a pale white solid. 28 H 48 N3O6[M+H] + MS ES Calculated value: 522.35, measured value: 522.30.

[0119] Step 2: In MeCN (17 mL), tert-butyl(S)-2-((tert-butyx (Cicarbonyl)amino)-3-(4-(2-(6-(dimethylamino)hexanamide) A stirred mixture of ethoxyphenyl propanoate (1.7g, 3.26mmol) NaHCO3 (2.74 g, 32.6 mmol) and MeI (1.019 mL, 16. 29 mmol was added at 25°C. The resulting mixture was stirred at 25°C for 16 hours. Solid Filter out the filtrate and concentrate the filtrate under reduced pressure to obtain the crude (S)-6-((2-(4-(3-(ter t-Butoxy)-2-((tert-Butoxycarbonyl)amino)-3-oxoprop Phenoxyethyl amino-N,N,N-trimethyl-6-oxohexane-1 - Aminium iodide (2.163 g, 3.26 mmol, 100% yield) as a yellow oil. It was obtained as C. 29 H 50 IN3O6[MI] + The MS ESI calculation value is 536.37. Actual measured value: 536.35.

[0120] Step 3: (S)-6-((2-(4-(3-(tert-butoxy) C)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)pheno Xy(ethyl)amino)-N,N,N-trimethyl-6-oxohexane-1-amino To the stirred mixture of Muyozide (2.163 g, 3.26 mmol), add TFA (10 mL, 1 30 mmol was added at 25°C. The resulting mixture was stirred at 25°C for 2 hours, and then... Concentrate under reduced pressure to obtain crude (S)-6-((2-(4-(2-amino-2-carboxyethyl Phenoxyethyl amino-N,N,N-trimethyl-6-oxohexane-1 -Aminium 2,2,2-trifluoroacetate (1.609g, 3.26mmol, A yield of 100% was obtained as a yellow oily substance. 22 H 34 F3N3O6[M-CF3COO ] + The MS ESI calculated value is 380.25, and the measured value is 380.15.

[0121] Step 4: In THF (8 mL) and water (8 mL) (S)-6-((2-(4-(2-A Mino-2-carboxyethyl)phenoxy)ethyl)amino)-N,N,N-trimethyl -6-oxohexane-1-aminium 2,2,2-trifluoroacetate (1.60 In a solution of 9g, 3.26 mmol, add NaHCO3 (1.369g, 16.30 mmol) ) and Fmoc-Osu (1.002 g, 2.93 mmol) were added at 25°C. The mixture was stirred at room temperature for 16 hours, and then the pH was adjusted to 3 with 1M HCl. The resulting mixture was purified by RP-flush under the following conditions: 18 Column (120 g); Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; (Gradient: 5% B) Hold for 5 minutes, rise to 38%B within 30 minutes, hold at 38%B for 2.6 minutes; reach 95% within 2 minutes. Rise to B, hold at 95% B for 5 minutes; Flow rate: 60 mL / min; Detector: UV210 nm; R T=31 min. The product-containing fraction was collected and evaporated in a vacuum, and (S)-6-((2-(4 -(2-((((9H-Fluorene-9-yl)methoxy)carbonyl)amino)-2- Carboxyethyl)phenoxy)ethyl)amino)-N,N,N-trimethyl-6-oxy Sohexane-1-aminium trifluoroacetate (1.12 g, 1.591 mmol) A white solid was obtained with a yield of 49%. 37 H 44 F3N3O8[M-CF3COO] + The MS ESI calculated value was 602.32, and the measured value was 602.25. 1 1H NMR (400 M) Hz,CD3OD)δ 7.78(d,J=7.6 Hz,2H),7.61-7.57 (m,2H),7.41-7.39(m,2H),7.37-7.28(m,2H),7 .17-7.14(m,2H),6.84-6.82(m,2H),4.35-4.14 (m,4H),3.97-3.95(m,2H),3.53-3.50(m,2H),3 .31-3.04(m,12H),2.88-2.86(m,1H),2.24-2.2 0(m,2H),1.75-1.63(m,4H),1.34-1.32(m,2H). 19 F NMR(376 MHz,CD3OD)δ-77.401. Synthesis scheme 3 [ka]

[0122] AEFNMe3 (S)-2-(4-(2-((((9H-fluorene-9-yl)methoxy)carbon (Lu)amino)-2-carboxyethyl)phenoxy)-N,N,N-trimethylethane- 1-Aminium chloride Step 1: tert-butyl(S)-3-(4-(2-amino) in MeOH (100mL) Ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate In a stirred solution of (7.5g, 17.74 mmol), add MeI (12.59g, 89 mmol) l) and NaHCO3 (7.45 g, 89 mmol) were added at room temperature. The mixture was heated for 40 minutes. The mixture was stirred at °C for 16 hours, then cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure. (S)-2-(4-(3-(tert-butoxy)-2-((tert-butoxycal Bonyl)amino)-3-oxopropyl)phenoxy)-N,N,N-trimethylethane -1-Aminium iodide (10g, 16.35 mmol, 92% yield) was converted into a pale yellow solid. C 23 H 39 N2O5[MI] + MS ESI calculated value: 423.29, measured value The value is 423.15.

[0123] Step 2: (S)-2-(4-(3-(tert-butoxy)-2) in DCM (20 mL) -((tert-butoxycarbonyl)amino)-3-oxopropyl)phenoxy)- N,N,N-trimethylethane-1-aminium iodide (10g, 18.17mmol) 40 mL of TFA was added to the stirred solution at room temperature. The resulting solution was incubated at 25°C for 2 hours. The mixture was stirred. The solvent was concentrated under reduced pressure to obtain (S)-2-(4-(2-amino-2-carboxy Ethyl)phenoxy)-N,N,N-trimethylethane-1-aminium-2,2,2- Lifluoroacetate (7g, 14.72 mmol, 81% yield) was obtained as a yellow solid. . C 14 H 23 N2O3[M-CF3COO] + MS ESI calculated value 267.17, actual Measured value: 267.05.

[0124] Step 3: (S)-2-(4-(2-amino) in THF (80 mL) and water (80 mL) -2-carboxyethyl)phenoxy)-N,N,N-trimethylethane-1-aminyl In a stirred solution of 2,2,2-trifluoroacetate (8g, 21.03 mmol), At warmth, Fmoc-OSu (7.09 g, 21.03 mmol) and NaHCO3 (5.3 (0g, 63.1 mmol) was added. The resulting solution was stirred at 25°C for 16 hours. The pH was adjusted to 3 with 6N HCl. The solvent was concentrated under reduced pressure, and the residue was RP under the following conditions. Purified by flash: 330g of C 18Column, 2%-2% in 5 minutes, 2% in 30 minutes %-40%, 98%-98% in 5 minutes, MeCN (2 mmol HCl) in water, RT=35 minutes (S)-2-(4-(2-((((9H-fluorene-9-yl)methoxy)carbon (Lu)amino)-2-carboxyethyl)phenoxy)-N,N,N-trimethylethane- 1-Aminium chloride (5.3489 g, 9.98 mmol, yield 47.5%) It was obtained as a white solid. C 29 H 33 N2O5[M-Cl] + MS ESI calculation value 489.24, measured value 489.25. 1 1H NMR (300 MHz, DMSO-d6) δ 12.85(br,1H),7.89(d,J=7.5 Hz,2H),7.74- 7.71(m,3H),7.67-7.65(m,2H),7.44-7.24(m,4 H),6.91(d,J=7.5 Hz,2H),4.41-4.40(m,2H),4 .24-4.10(m,4H),3.79-3.76(m,2H),3.17(s,9H ),3.08-3.06(m,1H),2.86-2.78(m,1H). Synthesis Scheme 4 [ka] AEFPEG1acidNMe3 [ka]

[0125] (S)-2-(3-((2-(4-(2-((((9H-Fluorene-9-Il)Meth Xy)carbonyl)amino)-2-carboxyethyl)phenoxy)ethyl)amino)- 3-Oxopropoxy)-N,N,N-trimethylethane-1-aminium-2,2,2- Trifluoroacetate Step 1: In EtOH (30 mL), tert-butyl 3-(2-bromoethoxy)propane Noate (2.5g, 9.88mmol) and trimethylamine hydrochloride (9.44g, Add NaHCO3 (12.44 g, 148 mmol) to a 99 mmol stirred solution at room temperature. The mixture was added. The mixture was stirred at 50°C for 16 hours, then cooled to room temperature, and the solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was suspended in DCM (30 mL). The solid was filtered off, and the filtrate was reduced. Concentrate under pressure to obtain 2-(3-(tert-butoxy)-3-oxopropoxy)-N,N N-trimethylethane-1-aminium (4.2g, 9.04 mmol, yield 92%) It was obtained as a colorless oily substance. 12 H 26 NO3[M] + MS ESI calculation value: 232.1 9. Measured value: 232.10.

[0126] Step 2: 2-(3-(tert-butoxy) in 4N HCl / dioxane (50 mL) -3-oxopropoxy)-N,N,N-trimethylethane-1-aminium (4.2g The solution of 9.04 mmol was stirred at 25°C for 2 hours. The solvent was concentrated under reduced pressure, and 2-( 2-Carboxyethoxy)-N,N,N-trimethylethane-1-aminium chloride ( 3.8 g, 7.18 mmol, yield 79% was obtained as an off-white solid. C8H1 8NO3[M-Cl] + The MS ESI calculated value was 176.13, and the measured value was 176.15.

[0127] Step 3: 2-(2-carboxyethoxy)-N,N,N-trimethyl in DMF (40 mL) Thilethane-1-aminium chloride (5.01 g, 9.46 mmol) and DIEA (6.89 mL, 39.4 mmol) of stirred solution, HATU (3.60 g, 9.46 ml) (mol) was added at room temperature. The solution was stirred at 25°C for 10 minutes. tert-butyl(S) -3-(4-(2-aminoethoxy)phenyl)-2-((tert-butoxycarbony Add aminopropanoate (3g, 7.88 mmol) and the resulting solution at room temperature. The mixture was stirred for 2 hours. After concentration under reduced pressure, the residue was subjected to RP-flush under the following conditions. Purified: C 18 Column, 330g, 1%-1% in 5 minutes, 1%-37% in 25 minutes, M in water eCN (0.05%), (S)-2-(3-((2-(4-(3-(tert-butoxy )-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenoxy C)ethyl)amino)-3-oxopropoxy)-N,N,N-trimethylethane-1- Aminium 2,2,2-trifluoroacetate (5g, 7.29 mmol, 92% yield) ) was obtained as a pale yellow solid. C 28 H 48 N3O7[M-CF3COO] + MS ES Calculated value: 538.35, measured value: 538.25.

[0128] Step 4: (S)-2-(3-((2-(4-(3-(tert-)) in DCM (10 mL) Butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl) Phenoxy)ethyl)amino)-3-oxopropoxy)-N,N,N-trimethylethanol n-1-aminium 2,2,2-trifluoroacetate (5g, 7.29mmol) TFA (40 mL) was added to the stirred solution at room temperature. The resulting solution was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure to obtain (S)-2-(3-((2-(4-(2-amino-2-ka (Quoxyethyl)phenoxy)ethyl)amino)-3-oxopropoxy)-N,N,N -Trimethylethane-1-aminium-2,2,2-trifluoroacetate (3.7g, 6.72 mmol, yielding 92%, was obtained as a yellow oily substance. 19 H 32 N3O5[M- CF3COO] + The MS ESI calculated value was 382.23, and the measured value was 382.15.

[0129] Step 5: In THF (50 mL) and water (50 mL) (S)-2-(3-((2-(4 -(2-amino-2-carboxyethyl)phenoxyethyl)amino)-3-oxop Ropoxy)-N,N,N-trimethylethane-1-aminium-2,2,2-trifluoro Acetate (3.7g, 6.72 mmol) and Na2CO3 (2.137g, 20. Add Fmoc-OSu (2.267 g, 6.72 mmol) to a 16 mmol stirred solution. The mixture was added at room temperature. The resulting mixture was stirred at 25°C for 16 hours. The pH was adjusted with 1N HCl. The solution was adjusted and purified by RP-flush under the following conditions: 18 Column, 33 0g, 1%-1% in 5 minutes, 1%-37% in 30 minutes, MeCN in water (0.05% TFA), (S)-2-(3-((2-(4-(2-((((9H-Fluorene-9-Il)Methoki C)carbonyl)amino)-2-carboxyethyl)phenoxy)ethyl)amino)-3 -Oxopropoxy)-N,N,N-trimethylethane-1-aminium-2,2,2- Lifluoroacetate (4.8452 g, 6.62 mmol, 98% yield) off-white It was obtained as a solid. 34 H 42 N3O7[M-CF3COO] + MS ESI calculation Value 604.30, measured value 604.25. 1 1H NMR (400 MHz, DMSO-d6) )δ 8.19(s,1H),7.90-7.88(m,2H),7.74-7.72( m,3H),7.44-7.40(m,2H),7.34-7.32(m,2H),7. 30-7.28(m,2H),7.20-7.18(m,2H),4.23-4.12( m,4H),3.94-3.91(m,2H),3.78-3.77(m,2H),3. 68-3.65(m,2H),3.49-3.47(m,2H),3.41-3.39( m,2H),3.04(s,9H),3.00-2.99(m,1H),2.83-2. 81 (m, 1H), 2.38 (t, J=6.0 Hz, 2H). 19 F NMR (376 MHz, DMSO-d6)δ-74.41. Synthesis scheme 5 [ka]

[0130] dProt4NH2C6acidNMe3 [ka]

[0131] 6-(((3S,5R)-1-(((9H-fluorene-9-yl)methoxy)carb Nyl)-5-carboxypyrrolidine-3-yl)amino)-N,N,N-trimethyl-6 -Oxohexane-1-aminium 2,2,2-trifluoroacetate Step 1: 6-(Dimethicone) in TEA (9.54 g, 94 mmol) and DCM (7 mL) A solution of (3.35g, 18.85mmol) hexanoyl chloride is prepared in DCM. (13mL) contains 1-(tert-butyl)2-methyl(2R,4S)-4-aminopyrrolic acid A stirred mixture of din-1,2-dicarboxylate (4.61 g, 18.85 mmol) The substance was added at 0°C. After stirring at 25°C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue, Silica gel column chromatography eluting with 0-30% MeOH (1% NH4OH) / DCM Purified by Raffy. The product-containing fraction was recovered and evaporated under vacuum, and 1-(ter t-butyl)2-methyl(2R,4S)-4-(6-(dimethylamino)hexaneamide ) Pyrrolidine-1,2-dicarboxylate (2.4g, 4.98 mmol, yield 26%) ) was obtained as a pale white solid. 19 H 36 N3O5[M+H] + MS ESI calculation value 3 86.26, actual measured value 386.35.

[0132] Step 2: 1-(tert-butyl)2-methyl(2R,4S)- in ACN (50mL) 4-(6-(dimethylamino)hexaneamide)pyrrolidine-1,2-dicarboxylate (2.4g, 6.23 mmol) and NaHCO3 (7.84g, 93 mmol) MeI (8.84 g, 62.3 mmol) was added to the stirred mixture at room temperature. After stirring for 6 hours, the solid is filtered off, and the filtrate is concentrated under reduced pressure to obtain 6-(((3S,5R)- 1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3- Il(amino)-N,N,N-trimethyl-6-oxohexane-1-aminium iodine A solution (3.28 g, 5.60 mmol, 90% yield) was obtained as a pale yellow solid. 20 H3 8IN3O5[MI] + The MS ESI calculated value was 400.28, and the measured value was 400.35.

[0133] Step 3: In THF (50 mL), add 6-(((3S,5R)-1-(tert-butoxyca (Rubonyl)-5-(methoxycarbonyl)pyrrolidine-3-yl)amino)-N,N,N -Trimethyl-6-oxohexane-1-aminium iodide (3.28g, 5.60mg) In a stirred solution of (mol), add LiOH (1N in water) (16.79 mL, 16.79 mmol) It was added at room temperature. After stirring at 25°C for 1 hour, the pH was adjusted to 6 with 1N HCl. The solvent was concentrated under reduced pressure to obtain 6-(((3S,5R)-1-(tert-butoxycal Bonyl)-5-carboxypyrrolidine-3-yl)amino)-N,N,N-trimethyl- 6-Oxohexane-1-aminium chloride (2.36 g, 5.03 mmol, yield 9 0% was obtained as a yellow solid. 19 H 36 ClN3O5[M-Cl] + MS ESI Calculated value: 386.26, measured value: 386.35.

[0134] Step 4: 6-((((3S,5R)-1-(tert-butoxy) in DCM (50 mL) Carbonyl)-5-carboxypyrrolidine-3-yl)amino)-N,N,N-trimethicone Lu-6-oxohexane-1-aminium chloride (2.36 g, 5.03 mmol) TFA (50 mL) was added to the stirred solution at room temperature. The resulting mixture was stirred at 25°C for 1 hour. Mix, then concentrate under reduced pressure to obtain 6-(((3S,5R)-5-carboxypyrrolidine -3-yl)amino)-N,N,N-trimethyl-6-oxohexane-1-aminium 2,2,2-trifluoroacetate (2.01 g, 4.53 mmol, 90% yield) It was obtained as a yellow solid. C 16 H28 F3N3O5[M-CF3COO] + MS ESI Calculated value: 286.21, measured value: 286.15.

[0135] Step 5: 6-(((3S, 5R)-5-ka in THF (50 mL) and water (50 mL) Luboxypyrrolidine-3-yl)amino)-N,N,N-trimethyl-6-oxohexa N-1-Aminium 2,2,2-trifluoroacetate (2.01g, 5.03mmo) In a stirred solution of l) and NaHCO3 (1.268 g, 15.10 mmol), Fmoc -OSu (1.698 g, 5.03 mmol) was added at room temperature. The mixture was stirred at 25°C for 16 hours. Afterward, the pH was adjusted to 3 using 1 N HCl, and the solvent was evaporated under reduced pressure. Residue Dissolve in THF / MeOH (1:1, 50 mL), filter off the solid, and treat the filtrate under the following conditions. Purified by P-flush:C 18 Column, 330g, 2%~2% in 8 minutes, 30 minutes 2%~35% in 10 minutes, 35%~95% in 10 minutes, 95%~95% in 8 minutes, MeCN / water (0. 05%TFA). This results in 6-(((3S,5R)-1-(((9H-Fluorine-9 -yl)methoxy)carbonyl)-5-carboxypyrrolidine-3-yl)amino)-N N,N-trimethyl-6-oxohexane-1-aminium-2,2,2-trifluoro Acetate (2.85 g, 4.49 mmol, yield 89%) was obtained as a pale yellow solid. 31 H 38 F3N3O7[M-CF3COO] + MS ESI calculated value 508.28, actual Measured value: 508.25. 1 H NMR(300 MHz,DMSO-d6)δ 8.20(d ,J=6.9 Hz,1H),7.93-7.90(m,2H),7.69-7.63( m,2H),7.47-7.41(m,2H),7.36-7.31(m,2H),4. 32-4.15(m,5H),3.68-3.55(m,1H),3.29-3.22( m,3H),3.03(s,9H),2.19-2.08(m,4H),1.69-1. 53 (m, 4H), 1.27-1.22 (m, 2H). 19 F-NMR (282 MHz) ,DMSO-d6)δ 74.261. Synthesis scheme 6 [ka]

[0136] dProt4NHPEG2acidNMe3 [ka]

[0137] 2-(2-(3-(((3S,5R)-1-(((9H-Fluorene-9-Il)Meth Xy)carbonyl)-5-carboxypyrrolidine-3-yl)amino)-3-oxopro Poxyethoxy-N,N,N-trimethylethane-1-aminium 2,2,2- Lifluoroacetate Step 1: 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethyl DMF (40ml) of ethane-1-aminium chloride (2.64g, 10.32mmol) In the stirred solution (L), DIEA (1.501 mL, 8.60 mmol) was added under a nitrogen atmosphere at 0°C. And HATU (3.27 g, 8.60 mmol) was added. The resulting solution was incubated at 0°C for 1 After stirring for 0 minutes, 1-(tert-butyl)2-methyl(2R,4S)-4-aminopropyl Add loridine-1,2-dicarboxylate (2.1g, 8.60 mmol), and 25 The solution was stirred at °C for 1 hour. The solution was purified by RP-flush under the following conditions: 18 mosquito Lamb, 330g, 2%~2% in 5 minutes, 2%~30% in 20 minutes, 98%~98% in 5 minutes, M eCN / water (0.05% TFA), RT=35 min. This resulted in 2,2,2-trifluoro Acetic acid, 2-(2-(3-(((3S,5R)-1-(tert-butoxycarbonyl)- 5-(methoxycarbonyl)pyrrolidine-3-yl)amino)-3-oxopropoxy) Ethoxy)-N,N,N-trimethylethane-1-aminium salt (4.4g, 7.46m A quantity of mol, yielding 87%, was obtained as a pale yellow oil. 21 H 40 N3O7[M-CF3COO ] + The MS ESI calculated value was 446.29, and the measured value was 446.35.

[0138] Step 2: 2,2,2-trifluoroacetic acid in THF (50 mL), 2-(2-(3-(( (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl) Pyrrolidine-3-yl)amino)-3-oxopropoxy)ethoxy)-N,N,N-to Li OH (1N in water) (23.55 mL, 23.55 mmol) was added at room temperature. The solution was stirred at 25°C for 1 hour. The pH was adjusted to 3 using 1N HCl, and the solvent was cooled under reduced pressure. Concentrated, 2-(2-(3-(((3S,5R)-1-(tert-butoxycarbon (Lu)-5-carboxypyrrolidine-3-yl)amino)-3-oxopropoxy)ethoxy (C)-N,N,N-trimethylethane-1-aminium chloride (3.7g, 7.12mg) A quantity of mol, yielding 91%, was obtained as a yellow oily substance. 20 H 38 N3O7[M-Cl] + of MS ESI calculated value: 432.27, measured value: 432.35.

[0139] Step 3: 2-(2-(3-(((3S,5R)-1-(tert -Butoxycarbonyl)-5-carboxypyrrolidine-3-yl)amino)-3-oxo Propoxyethoxy-N,N,N-trimethylethane-1-aminium chloride (3 To a stirred solution of 0.7g (7.12 mmol), TFA (20 mL) was added at room temperature. The mixture was stirred at 25°C for 1 hour. The solvent was concentrated under reduced pressure to obtain 2-(2-(3-(((3S, 5 R)-5-carboxypyrrolidine-3-yl)amino)-3-oxopropoxy)ethoxy (C)-N,N,N-trimethylethane-1-aminium-2,2,2-trifluoroacetate C (3.2 g, 6.47 mmol, yield 91%) was obtained as a yellow oily substance. 15 H3 0N3O5[M-CF3COO] + The MS ESI calculated value is 332.22, and the measured value is 332. twenty five.

[0140] Step 4: 2-(2-(3-(((3S,5 R)-5-carboxypyrrolidine-3-yl)amino)-3-oxopropoxy)ethoxy (C)-N,N,N-trimethylethane-1-aminium-2,2,2-trifluoroacetate In a stirred solution of phosphate (3.8g, 7.68mmol), add Na2CO3 (2.441g, 23mmol). (0.03 mmol) and Fmoc-OSu (2.59 g, 7.68 mmol) were added at room temperature. The mixture was stirred at 25°C for 16 hours. The pH was adjusted to 3 using 6N HCl. The solution was prepared and purified by RP-flush under the following conditions: 330 g of C 18 Kara M, 2%~2% in 5 minutes, 2%~30% in 20 minutes, 98%~98% in 5 minutes, MeCN / water ( 0.05% TFA), RT=25 min. This results in 2-(2-(3-(((3S,5R) -1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxyp Loridine-3-yl)amino)-3-oxopropoxy)ethoxy)-N,N,N-tri Methylethane-1-aminium 2,2,2-trifluoroacetate (4.1824g) 6.14 mmol, yield 80%, was obtained as a colorless semi-solid. 30 H 40 N3O7[M -CF3COO] + The MS ESI calculated value was 554.29, and the measured value was 554.20. 1 HN MR(400 MHz,DMSO-d6)δ 8.24-8.23(m,1H),7.9 2-7.89(m,2H),7.68-7.64(m,2H),7.45-7.32(m ,4H),4.48-4.23(m,4H),4.16-4.15(m,1H),3.8 3-3.82(m,2H),3.67-3.51(m,9H),3.27-3.25(m ,1H),3.09(s,9H),2.36-2.32(m,2H),2.20-2.1 1(m,2H). Synthesis scheme 7 [ka]

[0141] Prot4CH2Pyrim [ka]

[0142] (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)- 4-(pyrimidine-5-ylmethyl)pyrrolidine-2-carboxylic acid Step 1: 1-(tert-butyl)2-methyl(S)-4-methylenepyrrolidine-1, 2-Dicarboxylate (2.41 g, 9.99 mmol) and 9-BBN (80 mL) A solution of 40.0 mmol (0.5 N in THF) was stirred at 40°C for 1 hour. The solution was then left at room temperature. It was cooled and used directly in the next process. 12 H 21 BNO6[M-C8H 14 +H2O2 -H] - The MS ESI calculated value was 286.15, and the measured value was 286.25.

[0143] Step 2: 1-(tert-butyl)2-methyl(2S)-4-(((1R,5R)-9 -Borabicyclo[3.3.1]nonane-9-yl)methyl)pyrroridine-1,2-dical In a solution of THF (320 mL) containing a 14.5 g quinolate, K3PO4 (96 mL, 96 mmol, 1N in water) was added at room temperature. The solution was left at room temperature for 20 minutes. Stirred for minutes. 5-bromopyrimidine (5.08 g, 31.9 mmol) and PdCl Add 2(dtbpf)(2.081g, 3.19 mmol), and the resulting mixture is 60 The mixture was stirred at °C for 1.5 hours. The resulting solution was cooled to room temperature and diluted with brine (50 mL). Extraction was performed using EA (3 x 50 mL). The combined organic layer was washed with brine (2 x 25 mL). The mixture was then dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was removed using silica gel. The crude product was purified by column chromatography and eluted with 0-90% EA in PE. The crude product was obtained. The crude product was separated by SFC under the following conditions: Column: Chiralp akIG, 3×25cm, 5μm; Mobile phase A: CO2, Mobile phase B: IPA:MeCN=1 :1(0.1%2MNH3-MeOH);Flow rate:100mL / min;Gradient:A Isocratic 40% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220nm; RT1 (min): 8.93; RT2 (min): 11.32; Sample solvent: MeOH (0.1% 2MNH3-MeOH); Injection volume: 3.8 mL; Number of runs: 5. 8.93 minutes The fraction is collected and concentrated under reduced pressure to obtain 1-(tert-butyl)2-methyl(2S,4R)- 4-(pyrimidine-5-ylmethyl)pyrrolidine-1,2-dicarboxylate (4,3 g, 12.71 mmol, yield 40%) was obtained as a yellow oily substance. 16 H 23 N3O4 [M-Boc] + The MS ESI calculated value is 222.17, and the measured value is 222.15. 1 H NM R(400 MHz,CDCl3)δ 9.14(d,J=4.7 Hz,1H),8. 60(s,2H),4.39-4.12(m,1H),3.83-3.63(m,4H) ,3.17-3.06(m,1H),2.83-2.53(m,3H),2.14-1. 88 (m, 2H), 1.44-1.42 (m, 9H). Step 3: 1-(tert-butyl)2-methyl(2S,4R)-4-(pyrimidine-5) -Ilmethyl)pyrrolidine-1,2-dicarboxylate (4.3g, 13.38mmo) l) Stirring solution in THF (50 mL) with LiOH (40.1 mL in water, 40.1 mmol) (1, 1N) was added at room temperature. The solution was stirred at 25°C for 2 hours. Dissolve with 1N HCl. The pH of the solution is adjusted to 3, and then concentrated under reduced pressure to obtain (2S,4R)-1-(tert- Butoxycarbonyl)-4-(pyrimidine-5-ylmethyl)pyrrolidine-2-carbone The acid (4.1 g, 12.67 mmol, 95% yield) was obtained as a yellow solid. 15 H 20 N3O4[MH] - The MS ESI calculated value is 306.15, and the measured value is 306.15.

[0144] Step 4: (2S,4R)-1-(tert-butoxycarbonate) in DCM (90mL) (Lu)-4-(pyrimidine-5-ylmethyl)pyrrolidine-2-carboxylic acid (4.1g, 1 To a 2.67 mmol (TFA) stirred solution, 30 mL of TFA was added at room temperature. The solution was then heated to 25°C. The mixture was stirred for 1 hour. The solvent was concentrated under reduced pressure, and (2S,4R)-4-(pyrimidine-5- Ilmethyl)pyrrolidine-2-carboxylic acid (2.6g, 11.29 mmol, yield 89%) ) was obtained as a yellow solid. C 10 H 14 N3O2[M+H] + MS ESI calculation value 20 8.10, measured value 208.15.

[0145] Step 5: (2S,4R)-4-(pyrimidium) in THF (50 mL) and water (50 mL) (n-5-ylmethyl)pyrrolidine-2-carboxylic acid (2.6g, 12.55 mmol) Add Fmoc-OSu (3.81 g, 11.29 mmol) and NaHCO3 to the stirred solution. (5.27 g, 62.7 mmol) was added at room temperature. The resulting mixture was incubated at 25°C for 16 hours. The mixture was stirred. The pH of the mixture was adjusted to 3 using 1N HCl, and the solution was prepared under the following conditions. It was purified by RP-flush and 330g of C 18 Column, 5%~5% in 5 minutes, 25 5% to 40% per minute, 98% to 98% in 5 minutes, MeCN in water (0.05% TFA), RT= 30 minutes, (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbon (Lu)-4-(pyrimidine-5-ylmethyl)pyrrolidine-2-carboxylic acid (5.0 g, 11.53 mmol, yielding 92%, was obtained as an off-white solid. 25 H 24 N 3O4[M+H] + MS ESI calculated value: 430.17, measured value: 430.10; 1 HN MR(300 MHz,CD3OD)δ 9.18(d,J=13.2 Hz,1H), 8.68(d,J=6.9Hz,2H),7.80-7.75(m,2H),7.61 -7.58(m,2H),7.41-7.27(m,4H),4.42-4.31(m, 3H),4.23-4.17(m,1H),3.62-3.50(m,1H),3.18 -3.00(m,1H),2.76-2.70(m,2H),2.68-2.66(m, 1H), 2.12-2.02(m,2H). Synthesis scheme 8 [ka]

[0146] Pyrim [ka]

[0147] (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)- 4-(4-(pyrimidine-5-yl)benzyl)pyrrolidine-2-carboxylic acid Step 1: (2S,4R)-1 in water (10 mL) and 1,4-dioxane (10 mL) -(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(4-bromobene) A mixture of (zyl)pyrrolidine-2-carboxylic acid (1.2g, 2.370 mmol) contains pyryl Midine-5-ylboronic acid (0.294g, 2.370mmol), K3PO4 (1.5 (0.9g, 7.11 mmol) and Pd(dtbpf)Cl2(0.232g, 0.35 5 mmol) was added under argon at 25°C. The resulting mixture was stirred at 80°C for 2 hours. Next, the reaction mixture is cooled to room temperature and directly purified by RP-Flash under the following conditions. :Column:C 18 Gel column (330g); mobile phase A: water (0.01% TFA); transfer Dynamic Phase B: MeCN; (Gradient: Hold at 0%B for 5 minutes, rise to 52%B within 35 minutes) , held at 52%B for 3 minutes; rise to 95%B within 2 minutes, held at 95%B for 10 minutes); flow rate: 60 mL / min; Detector: UV254 and 210 nm; RT: 35 min. Product-containing fraction It is recovered and rotated and evaporated in a vacuum, (2S,4R)-1-(((9H-Fluorene-9- Helicobacter pylori (yl)methoxy)carbonyl)-4-(4-(pyrimidine-5-yl)benzyl)pyllinois Din-2-carboxylic acid (629 mg, 1.244 mmol, 52% yield) was prepared as a yellow solid. C 31 H 28 N3O4[M+H] + MS ESI calculated value: 506.20, measured value 506.15. 1 H NMR(300 MHz,CD3OD)δ 9.11-9.04( m,3H),7.78-7.76(m,2H),7.69-7.58(m,4H),7. 41-7.25(m,6H),4.38-4.19(m,4H),3.69-3.54( m,1H),3.29-3.08(m,1H),2.79-2.66(m,3H),2. 19-1.95 (m, 2H). Synthesis scheme 9 [ka]

[0148] PyrimAla4Ph4CO2H [ka]

[0149] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(2-(4-(tert-butoxycarbonyl)phenyl)pyrimidine-5-yl ) Propanoic acid Step 1: NiBr2-glyme (0.951g, 2.432m) in DMA (100mL) In a stirred solution of (mol), add 1,10-phenanthroline (0.527 g, 2.432 mmol) l) was added under a nitrogen atmosphere at 25°C. The resulting solution was stirred at 50°C for 1 hour, and then in a room. Cool to warm temperature, and add 2-chloro-5-iodopyrimidine (5.85g, 24.32mO) to it. l) tert-butyl(R)-2-((((9H-fluoren-9-yl)methoxy) Carbonyl (amino)-3-iodopropanoate (6g, 12.16 mmol), TB AI (4.66g, 12.16mmol) and zinc (1.590g, 24.32mmol) l) was added at room temperature. The resulting mixture was stirred at 25°C for 2 hours, and then H2O(20 Quenched with 0 mL and extracted with EA (2 x 500 mL). The combined organic layer was brined. Washed with (3 × 200 mL), dried with anhydrous Na₂SO₄, and filtered. The filtrate was subjected to reduced pressure. The solution was concentrated. The residue was purified by silica gel column chromatography to obtain 0-20% EA. Elutes with / PE, tert-butyl(S)-2-((((9H-fluorene-9-yl) Methoxycarbonylamino-3-(2-chloropyrimidine-5-yl)propanoate A solution (4g, 8.35 mmol, 70% yield) was obtained as an off-white solid. 26 H 27 ClN3O4[M+H] + MS ESI calculated value: 480.16, measured value: 480.2 5.

[0150] Step 2: In DCM (15 mL), tert-butyl(S)-2-((((9H-fluorescein). (-9-yl)methoxy)carbonyl)amino)-3-(2-chloropyrimidine-5-yl) Add TFA (30 mL) to a stirred solution of propanoate (6 g, 12.50 mmol). The solution was added at room temperature. The solution was stirred at 25°C for 3 hours, and then concentrated under reduced pressure. The residue was then... Purified by RP-flash using the following conditions: Column: Flash C 18 (3 30g); Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; (Gradient: 5%) Hold at B for 5 minutes, rise to 30% B within 15 minutes, hold at 30% B for 5 minutes; 95 within 20 minutes Increase to %B, hold at 95%B for 10 minutes; Flow rate: 90 mL / min; Detector: UV210 nm RT=40 min. The product-containing fraction is collected and evaporated in a vacuum, (S)-2-(((( 9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-chloropyri) Midine-5-yl)propanoic acid (2.56g, 6.04 mmol, yield 51%) in yellow oil It was obtained as a substance. C 22 H 19 ClN3O4[M+H] + The MS ESI calculation value is 424. 10. Measured value: 424.15.

[0151] Step 3: (S)-2-((((9H in water (20 mL) and dioxane (20 mL) -Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-chloropyrimid (4-(tert-but))propanoic acid (2.56g, 6.04mmol), (4-(tert-but) Xycarbonyl(phenyl)boronic acid (1.609g, 7.25mmol) and K3P To a stirred mixture of O4 (6.41 g, 30.2 mmol), add Pd(dtbpf)Cl2(0 0.590g (0.906 mmol) was added at room temperature. The resulting mixture was incubated at 80°C for 2 hours. The mixture was stirred, then cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to RP- under the following conditions. Purified by flash: Column: Flash C 18 (330g);Mobile phase A: water (0.1% TFA), mobile phase B: ACN; (gradient: 5% B held for 5 minutes, then 15 minutes) It rises to 30%B within 20 minutes, holds at 30%B for 5 minutes; rises to 95%B within 20 minutes, 95%B (Hold for 10 minutes); Flow rate: 90 mL / min; Detector: UV 210 nm; RT = 40 minutes. Product The contained fraction is recovered and evaporated in a vacuum, and (S)-2-((((9H-fluorene-9- (Iyl)methoxy)carbonyl)amino)-3-(2-(4-(tert-butoxycarbon) Nyl(phenyl)pyrimidine-5-yl)propanoic acid (2.5629g, 4.53mO) l, yielding 75%, was obtained as a yellow oily substance. 33 H 32 N3O6[M+H] + MS ESI calculated value: 566.22, measured value: 566.40. 1 1H NMR (300 MHz, CD) 3OD)δ 8.75(s,2H),8.42(d,J=8.3 Hz,2H),8.0 2(d,J=8.2 Hz,2H),7.75(d,J=7.5 Hz,2H),7.6 6-7.45(m,2H),7.42-7.15(m,4H),4.62-4.44(m ,1H),4.38-4.20(m,2H),4.12(t,J=7.0 Hz,1H) ,3.35-3.33(m,1H),3.11-2.97(m,1H),1.62(s, 9H). Synthesis scheme 10 [ka]

[0152] 3Pal4Ph4CO2H [ka]

[0153] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(6-(4-(tert-butoxycarbonyl)phenyl)pyridine-3-yl) Propanic acid Step 1: NiCl2-glyme (0.918g, 4.18mm) in DMA (100mL) In a stirred solution of ol), 1,10-phenanthroline (0.905 g, 4.18 mmol) was added. The resulting solution was stirred at 50°C for 1 hour. 2-chloro- 5-Iodopyridine (5g, 20.88 mmol), tert-butyl(R)-2-(( ((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropane Noate (12.36g, 25.06mmol), TBAI (8.01g, 20.88m Add (mol) and Zn (2.73 g, 41.8 mmol) to the above mixture at room temperature and obtain The mixture was stirred at 25°C for 2 hours. The reaction was quenched with H2O (200 mL). Extracted with ethyl acetate (2 x 500 mL). The combined organic layer was then treated with brine (3 x 200 mL). Washed with (), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was saturated. Purified by Ricagel column chromatography, and eluted with 0-30% ammonium in PE. And tert-butyl(S)-2-((((9H-fluoren-9-yl)methoxy) Carbonyl)amino)-3-(6-chloropyridine-3-yl)propanoate was obtained. C 27 H 28 ClN2O4[M+H] + MS ESI calculated value: 479.17, measured value: 47 9.20.

[0154] Step 2: tert-butyl(S)-2-((((9H-fluorene in DCM (5mL) -9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridine-3-yl) Add TFA (10 mL) to a stirred solution of propanoate (5 g, 10.48 mmol) at room temperature. The solution was added. The solution was stirred at 25°C for 1 hour. The solvent was concentrated under reduced pressure, and the residue was collected under the following conditions. Purified by RP flash: Column: Flash C 18 (330g); Mobile phase A: Water (0.1% TFA), mobile phase B: ACN; (Gradient: 5% B held for 5 minutes, Increase to 30%B within 15 minutes, hold at 30%B for 5 minutes, and then increase to 95%B within 20 minutes. Increase the concentration and hold at 95% B for 10 minutes; flow rate: 90 mL / min; detector: UV 210 nm; RT = 40 minutes. The fraction containing the product is collected and evaporated in a vacuum, (S)-2-((((9 H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridin We obtained 0-3-yl)propanoic acid. 23 H 20ClN2O4[M+H] + MS ES Calculated value: 423.10, measured value: 423.10.

[0155] Step 3: In THF (25 mL) and water (5 mL) (S)-2-((((9H-Fluoro Len-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridine-3-yl) (4-(tert-butoxy)) In a stirred solution of propanoic acid (3g, 7.09 mmol), Carbonyl(phenyl)boronic acid (1.890g, 8.51mmol) and K3PO4 (7.53 g, 35.5 mmol) was added under nitrogen at 25°C. The resulting solution was then heated at 25°C. Stirred for 10 minutes. Pd(dtbpf)Cl2 (0.694g, 1.064 mmol) The solution was added, and the mixture was then stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature and H2 Quenched with O (200 mL) and extracted with toluene (2 x 500 mL). Combined The cell layer was washed with brine (3 × 200 mL), dried with anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-flash under the following conditions: Column: Flash C 18 (330g);Mobile phase A: water (0.1%TFA), mobile phase B :ACN;(Gradient: Hold 5%B for 5 minutes, and increase to 60%B within 15 minutes, (Hold 60%B for 15 minutes, raise to 95%B within 10 minutes, and hold 95%B for 10 minutes.) Flow rate: 90 mL / min; Detector: UV 210 nm; RT = 55 min. The fraction containing the product was rotated. Collected and evaporated in a vacuum, (S)-2-((((9H-fluorene-9-yl)methoxymethyl (C)carbonyl)amino)-3-(6-(4-(tert-butoxycarbonyl)phen We obtained (pyridine-3-yl)propanoic acid. 34 H33 N2O6[M+H] + MS ESI calculated value: 565.23, measured value: 565.15; 1 1H NMR (400MHz, meta (Nol-d4)δ8.66(d,J=1.9Hz,1H), 8.12-8.07(m,3 H), 7.99-7.92(m, 3H), 7.77(d,J=7.5Hz,2H), 7. 59-7.56(m, 2H), 7.37-7.33(m, 2H), 7.30-7.22( m, 2H), 4.60-4.56(m, 1H), 4.29-4.27(m, 2H), 4. 14-4.10(m, 1H), 3.45-3.41(m, 1H), 3.14-3.10( m, 1H), 1.62(s, 9H).

[0156] Synthesis scheme 11 [ka]

[0157] Bip4CO2H [ka]

[0158] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4'-(tert-butoxycarbonyl)-[1,1'-biphenyl]-4-i Propanic acid Argon gas in THF (40 mL) (S)-2-((((9H-Fluorene-9- (6g) , 12.87 mmol), (4-(tert-butoxycarbonyl)phenyl)boronic acid (4.29g, 19.30 mmol) and K3PO4 (8.19g, 38.6 mmol) Pour the mixture of ) over the mixture for 10 minutes and let it bubble, then [1,1'-bis(di-tert -Butylphosphino)ferrocene]dichloropalladium(II) (0.839g, 1.2 87 mmol) was added. The resulting mixture was stirred at 50°C for 16 hours, and then EtO Dilute with Ac (300 mL), saturated NaHCO3 aqueous solution (3 × 80 mL), brine (2 The solution was washed with 40 mL of water, dried with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to 0-50% ¼ / P Elution was performed using a gradient of E. The product-containing fraction was recovered and rotated and evaporated in a vacuum. Residue The following conditions were met by re-purification using Combi-Flash: Column: C18 gel column (330g, 20-35μm); Mobile phase A: 0.5% aqueous TFA; Mobile phase B: MeC N; (Gradient: Hold at 0%B for 10 minutes, up to 62.3%B within 25 minutes, 62.3% Hold at B for 6.2 minutes, reduce to 95% B within 2 minutes, hold at 95% B for 10 minutes; Flow rate: 90 mL / min; Detector: UV 254 and 210nm; RT: 32.32 mins. Product-containing fraction The product is collected and concentrated under reduced pressure, and (S)-2-((((9H-fluorene-9-yl)methoxymethyl (C)carbonyl)amino)-3-(4'-(tert-butoxycarbonyl)-[1,1 '-biphenyl]-4-yl)propanoic acid was obtained. 35 H 34 NO6[M+1] + M S ESI calculated value: 564.23, measured value: 564.15. 1 1H NMR (300MHz, ME) Tanol-d4)δ 7.97-7.95 (m, 2H), 7.78-7.76 (m, 2H) , 7.61-7.53(m, 6H), 7.38-7.21(m, 2H), 4.51-4. 11(m, 4H), 3.32-3.25(m, 1H), 3.03-2.95(m, 1H) , 1.61 (s, 9H).

[0159] Synthesis scheme 12 [ka]

[0160] sbMeW4F [ka]

[0161] (2S,3S)-2-amino-3-(4-fluoro-1H-indole-3-yl) Tannic acid In a 1 L three-necked round-bottom flask, which has been purged with nitrogen and maintained in an inert atmosphere, 4-fluoro- 1H-Indole (10g, 1.00 equivalent), L-Threonine (10.6g, 1.20 equivalent) (Quantity), DMSO (100 mL) and potassium phosphate buffer (0.2 M, 300 mL, p H7.4) was added. The reaction mixture was heated to 65°C, and then PfTrpB-7E6(2. 5g, 25% by weight) and 3-hydroxy-2-methyl-5-([phosphonooxy]methyl (Lu)-4-pyridinecarboxaldehyde (0.078 g, 0.004 equivalents) was added. The resulting solution was stirred overnight at 65°C. Then, the mixture was cooled to room temperature and proceeded directly to the next step. It was used in contact with the device.

[0162] To the above reaction mixture, add THF (100 mL) and sodium carbonate (23.56 g, 3.0 Equivalents) (Quantity) and 2,5-dioxopyrrolidine-1-yl 9H-fluoren-9-ylmethyl A ionate (29.96 g, 1.20 equivalents) was added at 0°C. The resulting solution was left at room temperature. The mixture was stirred overnight. The pH was adjusted to 4 using 3M HCl, and the resulting solid precipitate was filtered off. The obtained solution was extracted with ethyl acetate (3 × 500 mL). The organic fraction was combined and brine was used. Washed with (1L), dried with anhydrous sodium sulfate, and concentrated under vacuum. The mixture was then treated with Me The samples were subjected to silica gel column chromatography using an OH / DCM ratio of 1:5. -MS:(ES,m / z):[M+1]:459. 1 1H NMR (300 MHz, DM) SO-d6)δ 12.60(s,1H),11.15(s,1H),7.87(d,J =7.6 Hz,2H),7.76-7.49(m,3H),7.47-7.34(m, 2H),7.34-7.16(m,4H),7.03(td,J=7.9,5.0 Hz ,1H),6.73(dd,J=11.8,7.7 Hz,1H),4.36(t,J= 8.5 Hz,1H),4.31-4.02(m,3H),3.51(q,J=7.4 Hz,1H),1.31(d,J=7.0 Hz,4H),0.78(s,1H). Synthesis scheme 13 [ka]

[0163] sbMeW4Cl [ka]

[0164] (2S,3S)-2-amino-3-(4-chloro-1H-indole-3-yl)pig Acid Purge the nitrogen and maintain an inert nitrogen atmosphere in a 1 L three-necked round-bottom flask, then add 4-chloromethyl chloride. Low-1H-indole (10g, 1.00 equivalent), L-threonine (14.09g, 1. (8 equivalents), DMSO (100 mL) and potassium phosphate buffer (0.2 M, 300 mL) Add (pH=7.4), heat the reaction mixture to 65°C, and then add PfTrpB-7E6 (7.5g, 25% by weight) and 3-hydroxy-2-methyl-5-([phosphonooxy ]methyl)-4-pyridinecarboxaldehyde (174 mg, 0.01 equivalents) was added. The resulting solution was stirred at 65°C for 36 hours. Then, the mixture was cooled to room temperature, and the next step was performed. I used it directly.

[0165] To the above reaction mixture, add THF (100 mL) and sodium carbonate (20.9 g, 3.0 equivalents). ) and 2,5-dioxopyrrolidine-1-yl 9H-fluoren-9-ylmethyl carboxy Bonate (31.0 g, 1.40 equivalents) was added at 0°C. The resulting solution was stirred overnight at room temperature. The mixture was stirred. The pH was adjusted to 4 using 3M HCl, and the resulting solid precipitate was filtered off. The extracted solution was removed with ethyl acetate (3 × 500 mL). The organic fractions were combined and brine (1 Washed with L), dried with anhydrous sodium sulfate, and concentrated under vacuum. HPLC-MS: ( ES,m / z):[M+1]:475.

[0166] Synthesis scheme 14 [ka]

[0167] sbMe1Nal [ka]

[0168] (2S,3S)-2-amino-3-(naphthalene-1-yl)butanoic acid Process 1: DMF (1.5L) medium (2S, 3R)-2-((((9H-Fluorene-9- (Iyl)methoxy)carbonyl)amino)-3-hydroxybutanoic acid (250g, 1.00 To the equivalent volume of the solution, benzyl bromide (250 g, 2.00 equivalents) was added dropwise at 20°C. Next, add cesium carbonate (477g, 2.00 equivalents) and stir the solution at 20°C for 3 hours. Mixed. Pour the reaction mixture into ice H2O (3L) and extract with HCl (500mL x 3). The organic phase was washed with 3% LiCl solution (500 mL x 2 times) and brine (500 mL). The product was purified, dried over sodium sulfate, and concentrated under vacuum at 40°C. The crude product was methyl tert - Polished with butyl ether:PE = 6:1. 1 1H NMR (400 MHz, CDCl) 3):δ 7.77(d,J=7.6 Hz,1H),7.40(d,J=8.0 Hz ,1H),7.31-7.36(m,10H),5.65-5.71 m,1H),5. 13-5.31(m,3H),4.39-4.43(m,3H),4.22-4.25( m, 1H), 1.25(d, J=6.4 Hz, 3H) Step 2: Under an inert nitrogen atmosphere, (2S,3R)-benzyl 2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydrox Sibutanoate (125 g, 1.00 equivalent) and DCE (750 mL) were added. Cool the solution to 0°C, then add NIS (195g, 3.00 equivalents) and PPh3 (228g) (3.00 equivalents) was added. The temperature was raised to 50°C and the reaction mixture was stirred for 3 hours. The substance was poured into ice H2O (500 mL) and extracted using DCM (500 mL x 2). Organic phase The residue was dried with sodium sulfate and concentrated under vacuum at 40°C. The residue was then subjected to silica gel column chromatography. Purified by tography (PE / alkyl = 1 / 0 to 0 / 1).1 H NMR ( 400 MHz, CDCl3):δ 7.78(d,J=7.6 Hz,2H),7.6 8(d,J=7.2 Hz,2H),7.33-7.43(m,9H),5.27-5. 68(m,1H),5.21-5.23(m,2H),4.39-4.52(m,3H) ,4.25-4.38(m,1H),1.91-1.95(m,3H). Step 3: Put 2-((((9H-fluoren-9-yl)methoxy into a three-necked round-bottom flask. Carbonyl)amino)-3-iodobutanoate, 1-iodonaphthalene (42.2g, 1.20 equivalents), TBAI (76.7g, 1.50 equivalents), Zn (19.0g, 2.10 An equivalent volume of () and DMA (750 mL) was added to the second three-necked round-bottom flask, and at 25°C, Cholineimidoamide 2HCl (42.2g, 1.20 equivalents), NiCl2 glyceride (7 0.61g (0.25 equivalents) and DMA (750mL) were added. Under argon, the second The contents of the flask were added to the first flask. The resulting mixture was then incubated at 25°C for 12 minutes. The mixture was stirred for a specified time. The reaction mixture was poured into ice H2O (3L) and extracted with butyl (1L x 2). The organic phase was dried with sodium sulfate and concentrated under vacuum at 40°C. The crude product was analyzed by reverse-phase HPLC. Purified by (MeCN:H2O). HPLC-MS:[M+23]:564. 1 H NMR(400MHz,CDCl3)δ:8.17-8.24(m,1H),8.1 5-8.17(m,1H),7.77-7.87(m,2H),7.76-7.77(m ,4H),7.30-7.41(m,10H),5.30-5.38(m,1H),4. 96-5.04(m,3H),4.85-4.87(m,1H),4.30-4.34( m,1H),4.18-4.26(m,4H),1.43-1.45(m,3H). Step 4: 143g of (2S)-benzyl 2-((((9H-fluorene-9-yl) Toxy(carbonyl)amino)-3-(naphthalene-1-yl)butanoate in SFC Therefore, separation was achieved. The organic phase was concentrated under vacuum at 35°C.

[0169] Peak 1: (2S,3R)-Benzyl 2-((((9H-Fluorene-9-Il)meth Xy(carbonyl)amino)-3-(naphthalene-1-yl)butanoate. 1 H NM R(400 MHz,DMSO-d6):δ 8.11-8.12(m,2H),8.1 0-8.11(m,1H),7.88-7.90(m,2H),7.54-7.88(m ,1H),7.44-7.53(m,2H),7.42-7.44(m,4H),7.3 3-7.42(m,3H),7.27-7.33(m,6H),7.08-7.09(m ,2H),4.91-4.94(m,1H),4.79-4.82(m,1H),4.5 8(t,J=8.0 Hz),4.17-4.25(m,4H),1.39(d,J=6 .8 Hz, 3H). Peak 2: (2S, 3S)-benzyl 2-((((9H-fluorene (Naphthalene-9-yl)methoxy)carbonyl)amino)-3-(naphthalene-1-yl)butano Um. 1 H NMR(400 MHz,DMSO-d6):δ 7.92-8.15( m,1H),7.86-7.92(m,1H),7.84-7.86(m,1H),7. 57-7.84(m,2H),7.56-7.57(m,1H),7.41-7.54( m,4H),7.30-7.38(m,4H),7.27-7.30(m,7H),5. 08-5.14(m,2H),4.65(t,J=8.0Hz),4.23-4.26 (m,1H),4.05-4.18(m,3H),1.30(d,J=6.8 Hz,3 H). Step 5: In a three-necked round-bottom flask, add (2S,3S)-benzyl2-((((9H-fluorescein). (Naphthalene-9-yl)methoxy)carbonyl)amino)-3-(naphthalene-1-yl)butano Eth (40.0g, 1.00 equivalent) and THF (200mL) were added. 10% humidity Add Pd / C (7.00g), purge the reaction mixture three times with H2, and then under H2 (15psi). The mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered through a CELITE pad and concentrated under vacuum at 35°C. It shrunk. The crude product was mixed with PE at 25°C for 1 hour. After filtration, the filtered cake was filtration into MeCN. The solution was dissolved in (100 mL) and concentrated under vacuum at 35°C to remove residual solvent. HPLC-MS :[M+23]:474. 1 1H NMR (400 MHz, DMSO-d6) δ 12. 78(s,1H),8.23(d,J=7.6Hz,1H),7.86-7.88(m ,1H),7.80-7.86(m,2H),7.61-7.80(m,2H),7.5 5-7.59(m,4H),7.481-7.55(m,1H),7.40-7.48( m,3H),7.27-7.29(m,2H),4.28-4.60(m,1H),4. 24-4.28(m,1H),4.17-4.24(m,2H),4.04-4.15( m, 1H), 1.36(d, J=6.8 Hz, 3H). Synthesis scheme 15 [ka]

[0170] TyrEtNAc [ka]

[0171] l-Tyrosine O-ethylacetamide or (S)-3-(4-(2-acetamide Toxy(phenyl)-2-aminopropanoic acid Step 1: Methyl(tert-butoxycarbonyl)-L-tyrofoam in DMF (150mL) Synate (10.0g, 33.9mmol), benzyl(2-bromoethyl)carbamate To (26.2g, 102 mmol) and TBAB (5.46g, 16.93 mmol) Potassium carbonate (14.04 g, 102 mmol) was added to the stirred solution at room temperature. The mixture was stirred at 50°C for 24 hours. The mixture was cooled to room temperature and quenched with water (250 mL). Extracted with ا(2 × 500 mL). The combined organic layer was brined (3 × 150 mL). Washed with L), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was removed. The solution was purified by silica gel column chromatography and then treated with 0-30% ammonium in PE. It leached out. C 25 H 32 N2O7[M+Na] + MS ESI calculated value 495.22, actual Measured value: 495.10; 1 H NMR(300 MHz,CDCl3)δ 7.38-7.3 2(m,5H),7.04(d,J=8.4 Hz,2H),6.81(d,J=8.4 Hz,2H),5.31(br,1H),5.21(s,2H),4.97(br,1 H),4.56-4.53(m,1H),4.03(t,J=5.0 Hz,2H),3 .72(s,3H),3.64-3.58(m,2H),3.06-3.01(m,2H ), 1.43(s,9H). Step 2: Methyl(S)-3-(4-(2-(((benzyl oxyl oxyphosphate) in THF (200 mL) (C)carbonyl)amino)ethoxy)phenyl)-2-((tert-butoxycarbony (L) Aminopropanoate (16.0g, 33.9mmol) and Acetic anhydride (6.3 In a 9 mL, 67.7 mmol) stirred solution, add Pd / C (3.60 g, 33.9 mmol, The dry (10% by weight) was added at room temperature under a nitrogen atmosphere. The mixture was degassed three times with hydrogen and then at 20°C. The mixture was stirred for 4 hours. DIPEA (17.74 mL, 102 mmol) was added to the mixture. The mixture was stirred at 20°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was silica gel. The sample was purified by column chromatography and eluted with 0-3% MeOH / DCM. C1 9H 28 N2O6[M+Na] + MS ESI calculated value: 403.19, measured value: 403.1 0; 1 H NMR(300 MHz,CDCl3)δ 7.05(d,J=8.4 Hz ,2H),6.85-6.80(m,2H),5.99(br,1H),5.32(br ,1H),4.99-4.97(m,1H),4.02(t,J=5.0 Hz,2H) ,3.72(s,3H),3.69-3.63(m,2H),3.10-2.89(m, 2H), 2.02(s,3H), 1.42(s,9H). Step 3: Methyl(S)-3-(4-(2-acetamide ethoxyethanol in THF (100mL) (1)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate(1 2.5g, 32.9 mmol) of lithium hydroxide (65.7 mL, 65.5 mL in water) is added to a stirred solution. 7 mmol, 1N was added at room temperature. The solution was stirred at 20°C for 2 hours. The pH of the solution was adjusted to 1 The solution was adjusted to 3 with N HCl. The aqueous layer was extracted with ethyl acetate (2 × 250 mL). Wash the organic layer with brine (150 mL), dry it with anhydrous sodium sulfate, filter it, and reduce the amount. It was concentrated under pressure.

[0172] MS ESI[M+H] + :367.10.

[0173] Step 4: (S)-3-(4-(2-acetamidoethoxy) phosphate in THF (20 mL) (Nyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (12.5g, 3 To a 0.7 mmol (0.7 mmol) stirred solution, add 4NHCl (200 mL) in dioxane at room temperature. The solution was stirred at 20°C for 1 hour. The solvent was concentrated under reduced pressure. MS ESI[M+H] + :267.05.

[0174] Step 5: In THF (100 mL) and water (100 mL), (S)-3-(4-(2-A Cetoamidoethoxy(phenyl)-2-aminopropane hydrochloride (9.50g, 25.1 A stirred mixture of mmol) and NaHCO3 (10.54 g, 126 mmol) is mixed with Fm oc-OSu (7.62 g, 22.59 mmol) was added at room temperature. This mixture was then diluted for 20 minutes. The mixture was stirred at °C for 1 hour. The pH of the solution was adjusted to 3 with 1N HCl. The aqueous phase was treated with ELISA. Extraction was performed using 2 x 500 mL solutions. The combined organic layers were washed with brine (150 mL) and then anhydrous water was used. The filtrate was dried with sodium bicarbonate and filtered. The filtrate was concentrated under reduced pressure, and the residue was dimethyl(2) Recrystallization was performed from 00 mL. The solid was recovered by filtration and dried under vacuum. MS E SI[M+H] + :489.05; 1 1H NMR (300MHz, methanol-d4)δ 7.79(d,J=7.6Hz,2H),7.62-7.57(m,2H),7.42- 7.26(m,4H),7.17-7.14(m,2H),6.83(d,J=8.4H z,2H),4.41-4.31(m,2H),4.29-4.10(m,2H),3. 96(t,J=4.8Hz,2H),3.51(t,J=5.4Hz,2H),3.19 -3.13(m,1H),2.92-2.84(m,1H),1.94(s,3H). Prot3Ph3F [ka]

[0175] (2S,3R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)- 3-(3-fluorophenyl)pyrrolidine-2-carboxylic acid Commercially available ((2S,3R)-3-(3-fluorophenyl) phosphate in acetone (16 mL) A solution of loridine-2-carboxylic acid (495 mg, 2.366 mmol) is mixed with water (8 mL). and sodium bicarbonate (2S,3R)-3-(3-fluorophenyl)pyrrolidine-2 - Add carboxylic acid (495 mg, 2.366 mmol) and stir the mixture for 10 minutes ( At a target pH of 9.5, Fmoc-OSu (878 mg, 2.60 mmol) was added, and the result was obtained. The mixture was stirred overnight at room temperature. The reactants were then treated with sodium bisulfate (1M, 75 mL) to remove acid. The phase was cured. The aqueous phase was washed with DCM, the organic phase was dried with anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. After concentrating the crude material under reduced pressure, RediSep Rf silica 8 was added. Purification was performed by column chromatography using a 0g pre-packaged column for 33 minutes. The compound was eluted with a 0-10% MeOH / DCM gradient over a certain period to obtain the title compound. HP LC-MS:[M+H] + :432.2; 1 1H NMR (500 MHz, CDCl3) δ 7.80(d,J=7.5 Hz,2H),7.62(t,J=7.1 Hz,2H ),7.44(t,J=7.4 Hz,2H),7.40-7.25(m,3H),7. 05-6.89(m,3H),4.60-4.46(m,2H),4.35-4.25( m,1H),3.79-3.50(m,3H),2.48-2.30(m,1H),2. 10⁻¹.96 (m, 1H). Prot4Bn3F4F [ka]

[0176] (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)- 4-(3,4-difluorobenzyl)pyrrolidine-2-carboxylic acid Commercially available (2S,4R)-4-(3,4-difluorobenzyl) in acetone (16 mL) )A solution of pyrrolidine-2-carboxylic acid (1000 mg, 4.15 mmol) is mixed with water (8 ml). Add L) and sodium bicarbonate (1741 mg, 20.73 mmol) and the mixture Stir for 10 minutes (target pH 9.5), then add Fmoc-OSu (1538 mg, 4.56 mmol). l) was added, and the resulting mixture was stirred overnight at room temperature. The reaction product was sodium bisulfate (1 The aqueous phase was acidified with M (38 ml). The aqueous phase was washed with DCM, and the organic phase was dried with anhydrous sodium sulfate. The material was dried and filtered. The filtrate was concentrated under reduced pressure. The crude material was treated with RediSep Rf silica 4. Using a 0g pre-packaged column, a 0-10% gradient of MeOH in DCM was used for 22 Purified by column chromatography with elution over several minutes, and concentrated under reduced pressure. The title compound was obtained. HPLC-MS: [M+H] + :464.4; 1 1H NMR (500 MHz, CDCl3)δ 7.76(d,J=7.1 Hz,2H),7.56(d, J=6.8 Hz,2H),7.45-7.30(m,4H),7.17-7.05(m ,1H),7.00-6.93(m,1H),6.89-6.82(m,1H),4.5 7-4.38(m,3H),4.33-4.23(m,1H),3.54-3.47(m ,1H),3.03(t,J=9.3Hz,1H),2.75-2.50(m,2H) ,2.38-2.32(m,1H),2.0-1.80(m,2H). Synthesis scheme 16 [ka]

[0177] BCP3Ph4CO2H [ka]

[0178] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(3-(4-(tert-butoxycarbonyl)phenyl)bicyclo[1.1.1 ]Pentan-1-yl)propanoic acid Step 1: 3-(methoxycarbonyl)bicyclo[1.1.1]pe in DCM (65 mL) tane-1-carboxylic acid (5g, 29.4mmol), 2-hydroxyisoindoline- 1,3-dione (5.27g, 32.3mmol) and DMAP (0.359g, 2. Add EDCI (6.20 g, 32.3 mmol) to a stirred solution of 94 mmol at room temperature. The mixture was stirred at 25°C for 16 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 0-30% E was obtained in PE. Elutes with A, and 1-(1,3-dioxoisoindorin-2-yl)3-methylbicyclo[ 1.1.1] Pentane-1,3-dicarboxylate was obtained. 1 1H NMR (400 M) Hz, CDCl3)δ 7.96-7.83(m,2H),7.86-7.75(m,2 H), 3.73 (s, 3H), 2.56 (s, 6H). Step 2: NiBr2.3H2O (1.549g, 5.68mm) in DMA (180mL) In a stirred solution of 0.40 ol, under a nitrogen atmosphere at room temperature, dtbbty (1.906 g, 7.10 mm) was added. (ol) was added. The resulting mixture was stirred at 50°C for 30 minutes. The mixture was cooled to room temperature. tert-butyl-4-iodobenzoate (7.2g, 23.67mmol), 1- (1,3-Dioxoisoindolin-2-yl)3-methylbicyclo[1.1.1]pentene Tan-1,3-dicarboxylate (7.46g, 23.67mmol), TMS-Cl (0.303 mL, 2.367 mmol) and zinc (7.74 g, 118 mmol) The mixture was added at room temperature. The resulting mixture was stirred at 25°C for 2 hours. The reaction product was brined. Quenched with (400 mL) and extracted with EA (3 x 800 mL). The combined organic layer was then bled. The lines were washed (3 x 300 mL) and dried with anhydrous sodium 2SO4. After filtration, the filtrate was reduced. The solution was concentrated under pressure, and the residue was purified by silica gel column chromatography. It elutes with 40% EA and methyl 3-(4-(tert-butoxycarbonyl)phenyl) Cyclo[1.1.1]pentane-1-carboxylate was obtained. 1 1H NMR (300 MHz, CDCl3)δ 7.98-7.88(m,2H),7.29-7.19(m, 2H),3.72(s,3H),2.34(s,6H),1.59(s,9H). Step 3: Methyl 3-(4-(tert-butoxycarbonyl)phenyl)bicyclo[1 .1.1]TH containing pentane-1-carboxylate (2.7g, 8.93 mmol) In a solution of F (17.86 mL), add LiOH (17.86 mL in water, 17.86 mmol, 1N HCl was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The solution was then dissolved in 1M HCl. The solution was acidified with (15 mL). The solution was extracted with EA (3 × 150 mL). The combined organic layers were then extracted. Washed with brine (3 x 150 mL), dried with anhydrous Na2SO4, and filtered. filtrate Concentrate under reduced pressure to obtain 3-(4-(tert-butoxycarbonyl)phenyl)bicyclo [1.1.1] Pentane-1-carboxylic acid (2.55 g, crude) was obtained. C 17 H 19 O 4 [MH] - The MS ESI calculated value was 287.14, and the measured value was 287.05.

[0179] Step 4: Benzyl(S)-2-(tert-butyl)-4-methyl in DMF (20 mL) Len-5-oxoxazolidine-3-carboxylate (602 mg, 2.081 mg) In the stirred solution of ol), add 3-(4-(tert-butoxycarbonyl)phenyl)bicyclo [1.1.1] Pentane-1-carboxylic acid (600 mg, 2.081 mmol), 4Cz IPN (32.8 mg, 0.042 mmol) and K2HPO4 (906 mg, 5.2 (0 mmol) was added. The reaction solution was irradiated with a 34W blue LED lamp and subjected to argon at room temperature. The mixture was stirred for 48 hours. The reaction was quenched with water (100 mL) and then mixed with EA (3 x 150 mL). Extracted. The combined organic layers were washed with brine (3 x 150 mL) and then with anhydrous sodium 2SO4. The sample was dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. - Purified by - and eluted with a gradient of 0-25% EA in PE, benzyl (2S,4 S)-4-((3(4-(tert-butoxycarbonyl)phenyl)bicyclo[1. 1.1]Pentan-1-yl(methyl)-2-(tert-butyl)-5-oxooxa Zolidine-3-carboxylate was obtained. 32 H 40 NO6[M-tBu+H] + M S ESI calculated value: 478.28, measured value: 478.15. 1 1H NMR (400 MHz, CDCl3)δ 7.94-7.84(m,2H),7.41-7.35(m,5H), 7.18(d,J=8.0Hz,2H),5.56(s,1H),5.24-5.12 (m,2H),4.34-4.31(m,1H),2.23-2.17(m,1H),2 .09-2.01(m,1H),1.99-1.83(m,6H),1.59(s,9H ), 0.97(s,9H). Step 5: Benzyl(2S,4S)-4-((3-(4-(ter) t-Butoxycarbonyl)phenyl)bicyclo[1.1.1]pentan-1-yl)methyl (Lu)-2-(tert-butyl)-5-oxoxazolidine-3-carboxylate In a solution of 1.6g, 3.00 mmol, add LiOH (7.50 mL, 7.50 mmol in water). (1, 1N) was added at 0°C. The solution was stirred at room temperature for 4 hours. The solution was cooled to 0°C and 1M was added. The pH was adjusted to 3-4 using HCl (7.5 mL). The resulting solution was then mixed with water (50 mL). Diluted with L) and extracted with EA (3 × 100 mL). The organic layer was then diluted with brine (3 × 100 mL). Washed with (), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and (S)- 2-(((benzyloxy)carbonyl)amino)-3-(3-(4-(tert-but Xycarbonyl(phenyl)bicyclo[1.1.1]pentan-1-yl)propanoic acid Obtained. C 27 H 31 NO6Na[M+Na] + MS ESI calculated value: 488.20, measured value The value is 488.10. 1 H NMR(400 MHz,CD3OD)δ 7.88-7.83 (m,2H),7.41-7.35(m,2H),7.35-7.25(m,3H),7 .24-7.19(m,2H),5.19-5.04(m,2H),4.24-4.20 (m,1H),2.13-2.01(m,1H),2.03-1.87(m,7H),1 .58 (s, 9H). Step 6: (S)-2-(((benzyloxy)carbonyl)amide in THF (40mL) (no)-3-(3-(4-(tert-butoxycarbonyl)phenyl)bicyclo[1.1 .1] In a solution of pentan-1-yl)propanoic acid (1.65 g, 3.54 mmol), P dC (0.377 g, 0.354 mmol, dry, 10% by weight) was stored under a nitrogen atmosphere at room temperature. It was added. The resulting mixture was degassed three times with hydrogen and stirred at room temperature for 2 hours. The resulting product ((S)-2-amino-3-(3-(4-(tert-butoxycarbonyl)phenyl Bicyclo[1.1.1]pentan-1-yl)propanoic acid (1.17g) is further refined. It was used in the next process without being processed. C 19 H 26 NO4 [M+H] + MS ESI meter Calculated value: 332.17, measured value: 332.15.

[0180] Step 7: In THF (40 mL) and water (40 mL) (S)-2-amino-3-(3- (4-(tert-butoxycarbonyl)phenyl)bicyclo[1.1.1]pentane- In the reaction mixture of 1-yl)propanoic acid (1.17 g, 3.53 mmol), NaHCO3 (1.483g, 17.65 mmol) and Fmoc-OSu (1.191g, 3.5 3 mmol was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture The solution was filtered. The filtered cake was washed with THF (2 × 100 mL). The solvent was concentrated under reduced pressure. The pH of the solution was adjusted to 4 with 1N HCl (17.6 mL), and EA (3 × 100 mL) was added. Extraction was performed using ). The combined organic layers were washed with brine (3 x 100 mL) and anhydrous sodium 2SO4. The solution was dried in step 4 and filtered. The resulting solution was then subjected to RP-flash chromatography. Purify and elute with 2-70% acetonitrile (0.05% TFA) in water, then (S)-2-( (((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(4 -(tert-butoxycarbonyl)phenyl)bicyclo[1.1.1]pentane-1- (Il)propanoic acid was obtained. 34 H 34 NO6[MH] - MS ESI 552.25 Calculated value, measured value: 552.40. 1 1H NMR (300 MHz, CD3OD) δ 7.9 0-7.76(m,2H),7.73-7.65(m,4H),7.40-7.24(m ,6H),4.52-4.37(m,2H),4.25-4.18(m,2H),2.1 4-2.03(m,1H),1.99-1.86(m,7H),1.60-1.54(m ,9H). Synthesis scheme 17 [ka]

[0181] Bip4CONH2 [ka]

[0182] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)propanoic acid (S)-2-((((9H-fluoren-9-yl)methoxy in THF (246 mL) Carbonyl amino acid-3-(4-iodophenyl)propanoic acid (15g, 29.2mg) In a stirred solution of (mol), add PdCl2(dtbpf)(2.86g, 4.38 mmol) Tribasic potassium phosphate (88 mL in water, 88 mmol, 1N) was added at room temperature. The solution was stirred at 50°C for 2 hours. The resulting solution was cooled to room temperature. The pH was adjusted using 1H HCl. Adjust to 3 and extract with EA (3 x 250 mL). Combine the organic layer and brine (4 x 20 Wash with 0 mL, dry with anhydrous Na2SO4, and filter. The filtrate was concentrated under reduced pressure, and the remaining The residue was recrystallized from EtOH (100 mL) and (S)-2-((((9H-fluorene-9 -yl)methoxy)carbonyl)amino)-3-(4'-carbamoyl-[1,1'-bi) Phenyl-4-yl)propanoic acid was obtained. 31 H 27 N2O5[M+H] + MS ESI calculated value: 507.18, measured value: 507.45. 1 1H NMR (400 MHz, DM) SO-d6)δ 12.87(s,1H),8.02(s,1H),8.07-7.96 (m,2H),7.94-7.82(m,2H),7.78-7.60(m,7H),7 .39-7.29(m,5H),7.29-7.19(m,2H),4.20-4.13 (m,4H),3.17-3.13(m,1H),2.93-2.90(m,1H). Synthesis scheme 18 [ka]

[0183] dProt4NMe3 [ka]

[0184] (3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)- 5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium chloride Step 1: 1-(tert-butyl)2-methyl(2R,4S) in MeOH (30 mL) )-4-aminopyrrolidine-1,2-dicarboxylate (3g, 12.28 mmol) To the mixture, add NaHCO3 (8.25 g, 98 mmol) and CH3I (4.61 mL) (73.7 mmol) was added at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 hours. The solution was filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was dissolved in DCM. Dissolve, filter, concentrate the filter in a vacuum, and (3S,5R)-1-(tert-butoxy (Cicarbonyl)-5-(methoxycarbonyl)-N,N,N-trimethylpyrrolidine-3 -Amium iodide was obtained. C 14 H 27 N2O4[MI] + MS ESI calculation value 287.20, measured value 287.15.

[0185] Step 2: (3S, 5R)-1-(tert-butoxycarbonyl) in THF (23mL) )-5-(methoxycarbonyl)-N,N,N-trimethylpyrrolidine-3-aminium A mixture of iodide (6.5g, 10.98mmol) and LiOH (21.97mL, 2 1.97 mmol (1 M in water) was added at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours. The obtained solution was acidified to pH 5 with 1M HCl, concentrated in vacuum, and then (3S,5 R)-1-(tert-butoxycarbonyl)-5-carboxy-N,N,N-trimethicone Lupyrolidine-3-aminium chloride was obtained. 13 H 25 N2O4[M-Cl] + of MS ESI calculated value: 273.18, measured value: 273.15.

[0186] Step 3: (3S,5R)-1-(tert-butoxycarbonyl) in DCM (20mL) )-5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium chloride (6 Mixture of 0.6g, 10.69 mmol) with TFA (20 mL, 260 mmol) around the edges. The reaction was added at a specific temperature. The reaction mixture was stirred at ambient temperature for 2 hours. The resulting solution was concentrated in a vacuum. , 2,2,2-trifluoroacetic acid, (3S,5R)-1-(tert-butoxycarbonate We obtained the salt (Lu)-5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium. C8H 17 N2O2[M-CF3COO] + MS ESI calculated value: 173.13, measured value 173.25.

[0187] Step 4: 2,2,2-trifluoroacetic acid, (3S,5R)-5-carboxy-N,N, Contains N-trimethylpyrrolidine-3-aminium salt (8.1g, 14.10 mmol) A mixture of THF (40 mL) and water (40 mL) contains NaHCO3 (5.92 g, 70 (0.5 mmol) and Fmoc-OSu (4.28 g, 12.69 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The resulting solution was acidified to pH 5 with dilute HCl. The solution was concentrated in a vacuum. The residue was suspended in DCM (containing 10% MeOH) and filtered. The filtrate was then removed. The solution was concentrated in a vacuum. The residue was purified by RP flushing under the following conditions: Column: Fl ash C 18 (330g); Mobile phase A: water (2mmol HCl), mobile phase B: ACN ;(Gradient: Hold at 2%B for 5 minutes, raise to 35%B within 15 minutes, 35%B Hold at 8 minutes, raise to 98%B within 5 minutes, and hold at 99%B for 5 minutes); flow velocity: 80m L / min; Detector: UV 210nm; RT=38 min. The product-containing fraction was collected and vacuumed. Concentrated inside, (3S,5R)-1-(((9H-fluorene-9-yl)methoxy) Rubonyl)-5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium chloride I got Lido. C 23 H 27 N2O4[M-Cl] + The MS ESI calculation value is 395.20. Actual measured value: 395.20. 1 H NMR(300 MHz,DMSO-d6)δ 13.30 (s,1H),7.94-7.89(m,2H),7.72-7.64(m,2H),7 .46-7.33(m,4H),4.57-4.14(m,5H),3.86-3.78 (m,2H),3.12-3.10(m,9H),2.83-2.73(m,1H),2 0.50-2.35 (m, 1H). Synthesis scheme 19 [ka]

[0188] F4SO2NH2 [ka]

[0189] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-sulfamoylphenyl)propanoic acid Step 1: Acetyl-L-phenylated chlorosulfonic acid (5.34 g, 45.8 mmol) A mixture of nyalanin (1 g, 4.83 mmol) was stirred at -10°C for 3 hours. The resulting solution was stirred at 25°C for 2 hours. The reaction mixture was added drop by drop to ice, and stirring continued. The mixture was then diluted with EA (500 mL) and washed with brine (3 × 250 mL). The solution was purified, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain the crude product. The substance was dissolved in NH4OH (15 mL, 28 wt%) and stirred at 100°C for 3 hours. The solution was concentrated under reduced pressure, and the pH was adjusted to 3 with 1N HCl. The solid was recovered by filtration and frozen. Dry and (S)-2-acetamido-3-(4-sulfamoylphenyl)propane Acid was obtained. C 11 H 15 N2O5S[M+H] + MS ESI calculated value 287.06, actual Measured value: 287.05. 1 H NMR(300 MHz,DMSO-d6)δ 8.32-8 .30(m,1H),7.75-7.70(m,2H),7.43-7.41(m,2H ),7.28(s,2H),4.49-4.31(m,1H),3.13-3.11(m ,1H),2.92-2.91(m,1H),1.78(s,3H). Step 2: (S)-2-acetamido-3-(4-sulfamoylphenyl)propanoic acid Suspend (5.1g, 17.81 mmol) in water (50mL) and adjust the pH of the mixture using LiO2. Adjusted to 5 with H(1M), and then adjusted to 7.5 with 0.25M buffer. Porcine kidney acylase ( 510 mg (17.81 mmol) was added to the mixture at 25°C. Then the resulting mixture The mixture was stirred at 25°C for 20 hours. The reaction product was not further purified and was (S)-2-amino-3 A solution of -(4-sulfamoylphenyl)propanoic acid was used directly in the following reaction: C9H 13 N2O4S[M+H] + The MS ESI calculated value is 245.05, and the measured value is 245.10.

[0190] Step 3: (S)-2-amino-3-(4-sulfamoylphenyl)propanoic acid (2. (3g, 9.42 mmol, dissolved in 50mL of water) Add THF (50mL), NaH CO3 (3.95g, 47.1 mmol) and Fmoc-OSu (3.18g, 9.4 2 mmol) was added at room temperature. The resulting mixture was stirred at 25°C for 16 hours. The pH was adjusted to 1. The reaction mixture was adjusted to 3 with N HCl. The reaction mixture was extracted with EA (3 × 120 mL). The organic layer was then separated. Washed with brine (120 mL) and dried over anhydrous sodium 2SO4. The solvent was concentrated under reduced pressure. The residue was then purified by RP-flush under the following conditions, and 330g of C was obtained. 18 Using a column 2% to 2% in 5 minutes, 2% to 30% in 30 minutes, ACN in water (0.05% NH4HCO3) Using (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) Amino-3-(4-sulfamoylphenyl)propanoic acid was obtained. 24 H 26 N3O 6S[M+NH4] + The MS ESI calculated value is 484.12, and the measured value is 484.10. 1 H NMR(300 MHz,CD3OD)δ 7.82-7.73(m,4H),7.68 -7.56(m,2H),7.38-7.35(m,4H),7.34-7.23(m, 2H),4.40-4.12(m,4H),3.31-3.30(m,1H),3.01 -2.98 (m, 1H). Synthesis scheme 20 [ka]

[0191] K3CH3NPEG4 [ka]

[0192] (S)-5-carboxy-1-(9H-fluoren-9-yl)-N,N,N-trimethicone Chil-3,11-dioxo-2,14,17,20,23-pentaoxa-4,10-di Azapentacosan-25-aminium-2,2,2-trifluoroacetate Step 1: In MeCN (100 mL), tert-butyl 1-bromo-3,6,9,12- To a stirred solution of tetraoxapentadecane-15-oate (19 g, 49.3 mmol) , NaHCO3 (12.43g, 148mmol) and dimethylamine hydrochloride (6.0 3 g (74.0 mmol) was added at ambient temperature. The reaction mixture was then incubated at 80°C for 3 hours. The mixture was stirred. The reaction progress was monitored by LC-MS and TLC. LC-MS showed that the main component was the desired one. This demonstrated that the product was present and no SM remained. The reaction mixture was then filtered, and the filtrate was obtained. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the result was 0- Elution was performed with a 15% MeOH / DCM gradient. The fractions containing the desired product were combined. Concentrate under reduced pressure to obtain tert-butyl2-methyl-5,8,11,14-tetraoxyx C obtained 2-azaheptadecan-17-oet. 17 H 36 NO6[M+H] + of MS ESI calculated value: 350.25, measured value: 350.35. 1 H-NMR (400MHz, Chloroform-d)δ3.91-3.88(m,2H), 3.73-3.69(m,2H) ), 3.67-3.66(m, 4H), 3.65-3.64(m, 4H), 3.63-3 .61(m, 4H), 3.11-3.08(m, 2H), 2.74(s, 6H), 2.5 2-2.49(m, 2H), 1.45(s, 9H).

[0193] Step 2: In DCM (100 mL), tert-butyl 2-methyl-5,8,11,14- Tetraoxa-2-azaheptadecane-17-oate (16.5g, 47.2 mmol) Add 2,2,2-trifluoroacetic acid (30 mL, 47.2 mmol) to the stirred solution of ) around The reaction solution was added at a specific temperature. The reaction solution was then stirred at ambient temperature for 2 hours. The progress of the reaction was observed using LC-MS. The reaction was monitored by TLC. LC-MS confirmed that the main component was the desired product. The solvent was concentrated under reduced pressure, and the residue was used directly in the next step. 13 H 28 NO6 [M+ H] + The MS ESI calculated value was 294.19, while the measured value was 294.35.

[0194] Step 3: 2-methyl-5,8,11,14-tetraoxa-2- in DMF (80 mL) In a stirred solution of azaheptadecane-17-acid (13.77g, 46.9 mmol), N-E Tyl-N-isopropylpropan-2-amine (12.13 g, 94 mmol) under a nitrogen atmosphere The substance was added under ambient air conditions at -40°C. The solution was stirred at -40°C for 2 minutes. HATU (21.42g) , 56.3 mmol) and tert-butyl(((9H-fluorene-9-yl)meth Add xy(carbonyl)-L-ricinate (17.93g, 42.2 mmol) to the solution. The mixture was stirred at -40°C for 3 hours. The reaction mixture was quenched with saturated NH4Cl (100 mL). Extraction was performed with ethyl acetate (2 x 300 mL). The combined organic layer was then treated with brine (3 x 80 mL). Washed, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was RP. Purified by flash under the following conditions: column, C18 330g, mobile phase: ACN Water (0.5% TFA), 5% to 5% in 5 minutes, 5% to 95% in 35 minutes, detector, UV 2 54 and 210 nm. RT: 26 minutes. The collected fractions were combined and concentrated under reduced pressure, then ter t-Butyl(S)-23-(((((9H-Fluorene-9-yl)methoxy)carbon (L)amino)-2-methyl-17-oxo-5,8,11,14-tetraoxa-2,1 8-Diazatetetracosan-24-Oate was obtained. 38 H 59 N3O9[M+H] + of MS ESI calculated value: 700.42, measured value: 700.40. 1 H-NMR (300 MHz, Methanol-d4)δ 7.84-7.81 (m, 2H), 7.72-7.68 (m, 2H) ), 7.44-7.39(m, 2H), 7.36-7.31(m, 2H), 4.46-4 .32(m, 2H), 4.27-4.00(m, 2H), 3.81-3.60(m, 16 H), 3.32-3.28(m, 2H), 3.22-3.18(m, 2H), 2.91( s, 6H), 2.43 (t, J=6.3Hz, 2H), 1.83-1.78 (m, 1H) , 1.71-1.66(m, 1H), 1.57-1.52(m, 2H), 1.47(s, 9H).

[0195] Step 4: In MeCN (80 mL), tert-butyl(S)-23-((((9H-full Oren-9-yl)methoxy)carbonyl)amino)-2-methyl-17-oxo-5, 8,11,14-tetraoxa-2,18-diazatetracosan-24-oate(13 In a stirred solution of (g, 18.57 mmol), add NaHCO3 (3.12 g, 37.1 mmol) ) and iodomethane (21.09 g, 149 mmol) were added at ambient temperature. The reaction solution was stirred at 70°C. The progress of the reaction was monitored by LC-MS and TLC. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was used directly in the next step. C 39 H 60 N3O9[M] + The MS ESI calculated value was 714.43, and the measured value was 714.41.

[0196] Step 5: In DCM (50 mL), (S)-5-(tert-butoxycarbonyl)-1- (9H-fluoren-9-yl)-N,N,N-trimethyl-3,11-dioxo-2, 14,17,20,23-pentaoxa-4,10-diazapentacosan-25-amini In a stirred solution of umiodide (12 g, 14.25 mmol), 2,2,2-trifluoro Acetic acid (30 mL, 14.25 mmol) was added at ambient temperature. Then, the reaction solution was heated to ambient temperature. The mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by LC-MS. The reaction solution was concentrated under reduced pressure. The residue was reduced and purified by RP flush under the following conditions: column, C18 330g Mobile phase: ACN / water (0.5% TFA), 5% to 5% in 5 minutes, 5% to 95% in 25 minutes. Hold at 21% for 8.2 minutes, detector, UV 254nm. RT: 35 minutes. Combined the collected fractions. Concentrate under reduced pressure, then (S)-5-carboxy-1-(9H-fluoren-9-yl)-N N,N-trimethyl-3,11-dioxo-2,14,17,20,23-pentaox SA-4,10-diazapentacosan-25-aminium-2,2,2-trifluoroaceta I obtained a code. 35 H 52 N3O9[M] + MS ESI calculated value: 658.37, measured value 658.30. 1 ¹H NMR (300 MHz, methanol-d4) δ 7.82-7.79 (m, 2H), 7.70-7.66(m, 2H), 7.42-7.29(m, 4H), 4 .39-4.35(m, 2H), 4.26-4.23(m, 2H), 3.93-3.88 (m, 2H), 3.72-3.52(m, 16H), 3.20-3.17(m, 11H) , 2.43(t,J=6.3Hz,2H), 1.89-1.87(m, 1H), 1.79 -1.71(m, 1H), 1.54-1.42(m, 4H).

[0197] Synthesis scheme 21 [ka]

[0198] Orn Me3 [ka]

[0199] (S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -4-carboxy-N,N,N-trimethylbutane-1-aminium-2,2,2-triph Luoroasetato Step 1: (S)-5-amino-2-((tert-butoxy) in MeOH (50 mL) A mixture of carbonyl(amino)pentanoic acid (4.6g, 19.80 mmol) and MeI (33.7g, 238 mmol) and KHCO3 (1.983g, 19.80 mmol) The mixture was added at ambient temperature. The resulting mixture was heated to 50°C and stirred for 12 hours. Reactants The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was dissolved in DCM (80 mL). Next, it was filtered again. The filtrate was concentrated under vacuum to obtain (S)-4-((tert-butoxy Cicarbonyl)amino)-5-methoxy-N,N,N-trimethyl-5-oxopentane -1-Amium iodide was obtained. 14 H 29 N2O4[MI] + MS ESI meter Calculated value: 289.21, measured value: 289.35.

[0200] Step 2: In MeOH (48 mL) and THF (24 mL), (S)-4-((tert -Butoxycarbonyl)amino)-5-methoxy-N,N,N-trimethyl-5-oxo A mixture of pentane-1-aminium iodide (7.4 g, 16.00 mmol) contains Li OH (48.0 mL, 48.0 mmol, 1 M water) was added at ambient temperature. The mixture was stirred at ambient temperature for 2 hours, then concentrated in a vacuum. Next, 48 mL of 1N HCl was added. It was added. The solvent was concentrated in a vacuum and (S)-4-((tert-butoxycarbonyl) Amino)-4-carboxy-N,N,N-trimethylbutane-1-aminium chloride Obtained. C 13 H 27 N2O4[M-Cl] + MS ESI calculated value: 275.20, measured value 275.20.

[0201] Step 3: (S)-4-((tert-butoxycarbonyl)amine in DCM (50mL) (7)-4-carboxy-N,N,N-trimethylbutane-1-aminium chloride (7. To a mixture of 5g (14.48 mmol), add TFA (25 mL, 324 mmol) at ambient temperature. It was added at [temperature] degrees. The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuum to obtain (S)- 4-amino-4-carboxy-N,N,N-trimethylbutane-1-aminium-2,2, 2-trifluoroacetate was obtained. C8H 19 N2O2[M-CF3COO] + MS ESI calculated value: 175.14, measured value: 175.20.

[0202] Step 4: (S)-4-amino-4-carb in THF (30 mL) and water (30 mL) Xy-N,N,N-trimethylbutane-1-aminium-2,2,2-trifluoroacetate A mixture of phosphate (10g, 13.88 mmol) and NaHCO3 (9.33g, 111m) Add (mol) and Fmoc-OSu (4.21 g, 12.49 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. The resulting solution was diluted to pH 3-4 with an aqueous HCl solution. The solution was acidified and then filtered. The filtrate was purified by RP-Flash under the following conditions: Ram: FlashC 18 (330g);Mobile phase A: water (0.05%TFA), mobile phase B: ACN; Gradient: Hold at 0%B for 5 minutes, rise to 33%B within 18 minutes, at 33%B Hold for 7 minutes; rise to 95%B within 5 minutes, hold at 95%B for 5 minutes; flow rate: 90 mL / min Detector: UV210nm; RT=40 min. The product-containing fraction was collected and freeze-dried. (S)-4-(((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -4-carboxy-N,N,N-trimethylbutane-1-aminium-2,2,2-triph Luoroacetate was obtained. 23 H 29 N2O4[M-CF3COO] + MS ESI Calculated value: 397.21, measured value: 397.15. 1 1H NMR (400 MHz, DMSO- d6)δ 12.85(br,1H),7.92-7.89(m,2H),7.74-7 .63(m,3H),7.44-7.40(m,2H),7.33-7.31(m,2H ),4.38-4.22(m,3H),4.02-3.98(m,1H),3.34-3 .20(m,2H),3.09(s,9H),1.79-1.51(m,4H). 19 F -NMR (376 MHz, DMSO-d6) - 73.64. Synthesis scheme 22 [ka]

[0203] Phe4pcCCA [ka]

[0204] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-((1s,4R)-4-(tert-butoxycarbonyl)cyclohexyl )phenyl)propanoic acid Step 1: In THF (30 mL), tert-butyl 4-(4,4,5,5-tetramethyl (-1,3,2-dioxaborolan-2-yl)cyclohexa-3-ene-1-carboxy A mixture of methyl(S)-2-((tert-))((tert-)))((tert-)))((tert-)))((tert-))) Toxycarbonyl(amino)-3-(4-iodophenyl)propanoate (15.5g) (38.2 mmol) and Pd(Ph3P)4 (2.210 g, 1.912 mmol) The mixture was added at room temperature. The reaction mixture was heated to 60°C for 4 hours. The resulting solution was mixed with water (100 mL). Quenched and extracted with ethyl acetate (3 x 300 mL). Combined the organic layers and brine ( Washed in 2 x 200 mL containers, dried with anhydrous sodium sulfate, and filtered. The filtrate was then subjected to vacuum. The product was concentrated to obtain the crude product. The residue was divided into ethyl acetate:petroleum ether-0:1 to 1:4 granules. Purified by silica gel chromatography with dient elution, tert-butyl 4 '-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3- Oxopropyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-ca A ruboxylate was obtained. 26 H 38 NO6Na[M+Na] + MS ESI calculated value, 482.26, measured value 482.10.

[0205] Step 2: tert-butyl 4'-((S)-2-((te rt-butoxycarbonyl(mino)-3-methoxy-3-oxopropyl)-2,3,4 ,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate (16g, 34 A mixture of 0.8 mmol) contains Pd-C (10% on carbon, approximately 55% water, 5.3 g, 4.98 mmol) was added at room temperature. The mixture was degassed three times with H2 and under an H2 (1.5 atm) atmosphere. The mixture was stirred under air pressure at room temperature for 1 hour. The resulting mixture was filtered. The filtrate was concentrated under vacuum and t ert-butyl(S)-4-(4-(2-((tert-butoxycarbonyl)amino) -3-methoxy-3-oxopropyl)phenyl)cyclohexane-1-carboxylate I got it. 26 H 41 NO6[M+H] + MS ESI calculated value: 462.28, measured value 462.30.

[0206] Step 3: tert-Butyl(S)-4-(4-(2-((te rt-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl) In a stirred solution of cyclohexane-1-carboxylate (15 g, 32.5 mmol), L IOH (65.0 mL, 65.0 mmol) was added at room temperature. The solution was stirred at 20°C for 1 hour. Mixed. The pH of the solution was adjusted to 3 with 1N HCl. The reactants were concentrated under reduced pressure, (S )-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(tert- Butoxycarbonyl(cyclohexyl)phenyl(propanoic acid) was obtained. 25 H 38 NO 6Na[M+Na] + The MS ESI calculated value was 470.26, and the measured value was 470.30.

[0207] Step 4: (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4 -(tert-butoxycarbonyl)cyclohexyl)phenyl)propanoic acid (14g, 31.3 mmol) was separated by Prep-SFC using the following conditions, column: CHI RAL ART Cellulose-SB, 3 x 25 cm, 5 μm; Mobile phase A: CO2 , Mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 80 mL / min; Radiant: 10%B; Detection: 220nm; RT1: 7.45; RT2: 8.38; Injection Under the conditions of volume: 1.3 mL; run count: 131, (S)-2-((tert-butoxycal Bonyl)amino)-3-(4-((1s,4R)-4-(tert-butoxycarbonyl Cyclohexyl phenyl propanoic acid (high-speed elution peak) was obtained. 25 H 38 NO 6Na[M+Na] + MS ESI calculated value: 470.26, measured value: 470.30. 1H NMR (300 MHz, chloroform-d) δ 7.11 (d, J = 3.0 Hz, 4H), 4.27(s,1H), 3.18-3.12(m, 1H), 2.91(s,1H), 2. 60(s,1H), 2.49(s,1H), 2.20(d,J=10.9Hz,2H), 1.78-1.52(m, 6H), 1.49(d,J=0.7Hz,9H), 1.36( s,9H).

[0208] As a slow-eluting peak, (S)-2-((tert-butoxycarbonyl)amino) -3-(4-((1r,4S)-4-(tert-butoxycarbonyl)cyclohexyl Phenylpropanoic acid was isolated. 25 H 38 NO6Na[M+Na] + MS E SI, calculated value 470.26, measured value 470.30. 1H NMR (300MHz, chloro Form-d)δ 7.14-7.06 (m, 4H), 4.25 (s, 1H), 3.14 (d ,J=12.3Hz,1H), 2.88(s,1H), 2.49-2.41(m, 1H) , 2.29-2.15(m, 1H), 2.05(d,J=12.2Hz,2H), 1.9 0(d,J=12.1Hz,2H), 1.69-1.47(m, 2H), 1.47(s, 11H), 1.34(s,9H).

[0209] Step 5: (S)-2-((tert-butoxycarbonyl)amine in THF (80mL) (no)-3-(4-((1s,4R)-4-(tert-butoxycarbonyl)cyclohex A mixture of sil(phenyl)propanoic acid (8.3g, 18.54mmol) and hydrogen chloride ( M / dioxane (9.27 mL, 18.54 mmol) was added gradually at room temperature. The product is concentrated under reduced pressure, and (S)-2-amino-3-(4-((1s,4R)-4-(t We obtained ert-butoxycarbonyl(cyclohexyl)phenyl(propanoic acid). 20 H 30 NO4 [M+H] + MS ESI: Calculated value 348.21, measured value 348.25.

[0210] Step 6: In THF (60 mL) and water (60.0 mL), (S)-2-amino-3-( 4-((1s,4R)-4-(tert-butoxycarbonyl)cyclohexyl)phen (L) Propanic acid (6g, 17.27 mmol) and NaHCO3 (7.25g, 86m In a stirred solution of (mol), add n-(9-fluorenylmethoxycarbonyloxy)succinate Mid (5.24 g, 15.54 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 3 with 1N HCl. The aqueous phase was converted to acetate ether (2 × 200 m Extracted with L). The combined organic layers were washed with brine (150 mL) and anhydrous Na2SO4. It was dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-flush. (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)- 3-(4-((1s,4R)-4-(tert-butoxycarbonyl)cyclohexyl) Phenylpropanoic acid was obtained. 35 H 41 NO6[M+H] + MS ESI, calculated value 570.28, measured value 570.15. 1 1H NMR (300MHz, methanol-d4) δ7.81(d,J=7.5Hz,2H), 7.61(d,J=7.5Hz,2H), 7 .43-7.27(m, 4H), 7.16(d,J=7.8Hz,2H), 7.07(d ,J=7.9Hz,2H), 4.45-4.33(m, 2H), 4.22-4.06(m , 2H), 3.26-3.14(m, 1H), 2.96-2.88(m, 1H), 2.5 9(s,1H), 2.48(s,1H), 2.15(s,2H), 1.61(d,J=5 0.5Hz, 6H), 1.49(s, 9H).

[0211] Synthesis scheme 23 [ka]

[0212] Phe4ptCCA [ka]

[0213] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-((1r,4S)-4-(tert-butoxycarbonyl)cyclohexyl )phenyl)propanoic acid Step 1: Add tert-butyl 4-(4,4,5,5-tetramethyl (Chill-1,3,2-dioxaborolan-2-yl)cyclohexa-3-ene-1-carb A mixture of xylates (18.25 g, 59.2 mmol) was subjected to methyl(S) under argon. -2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)pro Panoate (20g, 49.4mmol), Pd(PPh3)4 (2.85g, 2.46 8 mmol) and CsF (30.0 g, 197 mmol) were added. The reaction product was then processed using Algo The mixture was stirred at 60°C for 16 hours. The reaction mixture was quenched with water (150 mL) and EA (3 × Extraction was performed using 500 mL. The combined organic layers were dried with anhydrous MgSO4 and filtered. Residue The silica gel is eluted using an ethyl acetate:petroleum ether gradient of 0:1 to 1:5. Purified by chromatography, tert-butyl 4'-((S)-2-((ter t-Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2,3,4 ,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate was obtained. 26 H 37 NO6Na[M+Na] + MS ESI calculated value: 482.26, measured value: 482.3 0.

[0214] Step 2: Dichloromethane (200 mL) contains tert-butyl(R)-4'-((S)- 2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl )-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate (21g, 45.7 mmol) mixture is treated with Crabtree catalyst (14. 71g (18.28 mmol) was added. The suspension was degassed under vacuum and purged several times with H2. The reaction solution was stirred under 2 atm of H2 at room temperature for 24 hours. The reaction product was filtered. The filtrate was... The racemic product was concentrated in a vacuum. The racemic product was then subjected to preparative SF using the following conditions. Separation was performed using C. Column: CHIRALPAK IG, 5 × 25 cm, 10 μm; transfer Mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 20 0 mL / min; Gradient: Isocratic 25% B; Column temperature (°C): 35 ;Back pressure (bar): 100;Wavelength: 220nm;RT1 (min):Fraction that elutes at 4.15 The tert-butyl(1S,4R)-4-(4-((S)-2-((tert- Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)cyclo Hexane-1-carboxylate was obtained as an orange oily substance. 26 H 39 NO6Na[M +Na] + The MS ESI calculated value was 484.28, and the measured value was 484.35.

[0215] Step 3: tert-butyl (1S,4R)-4-(4-(( S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxop Ropil)phenyl)cyclohexane-1-carboxylate (10.5g, 22.75mg) A mixture of (mol) is surrounded by LiOH (1M in water) (45.5 mL, 45.5 mmol). The reaction was added at a temperature. The reaction mixture was stirred at ambient temperature for 2 hours. The resulting solution was then mixed with an aqueous HCl solution (1 The mixture was acidified with M) and extracted with EA (4 × 100 mL). The combined organic layer was then converted to anhydrous MgSO4. It was dried and filtered. The filtrate was concentrated under vacuum to obtain (S)-2-((tert-butoxy Carbonyl)amino)-3-(4-((1R,4S)-4-(tert-butoxycarbon Nyl(cyclohexyl)phenyl)propanoic acid was obtained. 25 H 37 NO6Na[M+N a] + The MS ESI calculated value was 470.26, and the measured value was 470.25.

[0216] Step 4: (S)-2-((tert-butoxycarbonyl)a in THF (100mL) Mino)-3-(4-((1R,4S)-4-(tert-butoxycarbonyl)cyclohe A mixture of xyl(phenyl)propanoic acid (9.5g, 21.23 mmol) and HCl ( 1,4-Dioxane (4M) (100 mL, 400 mmol) was added at ambient temperature. The substance was stirred at ambient temperature for 4 hours. The resulting solution was concentrated in a vacuum to obtain (S)-2-ami No-3-(4-((1R,4S)-4-(tert-butoxycarbonyl)cyclohexyl Phenylpropanoic acid was obtained. 20 H 30 NO4 [M+H] + MS ESI calculation Value 348.21, measured value 348.25.

[0217] Step 5: (S)-2-amino-3-(4-((1R,4S)-4-(tert-butoxy (7g, 20.15 mmol) cyclohexyl phenyl propanoic acid A mixture containing THF (30 mL) and water (30 mL) is mixed with sodium bicarbonate (8.46 g, 101 mmol) and n-(9-fluorenylmethoxycarbonyloxy) succinate I-imide (6.12 g, 18.13 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. Mixed. The resulting solution was acidified with HCl aqueous solution (1M) and extracted using EA (5 × 100 mL). The combined organic layers were dried with anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum. The crude product was obtained. The residue was purified by RP flash under the following conditions: Column: Fl ash C18 (330g); Mobile phase A: water (0.05%TFA), Mobile phase B: ACN; (Gradient: Hold at 2%B for 5 minutes, increase to 75%B within 15 minutes, then 76.5%) Hold at B for 6 minutes, increase to 95% B within 5 minutes, and hold at 95% B for 5 minutes; flow rate: 90 mL / min; Detector: UV 210nm; RT=31 min. Collect the product-containing fraction and... Concentrated in the air, (S)-2-((((9H-fluoren-9-yl)methoxy)carbon (Lu)amino)-3-(4-((1R,4S)-4-(tert-butoxycarbonyl)ci Chlohexyl(phenyl)propanoic acid was obtained. 35 H 40 NO6[M+H] + MS ESI calculated value: 570.29, measured value: 570.25. 1 1H NMR (400MHz, methyl NMR) Rule-d4) δ7.80-7.78(m, 2H), 7.60-7.58(m, 2H), 7 .40-7.38(m, 2H), 7.37-7.28(m, 2H), 7.16-7.14 (m, 2H), 7.06-7.04(m, 2H), 4.45-4.41(m, 1H), 4 .32-4.28(m, 1H), 4.15-4.055(m, 2H), 3.21-3.1 7(m, 1H), 2.91-2.88(m, 1H), 2.41-2.37(m, 1H), 2.19-2.17(m, 1H), 1.96-1.91(m, 2H), 1.78-1.7 5(m, 2H), 1.45-1.42(m, 10H), 1.40-1.32(m, 3H) .

[0218] Synthesis scheme 24 [ka]

[0219] YFN [ka]

[0220] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)-λ 2 - Azanail)-3-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazo (3-yl)phenyl)propanoic acid Step 1: (S)-2-((tert-butoxycarbonyl) in DCM (10 mL) A mixture of mino-3-(4-cyanophenyl)propanoic acid (5g, 17.22 mmol) tert-butyl N,N'-diisopropylcarbamimidate (17.25g, 86 mmol was added. The reaction was refluxed at 40°C for 2 hours. The resulting solution was concentrated under vacuum. The residue was purified by silica gel chromatography, and ethyl acetate:petroleum ether ( Elute with a gradient of 0:1 to 1:3, tert-butyl(S)-2-((tert We obtained butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate. C 19 H 26 N2O4Na[M+Na] + MS ESI calculated value: 369.19, measured value: 3 69.10.

[0221] Step 2: Hydroxylamine hydrochloride (6.62g, 95mg) in DMSO (120mL) To the solution of 0.91 ml, sodium bicarbonate (10.91 g, 130 mmol) was added at room temperature. Next, the temperature was raised to 45-50°C. At this temperature, tert-butyl(S)-2- ((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoe Add 6g (17.32 mmol) to the obtained solution and heat the mixture to 100°C. Then, the mixture was stirred at the same temperature for 18 hours. After completion, the reaction mixture was cooled to 15-20°C. Next, it was poured into water. The solution was stirred at 15-20°C for 15-20 minutes and then filtered. Wash the solid with water and dry it, then tert-butyl(S,E)-2-((tert-but Xycarbonyl)amino)-3-(4-(N'-hydroxycarbamimidoyl)phen (L) Propanoate was obtained. C 19 H 30 N3O5[M+H] + MS ESI calculation value 3 80.21, measured value 380.15.

[0222] Step 3: tert-butyl(S,E)-2-((tert-butoxycarbonyl)amine (N'-hydroxycarbamimidoyl)phenyl)propanoate Dissolve 5.5g (14.49 mmol) in t-butanol (100mL), then B OC2O (3.37 mL, 14.49 mmol) is slowly poured through a dropping funnel at 25-30°C. The chestnuts were added. After the addition was complete, the temperature was raised to 50-55°C and stirring was continued at the same temperature for 12 hours. After the reaction was complete, the reaction mixture was cooled to 15-20°C and stirred at 15-20°C for 60 minutes. A solid was obtained. The product was filtered, washed with tert-butanol, and heated under vacuum at 55-60°C. The crude product was obtained by drying. 24 H 38 N3O7[M+H] +MS ESI calculation value 4 80.26, measured value 480.35.

[0223] Step 4: tert-butyl(S,E)-3-(4-(N-(tert-butoxycarb (Nyl)-N'-hydroxycarbamimidoyl)phenyl)-2-((tert-butoxy Cicarbonyl amino propanoate (5.5g, 11.47 mmol) in DMF (6 The mixture was dissolved in 0 mL of water, and then the reaction mixture was heated to 110-115°C. The resulting solution was then prepared in the same way. The mixture was stirred at the same temperature for 12 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (600 mL). Wash with saturated NaCl aqueous solution (4 x 100 mL), dry with Na2SO4, and filter. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The product was prepared and eluted with a 0-70% ethyl acetate / PE gradient. The fraction containing the desired product was obtained. Combine and concentrate under reduced pressure to obtain tert-butyl(S)-2-((tert-butoxyca Rubonyl)amino)-3-(4-(5-oxo-4,5-dihydro-1,2,4-oxa Diazole-3-yl)phenyl)propanoate was obtained. 20 H 28 N3O6[M+ H] + The MS ESI calculated value was 406.19, and the measured value was 406.10. 1 1H NMR (400 MHz,DMSO-d6)δ 12.91(s,1H),7.73-7.72(m,2 H),7.48-7.43(m,2H),7.26-7.24(m,1H),4.07- 4.05(m,1H),3.03-3.01(m,1H),2.95-2.89(m,1 H), 1.33(s,9H), 1.32(s,9H). Step 5: In DCM (40 mL), tert-butyl(S)-2-((tert-butoxy Carbonyl)amino)-3-(4-(5-oxo-4,5-dihydro-1,2,4-ox A mixture of sadiazole-3-yl)phenyl)propanoate (4g, 9.87 mmol) TFA (40 mL, 519 mmol) was added to the mixture under argon at room temperature. The reaction mixture was then heated in the room. The mixture was stirred at warm temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product. 11 H 12 N3O4 [M+H] + The MS ESI calculated value was 250.07, and the measured value was 249.95.

[0224] Step 6: (S)-2-amino-3- in THF (20 mL) and H2O (20 mL) (4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) A mixture of phenyl)propanoic acid (2.1 g, 8.43 mmol) was subjected to heavy heating under argon at room temperature. Sodium carbonate (3.54 g, 42.1 mmol) and N-(9-fluorenylmethoxymethyl fluoride) Cicarbonyloxy)succinimide (2.56 g, 7.58 mmol) was added. The mixture was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 4 with 1N HCl. The aqueous phase was converted to acetic acid. Extraction was performed with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (3 x 50 mL). The solution was purified, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was collected as follows: The sample was purified by RP-flash and then processed on an AQ18 gel column (330g, 20-35μm). Using this method, mobile phase A is a 5 mM TFA aqueous solution, mobile phase B is MeCN, and the gradient is 0 Hold at %B for 5 minutes, raise to 55.3%B within 35 minutes, and hold at 55.3%B for 3.2 minutes. Hold the flow, then increase it to 95%B within 2 minutes, maintain it at 95%B for 10 minutes, and increase the flow velocity to 60 m / s The desired product was obtained using a flow rate of L / min, with detectors at UV254 and 210 nm, and a runtime of 35.32 minutes. The fractions containing (S)-2-((((9H-fluorene-9 -yl(methoxy)carbonyl)amino)-3-(4(5-oxo-4,5-dihydro -1,2,4-Oxadiazole-3-yl)phenyl)propanoic acid was obtained. 26 H2 0N3O6[MH] + The MS ESI calculated value was 470.14, and the measured value was 470.15. 1 H NMR(400 MHz,DMSO-d6)δ 12.91(s,1H),12.82 (s,1H),7.93-7.87(m,2H),7.78-7.72(m,3H),7 .68-7.62(m,2H),7.51-7.30(m,4H),7.28-7.26 (m,2H),4.27-4.15(m,4H),3.20-3.12(m,1H),2 0.99-2.92 (m, 1H). Synthesis scheme 25 [ka]

[0225] SbMe1Nal3Cl [ka]

[0226] (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) Amino)-3-(3-chloronaphthalen-1-yl)butanoic acid Step 1: tert-butyl 2-oxobutanoate (80.0) in toluene (2.40 L) (g, 506 mmol, 1.00 equivalent) and K2CO3 (210 g, 1520 mmol, A mixture of 3.00 equivalents contains 1-bromo-3-chloronaphthalene and P(t-Bu)3 Add HBF4 (11.7g, 40.5 mmol, 0.08 equivalents) and rinse the mixture with N2. Three purges were performed. Pd2(dba)3 (9.26g, 10.1mmol, 0.02 equivalents) The reaction mixture was added, purged three times with N2, and stirred under N2 at 110°C for 3 hours. The mixture is cooled to room temperature and poured into an aqueous solution of NH4Cl (3.00 L), and siRNA (2 Extraction was performed using 0.00L x 2. The organic layers were combined, washed with brine, and dried on Na2SO4. After filtering, the product was concentrated under reduced pressure. The crude product was then subjected to silica chromatography (SiO2 It was purified using petroleum ether / ethyl acetate (1 / 0 to 0 / 1).

[0227] Step 2: Tert-butyl 3-(3-chloronaphthalate) in DCM (1.00 L) at 0°C (1-yl)-2-oxobutanoate (100g, 314mmol, 1.00 equivalent) Add TFA (1.00 L) dropwise to the mixture and stir the mixture at ambient temperature for 2 hours. The reaction mixture was concentrated, and the crude product was separated by HPLC (column: Phenomenex L). una C18(250×70mm, 15μm); Mobile phase: H2O(0.1%TFA) / ACN; gradient: Purified by 35% to 65% B over 20.0 minutes.

[0228] Step 3: Lysine (114g, 779mmol, 3.5g) in DMSO (270mL) at 20℃. A mixture of 10 equivalents of Na2B4O7 (0.1M, 561mL) and Na2B4O7 Add 10H2O (28.8g, 75.4 mmol, 0.30 equivalents) and continue the process. Compound 3-(3-chloronaphthalen-1-yl)-2-oxobutanoic acid (66.0g, 25 1 mmol (1.00 equivalent) was added. Pyridoxal phosphate (2.44 g, 9.85 mmol, 0.05 equivalents) and the transaminase enzyme ProzomixTAm-24 8 (35.0 g) was added to the reaction mixture at 35°C. The reaction mixture was stirred at 45°C for 12 hours. The reaction mixture was cooled to 20°C and adjusted to pH 5.0 with 5N HCl (60.0 mL). Prepared and stirred at 20°C for 1 hour. Filter the mixture and fill the filter cake with H2O (500 mL x 3). Wash with (2S,3S)-2-amino-3-(3-chloronaphtha) and dry under reduced pressure. Len-1-yl)butanoic acid was obtained and used in the next step without purification.

[0229] Step 4: (2S,3S)-2-amino-3-(3-chloro) in HCl (540mL) Mixture of naphthalen-1-yl)butanoic acid (54.0 g, 205 mmol, 1.00 equivalent) The substance contains DIPEA (39.7g, 307mmol, 1.50 equivalents) and (9H-fluorine Len-9-yl)methyl(2,5-dioxopyrrolidine-1-yl)carbonate (82 (0.9g, 246 mmol, 1.20 equivalents) was added and the mixture was stirred for 12 hours. The precipitate was then removed. The filtrate was filtered and washed with 2.0 L of siRNA. The filtrate was concentrated to obtain the crude product, and this was then used. Preparative HPLC (Column: Phenomenexluna C18 250*150mm*1) 5 μm; Mobile phase: [H2O (0.04% HCl)-ACN]; Gradient: 25.0 min It was purified by (50-95%). 1 1H NMR: (400 MHz, DMS) O-d6)δ 12.8(s,1H),8.22(d,J=8.2 Hz,1H),7. 84-8.01(m,5H),7.53-7.72(m,4H),7.31-7.47( m,3H),7.18-7.30(m,2H),4.54(t,J=8.8 Hz,1H ),4.21-4.32(m,1H),3.95-4.19(m,3H),3.82(s ,3H),1.36(d,J=6.8 Hz,3H). SbMe1Nal3OMe [ka] (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) Amino)-3-(3-methoxynaphthalene-1-yl)butanoic acid Using a process similar to the synthesis of SbMe1Nal3Cl, from suitable starting materials, the title A compound was obtained. 1 H NMR:(400 MHz,DMSO-d6)δ 12.77(s ,1H),8.10(d,J=8.2 Hz,1H),7.84(t,J=8.8 Hz ,4H),7.60(d,J=7.4 Hz,1H),7.55(d,J=7.4 Hz ,1H),7.34-7.50(m,4H),7.13-7.29(m,3H),7.0 5(s,1H),4.53(t,J=8.2 Hz,1H),4.18-4.32(m, 1H),4.07-4.17(m,2H),3.93-4.01(m,1H),3.82 (s, 3H), 1.33 (d, J=6.8 Hz, 3H). SbMe1Nal3Me [ka] (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) Amino)-3-(3-methylnaphthalene-1-yl)butanoic acid Using a process similar to the synthesis of SbMe1Nal3Cl, from suitable starting materials, the title A compound was obtained. 1H NMR:(400 MHz,DMSO-d6)δ 8.24(d, J=6.8 Hz,1H),7.83-7.90(m,2H),7.77-7.82(m ,1H),7.57-7.64(m,1H),7.50-7.56(m,2H),7.3 4-7.49(m,5H),7.18-7.30(m,3H),4.43(t,J=7. 6Hz,1H),4.22-4.31(m,1H),4.08-4.17(m,2H) ,3.95-4.04(m,1H),2.40(s,3H),1.32(d,J=6.8 Hz, 3H). SbMe1Nal8F [ka]

[0230] (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) Amino)-3-(8-fluoronaphthalene-1-yl)butanoic acid Using a process similar to the synthesis of SbMe1Nal3Cl, from suitable starting materials, the title A compound was obtained. 1 H NMR:(400 MHz,DMSO-d6)δ 7.84(d, J=7.5 Hz,3H),7.78(d,J=8.1 Hz,1H),7.71(d, J=7.0 Hz,1H),7.57(d,J=7.3 Hz,1H),7.43-7. 53(m,4H),7.33-7.41(m,2H),7.17-7.33(m,3H) ,4.49(s,1H),4.19-4.37(m,2H),4.04-4.09(m, 2H), 1.32(d, J=6.6 Hz, 3H). Synthesis scheme 26 [ka]

[0231] Phe43Oxad1245Me [ka]

[0232] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-(5-methyl-1,2,4-oxadiazole-3-yl)phenyl)pro Panic acid Step 1: (S)-2-((tert-butoxycarbonyl)a in DCM (200mL) Stirring of mino-3-(4-cyanophenyl)propanoic acid (20.0 g, 68.9 mmol) Add tert-butyl(E)-N,N'-diisopropylcarbamidate to the mixed solution at room temperature. (69.0 g, 344 mmol) was added. The reaction mixture was stirred at 40°C for 5 hours. The mixture was concentrated under reduced pressure. The crude compound was subjected to biotage-isolera. The compound was purified using a licac column and eluted with 30% ethyl acetate / petroleum ether. The pure fractions are combined and concentrated under reduced pressure to obtain tert-butyl(S)-2-((tert-but Xycarbonyl)amino)-3-(4-cyanophenyl)propanoate was obtained. 19 H 26 N2O4[MH] + The MS ESI calculated value was 345.19, and the measured value was 345.25.

[0233] Step 2: Hydroxylammonium chloride (21.0 g) in DMSO (400 mL) Add sodium bicarbonate (34.6g, 411mmol) to a 302mmol (302mmol) stirred solution in a chamber It was added at warm temperature. Then, tert-butyl(S)-2-((tert-butoxycarbon (L)amino-3-(4-cyanophenyl)propanoate (19.0g, 54.8mm The reaction mixture was added at 45-50°C. The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to 15-20°C, quenched with water, and incubated at 15-20°C for 15-20 minutes. Stirring, filtering, washing with water and diethyl ether, drying under vacuum, tert- Butyl(S,E)-2-((tert-butoxycarbonyl)amino)-3-(4-(N '-hydroxycarbamimidoyl)phenyl)propanoate was obtained. 19 H 29 N 3O5[M+H] + The MS ESI calculated value is 380.21, and the measured value is 380.29.

[0234] Step 3: In triethyl orthoacetate (190 mL), tert-butyl(S,E)- 2-((tert-butoxycarbonyl)amino)-3-(4-(N'-hydroxycarbonyl)amino A solution of bamiimidoyl(phenyl)propanoate (19.0 g, 50.1 mmol) The mixture was stirred at 150°C for 5 hours. The reaction mixture was concentrated under reduced pressure. The crude compound was then processed using Biotag. The compound was purified using a silica column with e-isolera, and then 30% ethyl acetate was added to the solution. It was eluted with petroleum ether. The pure fraction was combined and concentrated under reduced pressure to obtain tert-butyl ( S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-methyl-1 ,2,4-Oxadiazole-3-yl)phenyl)propanoate was obtained. 21 H2 9N3O5[M+H] + The MS ESI calculated value was 402.21, and the measured value was 402.29.

[0235] Step 4: In DCM (80 mL), tert-butyl(S)-2-((tert-butoxy Carbonyl)amino)-3-(4-(5-methyl-1,2,4-oxadiazole-3- A stirred solution of phenylpropanoate (8.00 g, 19.8 mmol) is prepared at 0°C. TFA (80.0 mL, 1.04 mol) was then added. The reaction mixture was stirred at 24°C for 8 hours. Mixed. The reaction mixture was concentrated under reduced pressure. The crude compound was smeared with diethyl ether. When dried under reduced pressure, (S)-2-amino-3-(4-(5-methyl-1,2,4-o Xadiazole-3-yl)phenyl)propanoic acid was obtained. 12 H 13 N3O3[ M+H] + The MS ESI calculated value was 248.10, and the measured value was 248.07.

[0236] Step 5: In THF (50 mL) and water (50 mL), (S)-2-amino-3-(4- (5-methyl-1,2,4-oxadiazole-3-yl)phenyl)propanoic acid (4. To a stirred solution of 50g, 18.2 mmol, add sodium bicarbonate (7.64g, 91.0m (mol) and (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidine- 1-yl carbonate (5.53 g, 16.4 mmol) was added at room temperature. Reaction mixture The mixture was stirred at 25°C for 2 hours. The reaction mixture was acidified with 1N HCl (pH approximately 4) and acetic acid. Extraction was performed with ethyl acetate (2 x 300 mL). The combined organic layer was washed with brine (200 mL). The crude compound was dried with Na2SO4, filtered, and concentrated under reduced pressure. Lammagraphy (Conditions: Column: C18 gel column (100g), Mobile phase A: Water, Mobile phase A) The compound is purified using Phase B (acetonitrile) and then diluted with 45-100% acetonitrile / water. Elution was performed using a gradient. The pure fractions were combined and concentrated under reduced pressure to obtain (S)-2-((( (9H-Fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(5-methyl) Tyl-1,2,4-oxadiazole-3-yl)phenyl)propanoic acid was obtained. 27 H 23 N3O5[M+H] + The MS ESI calculated value was 470.16, and the measured value was 470.25. 1 H NMR(400 MHz,DMSO-d6):δ(ppm)12.85(brs ,1H),7.88(t,J=8.0Hz,4H),7.50-7.76(m,3H) ,7.35-7.47(m,4H),7.24-7.33(m,2H),4.10-4. 30(m,4H),3.16(dd,J=13.8 Hz,4.2 Hz,1H),2. 90-3.00 (m, 1H), 2.66 (s, 3H). Synthesis scheme 27 [ka]

[0237] Phe43Oxad1245MeOEt [ka]

[0238] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-(5-methyl-1,2,4-oxadiazole-3-yl)phenyl)pro Panic acid Step 1: (S)-2-((tert-butoxycarbonyl)a in DCM (200mL) Stirring of mino-3-(4-cyanophenyl)propanoic acid (20.0 g, 68.9 mmol) Add tert-butyl(E)-N,N'-diisopropylcarbamidate to the mixed solution at room temperature. (69.0 g, 344 mmol) was added. The reaction mixture was stirred at 40°C for 5 hours. The mixture was concentrated under reduced pressure. The crude compound was subjected to biotage-isolera. The compound was purified using a licac column and eluted with 30% ethyl acetate / petroleum ether. The pure fractions are combined and concentrated under reduced pressure to obtain tert-butyl(S)-2-((tert-but Xycarbonyl)amino)-3-(4-cyanophenyl)propanoate was obtained. 19 H 26 N2O4[MH] + The MS ESI calculated value was 345.19, and the measured value was 345.25.

[0239] Step 2: Hydroxylammonium chloride (21.0 g) in DMSO (400 mL) Add sodium bicarbonate (34.6g, 411mmol) to a 302mmol (302mmol) stirred solution in a chamber It was added at warm temperature. Then, tert-butyl(S)-2-((tert-butoxycarbon (L)amino-3-(4-cyanophenyl)propanoate (19.0g, 54.8mm The reaction mixture was added at 45-50°C. The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to 15-20°C, quenched with water, and incubated at 15-20°C for 15-20 minutes. Stirring, filtering, washing with water and diethyl ether, drying under vacuum, and obtaining a white solid. tert-butyl(S,E)-2-((tert-butoxycarbonyl)amino)- 3-(4-(N'-hydroxycarbamimidoyl)phenyl)propanoate was obtained. C 19 H 29 N3O5[M+H] + The MS ESI calculated value is 380.21, and the measured value is 380. 29.

[0240] Step 3: tert-butyl(S,E)-2-((tert -Butoxycarbonyl)amino)-3-(4-(N'-Hydroxycarbamimidoyl) A solution of phenyl)propanoate (4.0 g, 10.5 mmol) is mixed with triethylamine. (3.20g, 4.41mL, 31.6 mmol) was added, followed by 2-ethoxyacetate. Tyl chloride (1.55 g, 1.39 mL, 12.6 mmol) was added dropwise. The mixture was stirred at 120°C for 18 hours. The reaction mixture was concentrated under reduced pressure. The crude compound was then prepared. The compound was purified using a silica column with Biotage-isolera, and then 2 Elution was performed with 0% ethyl acetate / hexane. The pure fractions were combined and concentrated under reduced pressure to obtain tert- Butyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-( Ethoxymethyl)-1,2,4-oxadiazole-3-yl)phenyl)propanoyl C obtained by LC-MS 23 H 33 N3O6 detection: m / z 448.3 [M+H] + (1.40 minutes).

[0241] Step 4: In DCM (50 mL), tert-butyl(S)-2-((tert-butoxy Carbonyl)amino)-3-(4-(5-(ethoxymethyl)-1,2,4-oxadia Stirring of zole-3-yl)phenyl)propanoate (3.10 g, 6.93 mmol) TFA (7.90 g, 5.34 mL, 69.3 mmol) was added to the solution at 0°C. The reaction mixture was stirred at 24°C for 24 hours. The reaction mixture was concentrated under reduced pressure to obtain (S)-2-A Mino-3-(4-(5-(ethoxymethyl)-1,2,4-oxadiazole-3-yl Phenylpropanoic acid was obtained by LC-MS. 14 H 17 N3O4 detection: m / z 292.0[M+H] + (0.34 minutes).

[0242] Step 5: In THF (50 mL) and water (50 mL), (S)-2-amino-3-(4- (5-(ethoxymethyl)-1,2,4-oxadiazole-3-yl)phenyl)pro To a stirred solution of panic acid (2.50 g, 8.58 mmol), add sodium bicarbonate (3.60 g) , 42.9 mmol) and (9H-fluoren-9-yl)methyl(2,5-dioxo Pyrrolidine-1-yl) carbonate (2.89 g, 8.58 mmol) was added at room temperature. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was then acidified with 1N HCl (pH approximately 2). The mixture was cured and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was then brined (150 mL). Washed with (mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was then treated with Te Purified using ledyne ISCO, then filtered with 0-100% acetic acid using 80g of silica gel. Elution was performed with ethyl / hexane. The pure fractions were combined and concentrated under reduced pressure to obtain (S)-2-((( (9H-Fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(5-( Ethoxymethyl)-1,2,4-oxadiazole-3-yl)phenyl)propanoic acid Obtained. C obtained by LC-MS 29 H 27 N3O6 detection: m / z 514.3[M+H] + ( 1.31 minutes).

[0243] Synthesis scheme 28 [ka]

[0244] Phe42Oxad1345Me [ka]

[0245] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl)pro Panic acid Step 1: DMA (150 mL) contains 4-bromobenzohydrazide (30.0 g, 140 mL) To a stirred solution of (mol), add POCl3 (14.3 mL, 153 mmol) dropwise at 80°C. The mixture was added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was then cooled in ice water (1000 mL). Diluted with (), quenched with Na2CO3 solution, and extracted with DCM (1000 mL). Wash the prepared organic layer with brine (500 mL), dry it with anhydrous sodium sulfate, and filter it. The crude compound was concentrated under reduced pressure. The crude compound was purified by Biotage using a silica gel column. The compound was prepared and eluted with 30% ethyl acetate / petroleum ether. The pure fractions were combined under reduced pressure. Concentrate below to obtain 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazo I obtained the following: C9H7BrN2O[M+H] + MS ESI calculated value: 238.97, measured value 238.95.

[0246] Step 2: Nickel chloride, dimethoxyethane adduct (457 mg) in DMA (40 mL) 2.08 mmol) and picoline imidamide hydrochloride (656 mg, 4.16 mmol) The stirred solution of ) was stirred under argon at 50°C for 40 minutes. Then, TBAI (3.84 g, 10.4 mmol), (R)-2-((((9H-fluoren-9-yl)methoxy Carbonyl amino-3-bromopropanoate (5.00g, 10.4mmol) , 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole (2.49 React and mix (g, 10.4 mmol) and zinc (1.36 g, 20.8 mmol) at room temperature. The mixture was added to the substance. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was cooled in ice-cold water (150ml). Quenched with L) and extracted with HCl (3 x 70 mL). The combined organic layer was cooled in ice-cold water. Wash with 100 mL of brine, dry with anhydrous sodium sulfate, and filter. The crude compound was concentrated under reduced pressure. The crude compound was analyzed by biotage using a silica gel column. The compound was purified and eluted with 30% ethyl acetate / petroleum ether. The pure fraction was combined and reduced. Concentrate under pressure to obtain benzyl(S)-2-((((9H-fluoren-9-yl)methoxy. )carbonyl)amino)-3-(4-(5-methyl-1,3,4-oxadiazole-2 -yl(phenyl)propanoate was obtained. 34 H 29 N3O5[M+H] + MS ESI calculated value: 560.21, measured value: 560.33.

[0247] Step 3: In THF (75 mL), benzyl(S)-2-((((9H-fluorene-9- Il(methoxy)carbonyl)amino)-3-(4-(5-methyl-1,3,4-oxa) Diazole-2-yl)phenyl)propanoate (5.00g, 8.93 mmol) Pd / C (2.35 g, 625 μmol) was added to the stirred solution at room temperature. The reaction mixture was then mixed with water. The mixture was stirred at 25°C for 16 hours under an ambient atmosphere. The reaction mixture was filtered through a CELITE bed. The filtrate was concentrated under reduced pressure. The crude compound was stirred in DCM (10 mL) and diethyl ether was added. Lu was added. The precipitated solid was filtered and dried under reduced pressure, and (S)-2-((((9H -Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(5-methyl- 1,3,4-Oxadiazole-2-yl)phenyl)propanoic acid was obtained. 27 H 23 N3O5[M+H] + The MS ESI calculated value was 470.16, and the measured value was 470.22. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 12.82 (br s, 1H ),7.83-7.94(m,4H),7.77(d,J=8.4 Hz,1H),7. 62(d,J=6.4 Hz,2H),7.47(d,J=8.0 Hz,2H),7. 39(td,J=7.4Hz,2.8Hz,2H),7.23-7.35(m,2H ),4.07-4.36(m,4H),3.18(dd,J=14.0 Hz,4.4 Hz,1H),2.83-3.02(m,1H),2.57(s,3H). Synthesis scheme 29 [ka]

[0248] Ala2Oxad1345Me [ka]

[0249] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(5-methyl-1,3,4-oxadiazole-2-yl)propanoic acid Step 1: In THF (1L), (S)-4-(benzyloxy)-3-(((benzyloxy Stirring of carbonyl amino-4-oxobutanoic acid (35.0 g, 97.9 mmol) Add N-methylmorpholine (10.8 mL, 97.9 mmol) to the mixed solution at -15°C and Ethyl chloroformate (9.41 mL, 97.9 mmol) was added to the reaction mixture. The mixture was stirred at -15°C for 15 minutes. Then, acetohydrazide (7.26 g, 97.9 mmol) was added. The solution of (1) in THF (200 mL) was added dropwise to the reaction mixture at -15°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with ice water (500 mL) and EtO2 was added. Extraction was performed with Ac (3 × 150 mL). The combined organic layer was washed with brine (100 mL). Dry with sodium sulfate, filter, and concentrate under reduced pressure to obtain (S,Z)-N-acetyl- 4-(benzyloxy)-3-(((benzyloxy)carbonyl)amino)-4-oxy Sobutanehydrazonic acid was obtained. 21 H 23 N3O6[M+H] + MS ESI calculation value 414.16, measured value 414.14.

[0250] Step 2: (S,Z)-N-acetyl-4-(benzyloxy) in toluene (50 mL) -3-(((benzyloxy)carbonyl)amino)-4-oxobutanehydrazonic acid( Add Burgess reagent (7.781g) to a stirred solution of 10.00g, 21.77 mmol. (32.65 mmol) was added at 0°C. The reaction mixture was stirred at 80°C for 16 hours. The mixture was quenched with cold water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The substance was purified using Biotage with a 120g silica cartridge, and this compound It was eluted with 100% ELISA. The pure fractions were combined and concentrated under reduced pressure to obtain benzyl(S) -2-(((benzyloxy)carbonyl)amino)-3-(5-methyl-1,3,4- Oxadiazole-2-yl)propanoate was obtained. 21 H 21 N3O5[M+H] + The MS ESI calculated value is 396.15, and the measured value is 396.26.

[0251] Step 3: Benzyl(S)-2-(((benzyloxy)cal in MeOH (250mL) Bonyl)amino)-3-(5-methyl-1,3,4-oxadiazole-2-yl)pro A stirred solution of panoate (11.0 g, 25.0 mmol) is mixed with 10% Pearlman reagent. The medium (5.00 g, 4.70 mmol) was added at room temperature. The mixture was stirred at room temperature for 10 minutes. The reaction mixture was purged with N2 gas at room temperature for 5 minutes. The reaction mixture was then placed under an H2 balloon. The mixture was stirred at 5°C for 16 hours. The reaction mixture was filtered through a CELITE pad and MeOH (50 ml). Washed with L) and DCM (100 mL). The organic layer was concentrated under reduced pressure. The crude compound was n -Wash with pentane (3 x 50 mL), dry under reduced pressure, and (S)-2-amino-3- (5-methyl-1,3,4-oxadiazole-2-yl)propanoic acid was obtained. 1 HN MR(400MHz,DMSO-d6):δ(ppm)7.50-8.89(m,2H ),3.64(d,J=6.8 Hz,1H),3.56(dd,J=9.0 Hz,4 .6 Hz,1H),3.37-3.42(m,1H),2.45(s,3H). Step 4: (S)-2-amino-3-( in THF (35 mL) and H2O (35 mL) 5-Methyl-1,3,4-oxadiazole-2-yl)propanoic acid (4.20g, 22 To a stirred solution of 0.1 mmol, add sodium bicarbonate (2.84 g, 33.1 mmol) (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidine-1-yl) -Bonate (11.4 g, 33.1 mmol) was added at 0°C. The reaction mixture was then heated at 25°C. Stir for 16 hours, then dilute with toluene (100 mL) and prepare 1 M HCl (pH approximately 2~ 3) The solution was acidified. The aqueous layer was extracted with ELISA (2 × 100 mL). The combined organic layers were then extracted. Wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, and under reduced pressure. The crude compound was concentrated and purified using Biotage with an 80g silica cartridge. Then, this compound was eluted with 100% ethyl acetate. The pure fractions were combined and concentrated under reduced pressure. Wash the separated compound with n-pentane (2 × 100 mL), then wash with ether and pentane (9 The mixture was polished again using 0:10). A few drops of ethyl acetate (3 times) were added to the reaction mixture, and solidified. The body was filtered. The solid was washed with ether and dried under reduced pressure, (S)-2-((((9 H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methyl-1, 3,4-Oxadiazole-2-yl)propanoic acid was obtained. 21 H 19 N3O5[M+ H] + The MS ESI calculated value was 394.13, and the measured value was 394.22. 1 1H NMR (400 MHz,DMSO-d6):δ(ppm)13.10(brs,1H),7.89( d,J=7.6 Hz,2H),7.58-7.82(m,3H),7.42(t,J= 7.4 Hz,2H),7.32(td,J=7.4 Hz,0.9 Hz,2H),4 .33-4.45(m,1H),4.17-4.32(m,3H),3.27-3.30 (m,1H),3.13-3.22(m,1H),2.43(s,3H). Synthesis scheme 30 [ka]

[0252] TyrOCOPyrr [ka]

[0253] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-((pyrrolidine-1-carbonyl)oxy)phenyl)propanoic acid Step 1: tert-butyl (tert-butoxycarbonyl) in DCM (100 mL) - In a stirred solution of L-tyrosinate (20.00 g, 59.27 mmol), add DMA at room temperature. P (7.241g, 59.27mmol), TEA (16.5mL, 118.5mmol ) and pyrrolidine-1-carbonyl chloride (8.710 g, 65.20 mmol) Added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. Crude Dilute the compound with MeOH (100 mL), stir at room temperature for 30 minutes, and filter the precipitated solid. Then, wash with MeOH (2 × 20 mL), dry under vacuum, and (S)-4-(3-(te rt-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopro Pyr(phenylpyrrolidine-1-carboxylate) was obtained. 23 H 34 N2O6[M+ H] + The MS ESI calculated value was 435.24, and the measured value was 435.31.

[0254] Step 2: (S)-4-(3-(tert-butoxy)-2-(( tert-butoxycarbonyl)amino)-3-oxopropyl)phenylpyrrolidine- To a stirred solution of 1-carboxylate (12.00 g, 27.62 mmol), add TFA (6 3.83 mL (828.5 mmol) was added at room temperature. The reaction mixture was left at 25°C for 16 hours. The mixture was stirred. The reaction mixture was concentrated under reduced pressure, co-distilled with toluene (50 mL), and dried under vacuum. Dry and (S)-2-amino-3-(4-((pyrrolidine-1-carbonyl)oxy) Phenylpropanoic acid was obtained. 14 H 18 N2O4[M+H] + MS ESI calculation value 279.13, measured value 279.20.

[0255] Step 3: (S)-2-amino-3-(4) in acetone (50 mL) and water (50 mL) -((pyrrolidine-1-carbonyl)oxy)phenyl)propanoic acid (8.00g, 28 To a stirred solution of 0.7 mmol, add sodium bicarbonate (7.24 g, 86.2 mmol) (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidine-1-yl) -Bonate (10.7 g, 31.6 mmol) was added at room temperature. The reaction mixture was then heated at 25°C. The mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure. The aqueous layer was separated into diethyl ether (2 × 100). Wash with mL, acidify with 2N HCl (pH approximately 4), and 10% MeOH / DCM (2× Extraction was performed using 200 mL. The combined organic layers were dried with anhydrous Na2SO4, filtered, and then removed under reduced pressure. The crude compound was concentrated below. Diluted with 10% diethyl ether (100 mL) in hexane. Stir at 25°C for 30 minutes, filter the mixture, dry under reduced pressure, and (S)-2-((((9 H-Fluorene-9-yl)methoxy)carbonyl)amino)-3-(4((pyrrolidine C-1-carbonyl(oxy)phenyl(propanoic acid) was obtained. 29 H 28 N2O6[M +H] + The MS ESI calculated value is 501.19, and the measured value is 501.29. 1 1H NMR (40 0 MHz,DMSO-d6):δ(ppm)7.88(d,J=7.6 Hz,2H) ,7.56-7.72(m,2H),7.41(t,J=7.6 Hz,2H),7.2 7-7.36(m,2H),7.15(d,J=8.0Hz,2H),6.94(d, J=8.4 Hz,3H),3.71-4.39(m,4H),3.44-3.50(m ,2H),3.35-3.37(m,3H),3.05(dd,J=13.4 Hz,4 .6 Hz,1H),2.84-2.97(m,1H),1.79-1.96(m,4H ). Synthesis scheme 31 [ka]

[0256] Ala3Oxad1245Me [ka]

[0257] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(5-methyl-1,2,4-oxadiazole-3-yl)propanoic acid Step 1: (S)-2-((tert-butoxycarbonyl)a in DCM (100mL) In a stirred solution of mino-3-cyanopropanoic acid (24.00 g, 112.0 mmol), At warm temperature, tert-butyl(E)-N,N'-diisopropylcarbamimidate (80 mL, 336.1 mmol) was added. During the reaction, a thickened white precipitate formed. The mixture was stirred at 45°C for 5 hours. The reaction mixture was filtered and washed with DCM (2 x 50 mL). The filtrate was concentrated under reduced pressure. The crude compound was subjected to biotage-isolera. The compound was purified using a 20g silica cartridge, and then treated with 30% ethyl acetate / petroleum ether. Elution was obtained using elu. The pure fraction was combined and concentrated under reduced pressure to obtain tert-butyl(S)-2-(( We obtained tert-butoxycarbonyl)amino)-3-cyanopropanoate. 13 H 22 N2O4[M+H] + The MS ESI calculated value was 271.16, and the measured value was 271.20.

[0258] Step 2: tert-butyl(S)-2-((tert-but) in DMSO (150 mL) Xycarbonyl (amino)-3-cyanopropanoate (20.0g, 74.0mmol) To the stirred solution of ), add sodium bicarbonate (46.6 g, 555 mmol) and hydrochloride Silammonium (28.3 g, 407 mmol) was added at room temperature. Reaction mixture 10 The mixture was stirred at 0°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (200 mL). Extracted with HCl (2 x 300 mL). The combined organic layer was diluted with water (2 x 100 mL), and br Wash with a line (100 mL), dry with Na2SO4, filter, and concentrate under reduced pressure. (S)-2-((tert-butoxycarbonyl)amino)-4-(hydroxyamino) -4-tert-butyl iminobutanoate was obtained. 13 H 25 N3O5[M+H] + M S ESI calculated value: 304.18, measured value: 304.22.

[0259] Step 3: In ACN (100 mL), tert-butyl(S)-2-((tert-butyl(S) Cicarbonyl)amino)-4-(hydroxyamino)-4-iminobutanoate (9.5 To a stirred solution of 0g, 31.3 mmol, cesium carbonate (20.4g, 62.6 mmol) ) and acetyl chloride (2.45 mL, 34.4 mmol) were added at room temperature. Reaction mixture The mixture was stirred at 25°C for 3 hours. The reaction was monitored by TLC and LC-MS, and the TLC results were fresh. The reaction mixture showed a spot, and LC-MS indicated that the intermediate mass was 93%. The mixture was stirred under reflux for 3 hours. The reaction mixture was filtered through a CELITE pad and ACN (2 × 5 Washed with 0 mL. The filtrate was concentrated under reduced pressure. The crude compound was treated with Biotage-isol The compound was purified using a silica column in era, and then 30% ethyl acetate / petroleum A Elution was performed using tert. The pure fraction was combined and concentrated under reduced pressure to obtain tert-butyl(S)-2-( (tert-butoxycarbonyl)amino)-3-(5-methyl-1,2,4-oxadi Azole-3-yl)propanoate was obtained. 15 H 25 N3O5[M+H] + MS ESI calculated value: 328.18, measured value: 328.25.

[0260] Step 4: In DCM (20 mL), tert-butyl(S)-2-((tert-butoxy Carbonyl)amino)-3-(5-methyl-1,2,4-oxadiazole-3-yl) To a stirred solution of propanoate (5.80 g, 17.7 mmol), add TFA (20.5 mL) (266 mmol) was added at room temperature. The reaction mixture was stirred at 25°C for 16 hours. The mixture is concentrated under reduced pressure, co-distilled with toluene (10 mL), and dried under reduced pressure to obtain (S) -2-amino-3-(5-methyl-1,2,4-oxadiazole-3-yl)propane Acid was obtained: C6H9N3O3[M+H] + MS ESI calculated value 172.06, measured value 1 71.99.

[0261] Step 5: (S)-2-amino-3- in acetone (20 mL) and H2O (20 mL) (5-methyl-1,2,4-oxadiazole-3-yl)propanoic acid (4.20g, 2 Add sodium bicarbonate (4.12g, 49.1mmol) to a 4.5mmol stirred solution. (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidine-1-yl) Carbonate (9.11 g, 27.0 mmol) was added at room temperature. Reaction temperature: 25°C The mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure and treated with acid-base solution, and then mixed with 10% MeOH / Extraction was performed using DCM (2 x 200 mL). The combined organic layers were dried with Na2SO4 and filtered. The crude compound was concentrated under reduced pressure. 120g of the crude compound was filtered using Biotage-isolera. The compound was purified twice using a silica cartridge, and then eluted with 10% MeOH / DCM. The pure fractions were combined and concentrated under reduced pressure. The isolated compound was then mixed with 10% diethyl acetate in hexane. Wash with a fluorine and dry under reduced pressure. (L)methoxy)carbonyl)amino)-3-(5-methyl-1,2,4-oxadiazo) (Lu-3-yl)propanoic acid was obtained. 21 H 19 N3O5[M+H] + MS ESI meter Calculated value: 394.13, measured value: 394.19. 1 1H NMR (400 MHz, DMSO-d 6):δ(ppm)12.95(br s,1H),7.89(d,J=7.6 Hz, 2H),7.76(d,J=8.0 Hz,1H),7.68(d,J=7.6 Hz, 2H),7.42(t,J=7.4 Hz,2H),7.31(t,J=7.4 Hz, 2H),4.33-4.64(m,1H),4.10-4.33(m,3H),2.97 -3.21 (m, 2H), 2.55 (s, 3H). Synthesis scheme 32 [ka]

[0262] Phe4AcPip [ka]

[0263] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-(4-acetylpiperazine-1-yl)phenyl)propanoic acid Step 1: (S)-3-(4-bromophenyl)-2-((t Stirring of ert-butoxycarbonyl(amino)propanoic acid (6g, 17.43 mmol) Add XPhos Pd G2 (2.057 g, 2.61 mmol) to the solution under nitrogen at 25°C. It was added. The resulting solution was stirred at 100°C for 10 minutes. 1-(piperazin-1-yl) Ethane-1-one (2.234 g, 17.43 mmol) and Cs2CO3 (5.04 (g, 26.1 mmol) was added, and the resulting solution was stirred at 110°C for 2 hours. Cool to room temperature, quench with H2O (500 mL), and extract with ا (2 × 500 mL). Removed. Washed the combined organic layers with brine (3 x 200 mL) and dried with anhydrous Na2SO4. The material was dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was eluted with 0-60% ethyl acetate in PE. Purified by silica gel column chromatography, (S)-3-(4-(4-acetyl Lupiperazin-1-yl)phenyl)-2-((tert-butoxycarbonyl)amino ) Propanic acid was obtained. C 20 H 30 N3O5[M+H] + The MS ESI calculation value is 392. 21. Measured value: 392.25. 1 1H NMR (400 MHz, methanol-d4) δ7.1 2(d,J=8Hz,2H), 6.89(d,J=8Hz,2H), 4.16-4.13 (m, 1H), 3.72-3.65(m, 4H), 3.14-3.04(m, 4H), 2 .93-2.81(m, 2H), 2.13(s, 3H), 1.38-1.29(m, 9H) ).

[0264] Step 2: In DCM (30 mL), (S)-3-(4-(4-acetylpiperazine-1-I (10g) Phenyl-2-((tert-butoxycarbonyl)amino)propanoic acid (10g) To a stirred solution of 25.5 mmol, TFA (30 mL) was added at room temperature. The mixture was stirred at °C for 1 hour, and then concentrated under reduced pressure. Crude (S)-3-(4-(4-acetylpy Further purification of perazine-1-yl)phenyl)-2-aminopropanoic acid It was used directly in the next step. C 15 H 22 N3O3[M+H] + MS ESI calculation Value 292.16, measured value 292.20.

[0265] Step 3: In THF (25 mL) and water (25 mL), (S)-3-(4-(4-acetyl Lupiperazin-1-yl)phenyl)-2-(carboxyamino)propanoic acid (7g, 2 In a stirred solution of 0.87 mmol, add Fmoc-OSu (6.34 g, 18) under nitrogen at 25°C. (0.79 mmol) was added. Then, NaHCO3 (8.77 g, 104 mmol) was added. It was added. The resulting mixture was stirred at 25°C for 2 hours. The pH was adjusted to 5 with 1N HCl. The mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic layer was extracted with brine (3 × Washed with 100 mL, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions, and C18 silicone was obtained. Using a 330g sample, mobile phase A is water (0.1% TFA) and mobile phase B is MeCN. Hold the radiant at 5%B for 5 minutes, increase it to 55%B within 15 minutes, and hold at 55%B for 5 minutes. Hold the flow rate, then increase it to 95%B within 20 minutes, hold at 95%B for 5 minutes, and increase the flow rate to 90%. The flow rate was set to mL / min, the detector to UV210nm, and the RT to 45 minutes. The fraction containing the product was collected. Concentrated in a vacuum, (S)-2-((((9H-fluoren-9-yl)methoxy)carb Nyl)amino)-3-(4-(4-acetylpiperazine-1-yl)phenyl)propane Acid was obtained. C 30 H 32 N3O5[M+H] + MS ESI calculated value: 514.23, measured value The value is 514.30. 1 ¹H NMR (400 MHz, methanol-d4) δ 7.78-7.7 6(m, 2H), 7.61-7.52(m, 2H), 7.40-7.37(m, 2H), 7.32-7.22(m, 4H), 7.08-6.98(m, 2H), 4.47-4.4 3(m, 1H), 4.33-4.31(m, 1H), 4.14-4.02(m, 2H), 3.68-3.63(m, 4H), 3.23-3.08(m, 5H), 2.91-2.8 5 (m, 1H), 2.11 (s, 3H).

[0266] Synthesis scheme 33 [ka]

[0267] 3AzaPhe4AcPip [ka]

[0268] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(6-(4-acetylpiperazine-1-yl)pyridine-3-yl)propanoic acid Step 1: 1-(piperazine-1-yl)ethane-1-one (2) in DMF (150 mL) A mixture of 1.85 g and 170 mmol of 5-bromo-2-fluorinated fluoride was heated under argon at room temperature. Lopyridine (15g, 85 mmol) was added. The reaction was stirred at 100°C for 2 hours, and then... Then, dilute with HCl (300 mL), add H2O (3 × 80 mL), and saturated NaCl aqueous solution. The solution was washed with (80 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0-100% ¼ / Elution was performed using a PE gradient. The fractions containing the desired product were combined and concentrated under reduced pressure. , 1-(4-(5-bromopyridine-2-yl)piperazine-1-yl)ethane-1- On was obtained. C11H15BrN3O[M+H] + MS ESI calculated value: 284.03 and 286.03, measured values ​​283.90 and 285.90 Step 2: Nickel(II) chloride ethylene glycol dimethyl A in DMA (2 mL) Thel complex (0.696 g, 3.17 mmol) and 1,10-phenanthroline (0. A mixture of 571g (3.17 mmol) was heated at 50°C for 0.5 hours. DMA (2 mL) ) 1-(4-(5-bromopyridine-2-yl)piperazine-1-yl)ethane-1- ON (4.5g, 15.84mmol), tert-butyl(R)-2-((((9H- Fluoren-9-yl)methoxy)carbonyl)amino)-3-bromopropanoate ( 7.78g, 17.42 mmol) and tetrabutylammonium iodide (5.85g A mixture of (15.84 mmol) was added at 25°C. Then, zinc powder (2.071 g) was added. (31.7 mmol) was added. The resulting mixture was stirred at 50°C for 1 hour. The mixture was poured into water (300 mL) and extracted with alkyl hydroxide (3 × 300 mL). The organic layer Wash with water (100 mL) and brine (2 x 80 mL), then dry with anhydrous sodium sulfate. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Elute with DCM / MeOH (10:1), tert-butyl(S)-2-((((9H- Fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(4-acetyl(P) Perazin-1-yl)pyridine-3-yl)propanoate was obtained. C33H39N4O 5[M+H] + MS ESI calculated value: 571.28, measured value: 571.40 Step 3: tert-butyl(S)-2-((((9H-fluorene-9-yl)methoxy (C)carbonyl)amino)-3-(6-(4-acetylpiperazine-1-yl)pyridine DCM (70 mL) containing -3-yl)propanoate (7.3 g, 12.79 mmol) To the mixture of ), TFA (70 mL, 909 mmol) was added under argon at room temperature. The solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in THF (20 mL). The mixture was then dissolved and purified by reverse-phase combi-flash under the following conditions to produce The fraction containing the substance was recovered and concentrated under vacuum, and (S)-2-((((9H-fluorene-9- (Iyl)methoxy)carbonyl)amino)-3-(6-(4-acetylpiperazine-1-I (L)pyridine-3-yl)propanoic acid was obtained. Column: C18 silica gel column (330 g, 20~35μm); Mobile phase A: 5mM TFA aqueous solution; Mobile phase B: MeCN; Diento: Hold at 0%B for 10 minutes, up to 42.3%B in 35 minutes, hold at 42.3%B for 3.2 minutes. Hold to 95% B in 2 minutes, hold at 95% B for 10 minutes); Flow rate: 60 mL / min; Detector: UV254 and 210nm; RT=35.32 mins. C29H31N4O5[M+H] + The MS ESI calculated value is 515.22, and the measured value is 515.15. 1 1H NMR (300MHz) Methanol-d4)δ7.87-7.79(m, 4H), 7.62-7.55(m, 2 H), 7.42-7.27(m, 4H), 7.11-7.09(m, 1H), 4.51- 4.46(m, 1H), 4.32-4.09(m, 3H), 3.65-3.54(m, 8 H), 3.29-3.20(m, 1H), 2.94-2.89(m, 1H), 2.12( s,3H).

[0269] Synthesis scheme 34 [ka]

[0270] KPEG2acidNMe3 [ka]

[0271] (S)-5-carboxy-1-(9H-fluoren-9-yl)-N,N,N-trimethicone Chil-3,11-dioxo-2,14,17-trioxa-4,10diazanonadecane- 19-Aminium-2,2,2-trifluoroacetate Step 1: tert-butyl 3-(2-(2-bromoethoxy) in ACN (100 mL) In a solution of ethoxypropanoate (10g, 33.6 mmol), add Me2NH(5.4 9 g (67.3 mmol) was added at room temperature. The reaction mixture was stirred at 90°C for 16 hours. The resulting solution was diluted with water (200 mL), extracted with EA (3 × 300 mL), and combined. The organic layer was washed with brine (3 x 300 mL), dried with anhydrous sodium 2SO4, and filtered. The residue was purified by silica gel column chromatography to obtain 0-10% MeOH / D Elute with CM gradient, tert-butyl3-(2-(2-(dimethylamino) Ethoxy)ethoxy)propanoate was obtained. C 13 H 28 NO4 [M+H] + MS ESI calculated value: 262.20, measured value: 262.15.

[0272] Step 2: Tert-butyl in DCM (100 mL) and TFA (100 mL) at 0°C 3-(2-(2-(dimethylamino)ethoxy)ethoxy)propanoate (8g, 3 A 0.6 mmol solution was prepared. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution The solution is concentrated under reduced pressure to obtain 3-(2-(2-(dimethylamino)ethoxy)ethoxy)propane C9H20 NO4 [M+H] + MS ESI calculated value: 206.13, measured value 206.10.

[0273] Step 3: 3-(2-(2-(dimethylamino)ethoxy)ethoxy in DMF (100mL) Mixed solution of xy)propanoic acid (6.5g, 31.7mmol) with HATU (24.08g) (63.3 mmol), DIEA (6.08 mL, 34.8 mmol) and tert- Butyl(((9H-fluoren-9-yl)methoxy)carbonyl)-L-ricinate( 13.44 g (31.7 mmol) was added at -40°C. The resulting mixture was then heated at -40°C. After stirring for 4 hours, quench the mixture with water (100 mL) and extract with EA (3 x 500 mL). Removed. Washed the combined organic layers with brine (3 x 100 mL) and dried with anhydrous Na2SO4. The sample was dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Purified by [method], eluted with a 0-50% EA / PE gradient, and tert-butyl ( S)-17-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)- 2-methyl-11-oxo-5,8-dioxa-2,12-diazaoctadecane-18- I got Oyeth. 34 H 50 N3O7[M+H] + MS ESI calculation value: 612.36 The measured value was 612.45. 1 ¹H NMR (300 MHz, chloroform-d) δ7.79- 7.76(m, 2H), 7.63-7.61(m, 2H), 7.44-7.41(m, 2 H), 7.35-7.30(m, 2H), 6.92(s, 1H), 5.56-5.53( m, 1H), 4.26-4.21(m, 2H), 3.87-3.85(m, 2H), 3. 73-3.71(m, 2H), 3.62-3.53(m, 5H), 3.30-3.20( m, 4H), 2.88(s,6H), 2.50-2.48(m, 2H), 1.84-1. 82(m, 1H), 1.70-1.68(m, 1H), 1.57-1.40(m, 13H ).

[0274] Step 4: In ACN (50 mL), tert-butyl(S)-17-((((9H-fluorine Len-9-yl)methoxy)carbonyl)amino)-2-methyl-11-oxo-5,8 -Dioxa-2,12-diazaoctadecane-18-oate (1g, 1.635mO) To the solution of (1), add NaHCO3 (0.137 g, 1.635 mmol) and MeI (0. 102 mL (1.635 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The obtained solution was diluted with water (100 mL) and extracted with HCl (3 × 300 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried with anhydrous sodium 2SO4. The mixture was filtered. The residue was concentrated under reduced pressure to obtain (S)-5-carboxy-1-(9H-fluore). N-9-yl)-N,N,N-trimethyl-3,11-dioxo-2,14,17-tri Oxa-4,10-diazanonadecane-19-aminium iodide was obtained. 35 H 52 N3O7[M-tBu] + The MS ESI calculated value is 570.32, and the measured value is 570.30.

[0275] Step 5: In DCM (100 mL), (S)-5-carboxy-1-(9H-fluorene- 9-yl)-N,N,N-trimethyl-3,11-dioxo-2,14,17-triox SA-4,10-diazanonadecane-19-aminium iodide (7g, 10.03mmo) To the stirred solution of (l), TFA (100 mL) was added at room temperature. The reaction mixture was left at room temperature for 1 hour. The mixture was stirred. The filtrate was concentrated under reduced pressure, and the residue was purified by RP flushing under the following conditions. Column: Flash C18 (330g); Mobile phase A: Water (0.1% TFA); Mobile phase B:ACN; Flow rate: 100 mL / min; 2% B in 10 minutes; 2%~20% B in 5 minutes; 20 20%~50% B in minutes; Detector: UV 210 nm. RT: 35 mins), (S)-5-C Ruboxy-1-(9H-fluoren-9-yl)-N,N,N-trimethyl-3,11- Dioxo-2,14,17-trioxa-4,10-diazanonadeccan-19-aminius We obtained 2,2,2-trifluoroacetate. 31 H 44 N3O7 + [M] + MS ESI calculated value: 570.32, measured value: 570.30. 1 1H NMR (300 MHz, C) D3OD)δ 7.83-7.80(m,2H),7.71-7.67(m,2H),7 .43-7.30(m,4H),4.44-4.32(m,2H),4.27-4.12 (m,2H),3.92-3.89(m,2H),3.74-3.70(m,2H),3 .62-3.53(m,6H),3.26-3.17(m,11H),2.44-2.4 0(m,2H),1.89-1.70(m,2H),1.59-1.39(m,4H). Synthesis scheme 35 [ka]

[0276] Ala3Oxad1245MeOMe [ka]

[0277] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(5-(methoxymethyl)-1,2,4-oxadiazole-3-yl)propane acid Step 1: (tert-butoxycarbonyl)-L-aspartate in pyridine (250 mL) In a stirred solution of lagin (100.0 g, 430.6 mmol), add acetone (500 mL) A solution of DCC (88.84 g, 430.6 mmol) was added dropwise at room temperature. The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered and treated with acetone (2 × 100 mL). Washed. The filtrate was concentrated under reduced pressure. The residue was diluted with DCM (500 mL) and 2N HC. Washed with 1 (300 mL) and water (200 mL). The combined organic layer was treated with Na2SO4. The crude compound was dried, filtered, and concentrated under reduced pressure. The crude compound was then treated with NaHCO3 and 2N HCl. Purified by acid-base treatment, (S)-2-((tert-butoxycarbonyl) We obtained amino)-3-cyanopropanoic acid. C9H 14 N2O4[M+H] + MS ES Calculated value: 215.10, measured value: 215.11.

[0278] Step 2: (S)-2-((tert-butoxycarbonyl)amino)-3-cyanopropyl A stirring solution of panic acid (37.00 g, 172.7 mmol) in DCM (200 mL) is added to the room At warm temperatures, tert-butyl(E)-N,N'-diisopropylcarbamimidate (34.60 g, 172.7 mmol) was added. During the reaction, a coagulated white precipitate formed. The reaction mixture was stirred at 45°C for 5 hours. The reaction mixture was filtered and stored in DCM (2 × 100 m). Washed with L). The filtrate was concentrated under reduced pressure. The crude compound was subjected to Biotage-isolation. The compound was purified using a 120g silica cartridge, and this compound was then converted to 30% ethyl acetate. It was eluted with petroleum ether. The pure fraction was combined and concentrated under reduced pressure to obtain tert-butyl(S )-2-((tert-butoxycarbonyl)amino)-3-cyanopropanoate is obtained. C 13 H 22 N2O4[M+H] + MS ESI calculated value: 271.16, measured value: 27 1.16.

[0279] Step 3: tert-butyl(S)-2-((tert-but) in DMSO (200 mL) Xycarbonyl(amino)-3-cyanopropanoate (45.0g, 166mmol) To the stirred solution, add sodium bicarbonate (105 g, 1.25 mol) and hydroxyl chloride Ammonium (63.6 g, 916 mmol) was added at room temperature. Reaction mixture temperature: 100°C The mixture was stirred for 16 hours. The reaction mixture was cooled to 25°C, and then citric acid was added to water (200 mL). The mixture was then extracted with ethyl acetate (2 x 500 mL). The combined organic layer was dried with Na2SO4. The solution is filtered, concentrated under reduced pressure, and then tert-butyl(S)-2-( We obtained cyclo()amino)-4-(hydroxyamino)-4-iminobutanoate. C 13 H 25 N3O5[M+H] + The MS ESI calculated value is 304.18, and the measured value is 304. 30.

[0280] Step 4: In ACN (150 mL), tert-butyl(S)-2-((tert-butoxy Cicarbonyl)amino)-4-(hydroxyamino)-4-iminobutanoate (19. A stirring solution of 00g, 62.63 mmol of cesium carbonate (40.81g, 125.3 mmol) is added. ( mmol), 2-methoxyacetyl chloride (8.156 g, 75.16 mmol) The mixture was added at warm temperature. The reaction mixture was stirred at 25°C for 3 hours. Then, the reaction mixture was stirred at 80°C for 3 hours. The mixture was stirred for a certain amount of time. Then, the reaction mixture was quenched with water (100 mL) and toluene (2 × Extraction was performed using 150 mL. The combined organic layers were dried with Na2SO4, filtered, and then removed under reduced pressure. The crude compound was concentrated. 120g silica carton was prepared using Biotage-isolera. The compound was purified using a ridge and eluted with 40% ethyl acetate / petroleum ether. Combine the ingredients and concentrate under reduced pressure to obtain tert-butyl(S)-2-((tert-butoxy Carbonyl)amino)-3-(5-(methoxymethyl)-1,2,4-oxadiazole -3-yl)propanoate was obtained. C 16 H 27 N3O6[M+H] + MS ESI Calculated value: 358.19, measured value: 358.41.

[0281] Step 5: In DCM (60 mL), tert-butyl(S)-2-((tert-butoxy Carbonyl)amino)-3-(5-(methoxymethyl)-1,2,4-oxadiazole To a stirred solution of -3-yl)propanoate (11.0g, 30.8 mmol), TFA ( 47.4 mL (616 mmol) was added at room temperature. The reaction mixture was stirred at 25°C for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was co-distilled with toluene (20 mL) under reduced pressure. After drying, (S)-2-amino-3-(5-(methoxymethyl)-1,2,4-oxa Diazole-3-yl)propanoic acid was obtained. C7H 11 N3O4[M+H] +MS E SI calculated value: 202.07, measured value: 202.17.

[0282] Step 6: (S)-2-amino-3- in acetone (30 mL) and H2O (30 mL) (5-(methoxymethyl)-1,2,4-oxadiazole-3-yl)propanoic acid (6 In a stirred solution of 0.20g, 30.8mmol, sodium bicarbonate (5.18g, 61.6 mmol) and (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidine) -1-yl)carbonate (11.4 g, 33.9 mmol) was added at room temperature. The reaction mixture was then mixed. The mixture was stirred at 25°C for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to acid-base treatment. The combined organic layer was extracted with 10% MeOH / DCM (2 x 200 mL). The crude compound was dried with O4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was then processed using Biotag. The compound was purified twice using e-isolera with a 120g silica cartridge. The substance was eluted with 10% MeOH / DCM. The pure fraction was combined and concentrated under reduced pressure. The substance was isolated. The compound was washed with 10% diethyl ether in hexane and dried under reduced pressure to obtain the compound. .

[0283] The compound was analyzed by chiral SFC on a Chiralpak-AS-H column (3 × 25 cm²). Using a 5μm solution, a fixed composition of 80% CO2 and 20% (0.5% formic acid / IPA) was used, with a flow rate of 9 0g / min, temperature 30.0℃, back pressure 120.0bar, 75.0mg per infusion, stacked. The sample was further purified under conditions of 15.0 minutes.

[0284] The pure fractions were combined, concentrated under reduced pressure, and then freeze-dried separately to obtain the (R)-2-( (((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(5-(me Toxymethyl)-1,2,4-oxadiazole-3-yl)propanoic acid (C 22 H 21 N3O6[M+H] + The MS ESI calculated value was 424.14, and the measured value was 424.22. 1 H NMR (400MHz, DMSO-d6), VT90℃: δ(ppm)12.91(br s, 1H), 7.87(d, J=7.6Hz, 2H), 7.50-7.71(m, 3H ), 7.41(t, J=7.4Hz, 2H), 7.31(td, J=7.4, 1.0Hz , 2H), 4.69(s, 2H), 4.32-4.50(m, 1H), 4.15-4.3 0 (m, 3H), 3.35 (s, 3H), 3.04-3.17 (m, 2H)) and P (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amide (no)-3-(5-(methoxymethyl)-1,2,4-oxadiazole-3-yl)pro Panic acid was obtained. 22 H 21 N3O6[M+H] + MS ESI calculation value 424.14, Actual measured value: 424.22. 1 H NMR (400MHz, DMSO-d6) VT90℃:δ( ppm)12.80(brs, 1H), 7.87(d,J=7.6Hz,2H), 7.6 6(d,J=7.2Hz,2H), 7.58(brs, 1H), 7.41(t,J=7. 4Hz,2H), 7.25-7.36(m, 2H), 4.69(d,J=2.8Hz,2 H), 4.38-4.50(m, 1H), 4.14-4.32(m, 3H), 3.35( s,3H), 3.05-3.18(m,2H).

[0285] Preparation of the final compound: A. General procedure for synthesizing linear peptide precursors As illustrated below, using standard solid-phase synthesis with Fmoc / tBu chemistry The peptide shown in Figure 1 was synthesized. Chan, WC; White, PD "Fmoc Solid-Phase Synthesis: a Practical Appro ach”, Oxford University Press, Oxford, 2000 ;Steward, J.;Young, J. “Solid Phase Peptide "Synthesis", Pierce Chemical Company, Rock ford, 1984; Benoiton, NL “Chemistry of Pep” “Tide Synthesis”, CRC Press, New York, 2006; and Lloyd-Williams, P.; Albericio, F.; Giralt ,E. “Chemical Approaches to the Synthesis of Peptides and Proteins”,CRC Press,New York, 1997.

[0286] During peptide chain elongation, the α-amino group of each amino acid is 9H-fluoren-9-ylmethoxy. Protected with a carbonyl group (Fmoc). To avoid side reactions during the chain extension process, the reactive group was protected. All of the side chains of amino acids have acid-unstable protecting groups, and when treated with strong acids, they remain unchanged until the protective groups are removed. Effectively masks the responsive group. After each coupling step, the Fmoc group of the N-terminal amino acid Remove with piperidine or 4-methylpiperidine, wash the resin thoroughly, and then proceed to Fmoc Preparations were made for coupling the protected amino acid derivative.

[0287] The side-chain protecting groups used were 3Pal4CO2H, 3Pal4Ph4CO2H, alT, and a MeD, aMeS, Bip4CO2H, daMeD, daMeS, hS, Phe4COO H, Phe4Pyrim5CO2H, Proc4OH, PyrimAla4Ph4CO2 For H, S, and T, it is tert-butyl (tBu), Ac4cN, AlaP iperaz, aMeDab, aMeK, Dab, daMeK, K, PipH, and O For rn, it is tert-butoxycarbonyl (Boc), and for Q, it is trityl (Trt) is the case for R, which is 2,2,4,6,7-pentamethyldihydrobenzofur It is n-5-sulfonyl (Pbf), and for D, it is β-methylpentyl ester (OM It is pe).

[0288] Fmoc protective amino acids are typically Sigma-Aldrich, Novabio Obtained from suppliers such as chem, Chem-Impex, and Combi-Block. Ta.

[0289] B. Synthetic procedure used to prepare cyclic peptides Synthesis scheme 36 [ka]

[0290] Solid-phase synthesis of peptide protocol A As summarized in Scheme 36 above, standard solid-phase synthesis using Fmoc / tBu chemistry This is due to the Liberty Blue (trademark) synthesizer manufactured by CEM Corporation. Peptides were synthesized using a sizer.

[0291] N,N'-Diisopropylcarbodiimide (DIC) and ethylcyano(hydroxy Imino acetate (Oxyma) is used as a coupling agent to bond to the resin. An amide bond is formed between the free amino terminus of the protective peptide and the carboxylic acid of the Fmoc-protected amino acid. It was formed.

[0292] H-Gly-supported 2-chlorotrityl resin (200-400 mesh, load capacity 0.79 m³) mol / g, 1% cross-linked polystyrene (Novabiochem) was used in the synthesis. The amino acids were dissolved in DMF (N,N-dimethylformamide) at a concentration of 0.2 M. Equimolar amounts of Oxyma solution (0.5 M in DMF) and 2x molar excess of DIC solution (DMF) The amino acids were activated using 1.0 M of fluorine. Alternatively, the amino acids were activated using DMF (N,N- The amino acid was dissolved in dimethylformamide at a concentration of 0.125 M. ma Pure solution (containing 0.125M; 0.05M DIEA in DMF) and The reaction was activated using a 2x molar excess of DIC solution (0.25 M in DMF). The reaction was typical. This was performed on a 25 μmol scale.

[0293] All synthetic cycles involve the removal of Fmoc-amino acids with 20% piperidine in DMF. Protection (microwave-assisted heating at 90°C for 2 minutes) and Fmoc-protected amino acids / DIC / Ox Coupling using yma (may be repeated twice in the case of difficult couplings) (so Includes 5, 5, and 10 equivalents respectively; microwave-assisted heating at 90°C for 2 or 4 minutes. Then, Fmoc deprotection was performed using the desired monomer until a complete linear peptide was formed. The coupling cycle of Fmoc-protective amino acids was repeated.

[0294] Peptide Solid-Phase Synthesis Protocol B Alternatively, the peptide can undergo Fmoc / tBu chemistry as summarized in Scheme 36 above. Using the standard solid-phase synthesis method employed, Biotage® Syro II peptide was synthesized. It was synthesized manually on a synthesis apparatus. HATU and DIPEA were used as coupling agents. Then, the free amino terminus of the protective peptide bound to the resin and the carboxylic acid of the Fmoc protective amino acid are connected. An amide bond was formed between them. H-Gly supported 2-chlorotrityl resin (200~40 0 mesh, loading amount 0.79 mmol / g, 1% cross-linked polystyrene, Novabioch em) was used in the synthesis. All amino acids were dissolved in 1:1 DMF:NMP at a concentration of 0.2 M. The reaction was carried out on a typical 12 μmol scale.

[0295] All synthesis cycles included: (1) Fmoc protected amino acids / HA Coupling using TU / DIPEA (2 repeats) (4, 4, and 8 equivalents respectively; chamber) Warm; 15 minutes). The mixture was filtered and the peptidyl resin was washed with DMF (2 × 1 mL). 2) Fmoc deprotection (3 repetitions): 20% 4-methylpiperidine / DMF (1 mL; chamber) Warm; 3 minutes). Filter the mixture and wash the peptidyl resin with DMF (4 × 1 mL). Complete Fmoc deprotection and Fmo using the desired monomer until a linear peptide is formed. The coupling cycle of C-protective amino acids was repeated.

[0296] Selective cleavage and macrolactamization of protective peptides To cleave the protected linear peptide from the solid support, peptidyl resin (approximately 16m) is used. g) in 25% hexafluoroisopropanol (HFIP) in DCM at room temperature for 20 minutes. After processing and filtration, the solvent was removed under reduced pressure. The resulting residue was dissolved in DMF (5 mL). The mixture was prepared by adding HATU (0.44 equivalents) and DIPEA (2.5 equivalents). The mixture was stirred at room temperature for 5 minutes. Then, an additional 0.66 equivalents of HATU were added. UPLC- After macrolactamization was completed, as monitored by MS, the solvent was removed under reduced pressure.

[0297] Final side chain deprotection A solution of TFA / H2O / TIS (90 / 8 / 2, v / v / v, 1 mL) is applied to a crude protective cyclic puncture plate. It was added to the butyl ether. The mixture was stirred at room temperature for 10 minutes. Cold diethyl ether (15 mL) The peptide was added to the solution. The peptide was precipitated by centrifugation (3200 rpm, -10°C). The precipitate was washed with diethyl ether (2 x 10 mL) and dried overnight under vacuum. The deprotected cyclic peptide was obtained as a solid.

[0298] HPLC purification Purification is performed using Waters MS-Directed AutoPurification Using an HPLC / MS system, Waters X-Bridge Prep C 18. OBD Prep column (130 Å, 5 pm, column size 19 × 100 mm) This was performed by preparative reverse-phase high-performance liquid chromatography (RP-HPLC). Mobile phase: (A) 0.16% TFA in HPLC water and (B) 0.16% TFA in HPLC acetonitrile TFA; Flow rate: 25 mL / min; UV wavelength λ=215 nm; Gradient: 25~ over 5 minutes 50% B. Alternatively, purification can be done using an Agilent 1290 Infinity II preparative tray. Using an LC system and an LC-MSD XT mass spectrometer, Waters CSH-C The procedure was performed on an 18-column (19 x 250 mm, 5 μm). Mobile phase: (A) HPLC water 0.1% formic acid and (B) HPLC 0.1% formic acid in acetonitrile; flow rate: 25 mL / min; UV wavelength λ=215nm; gradient: 20% B over 2.5 minutes, 5% B over 2.5-20 minutes. 5% B. The UV absorption fraction containing the target m / z ions is recovered, and the fraction containing the product is divided into L Verified by C / MS.

[0299] The purity of the fraction was confirmed by UPLC, and this was then analyzed using reverse-phase WatersAcquityUPL. Measured using a C-MS system. Column: WatersXSelectCSHC18 Column (130 Å, 2.5 μm, column size 2.1 * 50 mm). Mobile phase: (A (B) 0.05% TFA in HPLC water and (B) 0.05% TF in HPLC acetonitrile A; Injection volume: 1μL; Flow rate: 1mL / min; UV wavelength λ=215nm; Gradient: 5-100% B in 5 minutes. Freeze-drying of the combined fraction containing pure peptides yields the most The cyclization product was obtained as a powder.

[0300] Biological assays: Procedure for IL-6 assay in MRC5 cells We evaluated the inhibition of IL-1β-induced IL-6 secretion in MRC5 cells. (2X EC8) Recombinant human IL-1β (BioLegend 579404) at a concentration of 0 was placed in a seeding medium. 0.025% BSA (Sigma A9) in EMEM (ATCC 30-2003) 576), 1X penicillin / streptomycin (Gibco 15070-063), 1X NEAA(Gibco 11140-050), 1X GlutaMax(Gibco (CO 35050-061) and 1X sodium pyruvate (Gibco 11360 Prepared under conditions containing -070). 20 μL of IL-1β was added to 384 wells of collagen. Add to a coated plate (Corning 354664) and ECHO555 liquid hydration solution. The compound, dispensed using a 200 nL syringe, was pre-incubated at ambient temperature for 1 hour. This involved using 3000 human lung fibroblast cells (MRC5 cells, ATCC CCL-171). Cells were added at a density of 20 μL / well. The cells were then treated with 10% fetal bovine serum (Gibco 1614). 0-071), 1X penicillin / streptomycin (Gibco 15070-063) ), 1X NEAA(Gibco 11140-050), 1X GlutaMax(G (Gibco 35050-061) and 1X sodium pyruvate (Gibco 113) In EMEM (ATCC 30-2003), a growth medium containing 60-070), Collagen By passing it through three times in a Gen-coated T175 flask (Greiner 661950) Prepare and sterilize with 0.25% trypsin-EDTA (Gibco 25200-056) 5 After digestion for several minutes, it was collected in seeding medium. 384 wells containing a final volume of 40 μL of cola The oxygen-coated plates were incubated overnight at 37°C in 5% CO2. (Manufacturer's professional) According to Tokol, the human AlphaLISAIL-6 kit (PerkinElmerAL To detect IL-6 using 223F), 5 μL of conditioned medium was added to 38 Transfer to a 4-well AlphaLISA plate (PerkinElmer 6005350) 20 μL of acceptor beads / biotinylated antibody mixture in a 384-well AlphaL The donor bead mix was added to an ISA plate and incubated at ambient temperature for 1 hour. Protect from light, add 25 μL to the plate, and incubate at ambient temperature for 30 minutes. The AlphaLISA plate is set up for AlphaScreen (laser exc 68 Using 0nm and EMIs 570nm, EnVision multimode preamplifier Read using a tone reader (Perkin Elmer Model 2104). Dose-response curve. and IC 50 The value is from Spotfire software (Tibco, Palo Alto The analysis was performed using a four-parameter logistic equation in CA.

[0301] Amino acid sequences and biological activity (MRC) of Examples 1-103 (SEQ ID NOs. 1-465) I C 50 ), calculated single isotope mass, molecular formula, calculated molecular weight and mass spectrum The data ([M+2H] / 2+ or [M+H]+) is shown in Figure 1.

[0302] The subject matter disclosed is to the extent of the specific embodiments and examples described herein. It should not be limited. In fact, in addition to what is described, various changes to this disclosure are as stated above. Such modifications will be apparent to those skilled in the art from the description and attached drawings. It is intended to be included within the scope of the patent claims.

[0303] All references cited herein (e.g., publications or patents or patent applications) ) is as if all individual references (e.g., publications or patents or patent applications) are all It is specifically and individually indicated that the whole is incorporated by reference for the purpose of [the purpose of the entirety of the project]. To the same extent, the entirety of it is incorporated herein by reference for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. Compound of formula (I) 【Chemistry 1】 (In the formula, R １ teeth, (i)R １ａ -C(O)N(H)-CH ２ CH ２ -O-、 R １ａ teeth, (a) C １ -C ３ Alkyl or (b)(CH ３ ) ３ N-CH ２ CH ２ -M- (In the formula, M is -CH) ２ -ien-CH ２ CH ２ -ien-CH ２ CH ２ CH ２ -, -O-CH ２ CH ２ - 、 or -O-CH ２ CH ２ -O-CH ２ CH ２ - is) and (ii)(CH ３ ) ３ N-CH ２ CH ２ -O-、 (iii) C １ (In the formula, C １ teeth: (a) Phenyl or 5-6 member monocyclic heteroaryl, wherein N, O and S A 5-6 member monocyclic heteroatom containing 1-3 heteroatoms independently selected from the group. It is a reel, (b) A 5-6 member heterocycloalkyl that is saturated and composed of N, O and S A 5-6 membered heterocycloalkyl group containing one or two heteroatoms selected from the group. (In the formula, C １ is either unsubstituted or halo, C １ -C ３ Alkyl, C １ -C ３ Full Oroalkyl, carboxy, C １ -C ３ Alkoxy, C ２ -C ３ Acyl and C １ -C ３ One to three R independently selected from the group consisting of alkoxymethyl compounds Ｃ１ Substituting with substituents (is) and (iii) (CH ３ ) ３ N-CH ２ CH ２ -O-, or (iv) group 【Chemistry 2】 And, R Ａ teeth, (-)-CO ２ H、 (--)-CO ２ NH ２ 、 (iii)-S(O) ２ NH ２ ,or (iv) Two or three heterogenes independently selected from the group consisting of N, O, and S A five-member heteroaryl ant, including the offspring. (In the formula, the 5-membered heteroaryl is either unsubstituted or halo, C) １ -C ３ Alkyl, C １ -C ３ Alkoxy, oxo, and C １ -C ３ Independently from the group consisting of alkoxymethyls (Substituted by one or two substituents selected by) R Ｂ These are amino, hydroxy, or fluoro, R ２ but, (i) Naphthyl, or (ii) A bicyclic heteroaryl having 9 to 10 members, wherein the 9 to 10 members bicyclic heteroaryl A loaryl is a heteroatom independently selected from the group consisting of N, O, and S. Includes (In the formula, R ２ is either non-substituted or halo, C １ -C ３ Alkyl and C １ -C ３ One or two R independently selected from the group consisting of alkoxys ２ａ Substituting with substituents (ru), R ３ は、-(CH ２ ) ｍ CO ２ H、-(CH ２ ) ｍ CO ２ NH ２ 、-(CH ２ ) ｍ CO ２ N(CH) ３ ) ２ 、 - (CH ２ ) ｍ CH ２ N(H)C(O)NH ２ , or - (CH ２ ) ｍ -C ３ and (In the formula, C ３ It contains 2 to 4 heteroatoms selected from the group consisting of N, O, and S. It is a five-membered heteroaryl; In the formula, C ３ is unsubstituted or selected from the group consisting of halo and C １ -C ３ alkyl (Substituted with one or two selected substituents); R ４ C １ -C ３ It is alkyl, R ５ is H, C １ -C ３ alkyl, or -CH ２ CO ２ H, or R ４ and Call R ５ These, together with the atoms to which they are attached, become pyrrolidinyl, piperidinyl, or form an azepinyl ring, X １ , X ２ and X ３ These are independently C(H) or N, R Ｄ teeth, (i) Ring C Ｄ And ring C Ｄ (a) phenyl, or (b) cyclohexyl Yes, ring C Ｄ is one A １ Replaced with A １ is, -CO ２ H, -CONH ２ , or -N (H)SO ２ CH ３ Is it, (ii) Hydroxyl, (iii)-CO ２ NH ２ ,or (iv)-OCH ２ CH ２ C(O)N(H)C(O)CH ３ And, A ２ is H, halo, or C １ -C ３ It is alkyl, R ６ は、-H、-NH ２ 、-C(O)N(CH ３ ) ２、 -(CH) ２ ) ｎ NH ２、 -(C) H ２ ) ｎ N(H)CH ３、 -(CH ２ ) ｎ N(CH ３ ) ３ 、-OH、 -(CH ２ ) ｎ OH、-OCH ３ ,-(EH ２ ) ｎ OCH ３ ,-(EH ２ ) ｎ CH ３ 、 -(CH) ２ ) ｎ N(H)C(O)NH ２ 、 -(CH ２ ) ｎ CH ２ C(O)OH、-(CH ２ ) ｎ N(H)C(O)CH ２ CH ２ O (CH) ２ CH ２ -O) ｑ -CH ２ CH ２ N(CH) ３ ) ３ 、 or -C ６ And, C ６ but, (i) a monocyclic aryl or heteroaryl with 5 to 6 members, the 5 to 6 members A cyclic heteroaryl is independently selected from the group consisting of N, O, and S. Monocyclic aryl or heteroaryl containing a telogen atom, (ii) A bicyclic aryl or heteroaryl with 9 to 10 members, the 9 to 10 One to four bicyclic heteroaryls are independently selected from the group consisting of N, O, and S. A bicyclic aryl or heteroaryl containing a heteroatom, or (iii) A monocyclic or bicyclic cycloalkyl group with 3 to 8 members, Here, C ６ is either unsubstituted or halo, amino, hydroxy, carboxy, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, C １ -C ３ Alkoxy and C １ - C ３ One to three R independently selected from the group consisting of alkoxymethyl compounds Ｃ６ Substituting with substituents It is done, R ７ but, H, C １ -C ４ Alkyl, -(CH ２ ) ｕ OH, - (CH ２ ) ｕ C(O)N(CH ３ ) ２ ,-(EH ２ ) ｕ N(CH) ３ ) ３ ,-(EH ２ ) ｕ OCH ３ 、 -(CH ２ ) ｕ C(O)NC(O)NH ２ 、 -(CH) ２ ) ｕ N(H)C(O)CH ２ CH ２ O(CH) ２ CH ２ -O) ｖ -CH ２ CH ２ N(CH) ３ ) ３ 、 or -CH ２ -C ７ And, C ７ but, (i) A five-membered molecule containing 2 to 4 heteroatoms selected from the group consisting of N, O, and S. heteroaryl, or (ii) A 5-6 member heterocycloalkyl that is saturated and contains one oxygen atom It is a 5-6 member heterocycloalkyl, Here, C ７ is either non-substituted or halo, C １ -C ３ Alkyl, C １ -C ３ a Lucoxi and C １ -C ３ One or two substituents selected from the group consisting of alkoxymethyl compounds. It has been replaced with, R ８ -H, -F, -OH, -NH ２ , -N(CH ３ ) ３ , (CH ３ ) ３ N-(CH ２ ) ｒ -C(O)-, or (CH) ３ ) ３ N-CH ２ CH ２ -O-(CH ２ CH ２ -O) ｓ -CH ２ CH ２ -C(O) ) - and R ９ is, -C ９ or -CH2-C ９ And, C ９ is a phenyl or a 5-6 member monocyclic heteroaryl, and is a 5-6 member monocyclic heteroaryl. The teloaryl is one or two heterogenes independently selected from the group consisting of N, O, and S. It is a 5-6 member monocyclic heteroaryl containing a child, C ９ is either non-substitutive or halo , amino, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl and C １ - C ３ One to three R independently selected from the group consisting of alkoxys Ｃ９ Substituting with substituents And further C ９ This is a single ring R Ｃ９Ｃ It may also be replaced with Ring R Ｃ９Ｃ teeth, (a) Phenyl, or (b) One or two heteroatoms independently selected from the group consisting of N, O, and S It contains a 5-6 member monocyclic heteroaryl, The subscript m is either 1 or 2. The subscript n is 1, 2, or 3. The subscript q is 1, 2, or 3. The subscript r is 3, 4, 5, or 6. The subscript 's' is either 1 or 2. The subscript t is either 0 or 1. The subscript u is 0, 1, 2, 3, or 4. The subscript v is 1, 2, or 3. The subscript 'w' is either 0 or 1), or The pharmaceutically acceptable salt.

2. C １ It is phenyl, R ２ It is indolyl or naphthyl, C ６ phenyl, indolyl, pyridyl, pyridadinyl or bicyclo[1.1.1 ] is pentanyl, C ９ is phenyl or pyrimidinyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ CH ３ -C(O)N(H)-CH ２ CH ２ -O- or 4-fluorophenyl A compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ２ The compound according to claim 1, wherein is unsubstituted or substituted naphthyl or indolyl or its pharmaceutically acceptable salt.

5. R ３ ga- (CH ２ ) ｍ CO ２ The compound according to claim 1, which is H, or the pharmaceutically acceptable compound or the compound which is H Tolerable salt.

6. The compound according to claim 5, wherein the subscript m is 1, or a pharmaceutically acceptable salt thereof. 。

7. R ４ and R ５ The compound according to claim 1 or the pharmaceutically acceptable compound wherein is methyl Obtain salt.

8. X １ and X ２ is C(H) and A １ is carboxyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R ６ but, (i) A substituted or unsubstituted 5- to 6-membered monocyclic aryl or heteroaryl, The aforementioned 5-6 member monocyclic heteroaryl contains 1-2 N atoms, and the monocyclic aryl also ku is heteroaryl, or (ii) A substituted or unsubstituted 9-10 member bicyclic heteroaryl, 1-2 The compound according to claim 1 or the drug, which is a bicyclic heteroaryl containing N atoms. A scientifically acceptable salt.

10. R ６ The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound is indolyl. 。

11. R ７ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is H.

12. R ８ is H or -NH ２ The compound according to claim 1 or the pharmaceutically acceptable Obtain salt.

13. R ９ However, the compound according to claim 1 is substituted at the 4-position of the pyrrolidinyl ring as shown in the illustration. Compounds or pharmaceutically acceptable salts thereof.

14. C ９ The compound according to claim 13, wherein is a substituted or unsubstituted phenyl or pyrimidinyl A substance or its pharmaceutically acceptable salt.

15. R ９ ga-CH ２ - (4-fluorophenyl) or pyrimidine-5-yl, claim The compounds described in item 1 or their pharmaceutically acceptable salts.

16. R １ CH ３ -C(O)N(H)-CH ２ CH ２ -O- or 4-fluorophenyl And, R ２ These are unsubstituted or substituted naphthyl or indolyl, R ３ is, -(CH ２ ) ｍ CO ２ It is H, R ４ and R ５ It is methyl, X １ and X ２ is C(H), A １ It is a carboxyl, A ２ H is, R ６ teeth, (i) A substituted or unsubstituted 5- to 6-membered monocyclic aryl or heteroaryl, The aforementioned 5-6 member monocyclic heteroaryl contains 1-2 N atoms, and the 5-6 member monocyclic heteroaryl contains 1-2 N atoms. Reel or heteroaryl, or (ii) A substituted or unsubstituted 9-10 member bicyclic heteroaryl, one to two It is a bicyclic heteroaryl containing an N atom, R ７ H is, R ８ is H or -NH ２ And, R ９ It is substituted at the 4-position of the pyrrolidinyl ring as shown in the diagram. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. R ６ However, it is an indolyl, R ９ This is a substituted -CH group at position 4 of the pyrrolidinyl ring as shown in the diagram. ２ - (4-Fluoro It is lophenyl) or pyrimidine-5-yl, The subscript m is 1. The compound according to claim 16 or a pharmaceutically acceptable salt thereof.

18. The compound of formula (I) is the compound of claim 1 or the drug having formula (IA). Scientifically acceptable salts 【Transformation 3】 (In the formula, R １ teeth, (i)R １ａ -C(O)N(H)-CH ２ CH ２ -O-、 R １ａ teeth, (a) Methyl, or (b) (CH ３ ) ３ N-CH ２ CH ２ -O-CH ２ CH ２ - or (ii) (CH ３ ) ３ N-CH ２ CH ２ -O-, or (iii) 4-carboxyphenyl, R ２ is, 【Chemistry 4】 or 【Transformation 5】 And, R ２ａ is halo or methyl, The subscript x is either 0 or 1. R ３ is, -CH ２ CO ２ H or -CH ２ -It is tetrazolyl, R ４ and R ５ Is it methyl? Alternatively, R ４ and R ５ Together with the atoms to which they are attached, they form piperidinyl Forming a ring, R Ｄ is 4-carboxyphenyl or hydroxy, R ６ teeth, 【Transformation 6】 or 【Transformation 7】 It is a base selected from, R ７ is H or methyl, R ８ -H, -NH ２ Or it is -OH, C ９ teeth, 【Transformation 8】 or 【Chemistry 9】 (It is a base selected from the others.)

19. A compound according to claim 1 or a drug selected from the group consisting of Sequence ID Nos. 1 to 465. A scientifically acceptable salt.

20. The following (each with sequence numbers 1, 2, 78, 80, 82, 92, 94, 95, 98, 99): Select from the group consisting of 100, 101, 102, 215, 216, 217, and 218. The compound described in claim 1: 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 、 and 【Chemistry 11】 、 or a pharmaceutically acceptable salt thereof.

21. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

22. A method for treating atherosclerosis, wherein the therapeutically effective amount is any of claims 1 to 20 Any compound described in item 1 or a pharmaceutically acceptable salt thereof, which requires such treatment A method that includes administering the substance to a target.

23. A method for treating vasculitis, described in any one of claims 1 to 20, in a therapeutically effective amount. The compound or a pharmaceutically acceptable salt thereof is administered to a subject requiring such treatment. A method that includes doing something.

24. A method for treating inflammatory disorders, wherein the therapeutically effective amount is described in any one of claims 1 to 20. The compound or a pharmaceutically acceptable salt thereof is administered to a subject requiring such treatment. A method that includes giving in to something.

25. An effective amount of the compound or a pharmaceutically acceptable salt thereof is orally administered to the subject. The method according to any one of the claims 22, 23, and 24.

26. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable compound in the treatment of compound or a pharmaceutically acceptable compound according to any one of claims 1 to 20. Possible use of salt.

27. A method for treating atherosclerosis, according to any one of claims 1 to 20. Use of a compound or a pharmaceutically acceptable salt thereof.

28. A compound according to any one of claims 1 to 20 or the for treating vascular inflammation Use of pharmaceutically acceptable salts.

29. A compound or so according to any one of claims 1 to 20 for treating inflammatory disorders The use of pharmaceutically acceptable salts.

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