Novel pegylated compounds, compositions comprising the same and uses thereof

Abstract

This invention provides a class of compounds with IL-17 inhibitory activity. Specifically, it provides a class of compounds with IL-17A / A and / or IL-17A / F inhibitory activity. These compounds can be used to prepare pharmaceutical compositions for treating diseases related to IL-17A / A and / or IL-17A / F activity. (I')

Description

Technical Field

[0001] This invention relates to novel IL-17 inhibitors, pharmaceutical compositions comprising said compounds, and their uses. Methods for treating, preventing, and managing inflammatory conditions using said compounds and compositions are also disclosed. Background Technology

[0002] Interleukin-17 (IL-17) is a T-cell-derived pro-inflammatory molecule that can stimulate epithelial cells, endothelial cells, and fibroblasts to produce other inflammatory cytokines and chemokines, including IL-6, IL-8, G-CSF, and MCP-1. The IL-17 cytokine family, including IL-17A through IL-17F, promotes the maintenance of adaptive and innate immunity (Gaffen SL. Structure and signaling in the IL-17 receptor family. Nat Rev Immunol. 2009; 9(8):556–567). Dysregulation of IL-17 expression may lead to inflammatory and autoimmune diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and multiple sclerosis (Li X, Bechara R, Zhao J et al. IL-17 receptor–based signaling and implications for disease. Nat Immunol. 2019;20(12):1594–1602). Therefore, they are promising new targets for the treatment of inflammatory diseases.

[0003] Interleukin-17A (IL-17A) is the most studied member of the IL-17 family. It is a pro-inflammatory cytokine that plays a key role in immune and autoimmune-related diseases, including psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis (Tollenaere MAX, Hebsgaard J, Ewald DA, et al. Signaling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways. British Journal of Dermatology. 2021;185(3):585–594; Ostling J, Geest M, Schofield JPR, et al. IL-17–high asthma with features of a psoriasis immunophenotype. Journal of Allergy and Clinical Immunology). 2019;144(5):1198–1213; Blauvelt A, Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriaticarthritis pathogenesis. Clin Rev Allergy Immunol. 2018;55(3):379–390; Kirkham BW, Kavanaugh A, Reich K. Interleukin-17A: a unique pathway in immune-mediated diseases psoriasis, psoriatic arthritis and rheumatoid arthritis. Immunology. 2014;141(2):133–142.IL-17A forms homodimers or heterodimers with IL-17A or IL-17F and is a major cytokine secreted primarily by Th17 cells. It signals through its membrane-bound receptors IL-17RA and IL-17RC, regulating the IL-17A signaling pathway and triggering various inflammatory and immune responses. Therefore, IL-17A has become a major research topic in the treatment of inflammation-related diseases.

[0004] Currently, three approved monoclonal antibodies (mAbs) – secukinumab, ixekizumab, and brodalumab – are being used in clinical practice as IL-17A inhibitors to treat various immune diseases. However, drawbacks such as non-oral administration, poor tissue penetration, lack of blood-brain barrier penetration, and often long half-lives limit the application scope of monoclonal antibodies.

[0005] In this regard, Leo Pharma A / S and Dice Alpha, Inc. have developed a series of small-molecule IL-17A inhibitors and began Phase I clinical trials in 2021 and 2022, respectively. Eli Lilly has developed a series of potent imidazo[1,2-b]pyridazine derivatives for the treatment of certain symptoms of psoriasis, rheumatoid arthritis, or multiple sclerosis. In 2021, Eli Lilly initiated a Phase I clinical trial for one of these compounds to investigate IL-17A-related diseases. Unfortunately, the clinical trial was discontinued due to hepatotoxicity.

[0006] Therefore, there is still a need to develop small molecule IL-17A inhibitors with improved properties, low toxicity, and high activity, especially IL-17A / A or IL-17A / F inhibitors. Summary of the Invention

[0007] The purpose of this invention is to provide a novel class of compounds of formula (I') as inhibitors of IL-17A / A or IL-17A / F.

[0008] In a first aspect of this invention, a compound of formula (I'), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product, or prodrug thereof, is provided: (I') in, Group The group is connected to the parent nucleus of formula (I') via a nitrogen atom, and is selected from the group consisting of: 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S; and 6-13 membered spiroheterocyclic groups containing one or more heteroatoms selected from O, N, and S; wherein the heterocyclic group may optionally be connected to one or more heteroatoms selected from hydrogen, halogen, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; X is N or C; When X is N, Rd2 does not exist; Group A is selected from the following: * A 5-12 membered heteroaryl group containing one or more nitrogen atoms, wherein the heteroaryl group is optionally substituted by one or more substituents, wherein the substituents are independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C... 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl and 4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl contains one or more heteroatoms independently selected from O, S and N; and *-NH-C(O)-R4, where R4 is selected from: C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 5-12 Aryl, 5-12 heteroaryl, -OC 3-7 cycloalkyl, -O-CH2-C 3-7 cycloalkyl and -O-CH2-C 5-7 The heteroaryl group may optionally be substituted by one or more substituents, said substituents being independently selected from halogens, hydroxyl groups, cyano groups, amino groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Alkoxy, phenyl, phenoxy, 5-6 membered heteroaryl and 4-7 membered heterocyclic alkyl; said heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms independently selected from O, S and N; R1 and R 1’ Independently selected from hydrogen, deuterium, and C 1-6 Alkyl, C2-6 alkenyl, C 2-6 Alkyne group, deuterated C 1-6 Alkyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl group, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy groups, halogens, halogenated C 1-6 Alkyl, cyano, -N(C) 1-6 Alkyl group, trifluoromethyl group, amino group, hydroxyl group; R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, -N(C 1-6 alkyl)2,-NH-C 1-6 Alkyl group, -NHC(O)-C 1-6 Alkyl, -NHC(O)-(C 3-7 cycloalkyl), -NHC(O)-(4-7 membered heterocyclic group), -NHC(O)-(4-7 membered heteroaryl group), -NHC(O)-O-NH-C 1-6 Alkyl group, -NHC(O)-NH-(C 3-7 cycloalkyl), -NHC(O)-NH-(C 1-6 alkyl), -NHC(O)-N(C) 1-6 Alkyl)(C 3-7 cycloalkyl), -NHC(O)-OC 1-6 Alkyl, -NHC(O)-OC 3-7 Cycloalkyl, -NHC(O)-N(C) 1-6 Alkyl)2, -NHC(O)-N(C 3-7 cycloalkyl)2, -NHC(O)-O-CH2-C 3-7 cycloalkyl, -NHSO2-C 1-6 Alkyl group, -NHSO2-NH-C 1-6 Alkyl group, -NHSO2-N(C 1-6 alkyl)2, -NHC(O)-(C 1-6 alkylene)-NHC(O)-C 1-6 Alkyl, -NHC(O)-(C 1-6 alkylene)-NHC(O)-OC 1-6 alkyl; Optionally substituted with one or more substituents, said substituents being independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Cycloalkyl, deuterium, halogen, cyano, trifluoromethyl, amino, hydroxyl; the heterocyclic or heteroaryl group comprises one or more heteroatoms independently selected from O, S, and N; R a and R a’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, cyano, trifluoromethyl, amino, hydroxyl, -C 1-3 Alkoxy, C 3-7 cycloalkyl and C 3-7 Heterocyclic group; the heterocyclic group comprises one or more heteroatoms independently selected from O, S and N; R3 is selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; R b and R b’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl and C 5-10 Heteroaryl; optionally substituted with one or more substituents, said substituents being independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, cyano, trifluoromethyl, amino, hydroxyl and -C 1-3 alkoxy; or R b and R b' Together with the carbon atoms they are attached to, they form C 3-8 Carbon ring, C 5-9 Spiral ring, C 5-10 Aromatic ring or 5-10 nucleotide aromatic heterocycle, optionally selected independently by one or more nucleotides selected from methylene (=CH2), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-3 Substituents of alkoxy, halogen, cyano, trifluoromethyl, amino, and hydroxyl groups; the substituents may optionally be substituted with one or more halogens and deuterium; L is absent or selected from -O- and -NH-; m is 0, 1, or 2; and Rd1 is selected from: * , , , as well as * Hydroxyl group, -OC 1-6 Alkyl, mercapto, -SC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2,-C 1-6 Alkyl group, -C(O)H, -C(O)C 1-6 Alkyl group, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C) 1-6 alkyl)2, -NHC(O)H, -NHC(O)(C 1-6 Alkyl groups), -SONH2, -SONHC 1-6 Alkyl, -SON(C 1-6 alkyl)2, sulfonic acid group, -SO2C 1-6 Alkyl groups, -SO2-NH2, -SO2-NHC 1-6 Alkyl, -SO2-N(C) 1-6 Alkyl)2, C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, -C(O)-C 3-8 Carbocyclic and -C(O)- 3-8 membered heterocyclic groups; each substituted by p of the following substituents: or two substituents (e.g.) Together, they form a heterocycle with more than 15 ring atoms and more than 5 oxygen atoms; Rd1 is optionally selected by one or more elements chosen from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; and each They can be the same or different; Y represents O, -CH2-O-, or a chemical bond; p is an integer selected from 1 to 16; n is an integer selected from 3 to 100; Re is selected from the following groups: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-12 Aromatic group (C 1-6 olefins), 5-12 membered heteroaryl groups (C 1-6 Alkynes), C 3-12 cycloalkyl (C 1-6 Alkenes), 3-12 membered heterocyclic groups (C 1-6 Alkenes, optionally substituted with one or more substituents, the substituents being independently selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heteroaryl, 4-7 membered heterocyclic, halogenated C 3-7 Cycloalkyl, halogenated 4-7 membered heterocyclic groups, halogenated C 1-6 Alkyl groups; wherein the heteroaryl and heterocyclic groups contain one or more heteroatoms selected from O, S, and N; Rd2 is selected from the following groups: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aromatic group, 5-12 heteroaryl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, optionally substituted with one or more substituents, the substituents being independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic, halogenated C 1-6 Alkyl groups; wherein the heteroaryl and heterocyclic groups contain one or more heteroatoms selected from O, S, and N; Group It is a 3-7 membered heterocycle containing one or more heteroatoms from the following: O, N and S, and X is C. Rd2 is connected to the rest of the molecule through a quaternary carbon, meaning that Rd2 is not a hydrogen atom. In another preferred embodiment, in formula (I'), R b and R b’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 6-10 Aryl and C 5-10 heteroaryl; optionally selected by one or more independently chosen from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7Cycloalkyl, halogen, cyano, trifluoromethyl, amino, hydroxyl and -C 1-3 Substitution of alkoxy groups; or R b and R b' Together with the carbon atoms they are attached to, they form C 3-8 Carbon ring, C 5-9 Spiral ring, C 5-10 Aromatic ring or 5-10 nucleotide aromatic heterocycle, optionally selected independently by one or more nucleotides selected from methylene (=CH2), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-3 Substituents include alkoxy, halogen, cyano, trifluoromethyl, amino, and hydroxyl groups; the substituents may optionally be substituted with one or more halogens. In another preferred embodiment, in formula (I'), Rd2 is selected from: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl groups, each optionally being selected independently by one or more elements selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl, halogenated C 1-6 Alkyl substituents; the heteroaryl and heterocyclic alkyl groups contain one or more heteroatoms independently selected from O, S, and N; Rd2 is connected to the rest of the structure via tertiary carbon.

[0009] In another preferred embodiment, the compound represented by formula (I') is represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product, or prodrug thereof: (I) in, Rd1 is , or selected from the following substituents: -hydroxyl, -alkyl (C 1-6 ), -mercapto, -alkylthio (C 1-6 -NH2, -alkylamino (C 1-6 ), -dialkylamino (C 1-6 ), alkyl (C 1-6 ), -carboxyl group, -alkylcarbonyl group (C 1-6 ), -carbamoyl, -alkylcarbamoyl (C 1-6 ), -dialkylcarbamoyl (C1-6 ), -carbamoylamino, -carbamoylalkyl (C 1-6 ), -sulfonylamino, -alkylsulfonylamino, -dialkylsulfonylamino, -sulfonyl, -alkylsulfonyl, -aminosulfonyl, -alkylaminosulfonyl, -dialkylaminosulfonyl, carbocyclic (C 3-8 ) and heterocyclic rings (3-8 members); each is substituted by p substituents as follows: And optionally selected by one or more elements chosen from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; and each substituent They can be the same or different; Rd2 is selected from: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl groups and 3-12-membered heterocycloalkyl groups, each optionally selected by one or more elements independently chosen from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl, halogenated C 1-6 Alkyl substituents; the heteroaryl and heterocyclic alkyl groups contain one or more heteroatoms independently selected from O, S, and N; Rd2 is connected to the rest of the structure via tertiary carbon. A, R1, R1', R2, R3, Re, p, n, m, L, Ra, Ra', Rb, and Rb' are as defined above.

[0010] In another preferred embodiment, the compound is represented by the following formula: (I) Among them, A, L, R a R a' R b R b' R3, R2, R1, R 1' Rd1, m and Rd2 are defined as above.

[0011] In another preferred embodiment, the group yes or Where X can be C or N, and when X is N, Rd1 does not exist. The ring C is selected from 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S, and C. 3-7 cycloalkyl; Preferably, the group yes , , or ; in, Optionally selected by one or more elements chosen from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents.

[0012] In another preferred embodiment, in the group middle, The group is selected from the following: 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S; 6-13 membered spirocyclic heterocyclic groups containing one or more heteroatoms selected from O, N, and S; wherein the heterocyclic group is optionally surrounded by one or more heteroatoms selected from hydrogen, halogen, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents, X as defined above.

[0013] In another preferred embodiment, p is selected from 1, 2, 3, 4, 5, 6, 7, 8, and preferably, p is selected from 1, 2, 3.

[0014] In another preferred embodiment, group A is selected from: *A 5-12-membered aromatic heterocycle, wherein the heteroaromatic ring contains one or more nitrogen atoms (preferably, group A is selected from 5-7-membered heteroaromatic rings), the heteroaromatic ring optionally being substituted by one or more substituents, the substituents being independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, phenyl, phenoxy, 5-6 membered heteroaromatic rings and 4-7 membered heterocycles, wherein the 5-6 membered heteroaromatic ring and the 4-7 membered heterocycle contain one or more heteroatoms selected from O, S, N; as well as *-NH-C(O)-R4, R4 (Selected from:) C 3-12Cycloalkyl, 3-12 membered heterocyclic, C 5-12 Aromatic group, 5-12 membered heteroaryl group, -OC 3-7 Cycloalkyl, -O-CH2-C 3-7 Cycloalkyl, -O-CH2- 5-7 heteroaryl; (preferably, R4 is selected from C 3-7 Cycloalkyl, 3-7-membered heterocyclic, C 6-10 Aromatic group, 5-7 membered heteroaromatic group, -OC 3-7 Cycloalkyl, -O-CH2-C 3-6 Cycloalkyl, -O-CH2- (5-7-membered heteroaryl); optionally substituted by one or more substituents, the substituents being independently selected from halogens, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Cycloalkoxy, phenyl, phenoxy, 5-6 membered heteroaryl, 4-7 membered heterocyclic; preferably substituted with one or more substituents, the substituents being independently selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Cycloalkoxy, phenyl, phenoxy, 5-6 membered heteroaryl, 4-7 membered heterocyclic; wherein the heterocyclic and heteroaryl groups contain one or more of the following atoms: O, S, N. In another preferred embodiment, L is absent, m is 0, and the compound is represented by the following formula (IA): (IA) Among them, fragment A, fragment B, and R b R b' R3, R2, R1, R 1' Rd1 and Rd2 are defined as above.

[0015] In another preferred embodiment, L is absent, m is 0, and the compound is represented by formula (IB): (IB) Among them, fragment A, fragment B, and R b R b' R3, R 2a R 2a' R1, R 1' Rd1 and Rd2 are defined as above.

[0016] In another preferred embodiment, L is absent, m is 0, and the compound is represented by formulas (Ia-1), (Ia-2), and (Ia-3): (Ia-1) (Ia-2) (Ia-3) in, Fragment A is selected from -NH-C(O)-R4, where R4 is selected from: C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, C 5-12 aryl, 5-12 heteroaryl, optionally selected by one or more independently chosen from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents of alkoxy, halogen, cyano, amino, and hydroxyl groups; the heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms independently selected from O, S, and N; R b and R b’ Each is independently selected from C 3-7 cycloalkyl; or R b and R b' Together with the carbon atoms to which they are attached, they can optionally be bonded by one or more methylene (=CH2), halomethylene, C 1-6 Alkyl, Halogenated C 2-6 Alkenyl or halogen-substituted C 3-8 Carbon rings; The ring C is selected from 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S, and C. 3-7 cycloalkyl; R3, R1, R2, Rd1, Re, p, n, and Rd2 are defined as above.

[0017] In another preferred embodiment, fragment A is selected from -NH-C(O)-R4, and R4 is selected from C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, C 6-10 Aryl and 5-7 heteroaryl groups, optionally selected independently from C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents of alkoxy, halogen, cyano, amino, and hydroxyl groups; the heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms independently selected from O, S, and N.

[0018] In another preferred embodiment, fragment A is selected from -NH-C(O)-R4, where R4 is selected from 5-7 heteroaryl groups; optionally, one or more components are independently selected from C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents include alkoxy, halogen, cyano, amino, and hydroxyl groups; the heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms independently selected from O, S, and N. In another preferred embodiment, fragment A is selected from -NH-C(O)-R4, where R4 is... ; Optionally selected by one or more independently chosen from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents of alkoxy, halogen, cyano, amino, and hydroxyl groups; the heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms independently selected from O, S, and N.

[0019] In another preferred embodiment, the compound is represented by formulas (Ib-1), (Ib-2), and (Ib-3): (Ib-1) (Ib-2) (Ib-3) in, Fragment A2 is a 5-12 heteroaryl group, optionally selected independently from C14 by one or more groups. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents of alkoxy, halogen, cyano, amino, and hydroxyl groups; the heteroaryl group comprises one or more heteroatoms independently selected from O, S, and N; R 2a and R 2a' Independently selected from: hydrogen, C 1-6 Alkyl, C 3-7Cycloalkyl; each group is optionally substituted by one or more substituents independently selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Cycloalkyl, deuterium, halogen, cyano, trifluoromethyl, amino, hydroxyl; The ring C is selected from 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S, and C. 3-7 cycloalkyl; R b R b' R3, R1, Rd1, Re, n, p, and Rd2 are as described above.

[0020] In another preferred embodiment, portion A2 is defined as R4. In another preferred embodiment, Rd1 is ; Optionally selected by one or more elements chosen from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents.

[0021] In another preferred embodiment, Rd1 is selected from -C(O)-H, -OC 1-6 Alkyl, -C(O)-NH2, -C 1-6 Alkyl, C 3-8 Carbocyclic group, -N(C) 1-6 Alkyl group 2, each substituted by p substituents as shown below: And optionally selected by one or more elements chosen from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; each They can be the same or different. In another preferred embodiment, Rd1 is selected from , , Preferably substituted with one or more of the following substituents: hydrogen, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogenated C 1-6 alkyl.

[0022] In another preferred embodiment, Rd1 is selected from amino groups, -NHC 1-6 alkyl, -C(O)H, -OC 1-6 Alkyl group, -C(O)NH2, -C 1-6 Alkyl, C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, -C(O)-C 3-8 Carbocyclic group, -C(O)- 3-8 membered heterocyclic group, -N(C 1-6 Alkyl group 2, each substituted with p of the following substituents: , or two substituents (e.g. Together, they form a heterocycle with more than 15 ring atoms and more than 5 oxygen atoms; preferably substituted with one or more of the following substituents: hydrogen, halogen, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogenated C 1-6 Alkyl; each substituent They can be the same or different. In another preferred embodiment, Rd1 is selected from amino, -NHC 1-6 alkyl, -C(O)H, -OC 1-6 Alkyl group, -C(O)NH2, -C 1-6 Alkyl, C 3-8 Carbocycloalkyl, 3-8 membered heterocyclic group, -C(O)- 3-8 membered heterocyclic group, -N(C 1-6 Alkyl group 2; is substituted by p substituents as follows Or two substituents connected to the same nitrogen atom (e.g., It forms a ring structure with this nitrogen atom, such as -(CH2CH2-O-). q -CH2CH2-; q is an integer selected from 3 to 30; optionally substituted with one or more of the following substituents: hydrogen, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogenated C 1-6 Each alkyl group They can be the same or different. In another preferred embodiment, Rd1 is * ; optionally substituted with one or more of the following substituents: hydrogen, halogen, C 1-6Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogenated C 1-6 alkyl; * Amine group, -NHC 1-6 alkyl, -C(O)H, -OC 1-6 Alkyl group, -C(O)NH2, -C 1-6 Alkyl, C 3-8 Carbonyl, 3-8 membered heterocyclic group, -C(O)-C 3-8 Carbocyclic group -C(O)- 3-8 membered heterocyclic group, -N(C 1-6 Alkyl group 2; is substituted by p substituents as follows: , or two substituents (e.g. Together, they form a heterocycle having more than 15 ring atoms and more than 5 oxygen atoms; preferably substituted with one or more of the following substituents: hydrogen, halogen, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogenated C 1-6 Alkyl; each Same or different; and n and Re as described above. In another preferred embodiment, yes , , or , Re as described above. In another preferred embodiment, n is selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30. In another preferred embodiment, q is an integer selected from the following range: 3-10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25. In another preferred embodiment, Y is O.

[0023] In another preferred embodiment, Y is -CH2-O-.

[0024] In another preferred embodiment, Y is a chemical bond.

[0025] In another preferred embodiment, Re is selected from C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic alkyl, C 6-10 Aryl (C 1-6 alkylene), 5-7 aryl (C 1-6 Alkylene), C 3-7 cycloalkyl (C 1-6 alkylene groups and 3-7 membered heterocyclic alkyl groups (C 1-6 Alkylenes, each optionally substituted with one or more substituents, said substituents being independently selected from hydrogen, halogens, C... 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7-membered heteroaryl, 4-7-membered heterocycloalkyl, halogenated C 3-7 Cycloyl, halogenated 4-7 membered heterocyclic cycloalkyl and halogenated C 1-6 Alkyl groups; preferably independently selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7-membered heteroaryl, 4-7-membered heterocycloalkyl and halogenated C 1-6 Alkyl substituents; the heteroaryl and heterocyclic alkyl groups contain one or more heteroatoms independently selected from O, S, and N. In another preferred embodiment, fragment A2 is a 5-7 membered heteroaryl group, optionally substituents by one or more heteroatoms independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents of alkoxy, halogen, cyano, amino, and hydroxyl groups; the heteroaryl group contains one or more heteroatoms independently selected from O, S, and N.

[0026] In another preferred embodiment, n is an integer selected from 3 to 50, preferably an integer selected from 3 to 30.

[0027] In another preferred embodiment, Re is selected from the following groups: C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 3-7 cycloalkyl (C 1-6 alkylene groups and 3-7 membered heterocyclic groups (C 1-6 Alkylenes; each optionally substituted with one or more substituents, said substituents being independently selected from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7Cycloalkyl, 4-7 membered heterocyclic alkyl, halogenated C 3-7 Cycloalkyl, halogenated 4-7 membered heterocyclic alkyl and halogenated C 1-6 Alkyl groups; preferably each optionally composed of one or more elements independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl, halogenated C 1-6 Alkyl substituents.

[0028] In another preferred embodiment, R3 is selected from halogens, preferably F.

[0029] In another preferred embodiment, R1 and R 1’ Independently selected from hydrogen, deuterium, and C 1-6 Alkyl group, preferably methyl group.

[0030] In another preferred embodiment, R1 is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl and Halogenated C 1-6 Alkyl; R 1’ It is halogen, deuterium, or hydrogen.

[0031] In another preferred embodiment, R1 is selected from methyl, R 1’ It is hydrogen.

[0032] In another preferred embodiment, R2 is selected from -NHC(O)-C 1-6 Alkyl group, -NHC(O)-NH-(C 3-7 cycloalkyl), -NHC(O)-NH-(C 1-6 alkyl), -NHC(O)-N(C) 1-6 Alkyl)(C 3-7 cycloalkyl), -NHC(O)-N(C 1-6 Alkyl)2, -NHC(O)-N(C 3-7 cycloalkyl)2, -NHC(O)-O-CH2- C 3-7 cycloalkyl, -NHSO2-NH-C 1-6 Alkyl group, -NHSO2-N(C 1-6 alkyl)2, -NHC(O)-(C 1-6 alkenyl)-NHC(O)-OC 1-6 alkyl; Optionally selected by one or more independently chosen from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Substitution with cycloalkyl, deuterium, halogen, cyano, trifluoromethyl, amino, or hydroxyl groups.

[0033] In another preferred embodiment, R2 is selected from -NHC(O)-NH-(C 3-7 cycloalkyl), -NHC(O)-NH-(C 1-6 alkyl), -NHC(O)-N(C) 1-6 Alkyl)(C 3-7 cycloalkyl), and -NHC(O)-N(C 1-6 Alkyl)2, -NHC(O)-N(C 3-7 cycloalkyl)2; Optionally selected by one or more independently chosen from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Substitution with cycloalkyl, deuterium, halogen, cyano, trifluoromethyl, amino, or hydroxyl groups.

[0034] In another preferred embodiment, R2 is selected from -NHC(O)-N(C) 1-6 Alkyl)(C 3-7 cycloalkyl), optionally composed of one or more independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Substitution with cycloalkyl, deuterium, halogen, cyano, trifluoromethyl, amino, or hydroxyl groups. In another preferred embodiment, R2 is selected from... and . In another preferred embodiment, Rd2 is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl and C 3-7 Cycloalkyl groups, each optionally composed of one or more elements independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl and halogenated C 1-6 Alkyl substituent substitution; preferably, Rd2 is selected from C 1-6 Alkyl, C 2-6 alkenyl and C 3-7Cycloalkyl groups; each optionally composed of one or more elements independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl and halogenated C 1-6 Alkyl substituents.

[0035] In another preferred embodiment, R b and R b’ Each is independently selected from C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl and C 5-7 Heteroaryl (preferably R) b and R b′ Each independently chooses C. 3-7 cycloalkyl; more preferably R b and R b' Each can independently choose its own freedom C 3-5 cycloalkyl; more preferably R b and R b′ Each is selected independently from C 3-4 cycloalkyl); Each is arbitrarily selected by one or more independent choices from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, cyano, trifluoromethyl, amino, hydroxyl and -C 1-3 The alkoxy group is substituted, preferably, each optionally by one or more substituents independently selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cyclic groups, halogens, cyano groups, trifluoromethyl groups, amino groups, hydroxyl groups, and -C 1-3 Alkoxy; Or R b and R b' Together with the carbon atoms they are attached to, they form C 3-7 Carbon rings, or 5-7 membered heterocycles (preferably, R) b and R b' Together with the carbon atoms attached to them, they form C 5-7 Carbon ring; more preferably, R b and R b' Together with the carbon atom it is attached to, they form C 6-7 Carbon ring; more preferably, R b and R b'Together with the carbon atom it is attached to, they form C 6-7 Cycloalkyl.

[0036] Each is optionally substituted by one or more substituents, said substituents being independently selected from methylene (=CH2), halogenated (=CH2), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-3 Alkoxy, halogen, cyano, trifluoromethyl, amino, hydroxyl; substituents may optionally be substituted with one or more halogens and deuterium (preferably substituents may optionally be substituted with one or more halogens).

[0037] In another preferred embodiment, R b and R b' Each is independently selected from C 3-7 Cycloalkyl groups, optionally composed of one or more independently selected from C10 and C20. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, halogen, cyano, trifluoromethyl, amino, hydroxyl and -C 1-3 Substitution of alkoxy groups; Or R b and R b' Together with the carbon atoms they are attached to, they form C 5-8 The carbocyclic ring may optionally be independently selected from methylene, halomethylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-3 Substituents of alkoxy, halogen, cyano, trifluoromethyl, amino, or hydroxyl groups; the substituents may optionally be substituted with one or more halogens.

[0038] In another preferred embodiment, X is N, Rd2 does not exist; Rd1 is . In another preferred embodiment, the compound is selected from the following compounds: Each n is independently selected from an integer between 3 and 50. Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product, or prodrug.

[0039] It should be understood that the compounds of the present invention are not limited to those listed above.

[0040] In another preferred embodiment, the compounds are those prepared in the examples.

[0041] In another preferred embodiment, the heterocyclic group and carbocyclic group may be saturated or partially unsaturated, or unsaturated, substituted or unsubstituted, aromatic or non-aromatic.

[0042] In some preferred embodiments, the heterocyclic group and carbocyclic group may be present in a fused, bridged or helical connection.

[0043] In another preferred embodiment, each group is a corresponding group in a specific compound in the examples.

[0044] In a second aspect of the invention, a pharmaceutical composition is provided comprising a compound according to the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, deuterated product or prodrug thereof, and a pharmaceutically acceptable excipient.

[0045] In another preferred embodiment, the pharmaceutical composition is used to prepare a single-component dosage form.

[0046] In another preferred embodiment, the single-unit dosage form provided herein is suitable for oral, mucosal, parenteral, topical, transdermal, or transdermal administration to patients.

[0047] In another preferred embodiment, examples of dosage forms include, but are not limited to: tablets; capsule tablets; capsules, such as soft elastic gelatin capsules; stamps; pills; lozenges; dispersions; suppositories; powders; aerosols; gels; liquid dosage forms suitable for oral or mucosal administration to patients, including suspensions, solutions, and elixirs; liquid dosage forms suitable for parenteral administration to patients; eye drops or other ophthalmic preparations suitable for topical administration; and reconfigurable sterile solids to provide liquid dosage forms suitable for parenteral administration to patients.

[0048] In another preferred embodiment, the dosage form comprises 1 mg to about 1000 mg, about 5 mg to about 500 mg, about 10 mg to about 350 mg, or about 50 mg to about 200 mg of a compound of the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, deuterated product, or prodrug thereof.

[0049] In another preferred embodiment, the pharmaceutical composition comprises a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product, or prodrug thereof, and optionally a second active agent for treating inflammatory diseases, proliferative diseases, and autoimmune diseases.

[0050] In a third aspect of the invention, a method for treating a disease or condition in a subject in need is provided, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product or prodrug of the second aspect of the invention, or a pharmaceutical composition thereof, wherein the disease or condition is selected from inflammatory diseases, proliferative diseases and autoimmune diseases.

[0051] In a fourth aspect of the invention, the use of a compound of the first aspect of the invention or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product or prodrug thereof, or a pharmaceutical composition of the second aspect of the invention, in the preparation of a medicament for the prevention or treatment of a disease or condition, wherein the disease or condition is selected from inflammatory diseases, proliferative diseases and autoimmune diseases.

[0052] In a fifth aspect of the invention, a method is provided for preventing or treating a disease or condition, wherein the disease or condition is selected from inflammatory diseases, proliferative diseases, and autoimmune diseases. This method includes a compound according to a first aspect of the invention, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product, or prodrug thereof, or a pharmaceutical composition according to a second aspect of the invention.

[0053] In another preferred embodiment, the disease or condition is selected from plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, aspartic arthritis, ankylosing spondylitis, hidradenitis suppurativa, palmoplantar psoriasis, airway inflammation, ankylosing spondylitis, asthma, rheumatoid arthritis, osteoarthritis, spondyloarthritis, bone erosion, intraperitoneal abscess and adhesions, IBD, Crohn's disease, allogeneic transplant rejection, psoriasis, psoriatic arthritis, certain types of cancer, vascular... Indications include: atherosclerosis and multiple sclerosis, lupus, allergen exposure, Helicobacter pylori-associated gastritis, bronchial asthma, asthma, allogeneic transplant rejection (e.g., kidney), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, rheumatoid arthritis (RA), inflammatory bowel disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye disease, uveitis, and non-infectious uveitis.

[0054] In another preferred embodiment, the compound of the first aspect of the invention or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, deuterated product or prodrug is administered in combination with another drug (“second active agent”) or treatment.

[0055] In another preferred embodiment, the second active agent comprises small molecules and macromolecules (e.g., proteins and antibodies).

[0056] In another preferred embodiment, other therapies that may be used in conjunction with the administration of the compounds provided herein include, but are not limited to, surgery, immunotherapy, biotherapy, radiotherapy, and other non-pharmacological therapies that may be used to treat or prevent the various diseases described herein.

[0057] It should be understood that, within the scope of this invention, each of the above-described technical features and each of the technical features specifically described below (such as embodiments) can be combined with each other to constitute new or preferred technical solutions. Due to space limitations, further details will not be elaborated here.

[0058] Brief description of the graphic Detailed Implementation

[0059] Through long-term and in-depth research, the inventors unexpectedly discovered a class of compounds with inhibitory effects on IL-17A / A or IL-17A / F. This invention is based on this discovery.

[0060] definition As used herein, unless otherwise stated, the terms used have the general meanings known to those skilled in the art. As used herein, unless otherwise specified, all chemical formulas are intended to cover any possible optical or geometric isomers (such as R-type, S-type, or racemic, or cis-trans isomers of alkenes, etc.).

[0061] As used herein, unless otherwise stated, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon having the number of carbon atoms described herein. Representative saturated straight-chain alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The term "alkyl" also includes cycloalkyl. In some embodiments, the alkenyl group is optionally substituted, as described elsewhere herein.

[0062] As used herein, unless otherwise stated, an alkenyl group refers to a straight-chain or branched hydrocarbon having a plurality of carbon atoms as described herein and containing one or more double bonds. Exemplary alkenyl carbon chains contain 2 to 20 carbons and 1 to 8 double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, butenyl, and 4-methylbutenyl. In some embodiments, the alkenyl group is optionally substituted, as described elsewhere herein.

[0063] As used herein, unless otherwise stated, an alkynyl group refers to a straight-chain or branched hydrocarbon having a plurality of carbon atoms as described herein and containing one or more triple bonds. Exemplary alkynyl carbon chains have 2 to 20 carbon atoms and contain 1 to 8 triple bonds. Exemplary alkynyl groups herein include, but are not limited to, ethynyl, propynyl, butynyl, isobutyl, pentyynyl, hexynyl, etc. As used herein, lower alkyl, lower alkenyl, and lower alkynyl groups refer to carbon chains having about 1 or about 2 carbon atoms to about 6 carbon atoms.

[0064] As used herein, unless otherwise stated, the term “carbocyclic” or “carbocyclic” refers to a non-aromatic ring or ring system containing only carbon atoms in its ring skeleton. When a carbocyclic group is a ring system, two or more rings may be connected together by fusion, bridging, or spirolinking. A carbocyclic group may have any degree of saturation, provided that at least one ring in the ring system is not an aromatic ring. Thus, carbocyclic groups include cycloalkyl, cycloalkenyl, and cycloynyl groups. A carbocyclic group may have 3 to 20 carbon atoms, although this definition also covers the occurrence of the term “carbocyclic” without specifying a numerical range. A carbocyclic group may also be a medium-sized carbocyclic group having 3 to 10 carbon atoms. A carbocyclic group may also be a carbocyclic group having 3 to 6 carbon atoms. A carbocyclic group may be specified as “C3-6 carbocyclic” or similar names. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, and spiro[2.5]octyl.

[0065] As used herein, unless otherwise stated, the term "cycloalkyl" refers to an alkyl group that is cyclic and contains 3 to 9, 3 to 6, or 3 to 5 carbon atoms without alternating or resonant double bonds between the carbon atoms. It may contain 1 to 4 rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. A cycloalkyl group may be substituted with one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused with an aryl or heteroaryl group. Bridged ring systems are also included in the definition of "cycloalkyl".

[0066] As used herein, unless otherwise stated, the terms "heterocyclic alkyl" or "heterocyclic group" refer to a cycloalkyl group in which one or more carbon atoms are substituted with heteroatoms, such as, but not limited to, N, S, and O. In some embodiments, the heterocyclic alkyl group contains 2 to 8, 2 to 7, 2 to 5, or 2 to 4 carbon atoms. Heterocyclic alkyl groups can be attached to the host structure at heteroatoms or carbon atoms to produce stable compounds. Exemplary heterocyclic alkyl groups or heterocyclic groups include, but are not limited to, morpholinyl, thiomorpholinyl, pyranyl, imidazoalkyl, oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, piperidinyl, azacyclic butyl, oxacyclic butyl, and piperazineyl.

[0067] As used herein, unless otherwise stated, the term "aromatic" refers to a ring or ring system having a conjugated π-electron system, including carbocyclic aromatics (such as phenyl) and heterocyclic aromatic groups (such as pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent atomic pairs) groups, provided that the entire ring system is aromatic.

[0068] As used herein, unless otherwise stated, the term "aryl" refers to a carbocyclic aromatic ring containing 5 to 10 ring atoms. All ring atoms in a carbocyclic aryl group are carbon atoms. Aromatic ring structures include compounds having one or more ring structures, such as monocyclic and bicyclic compounds. Exemplary aryl groups include phenyl and naphthyl.

[0069] As used herein, unless otherwise stated, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system, in some embodiments about 5 to about 10 members, wherein one or more atoms in the ring system, in one embodiment 1 to 3, are heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, or sulfur. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroleyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzodiazolyl, benzotriazolyl, phenyloxazolyl, furanpyridyl, imidazolepyridyl, midazothiazolyl, indoleyl, indazoleyl, isobenzofuranylisobenzothiophenyl, isoindoleyl, isoquinolinyl, isothiazolyl, naphridyl, oxazolylpyridyl, phthalazinyl, pteridinyl, purineyl, pyridyl, pyrrolopyridyl, quinolinyl, quinoxalolinyl, quinazolinyl, thiadiazolylpyridyl, and thienopyridyl. Heteroaryl groups can be fused to an aromatic ring, heterocyclic ring, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents, as described elsewhere herein.

[0070] As used herein, unless otherwise stated, the terms "alkoxy" or "alkyloxy" or "alkyloxy group" refer to a stable straight-chain or branched or cyclic hydrocarbon group, or a combination thereof, consisting of the stated number of carbon atoms and one or more, in one embodiment, one to three oxygen atoms, wherein at least one oxygen atom is located at the position where the alkoxy group is attached to the remainder of the molecule. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy. In one embodiment, the alkoxy group may optionally be substituted, as described elsewhere herein.

[0071] As used herein, unless otherwise stated, the term "halogen" means F, Cl, Br, or I. A "halogenated" or "halogenated" group means that one or more hydrogen atoms in the group are replaced by a halogen.

[0072] As used herein, unless otherwise stated, the term "methylene" refers to =CH2.

[0073] As used in this article, and They are equivalent.

[0074] As used herein, unless otherwise stated, the term “oxo” is represented by (=O) as an alternative to other common representations.

[0075] As used herein, unless otherwise stated, the term "deuterium" refers to an isotope of hydrogen with one proton and one neutron in its nucleus, and has twice the mass of ordinary hydrogen, usually denoted by "D". A "deuterated" group is one in which one or more hydrogen atoms are replaced by deuterium (D).

[0076] If no number of any given substituents is specified, one or more substituents may be present.

[0077] When using things like "C" 1-8 When expressed as "etc.", this means that the functional group can have 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0078] When expressions such as "3-12-membered" are used, it means that the group has 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms or heteroatoms as ring atoms.

[0079] As used herein, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced by a specific substituent. A specific substituent is either the substituent described above or the substituent appearing in each example. Unless otherwise specified, a substituent group may have a substituent selected from the particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic alkyl groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirocyclic bicyclic system in which the two rings share a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible substituents, such as (but not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl group, C 2-10 Ester, C 1-12 Alkoxycarbonyl, amino, alkoxy, C 1-10 Sulfonyl groups, etc.

[0080] As used herein, unless otherwise stated, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid, including both inorganic and organic acids. Suitable non-toxic acids include inorganic and organic acids, such as, but not limited to, hydrobromic acid, hydrochloric acid, acetic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furanoic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycine, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.

[0081] As used herein, unless otherwise stated, the term "solvent" refers to a compound that further comprises stoichiometric or nonstoichiometric amounts of solvent bound by noncovalent intermolecular forces. When the solvent is water, the solvate is a hydrate. As used herein, unless otherwise stated, the term "stereoisomer" includes all stereoisomerically pure and stereoisomerically enriched compounds provided herein. As used herein, unless otherwise stated, the term "enantiomer" includes all enantiomerically pure and enantiomerically enriched compounds provided herein.

[0082] As used herein, unless otherwise stated, the term "stereoisopure" refers to a composition containing one stereoisomer of a compound and substantially free of other stereoisomers of that compound. For example, a stereopure composition of a compound having one chiral center will substantially free of the enantiomers of that compound. A stereopure composition of a compound having two chiral centers will substantially free of other diastereomers of that compound. A typical stereoisomeric pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound; more than about 90% by weight of one stereoisomer of the compound and about 10% by weight of another stereoisomer of the compound; more than about 95% by weight of a stereoisomer of a compound and less than about 5% by weight of other solid isomers of the compound; less than about 97% by weight of a stereoisomer of a compound and more than about 3% by weight of other stereoisomers of the compound; more than about 98% by weight of a stereoisomer of a compound and less than about 2% by weight of other stereoisomers of the compound; or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of other solid isomers of the compound.

[0083] As used herein, unless otherwise stated, the term "enantiomeric purity" refers to a stereopure composition of compounds having a single chiral center. Similarly, the term "enantiomeric enrichment" refers to a stereoenriched composition of compounds having a single chiral center.

[0084] As used herein, unless otherwise stated, the prefixes R and S are used to indicate the absolute configuration of a molecule around its chiral center.

[0085] As used herein, unless otherwise stated, the terms "approximately" or "approximately" refer to an acceptable error in a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In some embodiments, the terms "approximately" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms "approximately" or "approximately" mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0086] As used herein, unless otherwise stated, the term "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Each carrier must be "acceptable," meaning it is compatible with the other components of the formulation and is harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragali powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical preparations.

[0087] As used herein, unless otherwise stated, the terms “subject,” “individual,” and “patient” are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, canines, equines, felines, pigs, cattle, ungulates, lagomorphs, etc.). In various embodiments, a subject may be a person cared for by a physician or other healthcare worker in a hospital, outpatient clinic, or other clinical setting (e.g., adult male, adult female, adolescent male, adolescent female, boy, girl). In some embodiments, a subject may not be under the care or prescription of a physician or other healthcare worker.

[0088] As used herein, unless otherwise stated, the phrase “subject in need” means a subject who has or is at risk of a pathological condition requiring prevention or treatment with the compounds or salts described herein, as described below.

[0089] As used herein, unless otherwise stated, the terms "administration," "application," and "administration" are defined as providing a subject with the composition via routes known in the art, including but not limited to intravenous, intra-arterial, oral, parenteral, oral, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, mucosal, or intraperitoneal administration. In some embodiments, the composition may be administered orally. The terms "administration," "dosage," "application," and "administering a compound" should be understood as providing an individual in need with the compound of the present invention or a prodrug of the compound of the present invention.

[0090] As used herein, unless otherwise stated, the terms "effective amount" or "therapeutic effective amount" refer to an amount of the compound or salt described herein sufficient to achieve the intended application, including but not limited to the treatment of disease, as described below. Therapeutic effective amounts can vary depending on the intended application (in vitro or in vivo) or the subject being treated and the disease condition, such as the subject's weight and age, the severity of the disease condition, the route of administration, etc., which can be readily determined by those skilled in the art. The term can also be applied to doses that can induce a specific response in target cells, such as reduced proliferation or downregulation of target proteins. Specific doses can vary depending on the specific compound selected, the administration regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue of administration, and the physical delivery system carrying it.

[0091] As used herein, unless otherwise stated, the term "treatment" or "treatment" refers to a method for obtaining a beneficial or intended outcome for a disease, disability, or medical condition, including but not limited to therapeutic and / or preventive benefits. In some embodiments, treatment or treatment involves administering a compound or composition disclosed herein to a subject. Therapeutic benefits may include eradication or improvement of the underlying disease being treated. Furthermore, therapeutic benefits may be obtained by eradicating or improving one or more physiological symptoms associated with the underlying disease, for example, by observing improvement in the subject, even though the subject may still have the underlying disease. In some embodiments, for preventive benefits, the composition is administered to a subject at risk of developing a specific disease, or to a subject reporting one or more physiological symptoms of a disease, even if such a disease may not have been diagnosed. Treatment may include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or may include reducing the frequency with which a patient experiences symptoms such as a disease, defect, disability, or adverse condition. Treatment herein may be used to refer to a method of treatment or improvement resulting in a disease or condition to some degree, and may be considered as a range of outcomes for this purpose, including but not limited to complete prevention of the condition.

[0092] As used herein, unless otherwise stated, the terms “treatment,” “curing,” and “treatment” mean the eradication or improvement of a disease or condition, or one or more symptoms associated with a disease or condition. In some embodiments, these terms refer to minimizing the spread or exacerbation of a disease or disorder resulting from the administration of one or more preventive or therapeutic agents to a subject suffering from such a disease or condition.

[0093] As used herein, unless otherwise stated, the term “prevention” means the use or administration of compounds provided herein, whether or not additional active compounds are added, prior to the onset of symptoms, particularly in patients at risk of developing the diseases or conditions described herein. The term “prevention” includes suppressing or alleviating symptoms of a specific disease. In some embodiments, patients with a family history of the disease are candidates for prevention programs. Furthermore, patients with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term “prevention” may be used interchangeably with “preventive treatment.”

[0094] It should be noted that if there is a difference between the described structure and its name, the described structure should be given greater weight. Furthermore, if the stereochemistry of a structure or part thereof is not indicated by, for example, thick or dashed lines, the structure or part thereof should be interpreted as encompassing all its stereoisomers.

[0095] Drug components and administration methods Because the compounds of the present invention have excellent inhibitory activity against IL-17A / A and / or IL-17A / F, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases induced by IL-17A / A and / or IL-17A / F.

[0096] The pharmaceutical compositions of the present invention comprise a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. A “safe and effective amount” refers to an amount of the compound sufficient to significantly improve the condition without producing serious side effects. Typically, each dose of the pharmaceutical composition contains 1-2000 mg of the polymorph of the present invention, preferably 5-200 mg of the polymorph of the present invention per dose. Preferably, “one dose” is one capsule or one pill.

[0097] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers, or gel materials suitable for human use, which should have sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that each component of the composition can be miscible with the compounds of this invention and can be mixed with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0098] There are no particular restrictions on the administration routes of the compounds or pharmaceutical compositions of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and local administration.

[0099] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with any of the following: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain complex silicates, and sodium carbonate; (e) dissolution inhibitors, such as paraffin; (f) absorption enhancers, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, dosage forms may also include buffer solutions.

[0100] Solid dosage forms, such as tablets, sugar pills, capsules, pellets, and granules, can be prepared using coating and shell materials, such as casings and other materials well known in the art. They may contain light-blocking agents, and the release of the active compound or compounds in the composition may be delayed at a site in the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If desired, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0101] Oral liquid dosage forms include pharmaceutically acceptable lotions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may also contain any conventional inert diluents known in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or combinations thereof.

[0102] In addition to these inert diluents, the composition may also include additives such as wetting agents, emulsifiers and suspensions, sweeteners, corrective agents and flavorings.

[0103] In addition to active compounds, suspensions may also include suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0104] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0105] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, and propellants (if necessary).

[0106] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the present invention can form PROTACs with other small molecule compounds or ADCs with other large molecule compounds such as monoclonal antibodies for administration.

[0107] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need, wherein the dosage is a pharmaceutically effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 5-500 mg. Of course, the specific dosage will also depend on various factors, such as the route of administration and the patient's health condition, which are all within the skill of an experienced physician.

[0108] The main advantages of this invention include: (1) The compounds of the present invention have excellent inhibitory activity against IL-17A / A and / or IL-17A / F.

[0109] (2) Compared with current small molecule compounds that target IL-17A / A and / or IL-17A / F, the compounds of the present invention have higher metabolic stability.

[0110] (3) The compounds of the present invention have increased or comparable activity compared with macromolecules such as monoclonal antibodies. The invention will be further described below with reference to specific embodiments. It should be understood that these examples are for illustration only and not for limiting the scope of the invention. The experimental methods in the following embodiments, without specific conditions, generally follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described can be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0111] Unless otherwise stated, the experimental materials and reagents used in the following examples are commercially available.

[0112] In the following embodiments, 1 H NMR indicates 1 H nuclear magnetic resonance, MS stands for mass spectrometry.

[0113] Example 1: Synthesis of N-((S)-2-((4-((2S,3R)-4-(4-((2,5,8,11,14,17,20-7-oxadodocan-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(difluoromethylene)cyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide Step 1: A suspension of methyl (2S)-2-amino-2-(4-hydroxyphenyl)acetic acid hydrochloride (19 g, 87.3 mmol) in dioxane (150 mL) was added to an aqueous solution (300 mL) of potassium carbonate (24.13 g, 175 mmol). Then, di-tert-butyl carbonate (Boc₂O) (21.91 g, 100.3 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. After dilution with water (100 mL), the mixture was extracted with ethyl acetate (200 mL x 3 times). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by rapid column chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 2, v / v) yielded methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (20 g, 71.1 mmol, yield: 81.4%) as a pale white solid. MS (ESI, m / z): 304.2 [M+Na] + . Step 2: Methyl(S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (6.8 g, 24.2 mmol) was dissolved in acetic acid (45 mL), and platinum dioxide (0.82 g, 3.6 mmol) was added. The reaction mixture was stirred at 50 °C for 2 days under 0.3 MPa hydrogen pressure. The mixture was then filtered, and the filtrate was concentrated under vacuum to obtain a crude product. This crude product was purified by rapid chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give methyl(S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate (4.4 g, 15.3 mmol, yield: 63.2%) as a pale yellow solid. MS (ESI, m / z): 310.3 [M+Na] + . Step 3: At -78°C, a solution of dimethyl sulfoxide (DMSO) in dichloromethane (5 mL) was added to a solution of oxaloyl chloride (2.74 g, 21.6 mmol) in 20 mL of dichloromethane. The mixture was stirred at -78°C for 5–10 minutes. Then, a solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate (3.1 g, 10.8 mmol) in dichloromethane (5 mL) was slowly added. The final mixture was stirred at -77°C for 1 hour. The reaction was quenched with triethylamine. The mixture was then diluted with water (50 mL) and the pH was adjusted to 3 with 1N HCl. Extraction was performed with dichloromethane (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 2, v / v) to give a pale yellow oily (S)-2-((tert-butoxycarbonyl)amino)-2-(4-oxocyclohexyl)acetic acid methyl ester (2.1 g, 7.4 mmol, yield: 68.5%). MS (ESI, m / z): 308.0 [M+Na] + . Step 4: At -50°C under nitrogen, add a 4 mL solution of t-BuOK (1.49 g, 13.3 mmol) in DMF to a 16 mL solution of (S)-2-((tert-butoxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate (2.1 g, 7.4 mmol) and 2-(difluoromethane)sulfonylpyridine (1.72 g, 8.8 mmol). Then stir the mixture at room temperature for 2 hours. Dilute with water (200 mL) and extract with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by rapid chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give a pale yellow oily (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetate (1.5 g, 4.7 mmol, yield: 63.5%). MS (ESI, m / z): 342.1 [M+Na] + . Step 5: Lithium hydroxide monohydrate (79 mg, 1.88 mmol) was added to a tetrahydrofuran / water solution (10 mL) of (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid (400 mg, 1.25 mmol) in a 1:1 (10 mL) solution. The mixture was stirred overnight at room temperature. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The aqueous solution was then adjusted to pH 3 with 1 N HCl. Extraction was performed with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a colorless oily product (S)-2-(((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid (400 mg, crude). It was used directly for the next step. MS (ESI, m / z): 327.9 [M+Na] + . Step 6: Add 40 mL of 3N hydrochloric acid in methanol to a 20 mL solution of (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyric acid (4 g, 11.7 mmol). Stir the reaction mixture at 60 °C for 16 hours. Concentrate the mixture under reduced pressure to give crude (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)butyrate methyl ester (3.0 g, 11.7 mmol, yield: 100.0%) as a yellow solid. MS (ESI, m / z): 256.9 [M+H] + . Step 7: At 0°C, triphosgene (1.39 g, 4.6 mmol) was added to a solution of methyl (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)butyrate (2 g, 7.8 mmol) and diisopropylethylamine (4.03 g, 31.2 mmol) in dichloromethane (40 mL). The mixture was stirred at 0°C under nitrogen for 10 minutes. A solution of N-methylcyclopropylamine hydrochloride (2.52 g, 23.3 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (50 mL x 3). The organic layer was washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid silica gel chromatography (elution gradient: 0 to 50% ethyl acetate in hexane) to give methyl (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(3-fluoro-4-nitrophenyl)butyrate (1.7 g, 4.8 mmol, yield: 61.54%). MS (ESI, m / z): 353.9 [M+H] + . Step 8: Add 10% Pd / C (0.51 g, 0.48 mmol) to a solution of methyl (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(3-fluoro-4-nitrophenyl)butyrate (1.7 g, 4.8 mmol) in ethyl acetate (30 mL). Stir the reaction mixture at 25 °C for 4 hours under hydrogen atmosphere. Filter the mixture through a diatomaceous earth mat and concentrate under reduced pressure. Purify the crude product by rapid silica gel chromatography (elution gradient: 0 to 60% ethyl acetate in hexane) to give methyl (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1.4 g, 4.3 mmol, yield: 89.58%) as a white solid. MS (ESI, m / z): 323.9 [M+H] + . Step 9: Diisopropylethylamine (0.8 g, 6.2 mmol) was added to a solution of (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1.0 g, 3.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid (1.42 g, 4.6 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by rapid silica gel chromatography (elution gradient: 0 to 70% ethyl acetate in hexane) to give a white solid (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1.5 g, 2.5 mmol, yield: 80.65%). MS (ESI, m / z): 610.8 [M+H] + . Step 10: Add trifluoroacetic acid (3 mL) to a solution of methyl (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1.5 g, 2.5 mmol) in dichloromethane (15 mL). Stir the reaction mixture at 25 °C for 2 hours. Concentrate the mixture under reduced pressure. Alkalize the residue with a saturated aqueous solution. Extract with sodium bicarbonate solution and ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white solid (2R,3S)-3-(4-((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1.25 g, 2.4 mmol, 96.00% yield). MS (ESI, m / z): 511.3 [M+H] + . Step 11: Add diisopropylethylamine (0.52 g, 4 mmol) to a stirred solution of (2R,3S)-3-(4-((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1 g, 2 mmol), 2-ethylpyrazole-3-carboxylic acid (0.42 g, 3 mmol), and HATU (1.14 g, 3 mmol) in DMF (N,N-dimethylformamide) (20 mL). Stir the reaction mixture at 25 °C for 2 hours. Pour the reaction mixture into water (100 mL) and extract with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a crude product. This crude product was purified by rapid silica gel chromatography (elution gradient: 0-80% ethyl acetate in hexane) to give a white solid (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-(S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyrate (1.2 g, 1.9 mmol, yield: 95.0%). MS (ESI, m / z): 633.3 [M+H] + . Step 12: Add dropwise a solution of methyl (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyrate (1.2 g, 1.9 mmol) in tetrahydrofuran (10 mL) and a solution of lithium hydroxide monohydrate (160 mg, 0.38 mmol) in water (3 mL). Stir the reaction mixture at 25 °C for 2 hours. Dilute the mixture with water (20 mL), acidify with 1N HCl, and extract with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-(S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyric acid (1.05 g, 1.7 mmol, yield: 89.47%). MS (ESI, m / z): 619.2 [M+H] + . Step 13: Add 4-((2,5,8,11,14,17,20-heptaoxadododecyl)oxy)-4-(trifluoromethyl)piperidine (0.06 g, 0.12 mmol) to a DMF (1 mL) solution of (2R,3S)-2-(3-cyclopropyl-3-methylureido)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carbamoyl)acetamido)-3-fluorophenyl)butyric acid (50 mg, 0.081 mmol), HATU (46.20 mg, 0.12 mmol) and diisopropylethylamine (31.41 mg, 0.24 mmol) and stir at room temperature for 16 hours. The mixture was purified by HPLC and eluted with acetonitrile in pure water (0.1% trifluoroacetic acid) to give N-((S)-2-((2S,3R)-4-(4-(2,5,8,11,14,17,20-heptaoxadocosano-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(difluoromethylene)cyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (52.89 mg, 0.05 mmol, 59.85% yield), as a white solid. MS (ESI, m / z): 1092.3 [M+H] + Example 2: Synthesis of N-((S)-2-((4-(2S,3R)-4-(4-((2,5,8,11,14,17,20,23-octaoxapentanodecane-25-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(difluoromethylene)cyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide At room temperature, 4-((2,5,8,11,14,17,20,23-octaoxapentane-25-yl)oxy)-4-(trifluoromethyl)piperidine (35 mg, 0.06 mmol, 1.35 eq) was added to a DMF (1 mL) solution of (2R,3S)-2-(3-cyclopropyl-3-methylureido)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyric acid (30 mg, 0.05 mmol, 1 eq), HATU (27.38 mg, 0.07 mmol, 1.5 eq) and diisopropylethylamine (18.61 mL), and stirred for 16 hours. The purified mixture was prepared to give N-((S)-2-((2S,3R)-4-(4-((2,5,8,11,14,17,20,23-octaoxapentanodecane-25yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(difluoromethylene)cyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (3.68 mg, 0.003 mmol, 6.67% yield), a white solid. 1 HNMR (400 MHz, MeOD-d4) δ 7.92 (dt, J = 83.4, 8.1 Hz, 1H), 7.49 (dd, J = 4.3,2.1 Hz, 1H), 7.19 – 7.04 (m, 2H), 6.88 (dd, J = 10.7, 2.1 Hz, 1H), 6.36 –6.23 (m, 1H), 4.65 – 4.48 (m, 9H), 4.28 (d, J = 13.6 Hz, 1H), 3.98 – 3.81 (m,1H), 3.62 – 3.56 (m, 23H), 3.55 – 3.46 (m, 3H), 3.35 (d, J = 1.7 Hz, 3H), 3.19 (dd, J = 40.2, 10.2 Hz, 3H), 2.88 (d, J = 3.0 Hz, 3H), 2.85 – 2.65 (m,2H), 2.55 (dd, J = 29.9, 9.0 Hz, 4H), 2.19 (t, J= 7.5 Hz, 1H), 2.03 – 1.62(m, 8H), 1.32 – 1.15 (m, 6H), 1.04 – 0.82 (m, 4H), 0.73 (s, 2H), 0.53 (t, J =11.2 Hz, 1H). MS (ESI, m / z): 1135.8 [M+H] + . Example 3: Synthesis of N-((S)-2-((4-(2S,3R)-4-(4-((2,5,8,11,14,17,20-heptaoxadocosane-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide Step 1: The mixture of (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (690 mg, 2.13 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-(1r,4S)-4-methylcyclohexyl)acetic acid (580 mg, 2.13 mmol), HATU (1215 mg, 3.19 mmol) and diisopropylethylamine (550.6 mg, 4.26 mmol) in tetrahydrofuran (40 mL) was stirred overnight at 25°C. The crude product was then concentrated under vacuum and purified by rapid chromatography (elution gradient: ethyl acetate / hexane, 0-50%) to give a yellow oily compound (2R,3S)-3-(4-((S)-2-(tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (670 mg, 1.16 mmol, yield: 54.5%). MS (ESI, m / z): 577.6 [M+1] + . Step 2: A solution of dioxane (10 mL) containing 4N HCl was added to a solution of (2R,3S)-3-(4-((S)-2-(tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (670 mg, 1.16 mmol) in dichloromethane (15 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to give methyl (2R,3S)-3-(4-((S)-2-amino)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (600 mg, 1.26 mmol, yield: 100%) as a yellow solid. MS (ESI, m / z): 477.1 [M+H] + . Step 3: A mixture of (2R,3S)-3-(4-((S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (600 mg, 1.26 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.45 mmol), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (716 mg, 1.89 mmol), and diisopropylethylamine (562 mg, 4.35 mmol) in DMF (7 mL) was stirred at room temperature for 16 hours. It was then diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by rapid chromatography (elution gradient: ethyl acetate / hexane, 0-80%) to give a yellow oily compound (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-(S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyrate (450 mg, 0.75 mmol, yield: 59.7%). MS (ESI, m / z): 599.6 [M+H] + . Step 4: Lithium hydroxide monohydrate (42.6 mg, 1.76 mmol) was added to a tetrahydrofuran / water solution of methyl (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyrate (450 mg, 0.75 mmol) in 2:1 (30 mL) and the mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 2 with hydrochloric acid (1N) and extracted with ethyl acetate (20 mL * 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyric acid (420 mg, 0.72 mmol, yield: 95.78%). MS (ESI, m / z): 585.2 [M+H] + . Step 5: Stir a 2 mL solution of a mixture of (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyric acid (40 mg, 0.068 mmol), 4-((2,5,8,11,14,17,20-heptaoxadodienoyl)oxy)-4-(trifluoromethyl)piperidine (40.11 mg, 0.082 mmol), HATU (38.8 mg, 0.1 mmol), and diisopropylethylamine (26.4 mg, 0.2 mmol) in DMF at room temperature for 16 hours. The mixture was purified to give compound N-((S)-2-((2S,3R)-4-(4-(2,5,8,11,14,17,20-heptaoxadodocan-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole 5-carboxamide (25 mg, 0.023 mmol, yield: 34.7%). 1 H NMR (400 MHz, MeOD- d4) δ 7.91 (dt, J = 80.9, 8.2 Hz, 1H), 7.55 – 7.42 (m, 1H), 7.20 – 7.02(m, 2H), 6.86 (dd, J = 10.9, 2.0 Hz, 1H), 6.32 – 6.18 (m, 1H), 4.53 (dd, J =12.4, 4.9 Hz, 3H), 4.07 (dd, J = 161.8, 13.7 Hz, 2H), 3.64 – 3.49 (m, 27H), 3.35 (d, J = 2.1 Hz, 3H), 3.26 – 3.10 (m, 2H), 2.88 (d, J = 2.8 Hz, 3H), 2.84– 2.70 (m, 1H), 2.59 (d, J = 3.7 Hz, 1H), 2.00 – 1.62 (m, 8H), 1.40 – 1.28(m, 9H), 1.05 – 0.85 (m, 8H), 0.73 (s, 2H), 0.54 (s, 1H). MS (ESI, m / z):1059.6 [M+H] + . Example 4: Synthesis of N-((S)-2-((4-(2S,3R)-4-(4-((2,5,8,11,14,17,20,23,26-nonoxacaoctadecane-28-yl)oxy)-4-isopropylpiperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide To a mixture of (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyric acid (30 mg, 0.051 mmol) in N,N-dimethylformamide (1.5 mL), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (23.27 mg, 0.061 mmol) and ethyl diisopropylamine (19.77 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 0.5 hours. A solution of 4-((2,5,8,11,14,17,20,23,26-nonoxooctadecane-28-yl)oxy)-4-isopropylpiperidine hydrochloride (30.10 mg, 0.051 mmol) in N,N-dimethylformamide (0.5 mL) was added to the mixture, and the mixture was stirred at room temperature for 12 hours. The mixture was purified by HPLC (0.1% FA) to obtain N-((S)-2-((4-(2S,3R)-4-(4-((2,5,8,11,14,17,20,23,26-nonoxa-28-alkyl-28-yl)oxy)-4-isopropylpiperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide. 1 H NMR (400 MHz, DMSO- d 6) δ9.82 (d, J = 14.1 Hz, 1H), 8.43 (d, J = 8.6 Hz, 1H), 7.77 (dt, J = 69.5, 8.2Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.21 – 7.10 (m, 1H), 7.05 – 6.97 (m, 2H), 6.12 (dd, J = 29.2, 9.1 Hz, 1H), 4.82 (dd, J = 21.4, 11.8 Hz, 1H), 4.59 –4.44 (m, 3H), 4.02 (s, 1H), 3.73 (s, 1H), 3.53 – 3.40 (m, 36H), 3.23 (s, 3H), 3.15 – 2.96 (m, 2H), 2.74 (d, J= 7.2 Hz, 3H), 2.58 (dd, J = 10.9, 5.8 Hz,1H), 1.88 – 1.61 (m, 6H), 1.53 – 1.06 (m, 12H), 0.92 – 0.51 (m, 17H). MS(ESI, m / z): 1142.1 [M+Na] + . Example 5: Synthesis of N-((S)-2-(4-(2S,3R)-4-(4-(2,5,8,11,14,17,20,23,26-nonoxacaoctadecane-28-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide To a solution of (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyric acid (30.0 mg, 0.05 mmol), HATU (29.09 mg, 0.076 mmol), and diisopropylethylamine (19.7 mg, 0.15 mmol) in DMF (N,N-dimethylformamide) (1 mL), 4-((2,5,8,11,14,17,20,23,26-nonaoxyoctadecane-28-yl)oxy)-4-(trifluoromethyl)piperidine (47.3 mg, 0.082 mmol) was added. The mixture was stirred at room temperature for 2 hours. LCMS indicated that the reaction was complete. The mixture was purified by HPLC to obtain N-((S)-2-((2S,3R)-4-(4-((2,5,8,11,14,17,20,23,26-nonoxooctadecane-28-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (7.9 mg, 0.007 mmol, 13.8% yield), as a white solid. 1 H NMR (400 MHz, MeOD- d 4)δ 7.91(dt, J = 80.6, 8.2 Hz, 1H), 7.49 (dd, J= 4.2, 2.1 Hz, 1H), 7.17 – 6.84 (m,3H), 5.02 – 4.92 (m, 1H), 4.58 – 4.48 (m, 3H), 4.31 – 4.22 (m, 1H), 3.87 (d, J = 13.3 Hz, 1H), 3.73 – 3.53 (m, 36H), 3.35 (d, J = 1.3 Hz, 3H), 2.88 (d, J = 2.9 Hz, 3H), 2.58 (td, J = 6.7, 3.4 Hz, 1H), 1.93 – 1.72 (m, 7H), 1.56 –0.87 (m, 20H), 0.77 – 0.68 (m, 2H). MS (ESI, m / z): 1146.3 [M+H] + . Example 6: Synthesis of N-((S)-2-(4-((2S,3R)-4-(4-(2,5,8,11,14,17,20,23,26,29-decaoxatriacontane-31-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide Add 4-((2,5,8,11,14,17,20,23,26,29-deoxyphenanthrene-31-yl)oxy)-4-(trifluoromethyl)piperidine (51.0 mg, 0.082 mmol) to a solution of (2R,3S)-2-(3-cyclopropyl-3-methylureido)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyric acid (30.0 mg, 0.05 mmol), HATU (29.09 mg, 0.076 mmol), and diisopropylethylamine (19.7 mg, 0.15 mmol) in DMF (N,N-dimethylformamide) (1 mL). Stir the mixture at room temperature for 2 hours. The mixture was purified by HPLC and eluted with acetonitrile in water (0.1% FA) to give N-((S)-2-((2S,3R)-4-(4-(2,5,8,11,14,17,20,23,26,29-decoxatriane-31-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (20.12 mg, 0.007 mmol, 13.8% yield), a white solid. 1 H NMR (400MHz, MeOD- d 4) δ 7.92 (dt, J = 81.2, 8.2 Hz, 1H), 7.49 (dd, J = 4.4, 2.1 Hz,1H), 7.19 – 6.98 (m, 2H), 6.86 (dd, J = 11.2, 2.1 Hz, 1H), 6.41 – 6.14 (m,1H), 4.99 – 4.90 (m, 1H), 4.62 – 4.45 (m, 3H), 4.28 (d, J = 13.1 Hz, 1H), 3.87 (d, J = 14.1 Hz, 1H), 3.71 – 3.49 (m, 40H), 3.35 (d, J = 0.9 Hz, 3H), 3.27 – 3.09 (m, 2H), 2.88 (d, J = 2.9 Hz, 3H), 2.81 (d, J= 2.3 Hz, 1H), 2.59(td, J = 6.7, 3.5 Hz, 1H), 1.98 – 1.67 (m, 8H), 1.42 – 1.32 (m, 7H), 1.29 –1.13 (m, 3H), 1.07 – 0.85 (m, 8H), 0.74 (d, J = 9.1 Hz, 2H), 0.54 (d, J = 4.2Hz, 1H). MS (ESI, m / z): 1190.3 [M+H] + . Example 7: Synthesis of N-((S)-1-((4-(2S,3R)-4-(4-((2,5,8,11,14,17,20-heptaoxadocosano-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclobutyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Step 1: At room temperature, methyl (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1070 mg, 3.61 mmol) was added to a DMF (N,N-dimethylformamide) (15 mL) solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclobutylpropionic acid (900 mg, 2.78 mmol), HATU (1585.6 mg, 4.17 mmol), and diisopropylethylamine (718.6 mg, 5.56 mmol). The mixture was stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give an oily methyl (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclobutylpropionamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (560 mg, 0.93 mmol, 33.4% yield). MS (ESI, m / z): 603.4 [M+H] + Step 2: HCl / dioxane (4 M, 1 mL) was added to a mixture of (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclobutylpropamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (560 mg, 0.93 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give a white solid of (2R,3S)-3-(4-((S)-2-amino-3-dicyclobutylpropamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (530 mg, 1.05 mmol, 113.5% yield). MS (ESI, m / z): 503.4 [M+H] + . Step 3: At room temperature, methyl (2R,3S)-3-(4-(((S)-2-amino-3-dicyclobutylpropionamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (560 mg, 1.11 mmol) was added to a solution of 1-ethyl-1H-pyrazole-5-carboxylic acid (233.3 mg, 1.67 mmol), HATU (633.8 mg, 1.67 mmol), and diisopropylethylamine (286.9 mg, 2.22 mmol) in DMF (N,N-dimethylformamide) (15 mL). The mixture was stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (60 mL x 3). The organic layers were combined and then quenched with brine (100 mL x 3). Washed with 2 mL of the solution, dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a yellow oily methyl (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclobutyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyrate (530 mg, 0.85 mmol, 76.14% yield). MS (ESI, m / z): 625.2 [M+H] + . Step 4: Add lithium hydroxide monohydrate (71 mg, 1.7 mmol) dissolved in pure water (2 mL) to a tetrahydrofuran (10 mL) solution of methyl (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclobutyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyrate (530 mg, 0.85 mmol). Stir the mixture at room temperature for 4 hours. Quench the reaction mixture with aqueous solution HCl (1 M) and adjusted pH = 3. Add water (50 mL) to the reaction mixture and extract with ethyl acetate (50 mL * 3). The organic layers were combined, dried over sodium sulfate, and concentrated to give a green oily (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclobutyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propionamido)-3-fluorophenyl)butyric acid (490 mg, 0.80 mmol, 94.6% yield). MS (ESI, m / z): 611.1 [M+H] + . Step 5: At room temperature, add 4-((2,5,8,11,14,17,20-heptaoxadododecyl-22-yl)oxy)-4-(trifluoromethyl)piperidine (36 mg, 0.07 mmol) to a DMF (1 mL) solution of (2R,3S)-2-(3-cyclopropyl-3-methylureido)-3-(4-((S)-3,3-dicyclobutyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)propamido)-3-fluorophenyl)butyric acid (30 mg, 0.04 mmol), HATU (27.9 mg, 0.07 mmol), and diisopropylethylamine (19.0 mg, 0.15 mmol). Stir the mixture for 16 hours. The mixture was purified by HPLC to give a white solid N-((S)-1-(((2S,3R)-4-(4-((2,5,8,11,14,17,20-heptaoxadocosano-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclobutyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (10 mg, 0.01 mmol, 18.8% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.85 (d, J = 30.4 Hz, 1H), 8.52 – 8.40 (m, 1H), 7.79 (dd,J =41.1, 32.9 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.20 – 6.93 (m, 4H), 6.17 (dd, J = 27.4, 8.8 Hz, 1H), 4.87 – 4.64 (m, 5H), 4.53 – 4.42 (m, 3H), 4.14 (d, J =12.5 Hz, 1H), 3.95 (s, 1H), 3.63 – 3.41 (m, 32H), 3.23 (d, J = 1.3 Hz, 3H),3.15 – 2.95 (m, 2H), 2.74 (d, J = 6.1 Hz, 3H), 2.59 (s, 1H), 2.16 (dd, J =35.4, 27.5 Hz, 3H), 1.96 – 1.45 (m, 17H), 1.28 – 1.19 (m, 6H), 0.82 (d, J =6.9 Hz, 2H), 0.61 (d, J = 3.1 Hz, 2H). MS (ESI, m / z): 1083.8 [M+H] + . Example 8: Synthesis of N-((S)-2-(4-((2S,3R)-4-(4-(2,5,8,11,14,17,20,23,26-nonoxacaoctadecane-28-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-cycloheptyl-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide Step 1: To a solution of methyl (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (100 mg, 0.31 mmol) in tetrahydrofuran (10 mL), add (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid (252.72 mg, 0.93 mmol), diisopropylethylamine (119.70 mg, 0.93 mol), and HATU (129.29 mg, 0.34 mmol). Stir the mixture at 40 °C for 16 hours. Dilute the mixture with water (10 mL) and extract with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give a white solid (2R, 3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (80 mg, 0.14 mmol, yield: 44.86%). MS (ESI, m / z): 576.9 [M+H] + . Step 2: Add trifluoroacetic acid (2 mL) to a solution of (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (80 mg, 0.14 mmol) in dichloromethane (5 mL) and stir the mixture at 25 °C for 1 hour. Dilute the mixture with water (10 mL). Adjust the pH of the mixture to 8 with sodium bicarbonate and extract with ethyl acetate (10 mL * 3). Combine the organic layers, dry with anhydrous sodium sulfate, filter and concentrate under vacuum to give the product (2R,3S)-3-(4-((S)-2-amino-2-cycloheptylacetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (50 mg, 0.10 mmol, yield: 75.63%). MS (ESI, m / z): 477.0 [M+H] + . Step 3: To a DMF (20 mL) solution of methyl (2R,3S)-3-(4-((S)-2-amino-2-cycloheptaacetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (220 mg, 0.46 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (97.03 mg, 0.69 mmol), diisopropylethylamine (178.64 mg, 0.38 mmol), and HATU (192.95 mg, 0.51 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (elution gradient: petroleum ether / ethyl acetate = 1 / 10, v / v) to give a white solid (2R, 3S)-3-(4-((S)-2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (260 mg, 0.43 mmol, yield: 94.07%). MS (ESI, m / z): 599.3 [M+H] + . Step 4: Add a solution of lithium hydroxide (91.12 mg, 2.17 mmol) in water (5 mL) to a tetrahydrofuran (10 mL) solution of methyl (2R, 3S)-3-(4-((S)-2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (260 mg, 0.43 mmol). Stir the mixture at 25 °C for 2 hours. Dilute the mixture with water (20 mL). Adjust the pH of the mixture to 3 with 1N HCl and extract with ethyl acetate (20 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a white solid (2R,3S)-3-(4-((S)-2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyric acid (200 mg, 0.34 mmol, yield: 78.77%). MS (ESI, m / z): 585.3 [M+H] + . Step 5: Stir a mixture of (2R,3S)-3-(4-((S)-2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carbamoyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyric acid (30 mg, 0.051 mmol), 4-((2,5,8,11,14,17,20,23,26-nonoxooctadecane-28-yl)oxy)-4-isopropylpiperidine (44 mg, 0.076 mmol), HATU (29 mg, 0.078 mmol), and diisopropylethylamine (13 mg, 0.100 mmol) in DMF (2 mL) at room temperature for 16 hours. The mixture was purified by HPLC (mobile phase: acetonitrile-water (0.1% NH4HCO3), 35 / 65-75 / 25) to give the product N-((S)-2-(((2S,3R)-4-(4-(((2,5,8,11,14,17,20,23,26-nonoxooctadecane-28-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-cycloheptyl-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (16.35 mg, 0.016 mmol, yield: 27.8%). 1 H NMR (400 MHz, CD3OD- d 4) δ 7.91 (dt, J = 81.9, 8.2 Hz, 1H), 7.49(dd, J = 5.2, 2.1 Hz, 1H), 7.21 - 7.01 (m, 2H), 6.85 (dd, J = 11.5, 2.1 Hz, 1H), 4.93 (dd, J = 21.1, 9.7 Hz, 1H), 4.69 - 4.62 (m, 1H), 4.57 - 4.47 (m,2H), 4.28 (d, J = 13.1 Hz, 1H), 3.98 - 3.83 (m, 1H), 3.65 - 3.51 (m, 35H), 3.35 (d, J= 1.2 Hz, 3H), 3.27 - 3.08 (m, 2H), 2.92 - 2.86 (m, 3H), 2.84 -2.68 (m, 1H), 2.64 - 2.53 (m, 1H), 2.24 - 2.12 (m, 1H), 1.87 - 1.32 (m, 21H),1.08 - 0.97 (m, 1H), 0.96 - 0.87 (m, 2H), 0.78 - 0.67 (m, 2H), 0.60 - 0.47(m, 1H). MS (ESI, m / z): 1168.6 [M+23] + . Example 9: Synthesis of N-((S)-1-((4-(2S,3R)-4-(4-((2,5,8,11,14,17,20-7-oxadodocaned-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Step 1: A mixture of (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (900 mg, 2.78 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (2246 mg, 8.34 mmol), HATU (3171 mg, 8.33 mmol), and diisopropylethylamine (1796 mg, 13.90 mmol) in tetrahydrofuran (40 mL) was stirred at 50 °C for 16 hours. It was then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by rapid chromatography (elution gradient: ethyl acetate / hexane, 0-50%) to give a yellow oil of methyl (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1170 mg, 2.04 mmol, 73.2% yield). MS (ESI) m / z = 575.8 [M+H] + . Step 2: HCl / dioxane (5 mL, 4 M) was added to a solution of (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1170 mg, 2.04 mmol) in dichloromethane. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to give a yellow solid, (2R,3S)-3-(4-((S)-2-amino-3-dicyclopropylpropamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (1200 mg, 2.53 mmol, 124.2% yield). MS (ESI) m / z = 475.3 [M+H] + . Step 3: A mixture of (2R,3S)-3-(4-((S)-2-amino-3-dicyclopropylpropamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-methylurea)butyrate (100 mg, 0.21 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (44 mg, 0.32 mmol), HATU (120 mg, 0.32 mmol), and diisopropylethylamine (54 mg, 0.42 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. It was then diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification was achieved by rapid chromatography (elution gradient: ethyl acetate / hexane, 0-75%) to give a white solid (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyrate (54 mg, 0.09 mmol, yield: 43.0%). MS (ESI, m / z): 597.7 [M+H] + . Step 4: Lithium hydroxide monohydrate (12.6 mg, 0.30 mmol) was added to a tetrahydrofuran / water solution of methyl (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyrate (54 mg, 0.09 mmol) in 2:1 (3 mL). The mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 2 with dilute hydrochloric acid (1N) and extracted with ethyl acetate (20 mL * 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a white solid (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyric acid (33 mg, 0.057 mmol, yield: 62.6%). MS (ESI, m / z): 583.4 [M+H] + . Step 5: Stir a solution of (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyric acid (33 mg, 0.057 mmol), 4-((2,5,8,11,14,17,20-heptaoxadocosane-22-yl)oxy)-4-(trifluoromethyl)piperidine (42 mg, 0.086 mmol), HATU (33 mg, 0.088 mmol), and diisopropylethylamine (15 mg, 0.110 mmol) in DMF (3 mL) at room temperature for 16 hours. The compound N-((S)-1-((4-(2S,3R)-4-(4-(2,5,8,11,14,17,20-heptaoxadodocan-22-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (19.57 mg, 0.019 mmol, yield: 32.7%) was obtained as a yellow sugar-like solid by HPLC purification (mobile phase: acetonitrile-water (0.1% NH4HCO3, 35 / 65-75 / 25). 1 H NMR (400 MHz, CD3OD- d 4) δ 7.94 (dt, J = 44.3, 8.3Hz, 1H), 7.50 (dd,J = 4.7, 2.1 Hz, 1H), 7.20 - 7.04 (m, 2H), 6.85 (dd, J =14.2, 2.1 Hz, 1H), 5.02 - 4.88 (m, 2H), 4.58 - 4.49 (m, 2H), 4.33 - 4.23 (m,1H), 3.98 - 3.82 (m, 1H), 3.67 - 3.51 (m, 28H), 3.35 (s, 3H), 3.20 - 3.12 (m,1H), 2.88 (d, J = 2.7 Hz, 3H), 2.83 - 2.55 (m, 2H), 1.99 - 1.51 (m, 3H), 1.43- 1.33 (m, 6H), 1.11 - 0.68 (m, 8H), 0.66 - 0.17 (m, 9H). MS (ESI, m / z):1056.6 [M+H] + . Example 10: Synthesis of N-((S)-2-(4-((2S,3R)-4-(4-(2,5,8,11,14,17,20,23,26,29-decoxatriane-31-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-(methyl-d3)ureo)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide Diisopropylethylamine (13 mg, 0.100 mmol) was added to a DMF solution of (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamitoyl)-3-fluorophenyl)butyric acid (30 mg, 0.051 mmol), 4-((2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl)oxy)-4-(trifluoromethyl)piperidine (48 mg, 0.076 mmol), and HATU (29 mg, 0.077 mmol). The mixture was stirred at room temperature for 16 hours. The compound N-((S)-2-(4-(2S,3R)-4-(4-((2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl)oxy)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-(methyl-d3)ureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (33.19 mg, 0.028 mmol, 54.5% yield) was purified by preparative high performance liquid chromatography as a sugar-like solid. 1 H NMR (400 MHz, MeOD- d 4) δ 7.93 (dt, J =85.1, 8.4 Hz, 1H), 7.48 (dd, J = 5.1, 2.1 Hz, 1H), 7.23 – 7.01 (m, 2H), 6.86(dd, J = 11.4, 2.1 Hz, 1H), 4.93 (dd, J = 20.5, 9.7 Hz, 2H), 4.62 – 4.46 (m,3H), 4.28 (d, J= 11.7 Hz, 1H), 3.98 – 3.84 (m, 1H), 3.68 – 3.51 (m, 38H), 3.35 (s, 2H), 3.29 – 3.11 (m, 2H), 2.97 – 2.67 (m, 2H), 2.64 – 2.53 (m, 1H),1.97 – 1.52 (m, 8H), 1.41 – 1.16 (m, 9H), 1.08 – 0.85 (m, 8H), 0.78 – 0.67(m, 2H), 0.61 – 0.46 (m, 1H). MS (ESI, m / z): [M+Na] + = 1216.1 The following compounds were obtained using synthetic steps similar to those in Examples 1 to 10, as shown in Table 1.

[0114] Table 1 Example 42: Synthesis of N-((S)-1-((4-((2S,3R)-4-(9-((2,5,8,11,14,17,20-heptaoxadodecane-22-yl)oxy)-3-azaspiro[5.5]undecane-3-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide To a solution of (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyric acid (100 mg, 0.17 mmol, 0.9 eq) in DMF (2 mL), HATU (98 mg, 0.26 mmol, 1.4 eq) and diisopropylethylamine (67 mg, 0.52 mmol, 2.7 eq) were added. The reaction mixture was stirred at room temperature for 0.5 h, and then 9-((2,5,8,11,14,17,20-heptaoxadocosane-22-yl)oxy)-3-azaspiro[5.5]undecane hydrochloride (100 mg, 0.19 mmol, 1.0 eq) was added, and stirring was continued at room temperature for 1 h. The reaction was then quenched with water (2 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile and 0.1% FA aqueous solution, 50% to 60%) to give N-((S)-1-((4-((2S,3R)-4-(9-((2,5,8,11,14,17,20-heptaoxadodecane-22-yl)oxy)-3-azaspiro[5.5]undecane-3-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (87.4 mg, 48.2%). 1 H NMR (400 MHz, DMSO- d 6): δ ppm 9.91 (d, J = 5.6 Hz, 1H), 8.39 (dd, J = 8.8, 1.2 Hz, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.47 (t, J = 2.0Hz, 1H), 7.18 – 6.94 (m, 3H), 6.10 (d, J = 8.8 Hz, 1H), 5.03 – 4.90 (m, 1H), 4.76 (t, J = 9.2 Hz, 1H), 4.47 (q, J= 7.2 Hz, 2H), 3.60 – 3.35 (m, 30H), 3.23 (s, 3H), 3.22 – 2.92 (m, 4H), 2.73 (s, 3H), 1.70 – 1.40 (m, 3H), 1.39 –0.99 (m, 13H), 0.97 – 0.71 (m, 7H), 0.69 – 0.51 (m, 3H), 0.50 – 0.41 (m, 1H), 0.40 – 0.10 (m, 7H). MS: 528.8 [M / 2+H] + . Example 43: Synthesis of N-((S)-1-((2S,3R)-4-(4-(2,5,8,11,14,17,20-heptaoxadocos-22-yl)oxy)-4'-(trifluoromethyl)-[1,4'-piperidin]-1'-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-cyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Diisopropylethylamine (297 mg, 2.30 mmol, 5.0 eq) was added to a DMF (2 mL) solution of 4-((2,5,8,11,14,17,20-heptaoxadocosano-22-yl)oxy)-4'-(trifluoromethyl)-1,4'-bipiperidine hydrochloride (280 mg, 0.46 mmol, 1.0 eq) and (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyric acid (268 mg, 0.46 mmol, 1.0 eq). HATU (262 mg, 0.69 mmol, 1.5 equivalence) was added at room temperature. The mixture was then stirred overnight at 25 °C. The mixture was cooled to 0°C, quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), and the combined organic phases were washed with brine (5 mL x 5), dried with sodium sulfate, and concentrated to obtain the residue. The residue was then purified by preparative HPLC (acetonitrile and 0.1% FA aqueous solution, 50% to 53%) to give N-((S)-1-((4-((2S,3R)-4-(4-(2,5,8,11,14,17,20-heptaoxadodoco-22-yl)oxy)-4'-(trifluoromethyl)-[1,4'-piperidine]-1'-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (85.2 mg). 1 H NMR (400 MHz, DMSO- d 6): δppm 9.93 – 9.80 (m, 1H),8.47 – 8.32 (m, 1H), 7.93 – 7.75 (m, 1H), 7.51 – 7.41 (m, 1H), 7.20 – 7.10(m, 1H), 7.09 – 7.02 (m, 1H), 7.00 – 6.91 (m, 1H), 6.25 – 6.08 (m, 1H), 5.04 – 4.92 (m, 1H), 4.90 – 4.74 (m, 1H), 4.56 – 4.40 (m, 2H), 4.23 – 4.00 (m,1H), 3.92 – 3.70 (m, 1H), 3.60 – 3.40 (m, 28H), 3.23 (s, 3H), 3.20 – 2.80 (m,4H), 2.79 – 2.70 (m, 3H), 2.62 – 2.51 (m, 2H), 2.48 – 2.20 (m, 2H), 2.13 –1.60 (m, 4H), 1.53 – 1.36 (m, 1H), 1.35 – 1.13 (m, 8H), 0.98 – 0.68 (m, 6H), 0.67 – 0.10 (m, 11H). MS: 1139.6 [M+H] + . Example 44: Synthesis of N-((S)-2-((2S,3R)-4-(4-(2,5,8,11,14,17,20,23,26,29,32-undecoxatritetradecane-34-yl)oxy)-4-isopropylpiperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide Step 1: Add 4 mL of an aqueous solution of sodium hydroxide (310 mg, 7.74 mmol) to a solution of 2,5,8,11,14,17,20,23,26,29,32-undecanetetradecane-34-ol (2 g, 3.87 mmol) in tetrahydrofuran (20 mL). Stir the mixture at 25 °C for 30 min, then add p-toluenesulfonyl chloride (2.21 g, 11.6 mmol). Stir the mixture at room temperature for 12 h. Quench the reaction mixture with water (50 mL) and extract with dichloromethane / methanol (10 / 1, 30 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was purified by rapid silica gel chromatography to 2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl-4-methylbenzenesulfonate (2.33 g, 3.4 mmol, 89.7% yield). MS (ESI, m / z): [M+H] + = 671.4 Step 2: Sodium iodide (729.2 mg, 4.86 mmol) was added to a tetrahydrofuran (25 mL) solution of 2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl-4-methylbenzenesulfonate (2.33 g, 3.48 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane / methanol (10 / 1, 30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a yellow oily 34-iodo-2,5,8,11,14,17,20,23,26,29,32-undecoxetane (2.11 g, 3.37 mmol, 96.8% yield). MS (ESI, m / z): [M+H] + = 627.2 Step 3: At 0°C, sodium hydride (322.8 mg, 7.47 mmol) was added to a mixture of tert-butyl 4-hydroxy-4-(prop-1-en-2-yl)piperidin-1-carboxylate (650 mg, 2.69 mmol) in anhydrous DMF (10 mL). The mixture was stirred at room temperature for 0.5 h, and then 34-iodo-2,5,8,11,14,17,20,23,26,29,32-undecoxetane (1.7 g, 2.49 mmol) was added. The mixture was stirred at 50°C for 48 h. The oily form of tert-butyl 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxatritetradecane-34-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid (390 mg, 0.56 mmol, 20.8% yield) was obtained by preparative high-performance liquid chromatography (0.1% FA) . MS (ESI, m / z): [M+NH4] + = 757.4 Step 4: Add Pd / C (20 mg) to a methanol (2 mL) solution of 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxatetradecane-34-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid tert-butyl ester (180 mg, 0.24 mmol). Stir the mixture at room temperature under hydrogen for 12 hours. The mixture was filtered through a diatomaceous earth mat, and the resulting mixture was purified by rapid silica gel chromatography (elution gradient: 0 to 10% methanol in dichloromethane, v / v) to give an oily tert-butyl 4-((2,5,8,11,14,17,20,23,26,29,32-undecanotritetradecano-34-yl)oxy)-4-isopropylpiperidine-1-carboxylic acid (40 mg, 0.05 mmol, 22.17% yield). MS (ESI, m / z): [M+NH4] + = 759.5 Step 5: Add 4M hydrogen chloride / 1,4-dioxane (1 mL) to a solution of 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl)oxy)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.054 mmol) in dichloromethane (2 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under vacuum to give a yellow oil of 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl)oxy)-4-isopropylpiperidine (30 mg, 0.05 mmol, 86.7% yield). MS (ESI, m / z): [M+H]+ = 642.4 Step 6: Add 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate (29.09 mg, 0.076 mmol) and diisopropylethylamine (19.77 mg, 0.15 mmol) to a DMF (1.5 mL) solution of (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)-3-fluorophenyl)butyric acid (30 mg, 0.051 mmol) and diisopropylethylamine (19.77 mg, 0.15 mmol). Stir the mixture at 25 °C for 0.5 hours. Then, 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl)oxy)-4-isopropylpiperidine (39 mg, 0.061 mmol) in DMF (0.5 mL) was added to the mixture, and the mixture was stirred at 25 °C for 12 hours. The mixture was purified by HPLC (0.1% FA) to obtain N-((S)-2-((4-(2S,3R)-4-(4-((2,5,8,11,14,17,20,23,26,29,32-undecoxatritetradecane-34yl)oxy)-4-isopropylpiperidin-1-yl)-3-(3-cyclopropyl-3-methylureido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (9.4 mg, 0.01 mmol, 14.5% yield) as a yellow sugar-like solid. 1 HNMR (400 MHz, MeOD- d 4) δ 8.05 – 7.76 (m, 1H), 7.49 (s, 1H), 7.22 – 7.01 (m,2H), 6.87 (d, J = 6.3 Hz, 1H), 6.26 (t, J = 10.0 Hz, 1H), 4.95 (d, J = 9.8Hz, 1H), 4.54 (d, J = 7.3 Hz, 4H), 4.15 (d, J = 11.2 Hz, 1H), 3.74 – 3.52 (m,43H), 3.35 (s, 3H), 3.25 – 3.08 (m, 2H), 2.89 (d, J= 4.7 Hz, 3H), 2.83 –2.51 (m, 2H), 1.80 (t, J = 32.6 Hz, 6H), 1.53 – 1.17 (m, 12H), 0.87 (dt, J =44.5, 34.8 Hz, 12H), 0.56 (dd, J = 60.7, 7.1 Hz, 3H). MS (ESI, m / z): [M+Na] + =1230.7 Example 45: Synthesis of N-((S)-1-((2S,3R)-4-(4-(2,5,8,11,14,17,20,23-octaoxapentanodecane-25yl)oxy)-4-isopropylpiperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide To a solution of (2R,3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyric acid (165 mg, 0.28 mmol, 1.0 eq) in DMF (3.4 mL), HATU (162 mg, 0.43 mmol, 1.5 eq) and diisopropylethylamine (92 mg, 0.71 mmol, 2.5 eq) were added. The reaction mixture was then stirred at room temperature for 0.5 h. Then, 4-((2,5,8,11,14,17,20,23-octaoxapentane-25yl)oxy)-4-isopropylpiperidine (170 mg, 0.34 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (4 mL) and extracted with ethyl acetate (8 mL * 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high performance liquid chromatography (acetonitrile and 0.1% FA aqueous solution, 20-40%) to give a white solid N-((S)-1-((2S,3R)-4-(4-((2,5,8,11,14,17,20,23-octaoxapentane-25yl)oxy)-4-isopropylpiperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (88.1 mg, 29.3%). 1 H NMR (400 MHz, DMSO- d 6): δ ppm 9.89 (d, J = 5.6 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.90 – 7.71 (m, 1H), 7.50 – 7.44 (m, 1H), 7.23 –7.09 (m, 1H), 7.00 – 6.97 (m, 1H), 6.18 – 6.05 (m, 1H), 5.05 – 4.91 (m, 1H),4.89 – 4.75 (m, 1H), 4.57 – 4.39 (m, 2H), 4.16 – 3.97 (m, 1H), 3.78 – 3.66(m, 1H), 3.55 – 3.37 (m, 32H), 3.26 – 3.21 (m, 4H), 3.14 – 2.88 (m, 2H), 2.73(d,J = 7.6 Hz, 3H), 2.04 – 1.79 (m, 1H), 1.71 – 1.59 (m, 1H), 1.33 – 1.20(m, 9H), 0.91 – 0.70 (m, 8H), 0.66 – 0.40 (m, 8H), 0.39 – 0.09 (m, 7H). MS:537.9 [M / 2+H] + . Example 46: Synthesis of N-((S)-1-(((2S,3R)-4-(4-(1,4,7,10,13-pentaoxa-16-azacyclooctadecane-16-carbonyl)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide Step 1: At room temperature, CMPI (2.6 g, 10.0 eq) and diisopropylethylamine (2.2 g, 16.80 mmol, 5.0 eq) were added to a solution of 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-4-carboxylic acid (1.0 g, 3.36 mmol, 1.0 eq) and 1,4,7,10,13-pentaoxa-16-azacyclooctadecane (1.3 g, 5.05 mmol, 1.5 eq) in acetonitrile (10 mL). The mixture was then stirred at 65 °C for 1 hour. The mixture was then cooled, quenched with water (4 mL), extracted with ethyl acetate (4 mL x 3), and the combined organic phases were washed with brine (6 mL x 3), dried over sodium sulfate, and concentrated to obtain the residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to give a colorless oily tert-butyl 4-(1,4,7,10,13-pentaoxa-16-azacyclooctadecane-16-carbonyl)-4-(trifluoromethyl)piperidine-1-carboxylate (318 mg, 17.4%). 1 HNMR (400 MHz, DMSO- d 6): δ ppm 4.10 – 3.90 (m, 2H), 3.80 – 3.60 (m, 22H), 3.00 – 2.76 (m, 2H), 2.57 – 2.46 (m, 2H), 1.90 – 1.57 (m, 4H), 1.45 (s, 9H). LCMS:543.4 [M+H] + . Step 2: At room temperature, a solution of 4-(1,4,7,10,13-pentaoxa-16-azacyclooctadecane-16-carbonyl)-4-(trifluoromethyl)piperidine-1-carboxylate tert-butyl ester (300 mg, 0.55 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added to ethyl acetate (2.1 mL, 4N, 8.29 mmol, 15.0 eq). The mixture was then stirred overnight at room temperature. The solution was then concentrated to give a colorless, oily solution of 4-(1,4,7,10,13-pentaoxa-16-azacyclooctadecane-16-carbonyl)-4-(trifluoromethyl)piperidine hydrochloride (270 mg, crude).

[0115] Step 3: Add HATU (312 mg, 0.83 mmol, 1.5 eq), diisopropylethylamine (356 mg, 2.75 mmol, 5.0 eq), and (2R, 3S)-2-(3-cyclopropyl-3-methylurea)-3-(4-((S)-3,3-dicyclopropyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)propamido)-3-fluorophenyl)butyric acid (385 mg, 0.66 mmol, 1.2 eq) to a DMF (2 mL) solution of 4-(1,4,7,10,13-penta-16-azacyclooctadecane-16-carbonyl)-4-(trifluoromethyl)piperidine hydrochloride (270 mg, 0.55 mmol, 1.0 eq) to a DMF (2 mL) solution. Then stir the mixture at room temperature for 3 hours. The mixture was then quenched with water (2 mL), extracted with ethyl acetate (2 mL * 3), and the combined organic phases were washed with brine (3 mL * 3), dried with sodium sulfate and concentrated to obtain the residue. The residue was purified by preparative TLC (dichloromethane / methanol = 10:1) to give N-((S)-1-((4-((2S,3R)-4-(4-(1,4,7,10,13-pentaoxa-16-azacyclooctadecane-16-carbonyl)-4-(trifluoromethyl)piperidin-1-yl)-3-(3-cyclopropyl-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropyl-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (75 mg, 2-step yield 13.5%). 1 H NMR (400 MHz, DMSO- d 6): δppm 9.95 – 9.80 (m, 1H), 8.47 – 8.33 (m, 1H), 7.94 – 7.72 (m, 1H), 7.54 –7.42 (m, 1H), 7.27 – 7.11 (m, 1H), 7.10 – 6.94 (m, 2H), 6.26 – 6.09 (m, 1H), 5.05 – 4.92 (m, 1H), 4.90 – 4.71 (m, 1H), 4.60 – 4.40 (m, 2H), 4.30 – 3.82(m, 2H), 3.70 – 3.40 (m, 24H), 3.22 – 2.90 (m, 1H), 2.82 – 2.73 (m, 4H), 2.48– 2.37 (m, 2H), 2.35 – 2.17 (m, 1H), 1.84 – 1.45 (m, 1H), 1.38 – 1.12 (m,7H), 1.07 – 0.70 (m, 6H), 0.69 – 0.53 (m, 2H), 0.51 – 0.10 (m, 8H). LCMS:1007.6 [M+H] + . The following compounds were obtained using synthetic steps similar to those in Examples 42 to 46, as shown in Table 2.

[0116] Table 2 Synthesis of Intermediate A-1: ​​(2R,3S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyric acid Step 1: 1-(3-fluoro-4-nitrophenyl)ethyl ketone (50 g, 273 mmol) was dissolved in methanol (600 mL), and sodium borohydride (6.2 g, 164 mmol) was added at 0°C. The mixture was stirred at 0°C for 1.5 hours. The reaction was quenched with ice water (800 mL), and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL) and dried over sodium sulfate. The mixture was concentrated under vacuum to give 1-(3-fluoro-4-nitrophenyl)ethanol (49 g, 264.6 mmol, yield: 96.9%) as a brown oil. 1HNMR (400 MHz, CDCl3) δ 8.05 (dd, J = 8.3, 7.7 Hz, 1H), 7.35 – 7.27 (m, 2H), 4.99 (q, J = 6.5 Hz, 1H), 2.07 (s, 1H), 1.52 (d, J = 6.5 Hz, 3H). Step 2: At 0°C, triphenylphosphine (83.28 g, 317.5 mmol) and tetrabromomethane (105.30 g, 317.5 mmol) were added to a solution of 1-(3-fluoro-4-nitrophenyl)ethanol (49 g, 265 mmol) in dichloromethane (600 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under vacuum and purified by rapid chromatography (ethyl acetate / hexane = 0–10%) to give a pale yellow oil of 4-(1-bromoethyl)-2-fluoro-1-nitrobenzene (53 g, 213.7 mmol, yield: 80.8%). 1 H NMR (400 MHz, CDCl3) δ 8.10 - 8.02 (m, 1H), 7.42 - 7.32 (m, 2H), 5.13 (q, J = 6.9 Hz, 1H), 2.04 (d, J = 6.9 Hz, 3H). Step 3: Under stirring, sodium hydroxide (12 g, 301 mmol) was added to a DMF (300 mL) solution of 1-{[(2R)-1-benzylpyrrolidine-2-yl]carbonyl}-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelhecyclononane-4-one (30 g, 60.2 mmol). Then, 4-(1-bromoethyl)-2-fluoro-1-nitrobenzene (20.9 g, 84.2 mmol) dissolved in DMF (30 mL) was added to the solution. The mixture was stirred under nitrogen, and after the reaction was complete, the reaction mixture was quenched with ice water (1200 mL) and extracted with ethyl acetate (600 mL * 3). The organic layers were combined, washed with brine (600 mL x 2), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid chromatography (elution gradient: ethyl acetate / hexane = 0-55%) to give intermediate A-1A (12 g, 18 mmol, yield: 29.9%). MS (ESI) m / z = 665.2 [M+H] + . Steps 4-5: Add 3 NHCl / methanol = 1:1 (400 mL) to a methanol (300 mL) solution of intermediate A-1A (31 g, 46.6 mmol), and stir the mixture at 70 °C for 10 minutes. Dilute the mixture with water (100 mL) and wash with dichloromethane (400 mL x 3). Adjust the pH to 10 by adding sodium carbonate to the water, and add tetrahydrofuran (500 mL) and Boc₂O (108 g, 466 mmol). Stir the mixture further at room temperature for 16 hours. Dilute the mixture with ethyl acetate (1000 mL) and wash with water (600 mL x 3). The combined liquid layers were adjusted to pH 3 with 4M HCl, washed with ethyl acetate (600 mL * 3), and the combined organic layers were concentrated to give a pale yellow solid crude product (2R,3S)-2-(((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-nitrophenyl)butyric acid (11 g, 32.1 mmol, yield: 68.9%). MS (ESI) m / z = 365.0 [M+Na] + . Intermediate A-2: Synthesis of (S)-2-((tert-Butoxycarbonyl)amino)-3,3-dicyclobutylpropionic acid Step 1: Magnesium bromo(cyclobutyl)magnesium (42.8 mL, 21.4 mmol, 0.5 M tetrahydrofuran solution) was added to a tetrahydrofuran (50 mL) solution of cyclobutaneformaldehyde (1500 mg, 17.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (60 mL x 3). The organic layers were combined, washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a colorless oily compound, dicyclobutylmethanol (750 mg, 5.4 mmol, yield: 30.0%). 1 H NMR (400 MHz, CDCl3) δ 3.39 (t, J = 6.9 Hz, 1H), 2.36 – 2.23 (m, 2H), 1.95 – 1.72 (m, 12H). Step 2: At 0°C, imidazole (425 mg, 6.2 mmol) and triphenylphosphine dibromide (2637 mg, 6.2 mmol) were added to a solution of dichloromethane (20 mL) containing dicyclobutylmethanol (730 mg, 5.2 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and dichloromethane (50 mL x 3) was extracted. The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by rapid chromatography (elution gradient: petroleum ether) to give a colorless oily compound (bromomethylene)dicyclobutane (540 mg, 2.7 mmol, crude). No further purification was required for the next step.

[0117] Step 3: Under stirring, powdered sodium hydroxide (381 mg, 9.5 mmol) was added to a DMF (15 mL) solution of NI-(S)-BPB-GLY (950 mg, 1.9 mmol). Then, (bromomethylene)bicyclobutane (988 mg, 4.9 mmol) was added to the solution. The mixture was stirred under nitrogen, and after the reaction was complete, the reaction mixture was quenched with ice water (150 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was purified by rapid chromatography (elution gradient: petroleum ether / ethyl acetate = 1 / 1, v / v) to give intermediate A-2A (280 mg, 0.45 mmol, yield: 10.1%). MS (ESI) m / z = 620.2 [M+H] + . Step 4: The mixture of intermediate A-2A (280 mg, 0.45 mmol) in 3M HCl / methanol = 1:1 (15 mL) was stirred at 70 °C for 1 hour and concentrated. The residue was diluted with water (10 mL) and washed with dichloromethane (10 mL x 2). Sodium carbonate was added to the combined liquid layers to adjust the pH to 10, followed by tetrahydrofuran (20 mL) and Boc2O (492 mg, 2.26 mmol). The mixture was further stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL x 2). 4M HCl was added to the combined liquid layers to adjust the pH to 3. The mixture was then washed with ethyl acetate (50 mL x 3), and the combined organic layers were concentrated to give a yellow solid product (S)-2-((tert-Butoxycarbonyl)amino)-3,3-dicyclobutylpropionic acid (65 mg, 0.22 mmol, yield: 48.4%). MS (ESI) m / z = 320.2 [M+Na] + . Synthesis of intermediate A-3: (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-(methyl-d3)ureo)butyrate methyl ester Step 1: To a solution of 2 g (12.6 mmol) cyclopropyl tert-butyl carbamate and sodium hydrogen hydride (0.76 g (18.9 mmol) in tetrahydrofuran (20 mL), a solution of iodomethane-d3 (2.74 g (18.9 mmol)) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at 0 °C for 10 min. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a yellow oily cyclopropyl(methyl-d3) tert-butyl carbamate (1.2 g, 6.8 mmol, yield: 53.97%). MS (ESI) m / z = 175.0 [M+H] + . Step 2: A solution of dioxane (10 mL, 40 mmol) in 4N HCl was added to a solution of 1.2 g (6.8 mmol) of tert-butyl cyclopropylcarbamate in ethyl acetate (10 mL). The reaction mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure to give a yellow gel-like N-(methyl-d3)cyclopropylamine hydrochloride (0.5 g, 6.7 mmol, yield: 97.1%). 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 9.18 (s, 2H), 2.66 – 2.63 (m, 1H), 0.85 – 0.83 (m, 2H), 0.73 – 0.70 (m, 2H). Step 3: At 0°C, triphosgene (86 mg, 0.31 mmol) was added to a solution of (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)butyrate (100 mg, 0.39 mmol) and diisopropylethylamine (100 mg, 0.78 mmol) in dichloromethane (10 mL). The mixture was stirred at 0°C under nitrogen for 10 minutes. A solution of N-(methyl-d3)cyclopropylamine hydrochloride (80 mg, 0.78 mmol) in dichloromethane (2 mL) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was purified by rapid silica gel chromatography to obtain a yellow, gelatinous methyl (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(3-fluoro-4-nitrophenyl)butyrate (110 mg, 0.31 mmol, yield: 79.5%). MS (ESI) m / z = 356.9 [M+H] + . Step 4: Add 10% Pd / C (65 mg, 0.06 mmol) to a solution of methyl (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(3-fluoro-4-nitrophenyl)butyrate (110 mg, 0.31 mmol) in ethyl acetate (10 mL). Stir the reaction mixture at 25 °C for 3 hours under a hydrogen atmosphere. Filter the mixture through a diatomaceous earth mat, and concentrate the filtrate under reduced pressure to give the crude product. Purify the crude product by rapid silica gel chromatography (elution gradient: 0 to 60% ethyl acetate in hexane) to give a white solid of methyl (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-(methyl-d3)ureo)butyrate (80 mg, 0.245 mmol, yield: 79.4%). MS (ESI) m / z = 326.9 [M+H] + . Intermediate A-4: Synthesis of 4-((2,5,8,11-tetraoxatridecane-13-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: In an ice bath, add dropwise (trifluoromethyl)trimethylsilane (12.34 g, 86.82 mmol) and tetrabutylammonium fluoride (0.64 mL, 0.64 mmol, 1 M tetrahydrofuran solution) to a mixture of 4-oxopiperidinyl-1-carboxylate (15.0 g, 64.31 mmol) in anhydrous tetrahydrofuran (75 mL). Stir the mixture at room temperature for 12 hours. Concentrate the mixture under vacuum and dilute with methanol (120 mL). Add hydrochloric acid (15 mL) to the mixture and stir at room temperature for 1 hour. Concentrate the mixture, dilute with water (200 mL), and extract with dichloromethane (150 mL x 3). Wash the combined organic layers with brine (100 mL x 3), dry with sodium sulfate, and concentrate under vacuum. The residue was crystallized from toluene (45 mL) at 90 °C to give a white solid, benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (14.8 g, 48.8 mmol, 75.9% yield). MS (ESI, m / z): = 376.2 [M+H] + . Step 2: Sodium hydride (260 mg, 6.6 mmol) was added to a mixture of 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (1.0 g, 3.3 mmol) in anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred at room temperature for 0.5 h, and then 13-bromo-2,5,8,11-tetraoxatridecane (1.79 g, 6.6 mmol) was added. The mixture was stirred at room temperature for 12 h. The mixture was quenched with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over sodium sulfate, and concentrated under vacuum. The colorless oily 4-((2,5,8,11-tetraoxatridecane-13-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (720 mg, 1.46 mmol, 44.3% yield) was purified by rapid silica gel chromatography. MS (ESI, m / z): = 494.3 [M+H] + . Step 3: Palladium on carbon (70 mg, 10% wt) was added to a methanol (10 mL) solution of benzyl 4-((2,5,8,11-tetraoxetane-13-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (710 mg, 1.44 mmol). The mixture was debenzylated with hydrogen and stirred at room temperature for 12 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum to give a colorless oily solution of 4-((2,5,8,11-tetraoxetane-13-yl)oxy)-4-(trifluoromethyl)piperidine (440 mg, 1.22 mmol, 85.1% yield). MS (ESI, m / z): = 360.2 [M+H] + . Synthesis of Intermediate A-5: 4-((2,5,8,11,14-pentahexadecane-16-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: Sodium hydride (126.6 mg, 5.27 mmol) was added to a DMF (10 mL) solution of benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (641 mg, 2.11 mmol). The mixture was stirred at 0 °C for 10 min, and 16-bromo-2,5,8,11,14-pentahexadecane (1.0 g, 3.17 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give a colorless oil of benzyl 4-((2,5,8,11,14-pentahexadecane-16-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (500 mg, 0.93 mmol, 44.01% yield). MS (ESI, m / z): = 537.5 [M+H] + Step 2: Pd / C (50 mg, 10% purity) was added to a methanol (20 mL) solution of 4-((2,5,8,11,14-pentahexadecane-16-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (500 mg, 0.93 mmol), and the mixture was stirred under hydrogen at room temperature for 16 hours. The mixture was filtered and concentrated under vacuum to give a white solid 4-((2,5,8,11,14-pentahexadecane-16-yl)oxy)-4-(trifluoromethyl)piperidine (350 mg, 0.86 mmol, 84.9% yield). MS (ESI, m / z): = 403.4 [M+H]+ Intermediate A-6: 4-((2,5,8,11,14,17-hexaoxane-19-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: Sodium hydride (316.8 mg, 7.92 mmol, 60% purity) was added to a DMF (5 mL) solution of benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (600 mg, 1.98 mmol). The mixture was stirred at 0 °C for 10 min, and 19-bromo-2,5,8,11,14,17-hexadecane (1.07 g, 2.97 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give a colorless oil of benzyl 4-((2,5,8,11,14,17-hexaoxane-19-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (410 mg, 0.71 mmol, 35.6% yield). MS (ESI, m / z): 582.8 [M+H] + Step 2: Pd / C (41 mg, 10% purity) was added to a methanol (10 mL) solution of 4-((2,5,8,11,14,17-hexaoxane-19-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (410 mg, 0.7 mmol), and the mixture was stirred under hydrogen at room temperature for 16 hours. The mixture was filtered and concentrated under vacuum to give a white solid 4-((2,5,8,11,14,17-hexaoxane-19-yl)oxy)-4-(trifluoromethyl)piperidine (260 mg, 0.58 mmol, 82.4% yield). MS (ESI, m / z): = 448.2 [M+H] + Intermediate A-7: 4-((2,5,8,11,14,17,20-heptaoxadocosane-22-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: Sodium hydride (264.0 mg, 6.6 mmol, 60% purity) was added to a solution of 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylic acid benzyl ester (1 g, 3.30 mmol, 1 eq) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at room temperature for 10 min, and then 22-bromo-2,5,8,11,14,17,20-heptaoxane (2 g, 4.95 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a green oily 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (500 mg, 0.80 mmol, 24.24% yield). MS (ESI, m / z): = 626.4 [M+H] + . Step 2: A methanol (12 mL) solution of 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (0.036 g, 0.13 mmol, 1 eq) was stirred under hydrogen at room temperature for 16 hours. The mixture was filtered and concentrated under vacuum to give a crude product as a white solid: 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-(trifluoromethyl)piperidine (200 mg, 0.13 mmol, 0.41 mmol, 42.4% yield). MS (ESI, m / z): = 492.2 [M+H] + . Synthesis of Intermediate A-8: 4-((2,5,8,11,14,17,20,23-octaoxapentanodecane-25-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: To a solution of 2,5,8,11,14,17,20,23-octaoxaconicosan-25 alcohol (1 g, 2.6 mmol, 1 eq) in tetrahydrofuran (2 mL), a solution of sodium hydroxide (170 mg, 4.16 mmol, 1.6 eq) in water (1 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then p-toluenesulfonyl chloride (500 mg, 2.6 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a green oily 2,5,8,11,14,17,20,23-octaoxaconitane-25-yl-4-methylbenzenesulfonate (470 mg, 0.87 mmol, 33.6% yield). MS (ESI, m / z): = 539.2 [M+H] + . Step 2: Sodium hydride (26.40 mg, 0.66 mmol, 2 eq, 60% purity) was added to a DMF (10 mL) solution of benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (100 mg, 0.33 mmol, 1 eq) at room temperature. The mixture was stirred for 10 minutes at room temperature, followed by the addition of 2,5,8,11,14,17,20,23-octaoxaconicosode-25-yl 4-methylbenzenesulfonate (27 mg, 0.49 mmol, 1.5 eq). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give an oily benzyl 4-((2,5,8,11,14,17,20,23-octaoxapentanodecane-25-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (50 mg, 0.07 mmol, 22.6% yield). MS (ESI, m / z): = 670.4 [M+H] + . Step 3: Pd / C (5 mg) was added to a methanol (12 mL) solution of 4-((2,5,8,11,14,17,20,23-octaoxacontano-25-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (50 mg, 0.075 mmol, 1 eq), and the mixture was stirred at room temperature under hydrogen for 16 hours. The mixture was filtered and concentrated under vacuum to give a crude product, a colorless oily product of 4-((2,5,8,11,14,17,20,23-octaoxacontano-25-yl)oxy)-4-(trifluoromethyl)piperidine (35 mg, 87.5% yield). MS (ESI, m / z): = 536.4 [M+H] + . Intermediate A-9: 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosane-28-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: Sodium hydride (132 mg, 3.3 mmol, 60% purity) was added to a DMF (10 mL) solution of 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (500 mg, 1.65 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes, and then 28-bromo-2,5,8,11,14,17,20,23,26-nonoxaoctacosane (1.22 g, 2.47 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless oil of benzyl 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (290 mg, 0.41 mmol, 24.7% yield). MS (ESI, m / z): = 714.4 [M+H] + Step 2: A methanol (12 mL) solution of 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (290 mg, 0.41 mmol) was stirred at room temperature under hydrogen for 16 hours. The mixture was filtered and concentrated under vacuum to give a white solid of 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-(trifluoromethyl)piperidine (210 mg, 0.36 mmol, 89.4% yield). MS (ESI, m / z): = 580.4 [M+H] + . Intermediate A-10: 4-((2,5,8,11,14,17,20,23,26,29-decoxatrione-31-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: At room temperature, a solution of sodium hydroxide (140 mg, 3.39 mmol, 1.6 eq) in water (1 mL) was added to a solution of 2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-ol (1 g, 2.12 mmol, 1 eq) in tetrahydrofuran (2 mL). The mixture was stirred at room temperature for 10 minutes, and then p-toluenesulfonyl chloride (1.21 g, 6.36 mmol, 1 eq) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a green oily 2,5,8,11,14,17,20,23,26,29-decaoxane-31-yl-4-methylbenzenesulfonate (750 mg, 1.20 mmol, 56.5% yield). MS (ESI, m / z): = 627.3 [M+H] + . Step 2: Sodium hydride (52.80 mg, 1.32 mmol, 2 eq) was added to a DMF (5 mL) solution of benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (200 mg, 0.66 mmol, 1 eq) at room temperature. The mixture was stirred for 10 minutes at room temperature, followed by the addition of 2,5,8,11,14,17,20,23,26,29-decaoxane-31-yl-4-methylbenzenesulfonate (620.5 mg, 0.99 mmol, 1.5 eq). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give an oily benzyl 4-((2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (450 mg, 0.59 mmol, 90.04% yield). LC / MS (ESI, m / z): [M +H] + = 627.4. Step 3: Pd / C (45 mg) was added to a methanol (12 mL) solution of 4-((2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (450 mg, 0.59 mmol, 1 eq), and the mixture was stirred under hydrogen at room temperature for 16 hours. The mixture was filtered and concentrated under vacuum to give a crude product, a colorless oily product of 4-((2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl)oxy)-4-(trifluoromethyl)piperidine (360 mg, 0.58 mmol, 97.2% yield). MS (ESI, m / z): = 624.4 [M+H] + . Intermediate A-11: 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxatetradecane-34-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: To a solution of 2,5,8,11,14,17,20,23,26,29,32-undecoxatetradecane-34-yl-34-ol (1 g, 1.94 mmol) in tetrahydrofuran (2 mL), a solution of sodium hydroxide (120 mg, 3.10 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then p-toluenesulfonyl chloride (1.11 g, 5.82 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a green oily 2,5,8,11,14,17,20,23,26,29,32-undecanetetratracene-3,4-yl-4-methylbenzenesulfonate (880 mg, 1.3 mmol, 67.8% yield). MS (ESI, m / z): [M+H] + =671.4. Step 2: Sodium hydride (158.4 mg, 3.96 mmol) was added to a DMF (5 mL) solution of benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (400 mg, 1.32 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes, and then 2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl 4-methylbenzenesulfonate (830 mg, 1.32 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give an oily 4-((2,5,8,11,14,17,20,23,26,29,32-undecanotritetradecane-34-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (290 mg, 0.38 mmol, 29.0% yield). MS (ESI, m / z): [M+H] + =802.4. Step 3: Pd / C (29 mg) was added to a methanol (12 mL) solution of 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (290 mg, 0.36 mmol), and the mixture was stirred at room temperature under hydrogen for 16 hours. The mixture was filtered and concentrated under vacuum to give a colorless oil of 4-((2,5,8,11,14,17,20,23,26,29,32-undecoxetane-34-yl)oxy)-4-(trifluoromethyl)piperidine (200 mg, 0.3 mmol, 82.8% yield). MS (ESI, m / z): [M+H] + = 668.4. Intermediate A-12: 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetane-37-yl)oxy)-4-(trifluoromethyl)piperidine Step 1: At room temperature, add a solution of sodium hydroxide (140 mg, 3.51 mmol) in water (2 mL) to a solution of 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetane-37-ol (1 g, 1.78 mmol) in tetrahydrofuran (2 mL). Stir the mixture at room temperature for 10 minutes and add p-toluenesulfonyl chloride (1.02 g, 5.34 mmol). Stir the mixture at room temperature for 16 hours. Quench the reaction mixture with water (50 mL) and extract with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetylheptadecane-37-yl 4-methylbenzenesulfonate (950 mg, 1.3 mmol, 74.5% yield). MS (ESI, m / z): [M+H] + =715.4. Step 2: Sodium hydride (198.00 mg, 4.95 mmol) was added to a DMF (5 mL) solution of 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (500 mg, 1.65 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes, and then 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetylheptadecane-37-yl 4-methylbenzenesulfonate (590 mg, 0.82 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give an oily 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetylheptadecane-37-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylic acid benzyl ester (260 mg, 0.31 mmol, 18.6% yield). MS (ESI, m / z): [M+H] + = 846.4. Step 3: Pd / C (29 mg) was added to a methanol (12 mL) solution of 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetylheptadecane-37-yl)oxy)-4-(trifluoromethyl)piperidine-1-carboxylate (290 mg, 0.36 mmol), and the mixture was stirred under hydrogen at room temperature for 16 hours. The mixture was filtered and concentrated under vacuum to give a crude product, which was a colorless oil of 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetylheptadecane-37-yl)oxy)-4-(trifluoromethyl)piperidine (200 mg, 0.3 mmol, 82.8% yield). MS (ESI, m / z): [M+H] + =712.4 Intermediate A-13: 4-((2,5,8,11,14,17,20-heptaoxadocosane-22-yl)oxy)-4-isopropylpiperidine hydrochloride Step 1: At 0°C, sodium hydride (179.20 mg, 4.48 mmol) was added to a mixture of tert-butyl 4-hydroxy-4-(prop-1-en-2-yl)piperidin-1-carboxylate (270 mg, 1.12 mmol) in anhydrous DMF (10 mL). The mixture was stirred at room temperature for 0.5 h, and then 22-bromo-2,5,8,11,14,17,20-heptaoxadecanoane (542.05 mg, 1.34 mmol) was added. The mixture was stirred at 40°C for 72 h. The mixture was purified by preparative HPLC (0.1% FA) to give a colorless oily tert-butyl 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid (73 mg, 0.13 mmol, 11.6% yield). MS (ESI, m / z): 586.4 [M+Na] + . Step 2: Pd / C (10 mg) was added to a methanol (3 mL) solution of 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid tert-butyl ester (73 mg, 0.13 mmol). The mixture was stirred at room temperature under hydrogen for 12 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum to give a colorless oily tert-butyl 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-isopropylpiperidin-1-carboxylic acid (70 mg, 0.12 mmol, 92.3% yield). MS (ESI, m / z): 588.4 [M+Na] + . Step 3: Add hydrogen chloride / 1,4-dioxane (1 mL, 4 M) to a solution of 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol) in dichloromethane (2 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under vacuum to give 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4-isopropylpiperidine hydrochloride (46 mg, 0.092 mmol, 76.7% yield). MS (ESI, m / z): 466.4 [M+Na] + . Intermediate A-14: 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-isopropylpiperidine hydrochloride Step 1: At 0 °C, magnesium isopropenyl magnesium bromide (5.47 g, 37.63 mmol) was added dropwise to an anhydrous tetrahydrofuran (30 mL) solution of tert-butyl 4-oxopiperidin-1-carboxylate (5.0 g, 25.09 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL) and concentrated under vacuum to remove the organic solvent. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL * 3), dried over sodium sulfate, and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (elution gradient: 10% to 20% ethyl acetate in hexane, v / v) to give a colorless oily tert-butyl 4-hydroxy-4-(prop-1-en-2-yl)piperidin-1-carboxylate (780 mg, 3.2 mmol, 12.7% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ 4.94 (d, J = 0.8 Hz, 1H), 4.75 (s, 1H), 4.54 (s, 1H), 3.74 (d, J = 10.4 Hz, 2H), 3.09 (d, J = 33.7 Hz, 2H), 1.72 (s, 3H), 1.65 – 1.46 (m, 4H), 1.39 (s, 9H). Step 2: At 0°C, sodium hydride (91.0 mg, 2.27 mmol) was added to an anhydrous DMF (10 mL) solution of 4-hydroxy-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid tert-butyl ester (440 mg, 1.82 mmol). The mixture was stirred at room temperature for 0.5 hours, and then 28-bromo-2,5,8,11,14,17,20,23,26-nonoxaoctacosane (894.37 mg, 1.82 mmol) was added. The mixture was stirred at 70°C for 48 hours. The mixture was purified by preparative HPLC (0.1% FA) to give a colorless oily tert-butyl 4-((2,5,8,11,14,17,20,23,26-nonoxataoctadecyl-28-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid (75 mg, 0.12 mmol, 6.6% yield). MS (ESI, m / z): 669.4 [M+NH4] + Step 3: Pd / C (8 mg) was added to a methanol (3 mL) solution of 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid tert-butyl ester (75 mg, 0.12 mmol). The mixture was stirred at room temperature under hydrogen for 16 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum to give a colorless oily 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-isopropylpiperidin-1-carboxylic acid tert-butyl ester (75 mg, 0.11 mmol, 91.7% yield). MS (ESI, m / z): 676.4 [M+Na] + Step 4: Add hydrogen chloride / 1,4-dioxane (1.0 mL, 4 M) to a solution of 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (75 mg, 0.11 mmol) in dichloromethane (1 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under vacuum to give a yellow oily 4-((2,5,8,11,14,17,20,23,26-nonoxaoctacosan-28-yl)oxy)-4-isopropylpiperidine hydrochloride (60 mg, 0.1 mmol, 90.9% yield). MS (ESI, m / z): 554.4 [M+H] + . Intermediate A-15: 4-((2,5,8,11,14,17,20,23,26,29-decoxatriane-31-yl)oxy)-4-isopropylpiperidine hydrogen chloride Step 1: To a solution of sodium hydroxide (338.56 mg, 8.46 mmol) in water (7 mL), add a solution of 2,5,8,11,14,17,20,23,26,29-deoxyphenetrene-31-ol (2.5 g, 5.29 mmol) in tetrahydrofuran (14 mL). Stir the mixture at room temperature for 30 minutes, then add p-toluenesulfonyl chloride (1.5 g, 7.94 mmol). Stir the mixture at 30 °C for 12 hours. Dilute the reaction mixture with water (40 mL) and extract with dichloromethane / methanol (10:1) (30 mL x 3). Combine the organic layers, wash with brine (30 mL x 2), dry with anhydrous sodium sulfate, and concentrate under vacuum to give the crude product. The crude product was purified by rapid silica gel chromatography (elution gradient: 0 to 10% methanol in dichloromethane, v / v) to give a colorless oil of 2,5,8,11,14,17,20,23,26,29-decaoxaproteane-31-yl-4-methylbenzenesulfonate (1.9 g, 3.03 mmol, 57.30% yield). MS (ESI, m / z): [M+H] + = 627.5. Step 2: Sodium iodide (680 mg, 4.54 mmol) was added to a tetrahydrofuran (20 mL) solution of 2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl 4-methylbenzenesulfonate (1.9 g, 3.03 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a yellow oil of 31-iodo-2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl (1.2 g, 2.1 mmol, 67.96% yield). MS (ESI, m / z): [M+H] + = 583.2. Step 3: At 0°C, sodium hydride (248.40 mg, 6.21 mmol) was added to an anhydrous DMF (5 mL) solution of tert-butyl 4-hydroxy-4-(prop-1-en-2-yl)piperidin-1-carboxylate (500 mg, 2.07 mmol). The mixture was stirred at room temperature for 0.5 hours, and then 31-iodo-2,5,8,11,14,17,20,23,26,29-decaoxatricarboxane-31-yl (1.2 g, 2.07 mmol) was added. The mixture was stirred at 50°C for 48 hours. The mixture was purified by preparative high-performance liquid chromatography (0.1% FA) to give a colorless oily tert-butyl 4-((2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylate (75 mg, 0.108 mmol, 5.2% yield). MS (ESI, m / z): [M+Na] + = 718.4. Step 4: Pd / C (10 mg) was added to a methanol (3 mL) solution of 4-((2,5,8,11,14,17,20,23,26,29-decoxatricarbox-31-yl)oxy)-4-(prop-1-en-2-yl)piperidine-1-carboxylate tert-butyl ester (65 mg, 0.093 mmol). The mixture was stirred at room temperature under hydrogen for 12 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum to give a colorless oily 4-((2,5,8,11,14,17,20,23,26,29-decoxatricarbox-31-yl)oxy)-4-isopropylpiperidine-1-carboxylate tert-butyl ester (65 mg, 0.093 mmol, 100% yield). MS (ESI, m / z): [M+Na] + = 720.4. Step 5: Add 4M hydrogen chloride / 1,4-dioxane (1 mL) to a solution of 4-((2,5,8,11,14,17,20,23,26,29-decoxatriane-31-yl)oxy)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (65 mg, 0.093 mmol) in dichloromethane (2 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under vacuum to give a yellow oily 4-((2,5,8,11,14,17,20,23,26,29-decoxatriane-31-yl)oxy)-4-isopropylpiperidine hydrochloride (60 mg, 0.095 mmol, 102.2% yield). MS (ESI, m / z): [M+H] + = 598.4. Intermediate A-16: 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl)oxy)-4-isopropylpiperidine Step 1: At 0°C, under nitrogen atmosphere, isopropyl magnesium bromide (16.1 mL, 32.2 mmol, 1.5 eq.) was added dropwise to a 0.6 M LaCl3-LiCl tetrahydrofuran solution (53.6 mL, 32.2 mmol, 1.5 eq.). The mixture was stirred at room temperature for 1 hour, and 4-oxopiperidin-1-carboxylic acid benzyl ester (5.0 g, 21.4 mmol, 1.0 eq.) in tetrahydrofuran (50 mL) was added dropwise, followed by stirring at room temperature for another 12 hours. AcOH (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL), washed with brine (50 mL x 3), dried over sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain a yellow oily 4-hydroxy-4-isopropylpiperidine-1-carboxylic acid benzyl ester (4.2 g, 69.5%). 1 H NMR (300 MHz, DMSO- d 6 ): δ ppm 7.39-7.28 (m, 5H), 5.05 (s, 2H), 4.06-4.01 (m, 1H), 3.81-3.78 (m, 2H), 3.31 (s, 1H), 3.07 (s, 2H), 1.56-1.40(m, 1H), 1.39-1.31 (m, 3H), 0.90-0.80 (m, 6H). MS: 260.0 [M-18] + . Step 2: ethyl 2-diazoethyl ester (6.6 g, 57.5 mmol, 5.0 eq) was added to a solution of 4-hydroxy-4-isopropylpiperidine-1-carboxylate (3.2 g, 11.5 mmol, 1.0 eq) and Rh2(OAc)4 (0.1 g, 0.23 mmol, 0.02 eq) in dichloromethane (90 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the mixture, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over sodium sulfate, and concentrated under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give a yellow oily product of 4-(2-ethoxy-2-oxoethoxy)-4-isopropylpiperidine-1-carboxylate (1.0 g was added in portions to give 1.4 g, 25.4%). 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 7.36-7.28 (m, 5H), 5.12 (s, 2H), 3.98-3.89(m, 4H), 3.15 (s, 2H), 1.87-1.76 (m, 1H), 1.59 (s, 4H), 1.30-1.24 (m, 4H),0.95-0.81 (m, 6H). MS: 364.1 [M+H] + . Step 3: At 0 °C, a solution of 2 M LiBH4 in tetrahydrofuran (6.6 mL, 13.2 mmol, 4.0 eq) was added dropwise to a solution of 4-(2-ethoxy-2-oxoethoxy)-4-isopropylpiperidine-1-carboxylic acid benzyl ester (1.2 g, 3.3 mmol, 1.0 eq) in tetrahydrofuran (4.5 mL). The mixture was stirred at room temperature for 12 hours. An aqueous solution of ammonium chloride (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (500 mL x 2), dried over sodium sulfate, and concentrated under vacuum to give a yellow solid of 4-(2-hydroxyethoxy)-4-isopropylpiperidine-1-carboxylic acid benzyl ester (0.6 g), which was used directly in the next step. 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 7.36-7.29 (m, 5H), 5.12 (s, 2H), 4.00 (s, 2H), 3.74 (s, 2H), 3.37 (t, J= 4.7 Hz, 2H), 3.06 (s, 2H), 2.00 (s,1H), 1.96-1.89 (m, 1H), 1.59 (s, 5H), 0.90-0.81 (d, J = 6.8 Hz, 6H). MS: 322.1 [M+H] + . Step 4: Under a nitrogen atmosphere and at 0°C, add 60% NaH (136 mg, 2.05 mmol, 1.0 eq) to a DMF (6 mL) solution of 4-(2-hydroxyethoxy)-4-isopropylpiperidine-1-carboxylate (533 mg, 1.66 mmol, 1.0 eq) and stir at 0°C for 0.5 hours. Then add 2,5,8,11,14,17,20,23-octaoxapentanodecane-25-yl 4-methylbenzenesulfonate (1.11 g, 2.05 mmol / L, 1.2 eq) to the mixture, heat the solution to 50°C and stir for 15 hours. Separate the organic phase, wash with brine (10 mL*2), dry with sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 30:1) to give an oily 4-((2,5,8,11,14,17,20,23-octaoxapentane-25yl)oxy)-4-isopropylpiperidine-1-carboxylic acid benzyl ester (230 mg, 21.7%). 1 H NMR (400MHz, CDCl3): δ ppm 7.37 – 7.33 (m, 5H), 5.11 (s, 2H), 3.68 – 3.59 (m, 36H), 3.56 – 3.52 (m, 2H), 3.40 (t, J = 8.0 Hz, 2H), 3.34 (s, 3H),1.94 – 1.84 (m,1H) 0.85 (d, J = 9.2 Hz, 6H). Step 5: At room temperature, 4-((2,5,8,11,14,17,20,23-octaoxapentanodecano-25yl)oxy)-4-isopropylpiperidine-1-carboxylic acid benzyl ester (230 mg, 0.36 mmol, 1.0 eq) was added to a methanol (5.4 mL) solution of Pd / C (23 mg) under hydrogen atmosphere. The mixture was stirred at room temperature for 15 hours. After completion, the solution was filtered and concentrated under reduced pressure to give a colorless oil of 4-((2,5,8,11,14,17,20,23-octaoxapentanodecano-25yl)oxy)-4-isopropylpiperidine (170 mg, 93.6%). 1 H NMR (400 MHz, CDCl3): δ ppm 3.69 – 3.62 (m, 28H), 3.57 – 3.52 (m,2H), 3.41 (t, J = 4.0 Hz, 2H), 3.37 (s, 3H), 3.01 – 2.87 (m, 2H), 2.86 – 2.76(m, 2H), 1.89 – 1.81 (m, 1H), 1.62 – 1.47 (m, 4H), 0.87 (d, J = 8.0 Hz, 6H). MS: 510.3 [M+H] + . Intermediate A-17: 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl)oxy)-4-isopropylpiperidine hydrochloride Step 1: Add a solution of sodium hydroxide (360 mg, 8.92 mmol) in water (4 mL) to a solution of 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-ol (2 g, 3.57 mmol) in tetrahydrofuran (20 mL). Stir the mixture at room temperature for 30 minutes, then add p-toluenesulfonyl chloride (2.04 g, 10.71 mmol). Stir the mixture at room temperature for 12 hours. Quench the reaction mixture with water (50 mL) and extract with dichloromethane / methanol (10:1) (30 mL x 3). Combine the organic layers, wash with brine (30 mL x 2), dry with anhydrous sodium sulfate, and concentrate under vacuum to give the crude product. The crude product was purified by rapid silica gel chromatography (elution gradient: 0 to 10% methanol in dichloromethane, v / v) to give a colorless oil of 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl-4-methylbenzenesulfonate (2.2 g, 3.1 mmol, 86.8% yield). MS (ESI, m / z): [M+H] + = 715.4. Step 2: Sodium iodide (692.49 mg, 4.62 mmol) was added to a tetrahydrofuran (25 mL) solution of 2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl 4-methylbenzenesulfonate (2.2 g, 3.08 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane / methanol (10:1) (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a yellow oily 37-iodo-2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl (1.7 g, 2.5 mmol, 81.2% yield). MS (ESI, m / z): [M+H] + = 671.2. Step 3: At 0°C, sodium hydride (298.80 mg, 7.47 mmol) was added to a mixture of tert-butyl 4-hydroxy-4-(prop-1-en-2-yl)piperidin-1-carboxylate (600 mg, 2.49 mmol) in anhydrous DMF (10 mL). The mixture was stirred at room temperature for 0.5 hours, and then 37-iodo-2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl (1.7 g, 2.49 mmol) was added. The mixture was stirred at 50°C for 48 hours. The mixture was purified by preparative HPLC (0.1% FA) to give a colorless oil of tert-butyl 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid (350 mg, 0.45 mmol, 18% yield). MS (ESI, m / z): [M+NH4) + = 801.6. Step 4: Add Pd / C (20 mg) to a methanol (2 mL) solution of 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl)oxy)-4-(prop-1-en-2-yl)piperidin-1-carboxylic acid tert-butyl ester (180 mg, 0.23 mmol). Stir the mixture at room temperature under hydrogen for 12 hours. The mixture was filtered through a diatomaceous earth mat, and the resulting mixture was purified by rapid silica gel chromatography (elution gradient: 0 to 10% methanol in dichloromethane, v / v) to give a colorless oil of 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxaheptadecane-37-yl)oxy)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.05 mmol, 22.17% yield). MS (ESI, m / z): [M+NH4] + = 803.6 Step 5: Add 4M hydrogen chloride / 1,4-dioxane (1 mL) to a solution of 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetane-37-yl)oxy)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.051 mmol) in dichloromethane (2 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under vacuum to give a yellow oily 4-((2,5,8,11,14,17,20,23,26,29,32,35-dodecoxetane-37-yl)oxy)-4-isopropylpiperidine (30 mg, 0.04 mmol, 85.9% yield). MS (ESI, m / z): [M+H] + = 686.4 Intermediate A-18: (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyric acid Step 1: At room temperature, methyl (2R,3S)-3-(4-amino-3-fluorophenyl)-2-(3-cyclopropyl-3-(methyl-d3)ureoyl)butyrate (500 mg, 1.53 mmol) was added to a DMF (15 mL) solution of (S)-2-(((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid (560.57 mg, 1.84 mmol), HATU (872.63 mg, 2.29 mmol), and diisopropylethylamine (593.2 mg, 4.59 mmol). The mixture was stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and then quenched with brine (100 mL x 3). Washed with 2 mL of the solution, dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (PE / ethyl acetate = 1:1) to give a colorless oily methyl (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-(methyl-d3)ureoyl)butyrate (520 mg, 0.85 mmol, 55.31% yield). MS (ESI, m / z): [M+Na] + = 636.5 Step 2: Add HCl / dioxane (4 M, 1 mL) to a mixture of (2R,3S)-3-(4-((S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-2-(3-cyclopropyl-3-(methyl-d3)ureo)butyrate (520 mg, 0.85 mmol) in dichloromethane (2 mL). Stir the mixture at room temperature for 2 hours. The mixture was concentrated to give a white solid, (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyrate (530 mg, 1.03 mmol, 121.8% yield). MS (ESI, m / z): [M+H] + = 514.4 Step 3: At room temperature, methyl (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxylic acid, 169.85 mg, 1.21 mmol), HATU (576.05 mg, 1.52 mmol), and diisopropylethylamine (391.60 mg, 3.03 mmol) in DMF (15 mL) was added. The mixture was stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (PE / ethyl acetate = 1:1) to give an oily methyl (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(4-(S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyrate (340 mg, 0.53 mmol, 52.8% yield). MS (ESI, m / z): [M+H] + = 636.5 Step 4: At room temperature, add a solution of lithium hydroxide (44 mg, 1.06 mmol) in water (2 mL) to a solution of (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyrate (340 mg, 0.53 mmol) in tetrahydrofuran (10 mL). Stir the mixture at room temperature for 4 hours. Quench the reaction mixture with aqueous solution HCl (1 M) and adjust the pH to 3. Add water (50 mL) to the reaction mixture and extract with ethyl acetate (50 mL * 3). The combined organic layers were dried over sodium sulfate and concentrated to a yellow solid, (2R,3S)-2-(3-cyclopropyl-3-(methyl-d3)ureo)-3-(4-((S)-2-(4-(difluoromethylene)cyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)butyric acid (300 mg, 0.48 mmol, 90.2% yield). MS (ESI, m / z): [M+H] + = 622.3 The following intermediates were synthesized using the same synthetic methods and steps: Intermediate A-22: 9-((2,2,8,11,14-17,20-heptaoxaecosane-22-enyl)oxy)-3-azaspiro[5.5]undecane hydrochloride Step 1: Under nitrogen atmosphere, a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylic acid (300 mg, 1.11 mmol, 1.0 eq) in tetrahydrofuran (6 mL) was stirred at 0 °C for 0.5 h, and NaH (134 mg, 60%, 3.34 mmol, 3.0 eq) was added at 0 °C. Then, 2,5,8,11,14,17,20-heptaoxadocosa-22-yl-4-methylbenzenesulfonate (1.10 g, 2.22 mmol, 2.0 eq) was added to the solution, and the mixture was stirred at 60 °C for 15 h. The reaction mixture was partitioned between water (6 mL) and ethyl acetate (10 mL). The organic phase was washed with brine (10 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to give a yellow oily 9-((2,5,8,11,14,17,20-heptaoxydodecane-22-yl)oxy)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (600 mg, 91.0%). 1H NMR (300 MHz, CDCl3): δ ppm 3.60 – 3.58 (m, 28H), 3.57 – 3.50 (m,2H), 3.44 – 3.22 (m, 9H), 1.83 – 1.71 (m, 2H), 1.69 – 1.57 (m, 2H), 1.44 (s,9H), 1.36 – 1.22 (m, 2H), 1.19 – 1.07 (m, 2H). MS: 536.3 [M-56+H] + . Step 2: A solution of 9-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (300 mg, 0.51 mmol, 1.0 eq) in HCl dioxane (3.0 mL, 4N) was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure to give a colorless oily solution of 9-((2,2,8,11,14-17,20-heptaoxadecano-22-yl)oxy)-3-azaspiro[5.5]undecane hydrochloride (230 mg, 85.9%). 1 H NMR (300MHz, CDCl3): δ ppm 3.67 – 3.52 (m, 28H), 3.38 (s, 3H), 3.46 – 3.27 (m, 1H), 3.20 – 3.03 (m, 4H), 1.87 – 1.63 (m, 8H), 1.52 – 1.37 (m, 2H), 1.32 – 1.16(m, 2H). The following intermediates were synthesized using the same synthetic methods and steps: Intermediate A-23: 4-((2,5,8,11,14,17,20-heptaoxadocosane-22-yl)oxy)-4'-(trifluoromethyl)-1,4'-bipiperidine hydrochloride Step 1: In a sealed tube, 1,5-dichloropentan-3-one (3.5 g, 22.40 mmol, 2.0 eq) was added to a solution of tert-butyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate (3.0 g, 11.18 mmol, 1.0 eq) in diisopropylethylamine (60 mL). The mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give tert-butyl 4-oxo-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylic acid (437 mg, 11.2%). 1 H NMR (300 MHz, CDCl3): δ ppm 4.18 – 3.83(m, 2H), 3.24 – 2.92 (m, 6H), 2.41 (t, J = 6.0 Hz, 4H), 2.20 – 2.00 (m, 2H), 1.84 – 1.67 (m, 2H), 1.47 (s, 9H). Step 2: Under nitrogen atmosphere, sodium borohydride (89 mg, 2.40 mmol, 1.8 eq) was added to a tetrahydrofuran (25 mL) solution of 4-oxo-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (460 mg, 1.31 mmol, 1.0 eq). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give a yellow oil of 4-hydroxy-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (437 mg, 94.4%). 1 H NMR (300 MHz, CDCl3): δ ppm 4.12 – 3.81 (m,2H), 3.80 – 3.64 (m, 1H), 3.15 – 2.80 (m, 4H), 2.52 (t, J= 11.1 Hz, 2H),2.15 – 1.97 (m, 2H), 1.96 – 1.82 (m, 2H), 1.75 – 1.56 (m, 2H), 1.55 – 1.36(m, 11H). MS: 353.1 [M+H] + . Step 3: Under nitrogen atmosphere, sodium hydroxide (60%, 102 mg, 2.55 mmol, 3.0 eq) was added to a tetrahydrofuran (3 mL) solution of 4-hydroxy-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (300 mg, 0.85 mmol, 1.0 eq). The mixture was stirred at 0 °C for 1 hour, and then 2,5,8,11,14,17,20-heptaoxadodecyl 4-methylbenzenesulfonate (842 mg, 1.70 mmol, 2.0 eq) was added at 0 °C and stirred overnight at 65 °C. The reaction mixture was cooled, quenched with saturated ammonium chloride aqueous solution (5 mL), and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless oily 4-((2,5,8,11,14,17,20-heptaoxadodoco-22-yl)oxy)-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (250 mg, 43.5%). 1 H NMR (400 MHz, CDCl3): δ ppm4.06 – 3.77 (m, 2H), 3.72 – 3.58 (m, 26H), 3.57 – 3.52 (m, 2H), 3.42 – 3.30(m, 4H), 3.14 – 2.85 (m, 4H), 2.57 – 2.40 (m, 2H), 2.12 – 1.97 (m, 2H), 1.96 – 1.82 (m, 2H), 1.72 – 1.56 (m, 2H), 1.56 – 1.40 (m, 11H). MS: 675.3 [M+H] + . Step 4: At room temperature, a solution of 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (270 mg, 0.40 mmol, 1.0 eq) in dichloromethane (3 mL) was added to ethyl acetate (1.5 mL, 4N, 6.00 mmol, 15.0 eq). The mixture was then stirred overnight at room temperature. The mixture was concentrated to give a colorless, oily 4-((2,5,8,11,14,17,20-heptaoxadecano-22-yl)oxy)-4'-(trifluoromethyl)-1,4'-bipiperidine hydrochloride (220 mg, crude), which was used directly in the next step.

[0118] The following intermediates were synthesized using the same synthetic methods and steps: Synthesis of Intermediate A-24: 4,4-Difluoro-1-(20-((4-(trifluoromethyl)piperidin-4-yl)oxy)-3,6,9,12,15,18-hexaoxoeicosyl)piperidine Step 1: To a solution of 4,4-difluoropiperidine hydrochloride (300 mg, 1.9 mmol, 1.0 eq) in acetonitrile (24 mL), 3,6,9,12,15,18-hexaoxaecoane-1,20-diylbis(4-methylbenzenesulfonate) (1.8 g, 2.9 mmol, 1.5 eq) and potassium carbonate (788 mg, 5.7 mmol, 3.0 eq) were added, and the mixture was stirred at 90 °C for 15 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile and 0.1% FA aqueous solution, 20 to 60%) to give an oily 20-(4,4-difluoropiperidin-1-yl)-3,6,9,12,15,18-hexaoxeicosyl-4-methylbenzenesulfonate (300 mg, 26.8%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.80 (d, J = 8.0 Hz, 2H), 7.34 (d, J =8.0 Hz, 2H), 4.16 (t, J = 4.4 Hz, 2H), 3.69 (t, J= 4.8 Hz, 2H) 3.67-3.58 (m,17H), 3.57 – 3.52 (m, 4H), 2.67 – 2.58 (m, 5H), 2.45 (s, 3H), 2.05 – 1.94 (m,4H), 1.30-1.22 (m, 2H). Step 2: Under a nitrogen atmosphere at 0°C, 60% NaH (68 mg, 1.02 mmol, 2.0 eq) was added to a DMF (6 mL) solution of 4-hydroxy-4-(trifluoromethyl)piperidin-1-carboxylate (300 mg, 0.5 mmol, 1.0 eq). The mixture was stirred at room temperature for 30 minutes, and 20-(4,4-difluoropiperidin-1-yl)-3,6,9,12,15,18-hexaoxoeicosyl-4-methylbenzenesulfonate (155 mg, 0.5 mmol, 1.0 eq) was added at room temperature. The solution was stirred at room temperature for 15 hours and partitioned between water (6 mL) and ethyl acetate (12 mL). The organic phase was separated, washed with brine (10 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 50 / 1) to give a yellow oily 4-((20-(4,4-difluoropiperidin-1-yl)-3,6,9,12,15,18-hexaoxeicosyl)oxy)-4-(trifluoromethyl)piperidin-1-carboxylic acid benzyl ester (300 mg, 82.4%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.44 – 7.28 (m,5H), 5.13 (s, 2H), 4.21 – 3.94 (m, 2H), 3.83- 3.52 (m, 26H), 3.29 – 2.99 (m,2H), 2.73 – 2.53 (m, 6H), 2.10 – 1.84 (m, 6H), 1.78 – 1.67 (m, 2H). Step 3: Pd / C (21 mg) was added to a methanol (4.2 mL) solution of 4-((20-(4,4-difluoropiperidin-1-yl)-3,6,9,12,15,18-hexaoxoeicosano-20-yl)oxy)-4-(trifluoromethyl)piperidin-1-carboxylic acid benzyl ester (210 mg, 0.29 mmol, 1.0 eq) at room temperature. The mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. After completion, the solution was filtered, and the filtrate was concentrated under reduced pressure to give a colorless oily product of 4,4-difluoro-1-(20-(4-(trifluoromethyl)piperidin-4-yl)oxy)-3,6,9,12,15,18-hexaoxoeicosanoyl)piperidine (140 mg, crude product).1 H NMR (300 MHz, CDCl3): δ ppm3.75 – 3.55 (m, 28H), 2.93 – 2.88 (m, 2H), 2.70 – 2.56 (m, 6H), 2.26 – 2.09(m, 1H), 2.05 – 1.86 (m, 6H), 1.78 – 1.57 (m, 2H). The following intermediates were synthesized using the same synthetic methods and steps: Intermediate A-25: 1-(2,5,8,11,14,17,20-heptaoxadocos-22-yl)-4-(4-(trifluoromethyl)piperidin-4-yl)piperazine hydrochloride Step 1: To a solution of tert-butyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate (3.0 g, 11.18 mmol, 1.0 eq) in diisopropylethylamine (90 mL), N-benzyl-2-chloro-N-(2-chloroethyl)ethyl-1-amine (6.0 g, 25.72 mmol, 2.3 eq) was added. The reaction mixture was stirred in a sealed tube at 120 °C for 72 hours under nitrogen. The reaction mixture was cooled, concentrated, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give a yellow oil of tert-butyl 4-(4-benzylpiperazin-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (412 mg, 8.6%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.50 – 7.27 (m, 5H), 4.10 –3.78 (m, 2H), 3.49 (s, 2H), 3.20 – 2.92 (m, 2H), 2.81 (s, 4H), 2.62 – 2.26(m, 2H), 2.10 – 1.89 (m, 2H), 1.70 – 1.50 (m, 4H), 1.46 (s, 9H). Step 2: Under hydrogen atmosphere, Pd / C (50 mg, 10%) and Pd(OH)₂ / C (50 mg) were added to a methanol (5 mL) solution of 4-(4-benzylpiperazin-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.17 mmol, 1.0 eq). The mixture was then stirred at 45 °C for 3 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated to obtain a yellow oily tert-butyl 4-(piperazin-1-yl, 4-(trifluoromethane)piperidine-1-carboxylic acid ester (345 mg, crude product).

[0119] Step 3: To a DMF (2.5 mL) solution of 2-(piperazin-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.74 mmol, 1.0 eq), 2,5,8,11,14,17,20-heptaoxadecano-22-yl 4-methylbenzenesulfonate (549 mg, 1.11 mmol, 1.5 eq), cesium carbonate (265 mg, 0.81 mmol, 1.1 eq), and KI (12 mg, 0.07 mmol, 0.1 eq) were added. The reaction mixture was stirred at 70 °C for 3 hours under nitrogen protection. After completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 4), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give a brown oily tert-butyl 4-(4-(2,5,8,11,14,17,20-heptaoxane-22-yl)piperazin-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (182 mg, two-step yield 32.5%). 1 H NMR (400 MHz, CDCl3): δ ppm 4.10 –3.58 (m, 28H), 3.57 – 3.51 (m, 2H), 3.37 (s, 3H), 3.14 – 2.91 (m, 2H), 2.81(s, 4H), 2.57 (t, J = 6.0 Hz, 2H), 2.53 – 2.30 (m, 2H), 2.10 – 1.92 (m, 2H), 1.70 – 1.58 (m, 2H), 1.45 (s, 9H). LCMS: 660.5 [M+H] + . Step 4: At room temperature, a solution of 4-(4-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)piperazin-1-yl)-4-(trifluoromethyl)piperidin-1-carboxylic acid tert-butyl ester (180 mg, 0.27 mmol, 1.0 eq) in dichloromethane (1.8 mL) was added. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated to give a brown oily product of 1-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)-4-(4-(trifluoromethyl)piperidin-4-yl)piperazine hydrochloride (176 mg, crude).

[0120] Intermediate A-26: 3-(2,5,8,11,14,17,20-heptaoxadocosane-22-yl)-3,9-diazaspiro[5.5]undecane hydrochloride Step 1: Under nitrogen atmosphere at room temperature, KI (13 mg, 0.08 mmol, 0.1 eq), cesium carbonate (304 mg, 0.94 mmol, 1.2 eq), and 2,5,8,11,14,17,20-heptaoxadecano-22-yl-4-methylbenzenesulfonate (507 mg, 1.03 mmol, 1.3 eq) were added to a DMF (4 mL) solution of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (200 mg, 0.79 mmol, 1.0 eq) and stirred at 70 °C for 15 hours. The reaction mixture was partitioned between saturated sodium bicarbonate solution (4 mL) and ethyl acetate (8 mL x 3). The organic phase was separated, washed with brine (10 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 30:1) to give a clear, oily tert-butyl 9-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid (250 mg, 54.4%). MS: 577.4 [M+H] + . Step 2: At room temperature, 200 mg (0.35 mmol, 1.0 eq) of 9-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester was added to a 4 M HCl solution in dioxane (2 mL). The mixture was stirred at room temperature for 2 hours. The solution was then concentrated under reduced pressure to obtain an oily 3-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)-3,9-diazaspiro[5.5]undecane hydrochloride (150 mg, 91.4%). MS: 477.3 [M+H] + . Intermediate A-27:(4-(2,5,8,11,14,17,20-heptaoxadocosano-22-yl)piperazin-1-yl)(4-(trifluoromethyl)piperidin-4-yl)methyl ketone hydrochloride Step 1: Add 2,5,8,11,14,17,20-heptaoxane-22-yl-4-methylbenzenesulfonate (1.0 g, 2.04 mmol, 0.45 eq), cesium carbonate (3.0 g, 9.08 mmol, 2.0 eq), and potassium iodide (113.0 mg, 0.68 mmol, 0.15 eq) to a DMF (15 mL) solution of piperazine-1-carboxylic acid benzyl ester (1.0 g, 4.54 mmol, 1.0 eq). Stir the reaction mixture overnight at 70 °C. After completion, dilute the reaction mixture with water (20 mL) and extract with ethyl acetate (15 mL x 3). Wash the combined organic layers with brine (15 mL x 4), dry with sodium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to 1:1) to give a yellow oily 4-(2,5,8,11,14,17,20-heptaoxadocarboyl)piperazine-1-carboxylate (430 mg, 39.1%). MS: 543.3 [M+H + . Step 2: Add Pd / C (65 mg) to a methanol (6 mL) solution of 4-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)piperazine-1-carboxylate (650 mg, 1.20 mmol, 1.0 eq). Replace the hydrogen gas three times with the mixture and stir overnight at room temperature. After completion, filter the mixture and concentrate the filtrate to give a yellow oily 1-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)piperazine (464 mg, 94.8%). MS: 409.3 [M+H] + . Step 3: To a DMF (5 mL) solution of 1-(2,5,8,11,14,17,20-heptaoxadecano-22-yl)piperazine (450 mg, 1.10 mmol, 1.0 eq), 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-4-carboxylic acid (328 mg, 1.10 mmol, 1.0 equivalence), HATU (629 mg, 1.65 mmol, 1.5 eq), and diisopropylethylamine (427 mg, 3.31 mmol, 3.0 eq) were added. The reaction mixture was stirred overnight at room temperature. After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to ethyl acetate) to give a yellow oily 4-(4-(2,5,8,11,14,17,20-heptaoxadocarboyl)piperazine-1-carbonyl)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (360 mg, 47.4%). 1 H NMR (400 MHz, CDCl3): δ ppm 4.10 – 3.85 (m, 2H), 3.80 –3.58 (m, 27H), 3.57 – 3.50 (m, 2H), 3.37 (s, 3H), 3.03 – 2.84 (m, 2H), 2.79 (s, 1H), 2.73 – 2.33 (m, 8H), 1.94 – 1.73 (m, 2H), 1.44 (s, 9H). MS: 688.3 [M+H] + . Step 4: To a solution of 250 mg (0.36 mmol, 1.0 eq) of 4-(4-(2,5,8,11,14,17,20-heptaoxadioctoyl)piperazin-1-carbonyl)-4-(trifluoromethyl)piperidin-1-carboxylic acid tert-butyl ester (ethyl acetate) in 3 mL of ethyl acetate, HCl / ethyl acetate solution (0.9 mL, 4N, 3.63 mmol, 10.0 eq) was added. The reaction mixture was stirred overnight at room temperature. The mixture was then concentrated to give a yellow solid (4-(2,5,8,11,14,17,20-heptaoxadioctoyl-22-yl)piperazin-1-yl)(4-(trifluoromethyl)piperidin-4-yl)methyl ketone hydrochloride (233 mg, crude). MS: 294.8 [M / 2+H] + . Experiment 1: IL-17A / A HEK reporter cell assay The ability of the compound to neutralize IL-17A / A activity was evaluated using a cell-based human IL-17 neutralization assay performed below. The human IL-17A reporter 293 cell line used in this assay (H IL17A reporter 293, Genomeditech, catalog number GM-C06721) consisted of HEK293 cells stably expressing human IL-17RA, IL-17RC, and the adaptor protein ActI. Upon stimulation with IL-17A / A, these cells congregated to drive the expression of the luciferase reporter gene. Luciferase signals from cell lysates, representing signaling pathway activation, were measured using the ONE Glo™ luciferase detection system (Promega, catalog number E6120).

[0121] H_IL17A Reporter 293 cells were seeded at a rate of 15,000 cells / well in white culture plate-96 (PerkinElmer, catalog number 6005680) in DMEM medium (Gibco, catalog number 10566016). The DMEM medium was supplemented with 10% fetal bovine serum (ThermoFisher, catalog number 10091148), 1% penicillin-streptomycin (ThermoFisher, catalog number 15140122), 100 μg / mL zebumycin (Genomeditech, catalog number GM-040407), 150 μg / mL hygromycin (Genemeditech, catalog number GM 040403-1), 1.5 μg / mL puromycin (Genomitech, category number GM 040401-1), and 3 μg / mL puromycin. Genomeditech (Cat No. GM-040404-1) was incubated overnight in a humid incubator at 37°C and 5% CO2.

[0122] The next day, the growth medium was removed, and 100 μL of fresh medium was added. Using acoustic pipetting, 100 nL of the test compound titrated in 100% DMSO was added to each well reserved for the test compound. The remaining wells accepted only an equal volume of DMSO as a carrier control, or secukinumab as a reference for the IL-17A / a inhibitor. The dose range of 0.001 nM to 10000 nM was evaluated. After adding human IL-17A / A protein (Novoprotein, catalog number C774) to a final concentration of 8.32 ng / mL, the system was incubated for 18 hours (18 ± 2 hours) for ONE Glo assay. The percentage of inhibition was calculated using the following equation: PC (positive control) was obtained from cells treated with only IL-17A / A protein and DMSO; NC (negative control) was obtained from cells only.

[0123] The inhibition curves were analyzed using XLFit, and the IC50 values ​​were determined using a 4-parameter nonlinear fitting method to illustrate the neutralization of human IL-17-mediated signal transduction and the activity of IL-17A / A inhibitors.

[0124] Experiment 2: IL-17A / F HEK reporter cell assay The ability of the compound to neutralize IL-17A / F activity was assessed using a cell-based human IL-17 neutralization assay performed essentially as follows. The human IL17A reporter 293 cell line used in this assay (H_IL17A reporter 293, Genomeditech, catalog number GM-C06721) consisted of HEK293 cells stably expressing human IL-17RA, IL-17RC, and the adaptor protein ActI. Upon stimulation with IL-17A / F, these cells conjoined to drive the expression of the luciferase reporter gene. Luciferase signals from cell lysates represented the signaling pathway activation profile and were measured using the ONE Glo™ luciferase detection system (Promega, catalog number E6120).

[0125] H_IL17A Reporter 293 cells were seeded at a rate of 15,000 cells / well in white culture plate-96 (PerkinElmer, catalog number 6005680) in DMEM medium (Gibco, catalog number 10566016). The DMEM medium was supplemented with 10% fetal bovine serum (ThermoFisher, catalog number 10091148), 1% penicillin-streptomycin (ThermoFisher, catalog number 15140122), 100 μg / mL zebumycin (Genomeditech, catalog number GM-040407), 150 μg / mL hygromycin (Genemeditech, catalog number GM 040403-1), 1.5 μg / mL puromycin (Genomitech, category number GM 040401-1), and 3 μg / mL puromycin. Blasticidin (Genomeditech, catalog number GM-040404-1) was incubated overnight in a humid incubator at 37°C and 5% CO2.

[0126] The next day, the growth medium was removed, and 100 μL of fresh medium was added. Using acoustic pipetting, 100 nL of the test compound titrated in 100% DMSO was added to each well reserved for the test compound. The remaining wells received either an equal volume of DMSO as a carrier control or secukinumab as a reference for the IL-17A / F inhibitor. The dose range of 0.001 nM to 10000 nM was evaluated. After adding human IL-17A and 17F (Novoprotein, catalog number CI60) to a final concentration of 30 ng / mL, the system was incubated for 18 hours (18 ± 2 hours) before a Glo assay. The percentage of inhibition was calculated using the following equation: PC (positive control) was obtained only from cells treated with IL-17A / F; NC (negative control) was obtained only from cells.

[0127] The inhibition curves were analyzed using XLFit, and the IC50 values ​​were determined using a 4-parameter nonlinear fitting method to illustrate the neutralization of human IL-17-mediated signal transduction and the activity of IL-17A / F inhibitors.

[0128] Experiment 3: IL-17F / F HEK reporter cell assay The ability of the compound to neutralize IL-17F / F activity was assessed using a cell-based human IL-17 neutralization assay performed essentially as follows. The human IL-17A reporter 293 cell line used in this assay (H_IL17A reporter 293, Genomeditech, catalog number GM-C06721) consisted of HEK293 cells stably expressing human IL-17RA, IL-17RC, and the adaptor protein ActI. Upon stimulation with IL-17F / F, these cells congregated to drive the expression of the luciferase reporter gene. Luciferase signals from cell lysates represented the signaling pathway activation profile and were measured using the ONE Glo™ luciferase detection system (Promega, catalog number E6120).

[0129] H_IL17A Reporter 293 cells were seeded at a rate of 15,000 cells / well in white culture plate-96 (PerkinElmer, catalog number 6005680) in DMEM medium (Gibco, catalog number 10566016). The DMEM medium was supplemented with 10% fetal bovine serum (ThermoFisher, catalog number 10091148), 1% penicillin-streptomycin (ThermoFisher, catalog number 15140122), 100 μg / mL zebumycin (Genomeditech, catalog number GM-040407), 150 μg / mL hygromycin (Genemeditech, catalog number GM 040403-1), 1.5 μg / mL puromycin (Genomitech, catalog number GM 040401-1), and 3 μg / mL puromycin. Blasticidin (Genomeditech, catalog number GM-040404-1) was incubated overnight in a humid incubator at 37°C and 5% CO2.

[0130] The next day, the growth medium was removed, and 100 μL of fresh medium was added. Using acoustic pipetting, 100 nL of the test compound titrated in 100% DMSO was added to each well reserved for the test compound. The dose range of 0.001 nM to 10000 nM was evaluated. After adding human IL-17F / F protein (Novoprotein, catalog number CA22) to a final concentration of 0.14 μg / mL, the system was incubated for 18 hours (18 ± 2 hours) for ONE Glo assay. The percentage of inhibition was calculated using the following equation: PC (positive control) was obtained from cells treated only with IL-17F / F protein and DMSO (dimethyl sulfoxide); NC (negative control) was obtained from cells only.

[0131] The inhibition curves were analyzed using XLFit, and the IC50 values ​​were determined using a 4-parameter nonlinear fitting method to illustrate the neutralization of human IL-17-mediated signal transduction and the activity of IL-17F / F inhibitors.

[0132] IL-17 is an immune cell-derived cytokine produced after infection with certain microorganisms. After binding to receptors on various cell types found in tissues, such as keratinocytes, fibroblasts, and epithelial cells, it triggers downstream signaling to coordinate ongoing tissue inflammation in order to clear invading pathogens.

[0133] We have developed a series of potential best-in-class oral IL-17 inhibitors, initially for the treatment of psoriasis, with the aim of achieving similar therapeutic effects to the FDA-approved injectable biologic secukinumab. To compare the efficacy of small molecule inhibitors against the IL-17A-specific antibody secukinumab in an in vitro neutralization assay, the relative inhibitory effects of IL-17A / A and IL-17A / F signaling were examined. This assay utilized reporter activity stimulated by either IL-17A / A or IL-17A / F as a surrogate marker of inflammatory activation. Potential efficacy curves were calculated relative to reporter cells activated by either IL-17A / A or IL-17A / F alone. Example 3 and secukinumab showed more potent IC50 values ​​against IL-17A / A at 0.0002 μM and 0.0011 μM, respectively, and stronger IC50 values ​​against similar IL-17A / F at 0.0017 μM and 0.028 μM, respectively. These data are consistent with reported secukinumab data. In summary, this example highlights the blocking effect of small molecule inhibitors on the same biochemical steps as those of anti-IL-17 antibodies. The cellular assay results are summarized in Table 3.

[0134] Table 3: IL-17 A / A and IL-17 A / F inhibition data of selected compounds Experiment 4: Human CYP 3A4 / 5 Inhibition Test: Research protocol (tested via BioDuro Sundia): a) Liver microsomes b) Equipment c) Chemicals d) Materials e) Preparation of buffer solutions and solutions a) Buffer i. 8.71 g dipotassium hydrogen phosphate dissolved in 950 ml water ii. Adjust the pH to 7.4 using hydrochloric acid. iii. Add water to a total volume of 1000 ml. iv. Filtration (0.45 µm filter). v. Store in a refrigerator at 4 degrees Celsius for later use. b) Quenching solution i. Prepare a solution of terfenadine / tolbutamide (1 mg / mL) in DMSO (dimethyl sulfoxide). ii. Dilute the above solution to 5 / 10 ng / mL (terfenadine / tolbutamide) by adding acetonitrile. c) Positive control solution i. Information on the positive control solution is as follows: ii. Prepare control solutions using DMSO (4-fold dilution, 6 non-zero concentrations) d) Substrate working solution i. The substrate working solution information is as follows: e) Working solution for liver microsomes i. Thaw the liver microsomes in a 37°C water bath before use. ii. Prepare the liver microsomal working solution according to the following steps: f) NADPH working solution i. Prepare a 5 mM NADPH working solution using phosphate buffer. g) Working solution of test compound i. The information on the tested compounds is as follows: ii. Prepare working solutions (4-fold dilution, 6 non-zero concentrations) f) Incubation a) Add 238.5 µL of liver microsome working solution to a 1.1 mL test tube.

[0135] b) Add 1.5 µL of the test compound / control working solution / DMSO and mix thoroughly by pipetting several times.

[0136] c) Pre-incubate in a 37°C shaking water bath for 5 minutes.

[0137] d) After pre-incubation, add 60µL of NADPH working solution and mix thoroughly several times with a pipette.

[0138] e) Incubate in a shaking water bath at 37°C for 10 minutes.

[0139] f) After incubation, immediately add 500µL of quenching solution and vortex for 1 minute.

[0140] g) Centrifuge all samples at 4000 rpm for 15 minutes at 4°C.

[0141] h) Take 300µL of the above supernatant in equal portions for further LC-MS / MS analysis.

[0142] g) LC / MS / MS analysis i) Instrument 27# ii) Analyte analysis: iii) Column: Atlantis T3 5 μm (2.1*50mm) iv) Mobile phase Mobile phase A: 0.1% formic acid aqueous solution Mobile phase B: 0.1% formic acid acetonitrile solution v) Analysis time: 3 min h) Data Analysis The IC50 was computed using Graph Pad Prism, and the data is as follows. Table 3 Table 4 Experimental Example 5: Time-dependent inhibition assay of human CYP3A4 / 5 inhibition: Research methods (tested by BioDuro Sundia): a. Liver microsomes b. Instruments c. Chemicals d. Materials e. Preparation of buffer solutions and solutions a) Phosphate buffer i. Dissolve 8.71 g of dipotassium hydrogen phosphate in 950 ml of water.

[0143] ii. Adjust the pH to 7.4 using H hydrochloric acid solution.

[0144] iii. Adjust the volume with water to a final volume of 1000 mL. iv. Filter the buffer solution using a 0.45µm filter.

[0145] v. Store in a refrigerator at 4°C for future use.

[0146] b) Quenching solution i. Prepare 1 mg / mL stock solutions of terfenadine and tolbutamide by dissolving appropriate amounts of terfenadine or tolbutamide in DMSO (dimethyl sulfoxide). ii. Prepare a quenching solution containing 5 / 5 / 10 ng / mL (terfenadine / buspirone / tolbutamide) by diluting the above stock solution in acetonitrile.

[0147] c) Positive control protocol i. Positive control information is shown in the table below: ii. Prepare control working solutions (4-fold dilution, 6 non-zero concentrations) using DMSO (dimethyl sulfoxide) from the above stock solution.

[0148] d) Substrate working solution i. Substrate information is shown in the table below: e) Liver microsomal solution i. Thaw the liver microsomes in a 37°C water bath before use.

[0149] ii. Prepare the liver microsomal working solution according to the following steps: f) NADPH working solution i. Prepare a 5 mM NADPH working solution using phosphate buffer.

[0150] g) Working solution of the test compound i. Information on the stock solution of the test sample is shown in the table below: ii. Prepare working solutions of the test compound (4-fold dilution, 6 non-zero concentrations) from 10 mM using DMSO from the above stock solution.

[0151] h. Incubation a) No pre-incubation with test compound i. Add 178.5 µL of liver microsome working solution to a 1.1 mL test tube.

[0152] ii. Pre-incubate in a shaker at 37°C for 30 minutes.

[0153] iii. Add 1.5 µL of the test compound / control working solution / DMSO and 60 µL of the substrate working solution, then add 60 µL of NADPH working solution to start the reaction. Mix by shaking at 1000 rpm for 10 seconds.

[0154] iv. Incubate in a shaker at 37°C for 10 minutes.

[0155] v. After incubation, immediately add 500µL of quenching solution and shake at 1000rpm for 90 seconds to mix thoroughly.

[0156] vi. Centrifuge all samples at 4000 rpm for 15 minutes at 4°C.

[0157] vii. Take 300µL of the above supernatant in equal portions for further LC-MS / MS analysis.

[0158] b) Pre-incubate the test compound with NADPH for 30 minutes. i. Add 178.5 µL of liver microsome working solution, 1.5 µL of test compound / control working solution / DMSO to a 1.1 mL test tube and 60 µL of NADPH working solution, and shake at 1000 rpm for 10 seconds to mix.

[0159] ii. Pre-incubate in a shaker at 38°C for 30 minutes.

[0160] iii. Add 60µL of substrate working solution to start the reaction, shake at 1000rpm for 10 seconds, and stir until homogeneous.

[0161] iv. Incubate in a shaker at 38°C for 10 minutes.

[0162] v. After incubation, immediately add 500µL of quenching solution and shake at 1000rpm for 90 seconds to mix thoroughly.

[0163] vi. Centrifuge all samples at 4000 rpm for 15 minutes at 4°C.

[0164] vii. Take 300µL of the above supernatant in equal portions for further LC-MS / MS analysis.

[0165] i. LC / MS / MS i. Instruments: 20# & 1# ii. Results Analysis: j. Data Analysis IC 50 The data was calculated using Graph Pad Prism and is shown below. Table 5

Claims

1. A compound of formula (I') and its pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product, or prodrug: (I') in: Excerpt The nitrogen atom is attached to the parent nucleus of formula (I'), and the group is selected from the following: 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S, and 6-13 membered spirocyclic heterocyclic groups containing one or more heteroatoms selected from O, N, and S; wherein the heterocyclic group is optionally surrounded by one or more heteroatoms selected from hydrogen, halogen, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; X is either N or C; When X is N, Rd2 does not exist; Fragment A is selected from the following groups: * A 5-12 membered heteroaryl group containing one or more nitrogen atoms, wherein the heteroaryl group is optionally selected independently from halogen, hydroxyl, cyano, amino, C... 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 3-7 Substitution with cycloalkoxy, phenyl, phenoxy, 5-6 membered heteroaryl and 4-7 membered heterocyclic alkyl groups, wherein the substituents comprise one or more heteroatoms independently selected from O, S and N; as well as *-NH-C(O)-R4, wherein R4 is selected from the following groups: C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 5-12 Aryl, 5-12 heteroaryl, -OC 3-7 cycloalkyl, -O-CH2- C 3-7 The cycloalkyl group and the -O-CH2- 5-7-membered heteroaryl group may optionally be substituted with one or more substituents, said substituents being independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Alkoxy, phenyl, phenoxy, 5-6 membered heteroaryl, and 4-7 membered heterocyclic alkyl; said heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms independently selected from O, S, and N; R1 and R 1’ Independently selected from hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, deuterated C 1-6 Alkyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl group, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy groups, halogens, halogenated C 1-6 Alkyl, -CN, -N(C) 1-6 Alkyl group, trifluoromethyl group, amino group, hydroxyl group; R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, -N(C 1-6 alkyl)2,-NH-C 1-6 Alkyl, -NHC(O)-C 1-6 Alkyl, -NHC(O)-(C 3-7 cycloalkyl), -NHC(O)-(4-7 membered heterocyclic), -NHC(O)-(4-7 membered heteroaryl), -NHC(O)-O-NH-C 1-6 Alkyl group, -NHC(O)-NH-(C 3-7 cycloalkyl), -NHC(O)-NH-(C 1-6 Alkyl), -NHC(O)-N(C) 1-6 Alkyl)(C 3-7 cycloalkyl), -NHC(O)-OC 1-6 Alkyl group, -NHC(O)-OC 3-7 Cycloalkyl, -NHC(O)-N(C) 1-6 alkyl)2,-NHC(O)-N(C 3-7 cycloalkyl)2, -NHC(O)-O-CH2-C 3-7 cycloalkyl, -NHSO2-C 1-6 Alkyl group, -NHSO2-NH-C 1-6 Alkyl, -NHSO2-N(C 1-6 alkyl)2, -NHC(O)-(C 1-6 alkenyl)-NHC(O)-C 1-6 Alkyl, -NHC(O)-(C 1-6 alkenyl)-NHC(O)-OC 1-6 Alkyl; the above substituents may optionally be substituted by one or more of the following substituents, said substituents being independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Cycloalkyl, deuterium, halogen, cyano, trifluoromethyl, amino, hydroxyl; the heterocyclic or heteroaryl group comprises one or more heteroatoms independently selected from O, S, and N; R a and R a’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, cyano, trifluoromethyl, amino, hydroxyl, -C 1-3 Alkoxy, C 3-7 cycloalkyl and C 3-7 Heterocyclic group; the heterocyclic group comprises one or more heteroatoms independently selected from O, S, and N; R3 is selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; R b and R b’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl and C 5-10 The heteroaryl group is optionally substituted with one or more substituents, said substituents being independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, cyano, trifluoromethyl, amino, hydroxyl and -C 1-3 Alkoxy; or R b and R b' Together with the carbon atoms they are attached to, they form C 3-8 Carbon ring, C 5-9 Spiral ring, C 5-10 Aromatic ring or 5-10 membered aromatic heterocycle, optionally selected independently by one or more methyl groups (=CH2), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-3 Substituents of alkoxy, halogen, cyano, trifluoromethyl, amino, and hydroxyl groups; the substituents may optionally be substituted with one or more halogens and deuterium; L is absent or selected from -O- and -NH-; m is 0, 1, 2; R a and R a’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, cyano, trifluoromethyl, amino, hydroxyl, -C 1-3 Alkoxy, C 3-7 cycloalkyl and C 3-7 Heterocyclic group; Rd1 is selected from: * , , , as well as *Hydroxy group, -OC 1-6 Alkyl, mercapto, -SC 1-6 Alkyl, amino, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2,-C 1-6 Alkyl group, -C(O)H, -C(O)C 1-6 Alkyl group, -C(O)NH2, -C(O)NH C 1-6 Alkyl, -C(O)N(C) 1-6 alkyl)2, -NHC(O)H, -NHC(O)(C 1-6 Alkyl groups), -SONH2, -SONHC 1-6 Alkyl, -SON(C 1-6 Alkyl group 2, -SO2H, -SO2C 1-6 Alkyl group, -SO2-NH2, -SO2-NHC 1-6 Alkyl, -SO2-N(C) 1-6 Alkyl)2, C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, -C(O)-C 3-8 Carbocyclic group, -C(O)- 3-8 membered heterocyclic group; substituted by p of the following substituents: , or two substituents (e.g. They clad together to form a heterocycle with more than 15 ring atoms and more than 5 oxygen atoms; Rd1 is optionally selected by one or more elements chosen from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; each substituent They can be the same or different; Y represents O, -CH2-O-, or a chemical bond; p is an integer chosen from 1 to 16; n is an integer chosen from 3 to 100; Re is selected from the following groups: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aromatic group, 5-12 membered heteroaryl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aromatic group (C 1-6 Alkenyl), 5-12 membered heteroaryl (C 1-6 alkenyl), C 3-12 cycloalkyl (C 1-6 alkenyl), 3-12 membered heterocyclic group (C 1-6 Alkenyl); each optionally substituted with one or more substituents, said substituents being independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heteroaryl, 4-7 membered heterocycloalkyl, halogenated C 3-7 Cycloalkyl, halogenated 4-7 membered heterocyclic alkyl and halogenated C 1-6 Alkyl; the heteroaryl and heterocyclic alkyl groups contain one or more heteroatoms independently selected from O, S, and N; Rd2 is selected from the following groups: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl groups, each optionally selected independently by one or more elements chosen from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl and halogenated C 1-6 Alkyl substituents; the heteroaryl and heterocyclic alkyl groups contain one or more heteroatoms independently selected from O, S, and N; When the group It is a 3-7 membered heterocyclic group containing one or more heteroatoms selected from O, N and S, and when X is C, Rd2 is connected to the rest of the structure through a tertiary carbon atom, that is, Rd2 is not a hydrogen atom.

2. The compound according to claim 1, wherein L is absent, m is 0, and the compound is represented by formulas (Ia-1), (Ia-2), and (Ia-3): (I-1) (I-2) (I-3) in, Fragment A is selected from -NH-C(O)-R4, where R4 is selected from the following groups: C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, C 5-12 Aryl, 5-12 heteroaryl, optionally selected by one or more independently chosen from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents of alkoxy, halogen, cyano, amino, and hydroxyl groups; the heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms independently selected from O, S, and N; R b and R b’ Each was independently selected from C 3-7 cycloalkyl; or R b and R b' Together with the carbon atoms attached to them, they form optional compounds such as one or more methylene groups (=CH2), halomethylene groups, and C groups. 1-6 Alkyl, Halogenated C 2-6 Alkenyl or halogen-substituted C 3-8 Carbon rings; The ring C is selected from 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S, or C 3-7 cycloalkyl; The definitions of R3, R1, R2, Rd1, Re, p, n, and Rd2 are as described in claim 1.

3. The compound according to claim 1, wherein, The compounds are represented by formulas (Ib-1), (Ib-2), and (Ib-3): (One-1) (One-2) (One-3) in, Group A2 is a 5-12 membered heteroaryl group, optionally composed of one or more independently selected C14 groups. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Substituents of alkoxy, halogen, cyano, amino, and hydroxyl groups; the heteroaryl group comprises one or more heteroatoms independently selected from O, S, and N; R 2a and R 2a' Independently selected from: hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl; each group is optionally substituted by one or more substituents independently selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Cycloalkyl, deuterium, halogen, cyano, trifluoromethyl, amino, hydroxyl; The ring C is selected from 3-7 membered heterocyclic groups containing one or more heteroatoms selected from O, N, and S, and C. 3-7 cycloalkyl; R b , R b ’ The definitions of R3, R1, Rd1, Re, n, p, and Rd2 are as described in claim 1.

4. The compound according to claim 1, wherein Rd1 is selected from: * , , ; Optionally selected by one or more elements chosen from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; * Amine group, -NHC 1-6 Alkyl, -C(O)H, -OC 1-6 Alkyl group, -C(O)NH2, -C 1-6 Alkyl, C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, -C(O)-C 3-8 Carbocyclic group, -C(O)- 3-8 membered heterocyclic group, -N(C 1-6 Alkyl group 2, each substituent is further replaced by p substituents as follows: , or two substituents (e.g. Together they form a heterocycle with more than 15 ring atoms and more than 5 oxygen atoms; Rd1 is optionally selected by one or more elements chosen from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl and halogenated C 1-6 Alkyl substituents; each Same or different.

5. The compound according to claim 1, wherein R b and R b' Each was independently selected from C 3-7 Cycloalkyl, optionally substituted with one or more substituents, said substituents being independently selected from hydrogen, C… 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogen, cyano, trifluoromethyl, amino, hydroxyl and -C 1-3 Alkoxy Or R b and R b' Together with the carbon atoms they are attached to, they form C 5-8 The carbocyclic ring may optionally be independently selected from methylene, halomethylene, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-3 Substituents of alkoxy, halogen, cyano, trifluoromethyl, amino, and hydroxyl groups; the substituents may optionally be substituted with one or more halogens and deuterium.

6. The compound according to claim 1, wherein the compound is selected from the following compounds: in, Each n is independently selected from an integer between 3 and 50. Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product, or prodrug.

7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, deuterated product or prodrug thereof, and a pharmaceutically acceptable excipient.

8. A method of treating a disease or condition in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product or prodrug of claim 1, or the pharmaceutical composition of claim 7, wherein the disease or condition is selected from inflammatory diseases, proliferative diseases and autoimmune diseases.

9. The method according to claim 8, wherein the disease or condition is selected from plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, psoriasis, eczema, psoriasis, and erythrodermic psoriasis, ankylosing arthritis, ankylosing spondylitis, hidradenitis suppurativa, palmoplantar psoriasis, airway inflammation, ankylosing spondylitis, asthma, rheumatoid arthritis, osteoarthritis, spondyloarthritis, bone erosion, abdominal abscess and adhesions, inflammatory bowel disease, Crohn's disease, allogeneic rejection, and psoriasis. Psoriatic arthritis, certain types of cancer, angiogenesis, atherosclerosis and multiple sclerosis, lupus, reactions to allergen exposure, Helicobacter pylori-associated gastritis, bronchial asthma, asthma, allogeneic rejection (e.g., kidney), systemic lupus erythematosus, lupus nephritis, Behcet's disease, ulcerative colitis, rheumatoid arthritis (RA), inflammatory bowel disease, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, an inflammatory eye disease, uveitis, and one or more of non-infectious uveitis.

10. The use of the compound of claim 1 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, hydrate, deuterated product or prodrug thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the prevention or treatment of a disease or condition, wherein the disease or condition is selected from inflammatory diseases, proliferative diseases and autoimmune diseases.

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