Il-17a modulator compound and use thereof

Abstract

Provided are a compound of formula (I), a cis or trans isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a metabolite thereof, a eutectic thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein Cy1, Cy2, R1, R2, R3, X, and n are defined in the specification.

Description

IL-17A regulator compounds and their uses Technical Field

[0001] This disclosure provides compounds and pharmaceutical compositions for regulating IL-17A, which can be used to treat inflammatory diseases such as psoriasis. Background Technology

[0002] Immune function is crucial for maintaining homeostasis, effective disease response, and responses to abnormal immune reactions. The interleukin-17 (IL-17) family of pro-inflammatory cytokines participates in tissue immune responses and plays a key role in chronic inflammation. IL-17 production can induce normal immune and inflammatory responses to pathogens, and can also contribute to chronic autoimmune diseases, including psoriasis, spondylitis, rheumatoid arthritis, and multiple sclerosis.

[0003] The IL-17 family consists of six subtypes (IL-17A to IL-17F), which participate in physiological functions such as inflammation and autoimmunity, and are related to the host's defense against various microbial pathogens and tissue inflammation (Gene, (2017), 614: 8-14). CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages, and dendritic cells in the body also participate in physiological functions such as inflammation and autoimmunity. Among the IL-17 family, IL-17F and IL-17A are most homologous, sharing approximately 50% of their amino acid sequences, and are usually co-expressed with IL-17A (Immunity (2004): 467-476). Both IL-17A and IL-17F are secreted by helper T cells (Th17) and expressed as the homodimer IL-17A / A or the heterodimer IL-17A / F.

[0004] The IL-17 receptor (IL-17R) family consists of five members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. All five receptors share the SEFIR domain. IL-17 secretion can stimulate the production of other pro-inflammatory cytokines (such as IL-1, IL-6, and IL-8, G-CSF, GM-CSF, and TNF), chemokines (CXCL1, CXCL2, CXCL5, CCL2, CCL7, and CCL20), matrix metalloproteinases (MMP1, MMP3, MMP9, and MMP13), and antimicrobial agents (β-defensins and S-100 proteins) (Frontiers in Immunolog, (2020) 11:947). IL-17A and IL-17F transmit signals by binding to the same receptor complex IL-17R (IL-17RA and IL-17RC) (Gene, (2017) 614: 8-14).

[0005] Overexpression of IL-17A is associated with a number of diseases, including but not limited to rheumatoid arthritis (RA), bone erosion, intra-abdominal abscess, inflammatory bowel disease, allogeneic transplant rejection, psoriasis, angiogenesis, atherosclerosis, asthma, and multiple sclerosis. Recent studies have also shown that IL-17A and IL-17A-induced Th17 cells are associated with the development of certain cancers (Ji & Zhang, Cancer Immunol. Immunother., 59: 979-987 (2010)). For example, IL-17-expressing Th17 cells have been shown to be involved in multiple myeloma (Cancer Immunol. Immunother., doil0.1182 / blood-2009-10-2460, Apr.15 (2010)) and are associated with poor prognosis in patients with hepatocellular carcinoma (HCC) (Zhang et al., J Hepatology 50: 980-89 (2009)).

[0006] Currently, there are no highly effective oral medications for treating moderate to severe psoriasis. In some cases, inhibiting IL-17A can increase the response to these diseases. Oral small molecule inhibitors have good tissue penetration, relatively short half-lives, are convenient to take, and patients can discontinue use at any time. After discontinuation, they are rapidly metabolized by the body, thus improving the timely management of potential risks associated with these drugs.

[0007] Currently, several small molecule inhibitors targeting the protein / protein interaction between IL-17A and IL-17RA have entered Phase I / II clinical trials, but no related drugs have been marketed. Therefore, there is a ongoing need to develop small molecule IL-17A modulators with different structures, especially those that can be taken orally.

[0008] Summary of the Invention

[0009] This disclosure provides compounds having the structure shown in formula (I), related derivatives thereof (e.g., cis-trans isomers, enantiomers, diastereomers, racemic mixtures, solvates, hydrates, metabolites, cocrystals, or pharmaceutically acceptable salts or prodrugs thereof), and pharmaceutical compositions comprising said compounds or related derivatives thereof. This disclosure also provides the use of said compounds in the preparation of medicaments for the prevention and / or treatment of IL-17A-mediated diseases, and further provides the use of said compounds, derivatives, and pharmaceutical compositions in the treatment or prevention of IL-17A-mediated diseases. The compounds or pharmaceutical compositions of this disclosure can be used to effectively combat IL-17A-mediated diseases and control the occurrence of IL-17A-mediated diseases.

[0010] This disclosure provides a compound of formula (I), its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its cocrystal, its pharmaceutically acceptable salt, or its prodrug.

[0011] Cy1 is a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, or S, wherein the 5-6 membered heteroaromatic ring is optionally surrounded by 1-3 heteroatoms selected from D, halogens, or C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The group substituted by the alkynyl group; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0012] Cy2 is a 4-8 membered saturated heterocycle containing 1-3 heteroatoms selected from N, O, or S, wherein the 4-8 membered saturated heterocycle is optionally surrounded by one or more heteroatoms selected from D, halogens, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The C is replaced by an alkoxy substituent. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl or halogenated C 1-6 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -OH, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2- The substituents of the 6-acetylenic group are replaced;

[0013] X is selected from CH, CF, or N;

[0014] n is selected from 0, 1, 2, 3 or 4;

[0015] R1 and R2 are each independently selected from C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0016] Or R1, R2 together with the carbon atoms they are attached to form Where R a and R b Selected independently from H, D, halogen, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl and C 3-6 cycloalkyl, or R a and R b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl;

[0017] R3 is selected from C 1-6 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycles, C 1-6Alkyl groups, -N(R6)(OR7), -N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)OR7, -N(R6)C(O)N(R8)(R9) and -N(R6)S(=O)2N(R8)(R9), wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy or 4-6 membered heterocycles optionally further selected from one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0018] R6 is selected from H, D, and C. 1-6 Alkyl, C 3-6 cycloalkyl groups and 4-6 membered heterocycles; the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocycles optionally further selected from one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0019] R7 is selected from C 1-6 Alkyl, C 3-6 cycloalkyl groups and 4-6 membered heterocycles; the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4-6 membered heterocycle may optionally be further selected from one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0020] R8 is selected from H and C. 1-6 Alkyl and C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6The cycloalkyl group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0021] R9 is selected from H and C. 1-6 Alkyl and C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is replaced by a substituent.

[0022] In some aspects of this disclosure, a pharmaceutical composition is provided comprising the compounds described herein, and a pharmaceutically or immunologically acceptable carrier or excipient.

[0023] Among some aspects of this disclosure, the use of the compounds of this disclosure in the preparation of medicaments for the prevention and / or treatment of autoimmune or inflammatory diseases is provided.

[0024] In some aspects of this disclosure, a method for preventing and / or treating autoimmune or inflammatory diseases is also provided, the method comprising administering to a subject in need an effective amount of the compound or pharmaceutical composition of this disclosure for prevention and / or treatment.

[0025] In some aspects of this disclosure, compounds or pharmaceutical compositions of the present disclosure are also provided for the prevention and / or treatment of autoimmune or inflammatory diseases.

[0026] Among some aspects of this disclosure is the use of the compounds or pharmaceutical compositions of this disclosure in regulating intercytokine-17 (such as IL-17A) levels.

[0027] Those skilled in the art can combine the foregoing technical solutions and features in any way without departing from the inventive concept and protection scope of this disclosure. Other aspects of this disclosure will be apparent to those skilled in the art due to the content of this disclosure. Detailed Implementation

[0028] Unless otherwise specified in this invention, the terminology used in this invention has the following meanings:

[0029] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds of this invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds of this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0030] In this article, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0031] "Halogenation" or "halogen substitution" refers to substitution by one or more halogen substituents selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents can be any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, the substitution can be by the same or different halogens. Common cases include 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0032] "Deuterium" refers to the hydrogen (H) isotope deuterium, which is synonymous with "D".

[0033] "Deuteration" or "deuterated product" refers to the situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, or alkynyl group is replaced by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and this upper limit, such as 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms, or 1 deuterium atom.

[0034] “C x-y A "group" refers to a group containing x to y carbon atoms, such as "C". 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0035] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. It is typically an alkyl group with 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., and the alkyl group may be further substituted with substituents.

[0036] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene include, but are not limited to, methylene, ethylene, etc. "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and this upper limit. Typically, alkyl groups are substituted with 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, the same or different halogens can be substituted. Specific examples include, but are not limited to, CF3, CH2Cl, CH2CF3, CCl2, etc.

[0037] "Alkoxy" or "alkyloxy" refers to -O-alkyl. For example, -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-2 Alkyl groups. Specific, non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy, etc.; the alkoxy groups may optionally be substituted with substituents.

[0038] "Haloalkoxy" refers to -O-haloalkyl. For example, -O-haloC 1-8 Alkyl, -O-halogenated C 1-6 Alkyl, -O-halogenated C 1-4 Alkyl or -O-halogenated C 1-2Alkyl groups; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be replaced in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substituents, 1-3 halogen substituents, 1-2 halogen substituents, or 1 halogen substituent. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0039] "Alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2... -Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group may optionally be further substituted with substituents.

[0040] "Alkenyl" refers to a straight-chain or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, alkenyl contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include vinylidene groups. The alkenyl group may optionally be substituted with substituents.

[0041] "Alynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 8 carbon atoms, and more commonly 2 to 6 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl; the alkynyl group may optionally be substituted with substituents.

[0042] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain cyclic heteroatoms. Cycloalkyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic groups can be fused, spirocyclic, bridged, or combinations thereof. Bicyclic or polycyclic groups may include one or more aromatic rings, but the ring system as a whole is not aromatic. The linking sites can be on aromatic or non-aromatic rings. Typically, cycloalkyl groups contain 3 to 20 carbon atoms, further containing 3 to 8 carbon atoms, and even further containing 3 to 6 carbon atoms; when they are monocyclic cycloalkyl groups, they contain 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms; when they are bicyclic or polycyclic cycloalkyl groups, they contain 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, and cyclohexenyl. The cycloalkyl group may optionally be substituted with substituents.

[0043] "Cycloalkylene" refers to the divalent group of a cycloalkyl group.

[0044] "Aryl" refers to an aromatic carbon ring that does not contain heteroatoms, including monocyclic aryl and fused-ring aryl. It typically contains 6 to 13 carbon atoms, more commonly 6 to 9 carbon atoms, and is further preferably phenyl. Non-limiting examples include phenyl, naphthyl, anthraceneyl, and phenanthrene. The aryl group may optionally be substituted with substituents.

[0045] "Carbocyclic" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbon ring, including aryl and cycloalkyl groups. The carbon ring can be monocyclic, bicyclic, or polycyclic, including bridged rings, fused rings, and spirocyclic rings, as well as combinations thereof. The carbon ring typically has 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting embodiments, monocyclic carbon rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, while bicyclic bridged rings, bicyclic fused rings, and bicyclic spirocyclic rings may optionally be substituted with substituents.

[0046] "Heterocyclic alkyl" refers to a non-aromatic carbon ring containing 1, 2, 3, or 4 saturated or partially unsaturated heteroatoms selected from N, O, and S. Heterocyclic alkyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic groups can be bridged rings, fused rings, spirocyclic rings, or combinations thereof. A bicyclic or polycyclic group may include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic. The linking sites can be on aromatic or non-aromatic rings. Typically, heterocyclic alkyl groups are 3 to 20-membered rings. When it is a monocyclic heterocyclic alkyl group, it is usually 3 to 15-membered, or 3-10-membered, or 3-8-membered, or 3-6-membered rings; when it is a bicyclic or polycyclic heterocyclic alkyl group, it is usually 5-12-membered, or 5-11-membered, or 6-9-membered rings. The heteroatoms N and S include their oxidation states. Non-limiting examples of heterocyclic alkyl groups include azirrobutyl, morpholino, piperazinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, pyranyl, azirropentenyl, azirrohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc., and the heterocyclic alkyl groups may optionally be substituted with substituents.

[0047] Unless otherwise specified, "heteroaromatic ring" or "heteroaryl" refers to an aromatic ring containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states. It can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be bridged rings, fused rings, spirocyclic rings, or combinations thereof. When it is bicyclic or polycyclic, it can be a fusion of a heteroaryl group and an aryl group, or a fusion of two heteroaryl groups, wherein either the heteroaryl group or the aryl group can be a linking site. Non-limiting embodiments include furanyl, thiophene, pyrroleyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indoleyl, purine, etc., wherein the heteroaryl group can optionally be substituted with substituents.

[0048] "Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing one to four heteroatoms selected from N, O, or S and their oxidation states. It includes heteroaryl and heterocyclic alkyl groups. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles, or combinations thereof. They are typically 3- to 12-membered, 5- to 12-membered, or 5- to 7-membered heterocycles. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxhexane, piperazine, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithiol, dihydrofuranyl. Heterocyclic compounds such as dihydropyranyl, dithiapentylyl, tetrahydrofuranyl, tetrahydropyrroliyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl can be optionally substituted by substituents.

[0049] "Hypo-heterocyclic group" refers to a divalent heterocyclic group that is substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic.

[0050] A "spirocyclic ring" refers to a polycyclic group in which rings share a single carbon atom (called a spiro atom). It may contain one or more double or triple bonds and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si, and their oxidation states. Spirocyclic rings are typically 6 to 14-membered, 6 to 12-membered, or 6 to 10-membered. Common spirocyclic rings are tri-spirotri- (representing a three-membered ring spirotri-membered ring), tri-spirotetra-, tri-spiropenta-, tri-spirohexa-, tetra-spirotetra-, tetra-spiropenta-, tetra-spirohexa-, penta-spiropenta-, or penta-spirohexa-. Non-limiting examples of spirocyclic rings include those that may be optionally substituted with substituents.

[0051] "Built rings" refer to polycyclic groups that share two adjacent ring atoms and a chemical bond with other rings. They may contain one or more double or triple bonds and can contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, fused rings are 5 to 20-membered, 5 to 14-membered, 5 to 12-membered, or 5 to 10-membered rings. Common fused ring types include trifused tetracyclic rings (representing fused rings formed by a three-membered and a four-membered ring; according to IUPC nomenclature, this could be a fused ring with either a three-membered or a four-membered ring as the base ring, and the same applies below), trifused pentacyclic rings, trifused hexacyclic rings, tetrafused tetracyclic rings, tetrafused pentacyclic rings, tetrafused hexacyclic rings, pentafused pentacyclic rings, pentafused hexacyclic rings, and hexafused hexacyclic rings. Non-limiting examples of fused rings include purines, quinolines, isoquinolines, benzopyrans, benzofurans, and benzothiophenes, and these fused rings may optionally be substituted with substituents.

[0052] A "bridged ring" refers to two rings sharing two non-adjacent ring atoms and may contain one or more double or triple bonds. A bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, a bridged ring has 5 to 2, 5 to 14, 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of bridged rings include adamantane. "Substitution" or "substituent" means, unless otherwise specified, any substitution at a position allowed by chemical theory, with the number of substituents conforming to the rules of chemical bonding. Exemplary substituents include, but are not limited to, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Heteroalkyl, C 5-12 Aryl, 5-12 heteroaryl, hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C) 1-6 Base)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6Alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 alkyl)2,-SO2NH(C 1-6 Alkyl), -802NH2, -SO2C 1-6 Alkyl groups, etc.

[0053] "Optional" or "optionally" means that the events or circumstances described below may but do not have to occur; this description includes...

[0054] The event or environment that occurs or does not occur. For example, "alkyl group that may be substituted by F" means that the alkyl group can but does not have to be substituted by F, including cases where the alkyl group is substituted by F and cases where the alkyl group is not substituted by F.

[0055] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0056] "Solvate" refers to a substance formed by the combination of the compound of the present invention or its salt with a stoichiometric or non-stoichiometric solvent through intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0057] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0058] compound

[0059] This disclosure provides a compound of formula (I), its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its cocrystal, its pharmaceutically acceptable salt, or its prodrug.

[0060] Cy1 is a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, or S, wherein the 5-6 membered heteroaromatic ring is optionally surrounded by 1-3 heteroatoms selected from D, halogens, or C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 1-6 Alkoxy, C 2-6alkenyl and C 2-6 The group substituted by the alkynyl group; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0061] Cy2 is a 4-8 membered saturated heterocycle containing 1-3 heteroatoms selected from N, O, or S, wherein the 4-8 membered saturated heterocycle is optionally surrounded by one or more heteroatoms selected from D, halogens, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The C is replaced by an alkoxy substituent. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl or halogenated C 1-6 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -OH, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2- The substituents of the 6-acetylenic group are replaced;

[0062] X is selected from CH, CF, or N;

[0063] n is selected from 0, 1, 2, 3 or 4;

[0064] R1 and R2 are each independently selected from C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0065] Or R1, R2 together with the carbon atoms they are attached to form Where R a and R b Selected independently from H, D, halogen, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl and C 3-6 cycloalkyl, or R a and R b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl;

[0066] R3 is selected from C 1-6 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycles, C 1-6 Alkyl groups, -N(R6)(OR7), -N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)OR7, -N(R6)C(O)N(R8)(R9) and -N(R6)S(=O)2N(R8)(R9), wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy or 4-6 membered heterocycles optionally further selected from one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0067] R6 is selected from H, D, and C. 1-6 Alkyl, C 3-6 cycloalkyl groups and 4-6 membered heterocycles; the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocycles optionally further selected from one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0068] R7 is selected from C 1-6 Alkyl, C 3-6 cycloalkyl groups and 4-6 membered heterocycles; the C 1-6 Alkyl, C 3-6The cycloalkyl group and the 4-6 membered heterocycle may optionally be further selected from one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0069] R8 is selected from H and C. 1-6 Alkyl and C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0070] R9 is selected from H and C. 1-6 Alkyl and C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is replaced by a substituent.

[0071] Preferably, Cy1 is a 5-membered heteroaromatic ring containing 2-3 heteroatoms selected from N, O, or S, wherein the 5-membered heteroaromatic ring is optionally surrounded by 1-3 heteroatoms selected from D, halogens, or C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The group substituted by the alkynyl group; the C 1- 6-alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted by a substituent; more preferably, the Cy1 is a pyrazolyl or oxadiazolyl group, wherein the pyrazolyl or oxadiazolyl group is optionally replaced by 1-3 substituents selected from D, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The C group is replaced by an alkynyl group. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted; more preferably, the Cy1 is 1,2,5-oxadiazolyl or pyrazolyl, wherein the 1,2,5-oxadiazolyl or pyrazolyl group is optionally replaced by 1-3 groups selected from D, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The C group is replaced by an alkynyl group. 1-6 Alkyl, C 3- 6-cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH2, -NH(C)1-4 alkyl), -N(C) 1- 4-alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0072] Particularly preferably, Cy1 is selected from the following structures:

[0073] Preferably, Cy2 is a 5-6 membered saturated heterocycle containing 1-2 heteroatoms selected from N, O, or S, wherein the 5-6 membered saturated heterocycle is optionally surrounded by one or more heteroatoms selected from D, halogens, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The C is replaced by an alkoxy substituent. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -OH, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted by a substituent; more preferably, the Cy2 is piperidinyl or piperazineyl, wherein the piperidinyl or piperazineyl group is optionally replaced by one or more substituents selected from D, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The C is replaced by an alkoxy substituent. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -OH, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted by a substituent; more preferably, the Cy2 is 1-piperidinyl or 1-piperazinyl, wherein the 1-piperidinyl or 1-piperazinyl group is optionally replaced by one or more substituents selected from D, halogen, C. 1-3 Alkyl, C 3-6cycloalkyl, halogenated C 1-3 Alkyl and Halogenated C 1-3 The C is replaced by an alkoxy substituent. 1-3 Alkyl, C 3-6 cycloalkyl, halogenated C 1-3 Alkyl and Halogenated C 1-3 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -OH, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0074] Particularly preferably, Cy2 is selected from the following structures:

[0075] Preferably, X is selected from CH or CF;

[0076] Preferably, n is 0 or 1; more preferably, n is 0.

[0077] Preferably, R1 and R2 are each independently selected from cyclopropyl groups, wherein the cyclopropyl groups are unsubstituted or substituted by one or more groups selected from D, halogens, -CN, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced;

[0078] Or R1, R2 together with the carbon atoms they are attached to form Where R a and R b Each is independently selected from H, D, F, Cl, CH3, CD3, or cyclopropyl, or R. a and R b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; more preferably, R a and R b Each is independently selected from H, D, F, Cl, or CH3.

[0079] Preferably, R3 is selected from C 1-3 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycles, C 1-3Alkyl groups, -N(R6)(R7), -N(R6)(OR7), -N(R6)C(O)R7, -N(R6)C(O)OR7, -N(R6)C(O)N(R8)(R9) and -N(R6)S(=O)2N(R8)(R9), wherein the C 1-3 Alkyl, C 3-6 cycloalkyl, C 1-3 The alkoxy group and the 4-6 membered heterocycle may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1- 3alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkyl and C 1-3 The alkoxy group is substituted; more preferably, R3 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy groups and -N(R6)(R7) or -N(R6)(OR7), the C 1-3 Alkyl and C 1-3 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkyl and C 1-3 The alkoxy group is replaced by a substituent.

[0080] Preferably, R6 is selected from H, D, and C. 1-3 Alkyl, C 3-6 cycloalkyl groups and 4-6 membered heterocycles; the C 1-3 Alkyl, C 3-6 The cycloalkyl group and the 4-6 membered heterocycle may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH(C) 1-4 Alkyl), N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 1-4 Alkyl and C 1-4 Alkyl group substitution; more preferably, R6 is selected from H, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkyl and C 1-3 The alkoxy group is replaced by a substituent.

[0081] Preferably, R7 is selected from C 1-3 Alkyl, C 3-6 cycloalkyl groups and 4-6 membered heterocycles; the C 1-3 Alkyl, C 3- The 6-cycloalkyl group and the 4-6-membered heterocycle may optionally be further selected from one or more elements chosen from D, halogen, -CN, -NH(C) 1- 4-alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 1-4 Alkyl and C 1-4 Alkyl group substitution; more preferably, R7 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkyl and C 1-3 The alkoxy group is replaced by a substituent.

[0082] Preferably, R8 is selected from C 1-3 Alkyl and C 3-6 cycloalkyl; the C 1-3 Alkyl and C 3-6 The cycloalkyl group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups.

[0083] Preferably, R9 is selected from H and C. 1-3 Alkyl and C 3-6 cycloalkyl; the C 1-3 Alkyl and C 3-6 The cycloalkyl group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH(C) 1-4 Alkyl), -N(C1-4 alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups.

[0084] Preferably, the compound of formula (I) is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0085] Products and their applications

[0086] The compounds of the present invention are potent inhibitors of IL-17A and, when administered to patients in need, can provide therapeutic benefits while avoiding certain problems associated with biological IL-17A signaling antagonists, such as IL-17 antibodies. Therefore, the compounds of the present invention are considered for use in treating conditions in which excessive IL-17A-mediated signaling plays a role, such as psoriasis, rheumatoid arthritis, spondyloarthritis, and multiple sclerosis, including alleviating certain immune-mediated symptoms. The compounds of the present invention are also considered for improving disease symptoms in psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, and COPD.

[0087] This disclosure also provides a product, which may be, for example, a medicine, a pharmaceutical composition, or a kit / pharmaceutical kit, containing an effective amount of the IL-17A modulator compound of this disclosure, and a pharmaceutically or immunologically acceptable carrier. The product, which may be, for example, a medicine, a pharmaceutical composition, or a kit / pharmaceutical kit, is believed to be useful for treating conditions in which excessive IL-17A-mediated signaling plays a role, such as psoriasis, rheumatoid arthritis, spondyloarthritis, and multiple sclerosis, including alleviating certain immune-mediated symptoms. The compounds of the present invention are also believed to be useful for improving disease symptoms in psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, and COPD.

[0088] The compounds or salts of the present invention are typically administered in the form of pharmaceutical compositions comprising a compound of formula (I) as an active ingredient or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. These compositions can be administered via a variety of routes, including oral, sublingual, nasal, subcutaneous, intravenous, and intramuscular. These pharmaceutical compositions and methods of their preparation are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy (University of the Sciences in Pheladelphia, ed., 21st edition, Lippincott Williams & Wilkins Co., 2005).

[0089] As used herein, the term "pharmaceuticalally acceptable" refers to a substance that is suitable for use in humans and / or animals without excessive adverse effects (such as toxicity, irritation, and allergic reactions), i.e., a reasonable benefit / risk ratio. As used herein, the term "effective amount" refers to an amount that is functional or active in humans and / or animals and is acceptable to humans and / or animals.

[0090] As used herein, the term "carrier" refers to a system that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound given, and can alter the way a drug enters the body and its distribution in the body, control the rate of drug release, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0091] As used herein, the term "pharmaceuticalally acceptable carrier" refers to a carrier used for the administration of therapeutic agents, including various excipients and diluents. This term refers to pharmaceutical carriers that are not essential active ingredients themselves and do not cause excessive toxicity upon administration. Suitable carriers are well known to those skilled in the art, and a thorough discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ 1991).

[0092] Pharmaceutically acceptable carriers in the composition may contain liquids such as water, saline, glycerol, and ethanol. Additionally, these carriers may contain auxiliary substances such as fillers, disintegrants, lubricants, glidants, effervescent agents, wetting agents or emulsifiers, flavoring agents, pH buffers, etc. Typically, these substances are formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium, with a pH usually around 5-8, preferably around 6-8.

[0093] "Pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic salt or salt class of the compounds of the present invention. Those skilled in the art will understand that the compounds of the present invention are capable of forming salts. The compounds of the present invention contain basic heterocycles and therefore react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. These pharmaceutically acceptable acid addition salts and conventional methods for preparing them are well known in the art. See, for example, P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, (VCHA / Wiley-VCH, 2008); SMBerge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0094] "Pharmaceutical composition" means one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or eutectics, mixed with other components, wherein the other components contain physiologically / pharmaceuticalally acceptable carriers and / or excipients.

[0095] "Excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g. croscarmellose sodium); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Oils and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and / or polyanhydride; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0096] The active substance in the product disclosed herein accounts for 0.001 to 99.9 wt% of the total weight of the composition; preferably 1 to 95 wt% of the total weight of the composition, more preferably 5 to 90 wt%, and more preferably 10 to 80 wt%. The balance consists of pharmaceutically acceptable carriers and other additives.

[0097] The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for use in human individuals and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, and at least one suitable pharmaceutically acceptable carrier, diluent, and / or excipient. Unit dosage forms include, but are not limited to, various solid dosage forms (such as tablets), liquid dosage forms, capsules, and sustained-release formulations. It should be understood that the amount of compound actually administered will be determined by a physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms. The compounds of the present invention, for example, in the pharmaceutical compositions of the present invention, are contemplated for long-term use in the treatment of IL-17A-mediated diseases, such as psoriasis, rheumatoid arthritis, and / or multiple sclerosis.

[0098] In another preferred embodiment of this disclosure, the product is a single dosage form or multiple dosage forms, and the content of the active substance is 0.01–2000 mg / dose, preferably 0.1–1500 mg / dose, more preferably 1–1000 mg / dose, and most preferably 0.5–800 mg / dose. In another preferred example of this disclosure, 1–6 doses of the composition of this disclosure are administered daily, preferably 1–3 doses; most preferably, the daily dose is 1 dose.

[0099] In addition, the products disclosed herein may also contain other active substances for improving and treating IL-17A-mediated diseases (such as autoimmune diseases or inflammatory diseases).

[0100] In some embodiments, other active substances for the prevention or treatment of IL-17A-mediated diseases (e.g., autoimmune diseases or inflammatory diseases) are administered before, simultaneously with, or after the product of this disclosure. These other active substances have activity for the prevention or treatment of IL-17A-mediated diseases (e.g., autoimmune diseases or inflammatory diseases) and / or their symptoms.

[0101] In a preferred embodiment, the product can be used to prevent or treat IL-17A-mediated diseases (such as autoimmune diseases or inflammatory diseases).

[0102] In some embodiments, the autoimmune disease or inflammatory disease is selected from diseases or conditions such as psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, atopic dermatitis, asthma, and / or COPD.

[0103] In some embodiments, the compounds or products of this application are administered as prophylactic drugs before the onset of IL-17A-mediated diseases (e.g., autoimmune diseases or inflammatory diseases) to prevent the occurrence of IL-17A-mediated diseases (e.g., autoimmune diseases or inflammatory diseases) or to reduce the severity of subsequent IL-17A-mediated diseases (e.g., autoimmune diseases or inflammatory diseases). In some embodiments, the compounds or products of this application are administered as therapeutic drugs after the onset of IL-17A-mediated diseases (e.g., autoimmune diseases or inflammatory diseases) to reduce the severity of the disease. In some embodiments, the compounds or products of this application are administered both as prophylactic and therapeutic drugs, either continuously or intermittently before and after the onset of IL-17A-mediated diseases (e.g., autoimmune diseases or inflammatory diseases).

[0104] As used herein, the term “patient” refers to a mammal, preferably a human. As used herein, the terms “treatment” or “relief” refer to all processes that may involve slowing, interrupting, halting, controlling, or stopping the progression of an existing disease and / or alleviating its symptoms, but do not necessarily imply the complete elimination of all symptoms. As used herein, the term “effective amount” of a compound of formula (I) or (II) refers to the amount, i.e., the dose, that effectively inhibits the IL-17A-mediated response in a patient. A preferred “effective amount” is determined to be the amount that can treat or eliminate the signs and symptoms of moderate to severe psoriasis in a patient compared to an untreated patient. In determining the effective amount or dose of a compound of formula (I) and / or (II), many factors are considered, including but not limited to the compound to be administered and its specific formulation; the size, age, and general health condition of the patient; the extent or severity of disease involvement; the individual patient’s response; the method of administration; and other relevant circumstances.

[0105] The present invention also provides a method for treating IL-17A-mediated diseases or conditions (e.g., autoimmune diseases or inflammatory diseases, such as those selected from psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondylitis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, and / or COPD), comprising administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0106] Furthermore, the present invention also provides compounds of formula (I) or pharmaceutically acceptable salts thereof for the treatment of IL-17A-mediated diseases or conditions (e.g., autoimmune diseases or inflammatory diseases, such as those selected from psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, and / or COPD).

[0107] Those skilled in the art can combine the foregoing technical solutions and features in any way without departing from the inventive concept and protection scope of this invention. Other aspects of this invention will be apparent to those skilled in the art from the disclosure herein.

[0108] Example

[0109] The present disclosure is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the disclosure. Those skilled in the art can make appropriate modifications and variations to the present disclosure, and such modifications and variations are all within the scope of the present disclosure.

[0110] Experimental methods not specifically described in the following examples may be performed using conventional methods in the art, such as referring to Molecular Cloning: A Laboratory Manual (3rd Edition, New York: Cold Spring Harbor Laboratory Press, 1989) or following the conditions recommended by the supplier.

[0111] Unless otherwise stated, percentages and parts are by weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to one skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein may be used in the methods of this disclosure. The preferred embodiments and materials described herein are for illustrative purposes only.

[0112] Some abbreviations are defined as follows:

[0113] CDI: 1,1'-carbonyldiimidazole; DAST: diethylaminosulfuric trifluoride; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC: 1,3-dicyclohexylcarbodiimide; DCE: dichloroethane; DCM: dichloromethane; DIC: 1,3-diisopropylcarbodiimide; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; DTBPF: 1,1'-bis(di-tert-butylphosphino)ferrocene; EDCI: refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOAc: refers to ethyl... Ethyl acetate; EtOH: ethanol; HATU: (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene ammonium hexafluorophosphate; HBTU: (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethylene ammonium hexafluorophosphate; HEPE: 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid; HOAt: 1-hydroxy-7-azobenzotriazole; HOBt: 1-hydroxybenzotriazole hydrate; IPA: isopropanol; LDA: lithium diisopropylamino; MeOH: methanol; MTBE: methyl tert-butyl ether; NB S: N-bromosuccinimide; NCS: N-chlorosuccinimide; NMP: N-methylpyrrolidone; Pd2(dba)3: tris(dibenzylacetone)palladium(0); PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; PCC: pyridinium chlorochromate; PyBOP: (benzotriazol-1-yl-oxytripyrrolidine-1-ylphosphonium hexafluorophosphate); PyBrOP: bromo(tripyrrolyl)phosphonium hexafluorophosphate; Rh-COD-[(S)-MaxPhos]-BF4: [((R)-tert-butylmethylphosphino)(di-tert-butylphosphino)amine] (1,5-Cyclooctadiene)rhodium(I)tetrafluoroborate; DIAD: diisopropyl azodicarboxylate; ESI: electro-spray ionization; SCX: strong cation exchange; SFC: supercritical fluid chromatography; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylbenzyl; CAN: acetonitrile; Boc: tert-butoxycarbonyl; br: broad peak; Bu: butyl; Cbz: phenoxycarbonyl; δ: chemical shift difference in NMR; Hz: Hertz; J: coupling constant; s: singlet; d: doublet; t: triplet; Ac: acetyl.

[0114] Detection methods

[0115] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (6) are given in units of 10⁻⁰ (ppm). NMR measurements were performed using a Bruker Avance III 400 and a Bruker Avance 400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD) as the solvents, and tetramethylsilane (TMS) as the internal standard.

[0116] MS determination was performed using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0117] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0118] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0119] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0120] intermediate synthesis

[0121] 1. Synthetic intermediate (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid Int-1

[0122] 1.1 Synthesis of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride 2a

[0123] (2S)-2-amino-2-(4-hydroxyphenyl)acetic acid 1a (50 g, 299.11 mmol) was dissolved in methanol (500 mL), and thionyl chloride (71 g, 598.22 mmol) was slowly added dropwise at an ice bath temperature. After reacting at room temperature for 1 hour, the mixture was heated to reflux and reacted for 12 hours. The reaction was then stopped, and the mixture was concentrated under reduced pressure to give (S)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride 2a (64 g, 294.93 mmol), a pale yellow solid, yield: 98.60%.

[0124] LC-MS: m / z(ESI)=363.1[2M+H] + .

[0125] 1,2(S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetic acid methyl ester 3a

[0126] (S)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride 2a (64 g, 294.93 mmol) was dissolved in 1,4-dioxane (300 mL) and water (500 mL), followed by the addition of potassium carbonate (93.62 g, 677.32 mmol) and di-tert-butyl dicarbonate (77.44 g, 354.84 mmol). The reaction was carried out at room temperature for 16 hours, the reaction was stopped, the mixture was concentrated under reduced pressure, ethyl acetate (500 mL) was added to dissolve the methyl ester, followed by the addition of water (200 mL), and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-((tert-butyloxycarbonyl)amino)-2-(4-hydroxyphenyl)acetic acid methyl ester 3a (90 g, 288.25 mmol), a pale yellow oil, yield: 89.36%.

[0127] LC-MS: m / z(ESI)=563.3[2M+H] + .

[0128] 1.3 Synthesis of (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetic acid methyl ester 4a

[0129] Methyl (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate 3a (62 g, 154.48 mmol) was dissolved in acetic acid (400 mL), and platinum dioxide (2 g, 8.81 mmol) was added. The mixture was then connected to a hydrogen gas bag, and the gas was purged three times. The reaction was carried out at 30 °C for 48 h. The reaction was stopped, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%-80%) to obtain (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate 4a (33 g, 114.98 mmol), a pale yellow oil, with a yield of 79.8%.

[0130] LC-MS: m / z(ESI)=597.3[2M+Na] + .

[0131] 1.4 Synthesis of (S)-2-((tert-Butoxycarbonyl)amino)2-(4-oxocyclohexyl)acetic acid methyl ester 5a

[0132] Methyl ((S)-2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate 4a (10.7 g, 37.24 mmol) was dissolved in dichloromethane (300 mL), and N-methylmorpholine oxide (6.54 g, 55.85 mmol) and tetrapropylammonium perruthenate (0.39 g, 1.12 mmol) were added. The reaction was carried out at room temperature for 4 hours, and the reaction was stopped. Water (200 mL) was added, and the mixture was extracted with dichloromethane (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-60%) to give (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate 5a (8.5 g, 29.79 mmol), a pale yellow solid, yield: 78.6%.

[0133] LC-MS: m / z(ESI) = 230.1 [M+H] + .

[0134] 1.5 Synthesis of (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid methyl 6a

[0135] Methyl (S)-2-((tert-butyloxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate 5a (8.5 g, 29.79 mmol) and 2-[(difluoromethyl)dioxo-λ-6-thio]pyridine (4.72 g, 59.58 mmol) were dissolved in N,N-dimethylformamide (100 mL), and potassium tert-butoxide (4.6 g, 65.54 mmol) was dissolved in tetrahydrofuran (100 mL). The mixture was added to the above solution at -70 °C, and the reaction was carried out at -70 °C for 4 hours. The reaction was then stopped, and 200 mL of saturated ammonium chloride solution (ice) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with 200 mL of saturated sodium chloride solution (x). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-60%) to obtain (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetate 6a (5 g, 15.66 mmol), a pale yellow oil, yield: 77.70%.

[0136] LC-MS: m / z(ESI)=342.2[M+Na] + .

[0137] 1.6 Synthesis of (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid Int-1

[0138] Methyl (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetate 6a (5 g, 15.66 mmol) was dissolved in tetrahydrofuran (50 mL) and water (10 mL), and lithium hydroxide (2.63 g, 62.63 mmol) was added. The reaction was carried out at room temperature for 4 hours, and the reaction was stopped. Petroleum ether (20 mL) was added for extraction. The pH of the aqueous phase was slowly adjusted to about 5 with 1N dilute hydrochloric acid solution, and ethyl acetate (100 mL) was added for extraction. The obtained organic phase was concentrated under reduced pressure and dried to give ((S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid Int-1 (4.5 g, 14.74 mmol), a pale yellow solid, yield: 94.14%.

[0139] LC-MS: m / z(ESI) = 306.2 [M+H] + .

[0140] 2. Synthetic intermediate (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetic acid Int-2

[0141] 2.1 Synthesis of (2S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetate 7a

[0142] Methyl (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate 5a (5 g, 17.523 mmol) and (fluoromethyl)tetrafluoroborate triphenylphosphine (13.39 g, 35.05 mmol) were dissolved in N,N-dimethylformamide (100 mL), and potassium tert-butoxide (2.16 g, 19.28 mmol) was dissolved in tetrahydrofuran (100 mL). The mixture was added to the above solution at an internal temperature of -70 °C, and the reaction was carried out at -70 °C for 4 hours. The reaction was then stopped, and 200 mL of saturated ammonium chloride solution (crystals) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with 200 mL of saturated sodium chloride solution (x). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-60%) to obtain (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetate 7a (4.5 g, 15.66 mmol), a pale yellow oil, yield: 85.23%.

[0143] LC-MS: m / z(ESI)=324.2[M+Na] + .

[0144] 2.2 Synthesis of (2S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetic acid Int-2

[0145] Methyl (2S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetate 7a (4.5 g, 15.66 mmol) was dissolved in tetrahydrofuran (50 mL) and water (10 mL), and lithium hydroxide (2.51 g, 59.73 mmol) was added. The reaction was carried out at room temperature for 4 hours, and the reaction was stopped. Petroleum ether (20 mL) was added for extraction. The pH of the aqueous phase was slowly adjusted to about 5 with 1N dilute hydrochloric acid solution, and ethyl acetate (100 mL) was added for extraction. The obtained organic phase was concentrated under reduced pressure and dried to give (2S)-2-((tert-Butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetic acid Int-2 (3.9 g, 13.57 mmol), a pale yellow solid, yield: 90.90%.

[0146] LC-MS: m / z(ESI) = 288.2 [M+H] + .

[0147] 3. Synthetic intermediate ((R)-2-(fluoromethyl)-1-methylpiperazine hydrochloride Int-3

[0148] 3.1 Synthesis of (R)-3-(hydroxymethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester 9a

[0149] 2-Methyl-2-propyl(3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid ester 8a (11.5 g, 53.17 mmol) was dissolved in acetonitrile (150 mL) and water (30 mL). Formaldehyde aqueous solution (12.61 g, 159.52 mmol, 38%) was added, and the mixture was reacted at room temperature for 2 hours. Sodium borohydride acetate (22.43 g, 106.34 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was stopped, and the pH was adjusted to approximately 8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane:methanol = 10:1 (100 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-3-(hydroxymethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester 9a (12 g, 52.10 mmol), a pale yellow oil, yield: 97.99%.

[0150] LC-MS: m / z(ESI) = 231.2 [M+H] + .

[0151] 3.2 Synthesis of (R)-3-(fluoromethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester 10a

[0152] (R)-3-(hydroxymethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester 9a (6 g, 26.05 mmol) was dissolved in dichloromethane (120 mL), and diethylaminosulfur trifluoride (62.99 g, 390.78 mmol) was slowly added dropwise under ice bath conditions. The reaction was carried out at room temperature for 18 hours, and the reaction was stopped. The pH was adjusted to about 8 by adding saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-3-(fluoromethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester 10a (1.3 g, 5.60 mmol), a pale yellow solid, yield: 21.5%.

[0153] LC-MS: m / z(ESI) = 233.2 [M+H] + .

[0154] 3.3 Synthesis of (R)-2-(fluoromethyl)-1-methylpiperazine hydrochloride Int-3

[0155] 10g (1.3g, 5.60mmol) of (R)-3-(hydroxymethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester was dissolved in 1,4-dioxane (5mL), and 10mL of 4M hydrogen chloride / 1,4-dioxane solution was added. The reaction was carried out at room temperature for 3 hours, the reaction was stopped, the solution was concentrated under reduced pressure and dried to give (R)-2-(fluoromethyl)-1-methylpiperazine hydrochloride Int-3 (1.1g, 5.36mmol), a white solid, yield: 95.84%.

[0156] LC-MS: m / z(ESI) = 133.2 [M+H] + .

[0157] 4. Synthetic intermediate 4-nitrophenyl (ethoxyamino)carbamate Int-4

[0158] Ethoxyalkylamine hydrochloride (3 g, 30.93 mmol) was dissolved in acetonitrile (30 mL), and 4-nitrophenyl chloroformate 11a (6.23 g, 30.93 mmol) and N,N-diisopropylethylamine (23.94 g, 185.57 mmol) were slowly added. The reaction was carried out at room temperature for 1 hour, and the reaction was stopped. Saturated sodium chloride solution (200 mL) was added, and the mixture was extracted with dichloromethane (10 mL). The organic phase was washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0%–3%) to give 4-nitrophenyl (ethoxyamino)carbamate Int-4 (5 g, 22.11 mmol), a pale yellow oil, with a yield of 71.47%.

[0159] LC-MS: m / z(ESI) = 227.1 [M+H] + .

[0160] Example 1: N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 1

[0161] 1.1 Synthesis of methyl 2-methylpropyl-2-yl{[(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]amino}carbamate 1-2

[0162] (2R,3S)-3-(3-fluoro-4-nitrophenyl)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)butyric acid 1-1 (3 g, 8.76 mmol) and N-methylpiperazine (1.17 mL, 10.52 mmol) were dissolved in N,N-dimethylformamide (50 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (5.00 g, 13.15 mmol) and N,N-diisopropylethylamine (5.66 g, 43.82 mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (100 mL) was added. The mixture was extracted with dichloromethane (100 mL). The organic phase was then treated with saturated sodium chloride solution (100 mL x 100 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to give methyl 2-methylpropyl-2-yl{[(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]amino}carbamate 1-2 (3.5 g, 8.25 mmol), a pale yellow oil, yield: 94.09%.

[0163] LC-MS: m / z (ESI) = 425.2 [M+H] + .

[0164] 1.2 Synthesis of (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)but-1-one 1-3

[0165] 1-2 methyl 2-methylpropyl-2-yl{[(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]amino}carbamate (3.5 g, 8.246 mmol) were dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 1 hour, the reaction was stopped, the solution was concentrated under reduced pressure, and dichloromethane (25 mL) was added to dissolve the carbamate. The solution was then neutralized with potassium carbonate solution (2.5 g dissolved in 25 mL of water), and then dissolved in dichloromethane (30 mL x 3) Extraction: The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)but-1-one 1-3 (2.50 g, 7.71 mmol), a pale yellow oil, yield: 93.63%.

[0166] LC-MS: m / z (ESI) = 325.2 [M+H] + .

[0167] 1.3 Synthesis of N-[(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-4

[0168] (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)but-1-one 1-3 (550 mg, 1.70 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of propionic anhydride (0.26 mL, 2.04 mmol) and N,N-diisopropylethylamine (328.74 mg, 2.54 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (60 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain N-[(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-4 (490 mg, 1.29 mmol), a pale yellow oil, yield: 75.96%.

[0169] LC-MS: m / z(ESI) = 381.2 [M+H] + .

[0170] 1.4 Synthesis of N-[(2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-5

[0171] N-[(2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-4 (490 mg, 1.29 mmol) was dissolved in ethanol (15 mL) and tetrahydrofuran (15 mL), and 10% Pd / C (200 mg) was added. The mixture was covered with a hydrogen balloon, and the gas was purged three times. The reaction was carried out at room temperature for 4 hours. The reaction was stopped, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure and dried to give N-[(2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-5 (430 mg, 1.23 mmol), a white solid, yield: 95.28%.

[0172] LC-MS: m / z(ESI) = 351.2 [M+H] + .

[0173] 1.5 Synthesis of 2-methylpropyl-2-yl{[(1S)-1-[4-(difluoromethylene)cyclohexyl]-2-({2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-(propionylamino)but-2-yl]phenyl}amino)-2-oxoethyl]amino}carbamate 1-6

[0174] N-[(2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-5 (100 mg, 0.29 mmol) and (2S)-2-[4-(difluoromethylene)cyclohexyl]-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)acetic acid Int-1 (104.55 mg, 0.34 mmol) were dissolved in N,N-dimethyl Formamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (162.76 mg, 0.43 mmol) and N,N-diisopropylethylamine (147.34 mg, 1.14 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain 2-methylpropyl-2-yl{[(1S)-1-[4-(difluoromethylene)cyclohexyl]-2-({2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-(propionylamino)but-2-yl]phenyl}amino)-2-oxoethyl]amino}carbamate 1-6 (70 mg, 0.11 mmol), a pale yellow oil, yield: 38.46%.

[0175] LC-MS: m / z (ESI) = 638.3 [M+H] + .

[0176] 1.6 Synthesis of N-[(2R,3S)-3-(3-fluoro-4-{[(2S)-2-amino-2-[4-(difluoromethylene)cyclohexyl]acetyl]amino}phenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-7

[0177] 2-Methylpropyl-2-yl{[(1S)-1-[4-(difluoromethylene)cyclohexyl]-2-({2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-(propionylamino)but-2-yl]phenyl}amino)-2-oxoethyl]amino}carbamate 1-6 (70 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 2 hours, then stopped, concentrated under reduced pressure, and dried to give N-[(2R,3S)-3-(3-fluoro-4-{[(2S)-2-amino-2-[4-(difluoromethylene)cyclohexyl]acetyl]amino}phenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-7 (50 mg, 0.093 mmol), a pale yellow solid, yield: 84.73%.

[0178] LC-MS: m / z (ESI) = 538.2 [M+H] + .

[0179] 1.7 Synthesis of N-[(1S)-1-[4-(difluoromethylene)cyclohexyl]-2-({2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl-4-oxo-3-(propionylamino)but-2-yl]phenyl}amino)-2-oxoethyl]-2-ethylpyrazole-3-carboxamide 1

[0180] N-[(2R,3S)-3-(3-fluoro-4-{[(2S)-2-amino-2-[4-(difluoromethylene)cyclohexyl]acetyl]amino}phenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl]propionamide 1-7 (50 mg, 0.093 mmol) and 2-ethylpyrazole-3-carboxylic acid (19.55 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (53.04 mg, 0.14 mmol) and N,N-diisopropylethylamine (60.10 mg, 0.47 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic phase was then treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by C18 column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to obtain N-[(1S)-1-[4-(difluoromethylene)cyclohexyl]-2-({2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-(propionylamino)but-2-yl]phenyl}amino)-2-oxoethyl]-2-ethylpyrazole-3-carboxamide 1 (15 mg, 0.023 mmol), white solid, yield: 24.45%.

[0181] LC-MS: m / z (ESI) = 660.2 [M+H] + .

[0182] 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 8.54 (d, J = 8.4Hz, 1H), 8.27 (d, J = 8.4Hz, 1H), 7.74 (t, J = 8.4Hz, 1H), 7.47 (d, J = 2.0Hz, 1H), 7.11 (dd, J=12.0, 2.0Hz, 1H), 7.04-6.94 (m, 2H), 4.85 (t, J=9.2Hz, 1H), 4.64-4.58 (m, 1H), 4.40-4.50 (m , 2H), 3.47-3.35(m, 2H), 3.28-3.21(m, 1H), 3.14-2.97(m, 2H), 2.45-2.35(m, 2H), 2.22-2.04(m, 4H), 2.03-1.98(m, 1H), 1.97 (s, 3H), 1.92-1.70 (m, 4H), 1.68-1.60 (m, 1H), 1.56-1.47 (m, 1H), 1.31-1.08 (m, 8H), 0.98 (t, J=7.6Hz, 3H).

[0183] Example 2: 1-Ethyl-N-((1S)-2-((2-fluoro-4-((2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 2

[0184] 2.1 Synthesis of tert-butyl((1S)-2-((2-fluoro-4-((2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate 2-1

[0185] N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)propionamide 1-5 (122 mg, 0.35 mmol) and (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetic acid Int-2 (150.04 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (5 mL). Add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (198.56 mg, 0.52 mmol) and N,N-diisopropylethylamine (179.99 mg, 1.39 mmol), react at room temperature for 20 hours, stop the reaction, add saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (50 mL), and saturate sodium chloride solution (50 mL) with the organic phase. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain tert-butyl((1S)-2-((2-fluoro-4-((2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate 2-1 (55 mg, 0.089 mmol), a pale yellow oil, yield: 25.49%.

[0186] LC-MS: m / z (ESI) = 620.4 [M+H] + .

[0187] 2.2 Synthesis of N-((2R,3S)-3-(4-(((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)propionamide 2-2

[0188] tert-Butyl(1S)-2-((2-fluoro-4-((2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate 2-1 (55 mg, 0.089 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 2 hours, the reaction was stopped, the mixture was concentrated under reduced pressure, and dried to give N-((2R,3S)-3-(4-((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)propamidoamide 2-2 (40 mg, 0.077 mmol), a pale yellow solid, yield: 86.73%.

[0189] LC-MS: m / z (ESI) = 520.3 [M+H] + .

[0190] 2.3 Synthesis of 1-ethyl-N(1S)-2-((2-fluoro-4-((2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 2

[0191] N-((2R,3S)-3-(4-((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)propionamide 2-2 (40 mg, 0.077 mmol) and 2-ethylpyrazole-3-carboxylic acid (21.57 mg, 0.154 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (43.90 mg, 0.115 mmol) and N,N-diisopropylethylamine (49.75 mg, 0.385 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (30 mL) was added. The mixture was extracted with ethyl acetate (40 mL). The organic phase was then treated with saturated sodium chloride solution (30 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use C... 18Column chromatography (acetonitrile: 0.5% ammonia = 5-95%) was used to separate and purify the product, yielding 1-ethyl-N-(1S)-2-((2-fluoro-4-((2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 2 (13 mg, 0.020 mmol), a white solid, yield: 26.32%.

[0192] LC-MS: m / z(ESI) = 642.3 [M+H] + .

[0193] 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.28 (d, J = 8.8Hz, 1H), 7.80-7.70 (m, 1H), 7.47 (d, J = 2.0Hz, 1H), 7.19-7.07 (m, 1H), 7.04-6.93 (m, 2H), 6.64 (d, J=87.6Hz, 1H), 4.86 (t, J=9.2Hz, 1H), 4.61 (t, J=8.4Hz, 1H), 4.46 (q, J=7.2Hz, 2H), 3.48-3.36(m, 2H), 3.30-3.20(m, 1H), 3.13-2.98(m, 2H), 2.75-2.65(m, 1H), 2.50-2.43(m, 1H), 2.22-2.12(m, 4H), 2.08- 2.01 (m, 1H), 1.98 (s, 3H), 1.94-1.61 (m, 5H), 1.55-1.45 (m, 1H), 1.30-1.17 (m, 7H), 1.15-1.05 (m, 1H), 0.98 (t, J=7.6Hz, 3H).

[0194] Example 3: N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 3

[0195] 3.1 Synthesis of N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 3-1

[0196] (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)but-1-one 1-3 (1.5 g, 4.62 mmol) and methoxyacetic acid (0.83 g, 9.25 mmol) were dissolved in N,N-dimethylformamide (15 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (2.64 g, 6.94 mmol) and N,N-diisopropylethylamine (2.39 g, 18.50 mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (60 mL). The organic phase was then treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 3-1 (1.5 g, 3.78 mmol), a pale yellow oil, yield: 81.82%.

[0197] LC-MS: m / z (ESI) = 397.2 [M+H] + .

[0198] 3.2 Synthesis of N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 3-2

[0199] N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide (1.5 g, 3.78 mmol) was dissolved in ethanol (25 mL) and tetrahydrofuran (25 mL), and 10% Pd / C (0.40 g, 3.78 mmol) was added. The mixture was covered with a hydrogen balloon, and the gas was purged three times. The reaction was carried out at room temperature for 4 hours. The reaction was stopped, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure and dried to give N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 3-2 (1.3 g, 3.55 mmol), a white solid, yield: 93.76%.

[0200] LC-MS: m / z (ESI) = 367.2 [M+H] + .

[0201] 3.3 Synthesis of ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)tert-butyl carbamate 3-3

[0202] N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 3-2 (200 mg, 0.55 mmol) and (2S)-2-[4-(difluoromethylene)cyclohexyl]-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)acetic acid (249.96 mg, 0.82 mmol) were dissolved in N,N-dimethyl... Formamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (311.30 mg, 0.82 mmol) and N,N-diisopropylethylamine (282.17 mg, 2.18 mmol). The reaction was carried out at room temperature for 20 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (30 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)carbamate tert-butyl ester 3-3 (150 mg, 0.23 mmol), a pale yellow oil, yield: 42.04%.

[0203] LC-MS: m / z (ESI) = 654.2 [M+H] + .

[0204] 3.4 Synthesis of (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)acetamide 3-4

[0205] Dissolve tert-butyl (S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)carbamate 3-3 (150 mg, 0.23 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and incubate at room temperature. The reaction was stopped after 2 hours, concentrated under reduced pressure, and dried to give (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)acetamide 3-4 (120 mg, 0.22 mmol), a pale yellow solid, yield: 94.47%.

[0206] LC-MS: m / z (ESI) = 554.2 [M+H] + .

[0207] 3.5 Synthesis of N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide

[0208] (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)acetamide 3-4 (120 mg, 0.22 mmol) and 2-ethylpyrazole-3-carboxylic acid (45.56 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (5 Add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (123.63 mg, 0.33 mmol) and N,N-diisopropylethylamine (140.08 mg, 1.08 mmol) to the solution. React at room temperature for 1 hour. Stop the reaction, add saturated sodium bicarbonate solution (30 mL), extract with ethyl acetate (40 mL), wash the organic phase with saturated sodium chloride solution (30 mL x 3), dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use C... 18The solution was separated and purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 3 (70 mg, 0.104 mmol), a white solid, yield: 47.79%.

[0209] LC-MS: m / z (ESI) = 676.2 [M+H] + .

[0210] 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 8.52 (d, J = 8.4Hz, 1H), 7.95 (d, J = 8.8Hz, 1H), 7.76 (t, J = 8.4Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.15 (dd, J=12.0, 2.0Hz, 1H), 7.06-6.95 (m, 2H), 4.93 (t, J=9.2Hz, 1H), 4.62 (t, J=8.4Hz, 1H), 4.46 (q, J=7.2Hz, 2H), 3.48-3.35 ( m, 2H), 3.85 (s, 2H), 3.30 (s, 3H), 3.30-3.22 (m, 1H), 3.18-3.10 (m, 1H), 3.08-2.98 (m, 1H), 2.45-2.35 (m, 2H), 2.22-2.13 (m, 2H) , 2.05-1.97(m, 1H), 1.98(s, 3H), 1.93-1.63(m, 5H), 1.55-1.45(m, 1H), 1.32-1.25(m, 4H), 1.24-1.17(m, 3H), 1.17-1.09(m, 1H).

[0211] Example 4: 1-Ethyl-N-((1S)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 4

[0212] 4.1 Synthesis of tert-butyl((1S)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate 4-1

[0213] N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 3-3 (130 mg, 0.36 mmol) and (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-(fluoromethylene)cyclohexyl)acetic acid (152.90 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (5 mg). L), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (202.34 mg, 0.53 mmol) and N,N-diisopropylethylamine (183.41 mg, 1.42 mmol) were added, and the reaction was carried out at room temperature for 20 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (30 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain tert-butyl ((1S)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate 4-1 (90 mg, 0.14 mmol), a pale yellow oil, yield: 39.90%.

[0214] LC-MS: m / z (ESI) = 636.2 [M+H] + .

[0215] 4.2 Synthesis of (2S)-2-amino-N-(2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)-2-(4-(fluoromethylene)cyclohexyl)acetamide 4-2

[0216] 90 mg (0.14 mmol) of tert-butyl(1S)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 2 hours, the reaction was stopped, the mixture was concentrated under reduced pressure, and dried to give (2S)-2-amino-N-(2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)-2-(4-(fluoromethylene)cyclohexyl)acetamide 4-2 (70 mg (0.13 mmol), a pale yellow solid, yield: 92.31%.

[0217] LC-MS: m / z (ESI) = 536.2 [M+H] + .

[0218] 4.4 Synthesis of 1-ethyl-N-((1S)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide

[0219] (2S)-2-amino-N-(2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)-2-(4-(fluoromethylene)cyclohexyl)acetamide (70 mg, 0.13 g) 2-ethylpyrazole-3-carboxylic acid 4-2 (27.47 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (74.54 mg, 0.20 mmol) and N,N-diisopropylethylamine (84.46 mg, 0.653 mmol) were added. The mixture was reacted at room temperature for 1 hour, and the reaction was stopped. Saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to C... 18Column chromatography (acetonitrile: 0.5% ammonia = 5-95%) was used for separation and purification to give 1-ethyl-N-((1S)-2-((2-fluoro-4-((2S,3R)-3-(2-methoxyacetamide)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide 4 (24.0 mg, 0.036 mmol), a white solid, yield: 27.92%.

[0220] LC-MS: m / z (ESI) = 658.2 [M+H] + .

[0221] 1 H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 8.52 (d, J = 8.4Hz, 1H), 7.95 (d, J = 8.8Hz, 1H), 7.80-7.72 (m, 1H), 7.48 (d, J = 2.0Hz , 1H), 7.14 (d, J=12.0Hz, 1H), 7.06-6.96 (m, 2H), 6.64 (d, J=87.2Hz, 1H), 4.93 (t, J=9.2Hz, 1H), 4.61 (t, J=8.4Hz, 1H), 4 .46(q, J=7.2Hz, 2H), 3.85(s, 2H), 3.48-3.35(m, 2H), 3.30(s, 3H), 3.27-2.98(m, 3H), 2.73-2.63(m, 1H), 2.23-2.10(m, 3H), 2.09-1.95(m, 4H), 1.93-1.63(m, 5H), 1.53-1.43(m, 1H), 1.30-1.25(m, 4H), 1.23-1.17(m, 3H), 1.16-1.05(m, 1H).

[0222] Example 5: 4-Cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-4-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 5

[0223] 5.1 Synthesis of (2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)tert-butyl carbamate 5-2

[0224] (2R,3S)-3-(3-fluoro-4-nitrophenyl)-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)butyric acid 5-1 (808.71 mg, 2.36 mmol) and (R)-2-(fluoromethyl)-1-methylpiperazine hydrochloride Int-3 (600 mg, 2.95 mmol) were dissolved in N,N-dimethylformamide (10 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.35 g, 3.54 mmol) and N,N-diisopropylethylamine (2.44 g, 18.90 mmol) were added, and the mixture was reacted at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to give (2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)carbamate 5-2 (800 mg, 1.75 mmol), a pale yellow oil, yield: 74.20%.

[0225] LC-MS: m / z (ESI) = 457.2 [M+H] + .

[0226] 5.2 Synthesis of (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)but-1-one 5-3

[0227] (2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)carbamate tert-butyl ester 5-2 (800 mg, 1.75 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature for 1 hour, and then the reaction was stopped. The solution was concentrated under reduced pressure and dried to give (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)but-1-one 5-3 (700 mg, 1.49 mmol), a pale yellow solid, yield: 84.91%.

[0228] LC-MS: m / z (ESI) = 557.2 [M+H] + .

[0229] 5.3 Synthesis of (S)-N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-4

[0230] (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)but-1-one (700 mg, 1.49 mmol) and (S)-2-methoxypropionic acid 5-3 (204.47 mg, 1.96 mmol) were dissolved in N,N-dimethylformamide (10 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.12 g, 2.95 mmol) and N,N-diisopropylethylamine (1.02 g, 7.86 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (60 mL). The organic phase was then treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain (S)-N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-4 (550 mg, 1.24 mmol), a pale yellow oil, yield: 63.29%.

[0231] LC-MS: m / z(ESI) = 443.2 [M+H] + .

[0232] 5.4 Synthesis of (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-5

[0233] Dissolve (S)-N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-4 (550 mg, 1.24 mmol) in ethanol (15 mL) and tetrahydrofuran (15 mL), add 10% Pd / C (300 mg), cover with a hydrogen balloon, and replace the gas 3 times. The reaction was carried out at room temperature for 4 hours, then stopped. The mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated and dried under reduced pressure to give (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-5 (500 mg, 1.21 mmol), a white solid, yield: 97.52%.

[0234] LC-MS: m / z(ESI) = 413.2 [M+H] + .

[0235] 5.5 Synthesis of (S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-4-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)tert-butyl carbamate 5-6

[0236] (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-5 (500 mg, 1.21 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid Int-1 (555.15 mg, 1.82 mmol) were dissolved in N,N Dimethylformamide (10 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (691.38 mg, 1.818 mmol) and N,N-diisopropylethylamine (626.70 mg, 4.85 mmol). The reaction was carried out at room temperature for 20 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (30 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain (S)-1-(4-(difluoromethylene)cyclohexyl(-2-((2-fluoro-4-((2S,3R)-4-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)tert-butyl carbamate 5-6 (200 mg, 0.29 mmol), a pale yellow oil, yield: 23.58%.

[0237] LC-MS: m / z(ESI) = 700.2[M+H] + .

[0238] 5.6 Synthesis of (S)-N-((2R,3S)-3-(4-((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-7

[0239] Dissolve 5-6 (200 mg, 0.29 mmol) of (S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-4-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-3-(S)-2-methoxypropamido)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)carbamate tert-butyl carbamate in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and incubate at room temperature. The reaction was stopped after 2 hours, concentrated under reduced pressure, and dried to give (S)-N-((2R,3S)-3-(4-((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-7 (150 mg, 0.25 mmol), a pale yellow solid, yield: 87.52%.

[0240] LC-MS: m / z(ESI) = 600.3 [M+H] + .

[0241] 5.7 Synthesis of 4-cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-4-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 5-8

[0242] The following were prepared: (S)-N-((2R,3S)-3-(4-((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxypropionamide 5-7 (150 mg, 0.25 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (57.83 mg, 0.38 mmol). Dissolve in N,N-dimethylformamide (5 mL), add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (142.67 mg, 0.38 mmol) and N,N-diisopropylethylamine (161.65 mg, 1.25 mmol), react at room temperature for 1 hour, stop the reaction, add saturated sodium bicarbonate solution (30 mL), extract with ethyl acetate (40 mL), wash the organic phase with saturated sodium chloride solution (30 mL x 3), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the crude product is subjected to C... 18The solution was purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give 4-cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((2-fluoro-4-((2S,3R)-4-((R)-3-(fluoromethyl)-4-methylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobut-2-yl)phenyl)amino)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 5 (50 mg, 0.068 mmol), a white solid, in a yield of 27.17%.

[0243] LC-MS: m / z (ESI) = 736.3 [M+H] + .

[0244] 1 H NMR (400MHz, DMSO-d6) δ10.03 (d, J=14.4Hz, 1H), 9.23 (dd, J=8.4, 3.2Hz, 1H), 8.20 (dd, J=1 5.2, 8.4Hz, 1H), 7.82-7.64 (m, 1H), 7.16 (dd, J=12.0, 2.0Hz, 1H), 7.10-6.98 (m, 1H), 5.02- 4.83 (m, 1H), 4.72 (q, J=8.0Hz, 1H), 4.55-4.23 (m, 2H), 4.07-3.71 (m, 3H), 3.28-2.95 (m, 5H ), 2.70-2.58(m, 1H), 2.48-2.35(m, 3H), 2.32-2.23(m, 1H), 2.19(s, 1H), 2.10-1.72(m, 8H), 1.62-1.48(m, 1H), 1.28-1.12(m, 10H), 1.03-0.95(m, 2H).

[0245] Example 6: N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 6

[0246] 6.1 Synthesis of tert-butyl carbamate ((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)carbamate 6-1

[0247] (2R,3S)-3-(3-fluoro-4-nitrophenyl)-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)butyric acid 6-1 (2.5 g, 7.30 mmol) and (2R)-1,2-dimethylpiperazine (1.0 g, 8.76 mmol) were dissolved in N,N-dimethylformamide (20 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (4.16 g, 10.95 mmol) and N,N-diisopropylethylamine (4.72 g, 36.49 mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (100 mL) was added. The mixture was extracted with dichloromethane (100 mL). The organic phase was then treated with saturated sodium chloride solution (100 mL x 100 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to give ((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)carbamate 6-2 (2.6 g, 5.93 mmol), a pale yellow oil, yield: 81.25%.

[0248] LC-MS: m / z(ESI) = 439.2 [M+H] + .

[0249] 6.2 Synthesis of (2R,3S)-2-amino-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)but-1-one 6-3

[0250] ((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)carbamate tert-butyl 6-2 (1.3 g, 2.97 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 1 hour, the reaction was stopped, the solution was concentrated under reduced pressure, and dichloromethane (25 mL) was added to dissolve the carbamate. The solution was then neutralized with potassium carbonate solution (2.5 g dissolved in 25 mL of water), and finally dissolved in dichloromethane (50 mL x 3) Extraction: The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-(4-methylpiperazin-1-yl)but-1-one 6-3 (0.9 g, 2.69 mmol), a pale yellow oil, yield: 91.00%.

[0251] LC-MS: m / z(ESI) = 339.2 [M+H] + .

[0252] 6.3 Synthesis of N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)-2-methoxyacetamide 6-4

[0253] N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)-2-methoxyacetamide 6-3 (600 mg, 1.77 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 2-methoxyacetic acid (207.63 mg, 2.31 mmol) and N,N-diisopropylethylamine (916.72 mg, 7.09 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (60 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)-2-methoxyacetamide 6-4 (600 mg, 1.46 mmol), a pale yellow oil, yield: 82.44%.

[0254] LC-MS: m / z(ESI) = 411.3 [M+H] + .

[0255] 6.4 Synthesis of N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 6-5

[0256] N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)-2-methoxyacetamide 6-4 (600 mg, 1.46 mmol) was dissolved in ethanol (15 mL) and tetrahydrofuran (15 mL), and 10% Pd / C (200 mg) was added. The mixture was covered with a hydrogen balloon, and the gas was purged three times. The reaction was carried out at room temperature for 4 hours. The reaction was stopped, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure and dried to give N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxyacetamide 6-5 (500 mg, 1.31 mmol), a pale yellow solid, yield: 89.90%.

[0257] LC-MS: m / z(ESI) = 381.3 [M+H] + .

[0258] 6.5 Synthesis of ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)tert-butyl carbamate 6-6

[0259] N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobut-2-yl)-2-methoxyacetamide 6-5 (300 mg, 0.79 mmol) and (2S)-2-[4-(difluoromethylene)cyclohexyl]-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)acetic acid Int-1 (361 mg, 1.18 mmol) were dissolved in N Add 5 mL of N,N-dimethylformamide, then add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (449.74 mg, 1.18 mmol) and N,N-diisopropylethylamine (407.66 mg, 3.15 mmol). React at room temperature for 18 hours. Stop the reaction, add 50 mL of saturated sodium bicarbonate solution, and extract with 50 mL of ethyl acetate. Extract the organic phase with 50 mL of saturated sodium chloride solution. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)tert-butyl carbamate 6-6 (270 mg, 0.40 mmol), a pale yellow oil, yield: 51.2%.

[0260] LC-MS: m / z (ESI) = 668.3 [M+H] + .

[0261] 6.6 Synthesis of (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 6-7

[0262] Dissolve tert-butyl carbamate 6-6 (110 mg, 0.17 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and... The reaction was carried out at room temperature for 2 hours, then stopped, concentrated under reduced pressure, and dried to give ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 6-7 (90 mg, 0.16 mmol), a pale yellow oil, yield: 90%.

[0263] LC-MS: m / z (ESI) = 568.3 [M+H] + .

[0264] 6.7 Synthesis of N-[(1S)-1-[4-(difluoromethylene)cyclohexyl]-2-({2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-(propionylamino)but-2-yl]phenyl}amino)-2-oxoethyl]-2-ethylpyrazole-3-carboxamide 6

[0265] Dissolve ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 6-7 (90 mg, 0.16 mmol) and 2-ethylpyrazole-3-carboxylic acid (33.33 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL), then add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (90.43 mg, 0.24 mmol) and N,N-diisopropylethylamine (102.46 mg, The reaction was carried out at room temperature for 1 hour (0.79 mmol), the reaction was stopped, saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by C18 column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 6 (63 mg, 0.091 mmol), a white solid, yield: 57.61%.

[0266] LC-MS: m / z(ESI) = 690.0 [M+H] + .

[0267] 1 H NMR (400MHz, DMSO-d6) δ9.92 (d, J=8.4Hz, 1H), 8.51 (d, J=8.4Hz, 1H), 8.02-7.60 (m, 2H), 7.48 (d, J=2.0 Hz, 1H), 7.20-7.11 (m, 1H), 7.09-6.96 (m, 2H), 4.95 (dt, J=18.8, 9.2Hz, 1H), 4.71-4.54 (m, 1H), 4.51-4 .35(m, 2H), 4.12-3.51(m, 4H), 3.31(s, 3H), 3.20-2.99(m, 1H), 2.54(s, 2H), 2.47(s, 1H), 2.40(d, J=13 .6Hz, 2H), 2.08 (s, 1H), 1.98 (s, 1H), 1.93-1.71 (m, 7H), 1.35-1.05 (m, 9H), 0.80 (dd, J=6.4, 4.4Hz, 3H).

[0268] Example 7: N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 7

[0269] 7.1 Synthesis of (S)-N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobut-2-yl)-2-methoxypropionamide 7-1

[0270] N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)-2-methoxyacetamide 6-3 (300 mg, 0.89 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (S)-2-methoxypropionic acid (129.28 mg, 1.24 mmol) and N,N-diisopropylethylamine (458.36 mg, 3.55 mmol) were added. The reaction was carried out at room temperature for 1 hour, and the reaction was stopped. Saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with dichloromethane (60 mL). The organic phase was then separated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain (S)-N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobut-2-yl)-2-methoxypropionamide 7-1 (300 mg, 0.71 mmol), a pale yellow oil, yield: 79.92%.

[0271] LC-MS: m / z (ESI) = 425.2 [M+H] + .

[0272] 7.2 Synthesis of (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxypropionamide 7-2

[0273] (S)-N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)-2-methoxypropionamide 7-1 (300 mg, 0.71 mmol) was dissolved in ethanol (15 mL) and tetrahydrofuran (15 mL), and 10% Pd / C (200 mg) was added. The mixture was covered with a hydrogen balloon, and the gas was purged three times. The reaction was carried out at room temperature for 4 hours. The reaction was stopped, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure and dried to give (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutan-2-yl)-2-methoxypropionamide 7-2 (250 mg, 0.63 mmol), a pale yellow solid, yield: 89.67%.

[0274] LC-MS: m / z (ESI) = 395.2 [M+H] + .

[0275] 7.3 Synthesis of ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)tert-butyl carbamate 7-3

[0276] (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxypropionamide 7-2 (100 mg, 0.25 mmol) and (2S)-2-[4-(difluoromethylene)cyclohexyl]-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)acetic acid (116.09 mg, 0.38 mmol) were dissolved in... N,N-dimethylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (144.58 mg, 0.38 mmol) and N,N-diisopropylethylamine (131.06 mg, 1.01 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)tert-butyl carbamate 7-3 (150 mg, 0.40 mmol), a pale yellow oil, yield: 86.79%.

[0277] LC-MS: m / z (ESI) = 682.3 [M+H] + .

[0278] 7.4 Synthesis of (S)-N-((2R,3S)-3-(4-((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxypropionamide 7-4

[0279] Dissolve tert-butyl carbamate 7-3 (150 mg, 0.40 mmol) in dichloromethane (5 mL), then add trifluoroacetic acid (2 mL). The reaction was carried out at room temperature for 2 hours, then stopped, concentrated under reduced pressure, and dried to give ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 7-4 (130 mg, 0.20 mmol), a pale yellow oil, yield: 90%.

[0280] LC-MS: m / z (ESI) = 582.3 [M+H] + .

[0281] 7.5 Synthesis of N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 7

[0282] ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 7-4 (100 mg, 0.17 mmol) and 2-ethylpyrazole-3-carboxylic acid (34.47 mg, 0.224 mmol) dissolved in N,N dimethyl... 5 mL of methylformamide was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (98.05 mg, 0.26 mmol) and N,N-diisopropylethylamine (111.10 mg, 0.86 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and 50 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with 3 x 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to C... 18The solution was separated and purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide 7 (30 mg, 0.042 mmol), a white solid, yield: 24.31%.

[0283] LC-MS: m / z (ESI) = 704.3 [M+H] + .

[0284] 1 H NMR (400MHz, DMSO-d6) δ9.92 (d, J=8.4Hz, 1H), 8.51 (d, J=8.4Hz, 1H), 8.12 (dd, J=31.2, 8.8Hz, 1H), 7.74 ( dt, J=56.8, 8.4Hz, 1H), 7.48 (d, J=2.0Hz, 1H), 7.20-6.89 (m, 3H), 4.92 (dt, J=26.8, 9.2Hz, 1H), 4.70-4.57 (m, 1H), 4.51-4.37 (m, 2H), 4.07-3.55 (m, 3H), 3.22 (s, 3H), 3.20-3.06 (m, 1H), 2.59-2.52 (m, 2H), 2.47-2 .35(m, 3H), 2.09(s, 1H), 2.03-1.95(m, 1H), 1.84-1.69(m, 7H), 1.33-1.12(m, 12H), 0.81(d, J=5.6Hz, 3H).

[0285] Example 8: N-(((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-(((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobut-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 8

[0286] ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 7-4 (130 mg, 0.20 mmol) and 2-isopropylpyrazole-3-carboxylic acid (46.98 mg, 0.34 mmol) were dissolved in N,N-dimethyl... Formamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (127.47 mg, 0.34 mmol) and N,N-diisopropylethylamine (147.43 mg, 1.12 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to C... 18 The solution was separated and purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide 8 (66.5 mg, 0.094 mmol), a white solid, yield: 42.28%.

[0287] LC-MS: m / z(ESI) = 718.3 [M+H] + .

[0288] 1H NMR (400MHz, DMSO-d6) δ9.91 (d, J=8.4Hz, 1H), 8.50 (d, J=8.4Hz, 1H), 8.12 (dd, J=31.2, 8.8Hz, 1H), 7.75 (dt, J=56.8, 8.4Hz, 1H ), 7.49 (d, J=1.6Hz, 1H), 7.15 (t, J=10.4Hz, 1H), 7.03 (dd, J=18.8, 8.8Hz, 1H), 6.94 (t, J=2.8Hz, 1H), 5.38 (dd, J=8.0, 5.2Hz, 1 H), 4.92 (dt, J=27.2, 9.2Hz, 1H), 4.67-4.48 (m, 1H), 4.05-3.54 (m, 3H), 3.22 (s, 3H), 3.17-3.03 (m, 1H), 2.57-2.53 (m, 2H), 2.4 7-2.31 (m, 3H), 2.08 (s, 1H), 2.03-1.94 (m, 1H), 1.93-1.73 (m, 7H), 1.39-1.30 (m, 6H), 1.26-1.13 (m, 9H), 0.81 (d, J=6.4Hz, 3H).

[0289] Example 9: 1-Cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide 9

[0290] ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide (100 mg, 0.17 mmol) and 2-cyclopropylpyrazole-3-carboxylic acid 7-4 (331.40 mg, 0.21 mmol) were dissolved in N,N diethylcarboxylic acid. Methylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (98.05 mg, 0.26 mmol) and N,N-diisopropylethylamine (111.10 mg, 0.86 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to C... 18The solution was purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give 1-cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide 9 (25 mg, 0.035 mmol), a white solid, yield: 20.32%.

[0291] LC-MS: m / z (ESI) = 716.3 [M+H] + .

[0292] 1 H NMR (400MHz, DMSO-d6) δ9.94 (d, J=9.2Hz, 1H), 8.52 (d, J=8.4Hz, 1H), 8.13 (dd, J=31.6, 8.8Hz, 1H), 7.75 (dt, J=55.4, 8.4Hz, 1H), 7.41 (d , J=1.6Hz, 1H), 7.18-7.10 (m, 1H), 7.07-7.00 (m, 1H), 6.97-6.91 (m, 1H), 4.92 (dt, J=26.4, 9.2Hz, 1H), 4.65 (dt, J=14.8, 8.4Hz, 1H), 4.41 (dd, J=7.6, 4.0Hz, 1H), 4.07-3.56 (m, 3H), 3.22 (s, 3H), 3.17-3.05 (m, 1H), 2.59-2.53 (m, 2H), 2.47-2.31 (m, 5H), 2.08 (s, 1H), 1.97 (s, 2H) ), 1.89 (s, 3H), 1.85-1.66 (m, 2H), 1.37-1.21 (m, 4H), 1.20-1.12 (m, 4H), 1.06 (t, J=3.2Hz, 2H), 0.98-0.88 (m, 2H), 0.81 (d, J=5.6Hz, 3H).

[0293] Example 10: 4-Cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 10

[0294] Dissolve ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(2-methoxyacetamido)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 7-4 (130 mg, 0.20 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (34.46 mg, 0.22 mmol) in N Add 5 mL of N-dimethylformamide, then add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (98.05 mg, 0.26 mmol) and N,N-diisopropylethylamine (111.10 mg, 0.86 mmol). React at room temperature for 1 hour, then stop the reaction. Add 50 mL of saturated sodium bicarbonate solution and extract with 50 mL of ethyl acetate. Filter the organic phase with 50 mL of saturated sodium chloride solution. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by C18 column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to obtain 4-cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 10 (16 mg, 0.022 mmol), white solid, yield: 12.97%.

[0295] LC-MS: m / z(ESI)=718.3[M+H]+.

[0296] 1H NMR (400MHz, DMSO-d6) δ10.03 (d, J=9.2Hz, 1H), 9.24 (d, J=8.0Hz, 1H), 8.13 (dd, J=31.6, 8.8Hz, 1H), 7.75 (dt, J=54.4, 8.4Hz, 1H ), 7.16 (dd, J=12.0, 5.6Hz, 1H), 7.05 (dd, J=22.4, 8.4Hz, 1H), 5.00-4.84 (m, 1H), 4.77-4.61 (m, 1H), 4.05-3.57 (m, 3H), 3.22 (s, 3 H), 3.18-3.05 (m, 1H), 2.56 (d, J=12.8Hz, 2H), 2.43-2.15 (m, 5H), 2.08 (s, 1H), 2.00 (s, 1H), 1.91 (s, 3H), 1.84-1.71 (m, 3H), 1.3 2 (d, J=11.2Hz, 1H), 1.25-1.22 (m, 3H), 1.18 (d, J=6.8Hz, 5H), 1.13 (dd, J=8.4, 2.6Hz, 2H), 1.02-0.93 (m, 2H), 0.86-0.77 (m, 3H).

[0297] Example 11: 4-Cyclopropyl-N-((S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-((R,E)-4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 11

[0298] 11.1 Synthesis of ((S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-((R,E)-4-(fluoromethylene)cyclohexyl)-2-oxoethyl)tert-butyl carbamate 11-1

[0299] (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxypropionamide 7-2 (100 mg, 0.25 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((R,E)-4-(fluoromethylene)cyclohexyl)acetic acid Int-2 (109.25 mg, 0.25 mmol) were dissolved in N Add 5 mL of N,N-dimethylformamide, 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (144.58 mg, 0.38 mmol) and N,N-diisopropylethylamine (131.06 mg, 1.01 mmol), and react at room temperature for 18 hours. Stop the reaction, add 50 mL of saturated sodium bicarbonate solution, and extract with 50 mL of ethyl acetate. Filter the organic phase with 50 mL of saturated sodium chloride solution. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-((R,E)-4-(fluoromethylene)cyclohexyl)-2-oxoethyl)tert-butyl carbamate 11-1 (100 mg, 0.40 mmol), a pale yellow oil, yield: 59.43%.

[0300] LC-MS: m / z (ESI) = 664.3 [M+H] + .

[0301] 11.2(S)-N-((2R,3S)-3-(4-(((S)-2-amino-2-((R,E)-4-(fluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxypropionamide 11-2

[0302] Dissolve 11-1 (100 mg, 0.40 mmol) of ((S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-((R,E)-4-(fluoromethylene)cyclohexyl)-2-oxoethyl)tert-butyl carbamate 11-1 (100 mg, 0.40 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and... The reaction was carried out at room temperature for 2 hours, then stopped, concentrated under reduced pressure, and dried to give (S)-N-((2R,3S)-3-(4-(((S)-2-amino-2-((R,E)-4-(fluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxypropionamide 11-2 (80 mg, 0.14 mmol), a pale yellow oil, yield: 90%.

[0303] LC-MS: m / z (ESI) = 564.3 [M+H] + .

[0304] 11.3 4-Cyclopropyl-N-((S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-((R,E)-4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 11

[0305] (S)-N-((2R,3S)-3-(4-(((S)-2-amino-2-((R,E)-4-(fluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-2-methoxypropionamide 11-2 (80 mg, 0.14 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (28.44 mg, 0.18 mmol) Dissolve in N,N-dimethylformamide (5 mL), add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (80.95 mg, 0.021 mmol) and N,N-diisopropylethylamine (91.72 mg, 0.71 mmol), react at room temperature for 1 hour, stop the reaction, add saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (50 mL), and saturate sodium chloride solution (50 mL) with the organic phase. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by C18 column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to obtain 4-cyclopropyl-N-((S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-((S)-2-methoxypropamido)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-((R,E)-4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 11 (14 mg, 0.020 mmol), white solid, yield: 14.10%.

[0306] LC-MS: m / z(ESI) = 700.1 [M+H] + .

[0307] 1H NMR (400MHz, DMSO-d6) δ10.04 (s, 1H), 9.25 (d, J=7.76Hz, 1H), 8.11 (dd, J=31.2, 8.8Hz, 1H), 7.88-7.60 (m, 1H), 7.28-6.95 (m, 2H), 6.63 (d, J=87.6Hz, 1H), 4.92 (dt, J=26.4, 9.2Hz, 1H), 4.78-4.61 (m, 1H), 4.05-3.54 (m, 3H), 3.22(s, 3H), 3.17-3.05(m, 1H), 2.69(d, J=13.6Hz, 1H), 2.58-2.54(m, 2H), 2.29-2.12(m, 2H), 2.10-1.98(m, 2H ), 1.91 (s, 3H), 1.83-1.58 (m, 4H), 1.35-1.08 (m, 12H), 0.98 (dd, J=4.8, 2.6Hz, 2H), 0.81 (dd, J=6.4, 3.6Hz, 3H).

[0308] Example 12: 4-Cyclopropyl-N-((S)-1,1-Dicyclopropyl-3-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)-1,2,5-oxadiazole-3-carboxamide 12

[0309] 12.1 Synthesis of 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-1

[0310] N-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)-2-methoxyacetamide 6-3 (200 mg, 0.59 mmol) was dissolved in acetonitrile (5 mL), and 4-nitrophenyl(ethoxyamino)carbamate (173.8 mg, 0.77 mmol) and N,N-diisopropylethylamine (229.18 mg, 1.77 mmol) were added. The reaction was carried out at 90 °C for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (60 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-1 (200 mg, 0.47 mmol), a pale yellow oil, yield: 79.53%.

[0311] LC-MS: m / z(ESI) = 426.2 [M+H] + .

[0312] 12.2 Synthesis of 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-2

[0313] 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-1 (100 mg, 0.24 mmol) was dissolved in ethanol (15 mL) and tetrahydrofuran (15 mL), and 10% Pd / C (200 mg) was added. The mixture was covered with a hydrogen balloon, and the gas was purged three times. The reaction was carried out at room temperature for 4 hours. The reaction was stopped, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure and dried to give 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-2 (80 mg, 0.202 mmol), a pale yellow solid, yield: 86.06%.

[0314] LC-MS: m / z (ESI) = 396.2 [M+H] + .

[0315] 12.3 Synthesis of ((S)-1,1-dicyclopropyl-3-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)tert-butyl carbamate 12-3

[0316] 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-2 (80 mg, 0.202 mmol) and ((2S)-3,3-dicyclopropyl-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)propionic acid Int-5, (CAS: 2548967-22-0, commercially available) (81.73 mg, 0.30 mmol) 3 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (115.38 mg, 0.303 mmol) and N,N-diisopropylethylamine (104.58 mg, 0.809 mmol) were added. The mixture was reacted at room temperature for 18 hours, and the reaction was stopped. Saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was then treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((S)-1,1-dicyclopropyl-3-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)tert-butyl carbamate 12-3 (100 mg, 0.155 mmol), a pale yellow oil, yield: 76.43%.

[0317] LC-MS: m / z (ESI) = 647.3 [M+H] + .

[0318] 12.4 Synthesis of ((S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 12-4

[0319] Dissolve 12-3 (100 mg, 0.155 mmol) of ((S)-1,1-dicyclopropyl-3-((4-(((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)carbamate tert-butyl ester 12-3 in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and... The reaction was carried out at room temperature for 2 hours, then stopped, concentrated under reduced pressure, and dried to give (S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 12-4 (90 mg, 0.132 mmol), a pale yellow oil, yield: 85.19%.

[0320] LC-MS: m / z (ESI) = 547.3 [M+H] + .

[0321] 12.5 Synthesis of 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)-1,2,5-oxadiazole-3-carboxamide 12

[0322] (S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 12-4 (90 mg, 0.132 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (32.99 mg, 0.214 mmol) were dissolved in N,N dimethyl... 5 mL of methylformamide was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (81.38 mg, 0.238 mmol) and N,N-diisopropylethylamine (85.11 mg, 0.659 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and 50 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with 3 x 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to C... 18The solution was purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)-1,2,5-oxadiazole-3-carboxamide 12 (4 mg, 0.006 mmol), a white solid, yield: 3.56%.

[0323] LC-MS: m / z (ESI) = 683.3 [M+H] + .

[0324] 1 H NMR (400MHz, DMSO-d6) δ9.99 (d, J=7.2Hz, 1H), 9.19 (t, J=10.4Hz, 2H), 7.76 (dt, J=30.4, 8.4Hz, 1H), 7.28-6.94 (m, 2H), 6.68 (dd, J=24.4, 9.2Hz, 1H), 5.03 (q, J=7.2Hz, 1H), 4.79 (q, J=9.2Hz, 1H), 4.00 (d , J=12.4Hz, 1H), 3.89-3.69(m, 3H), 3.18-3.05(m, 1H), 2.35-2.20(m, 1H), 2.08(s, 1H), 1.91(s, 2H), 1.35 (t, J=11.2Hz, 1H), 1.28-1.06 (m, 10H), 1.01-0.96 (m, 2H), 0.94-0.65 (m, 8H), 0.52-0.14 (m, 8H).

[0325] Example 13: 4-Cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((S)-3,4-dimethylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 13

[0326] 13.1 Synthesis of ((2R,3S)-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)tert-butyl carbamate 13-1

[0327] (2R,3S)-3-(3-fluoro-4-nitrophenyl)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)butyric acid (1 g, 2.92 mmol) and (2S)-1,2-dimethylpiperazine 6-1 (0.43 g, 3.798 mmol) were dissolved in N,N-dimethylformamide (10 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.67 g, 4.38 mmol) and N,N-diisopropylethylamine (1.89 g, 14.61 mmol) were added, and the mixture was reacted at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to give ((2R,3S)-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)carbamate tert-butyl ester 13-1 (1.2 g, 2.74 mmol), a pale yellow oil, yield: 93.68%.

[0328] LC-MS: m / z(ESI) = 439.2 [M+H] + .

[0329] 13.2 Synthesis of (2R,3S)-2-amino-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)but-1-one 13-2

[0330] ((2R,3S)-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)carbamate tert-butyl 13-1 (1.2 g, 2.74 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 1 hour, the reaction was stopped, the solution was concentrated under reduced pressure, and dichloromethane (25 mL) was added to dissolve the carbamate. The solution was then neutralized with potassium carbonate solution (2.5 g dissolved in 25 mL of water), and then dissolved in dichloromethane (30 mL x 3) Extraction: The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2R,3S)-2-amino-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)but-1-one 13-2 (0.9 g, 2.66 mmol), a pale yellow oil, yield: 97.00%.

[0331] LC-MS: m / z(ESI) = 339.2 [M+H] + .

[0332] 13.3 Synthesis of N-((2R,3S)-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)propionamide 13-3

[0333] (2R,3S)-2-amino-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)but-1-one 13-2 (0.9 g, 2.66 mmol) was dissolved in N,N-dimethylformamide (10 mL), propionic anhydride (415.36 mg, 3.19 mmol) and N,N-diisopropylethylamine (515.66 mg, 3.99 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (60 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain N-((2R,3S)-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)propionamide 13-3 (900 mg, 2.28 mmol), a pale yellow oil, yield: 85.79%.

[0334] LC-MS: m / z (ESI) = 395.3 [M+H] + .

[0335] 13.4 Synthesis of N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((S)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)propionamide 13-4

[0336] N-((2R,3S)-1-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)propionamide 13-3 (900 mg, 2.28 mmol) was dissolved in ethanol (15 mL) and tetrahydrofuran (15 mL), and 10% Pd / C (300 mg) was added. The mixture was covered with a hydrogen balloon, and the gas was purged three times. The reaction was carried out at room temperature for 4 hours. The reaction was stopped, filtered, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure and dried to give N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((S)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)propionamide 13-4 (800 mg, 2.195 mmol), a pale yellow solid, yield: 96.2%.

[0337] LC-MS: m / z (ESI) = 365.3 [M+H] + .

[0338] 13.5 Synthesis of ((1S)-2-((4-((2S,3R)-4-((S)-3,4-dimethylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)tert-butyl carbamate 13-5

[0339] N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((S)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)propionamide (100 mg, 0.274 mmol) and (2S)-2-[4-(fluoromethylene)cyclohexyl]-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)acetic acid 13-4 (125.97 mg, 0.438 mmol) were dissolved in N,N dimethyl... 5 mL of methylformamide was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (177.12 mg, 0.466 mmol) and N,N-diisopropylethylamine (141.85 mg, 1.097 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and 50 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with 50 mL of ethyl acetate. The organic phase was then treated with 50 mL of saturated sodium chloride solution. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain tert-butyl carbamate 13-5 (100 mg, 0.158 mmol), a pale yellow oil, yield: 57.58%.

[0340] LC-MS: m / z(ESI) = 634.2 [M+H] + .

[0341] 13.6 Synthesis of N-((2R,3S)-3-(4-((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-1-((S)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)propionamide 13-6

[0342] Dissolve 13-5 (100 mg, 0.158 mmol) of tert-butyl carbamate 13-5 in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and incubate at room temperature. The reaction was stopped after 2 hours, concentrated under reduced pressure, and dried to give N-((2R,3S)-3-(4-((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-1-((S)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)propionamide 13-6 (70 mg, 0.131 mmol), a pale yellow oil, yield: 83.13%.

[0343] LC-MS: m / z (ESI) = 534.2 [M+H] + .

[0344] 13.7 Synthesis of 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((S)-3,4-dimethylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 13

[0345] N-((2R,3S)-3-(4-((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamido)-3-fluorophenyl)-1-((S)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)propionamide 13-6 (70 mg, 0.13 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (30.33 mg, 0.197 mmol) were dissolved in N,N dimethyl... 5 mL of methylformamide was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (84.97 mg, 0.122 mmol) and N,N-diisopropylethylamine (67.81 mg, 0.525 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and 50 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with 50 mL of ethyl acetate. The organic phase was then saturated with 50 mL of sodium chloride solution. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by C18 column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to obtain 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((S)-3,4-dimethylpiperazin-1-yl)-4-oxo-3-propamidobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 13 (12 mg, 0.018 mmol), a white solid, yield: 13.66%.

[0346] LC-MS: m / z (ESI) = 670.3 [M+H] + .

[0347] 1H NMR (400MHz, DMSO-d6) δ10.00 (d, J=12.4Hz, 1H), 9.19 (dd, J=29.2, 8.4Hz, 1H), 8.30 (dd, J=25.2, 8.8Hz, 1H), 7.72 (dt, J=56.0, 7.6Hz, 1H), 7.19-6.93 (m, 2H), 6.64 (d, J=87.6Hz, 1H), 4.88 (dt, J=30.8, 9.6Hz, 1H), 4.71 (dt, J=15. 2, 8.0Hz, 1H), 4.11-3.62 (m, 2H), 3.18-2.87 (m, 2H), 2.65 (dd, J=34.8, 12.8Hz, 2H), 2.45-2.33 (m, 2H), 2.28-2.23 (m, 1H), 2.20-2.01 (m, 5H), 1.99-1.60 (m, 7H), 1.28-1.08 (m, 7H), 1.03-0.94 (m, 5H), 0.86 (dd, J=21.8, 6.2Hz, 3H).

[0348] Example 14: 4-Cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 14

[0349] 14.1 Synthesis of ((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)tert-butyl carbamate 14-1

[0350] 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-2 (100 mg, 0.25 mmol) and (2S)-2-[4-(fluoromethylene)cyclohexyl]-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)acetic acid Int-2 (101.71 mg, 0.35 mmol) were dissolved in... N,N-dimethylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (163.45 mg, 0.43 mmol) and N,N-diisopropylethylamine (130.73 mg, 1.01 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate tert-butyl ester 14-1 (100 mg, 0.15 mmol), a pale yellow oil, yield: 59.49%.

[0351] LC-MS: m / z (ESI) = 665.2 [M+H] + .

[0352] 14.2 Synthesis of (2S)-2-amino-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)-2-(4-(fluoromethylene)cyclohexyl)acetamide 14-2 Synthesize (1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)amino 100 mg (0.15 mmol) of tert-butyl formate 14-1 was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was reacted at room temperature for 2 hours, the reaction was stopped, the solution was concentrated under reduced pressure, and dried to give (2S)-2-amino-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)-2-(4-(fluoromethylene)cyclohexyl)acetamide 14-2 (70 mg, 0.124 mmol), a pale yellow oil, yield: 82.41%.

[0353] LC-MS: m / z (ESI) = 565.2 [M+H] + .

[0354] 14.3 Synthesis of 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 14

[0355] ((2S)-2-amino-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)-2-(4-(fluoromethylene)cyclohexyl)acetamide 14-2 (70 mg, 0.124 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (28.66 mg, 0.186 mmol) were dissolved in N Add 5 mL of N,N-dimethylformamide, then add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (80.16 mg, 0.213 mmol) and N,N-diisopropylethylamine (64.09 mg, 0.496 mmol). React at room temperature for 1 hour, then stop the reaction. Add 50 mL of saturated sodium bicarbonate solution and extract with 50 mL of ethyl acetate. Filter the organic phase with 50 mL of saturated sodium chloride solution. x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by C18 column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to obtain 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-(R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 14 (4 mg, 0.006 mmol), white solid, yield: 4.60%.

[0356] LC-MS: m / z(ESI) = 701.3 [M+H] + .

[0357] 1 H NMR (400MHz, DMSO-d6) δ10.02 (d, J=10.0Hz, 1H), 9.20 (q, J= 10.8, 10.4Hz, 2H), 7.87-7.60(m, 1H), 7.18-6.97(m, 2H), 6.78-6.44(m, 2H ), 4.90-4.54(m, 2H), 4.05-3.51(m, 4H), 3.20-2.99(m, 1H), 2.69(d, J=14. 4Hz, 1H), 2.59-2.53(m, 2H), 2.29-2.13(m, 2H), 2.11-2.00(m, 2H), 1.94-1 .59(m, 6H), 1.27-1.08(m, 13H), 1.01-0.93(m, 2H), 0.81(d, J=6.4Hz, 3H).

[0358] Example 15: 4-Cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 15

[0359] 15.1 Synthesis of ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)tert-butyl carbamate 15-1

[0360] Dissolve 1-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-3-ethoxyurea 12-2 (100 mg, 0.25 mmol) and (2S)-2-[4-(difluoromethylene)cyclohexyl]-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)acetic acid Int-1 (115.8 mg, 0.34 mmol) in... N,N-dimethylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (163.45 mg, 0.43 mmol) and N,N-diisopropylethylamine (130.73 mg, 1.01 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain (S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)tert-butyl carbamate 15-1 (100 mg, 0.146 mmol), a pale yellow oil, yield: 57.92%.

[0361] LC-MS: m / z (ESI) = 683.3 [M+H] + .

[0362] 15.2 Synthesis of ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 15-2

[0363] Dissolve 15-1 (100 mg, 0.146 mmol) of (S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)carbamate tert-butyl ester 15-1 (100 mg, 0.146 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and incubate at room temperature. The reaction was stopped after 2 hours, concentrated under reduced pressure, and dried to give ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 15-2 (70 mg, 0.12 mmol), a pale yellow oil, yield: 82.03%.

[0364] LC-MS: m / z (ESI) = 583.3 [M+H] + .

[0365] 15.3 Synthesis of 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 15

[0366] ((S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 15-2 (70 mg, 0.12 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (27.77 mg, 0.18 mmol) were dissolved in N, N-dimethylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (77.66 mg, 0.204 mmol) and N,N-diisopropylethylamine (62.11 mg, 0.48 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to C... 18 Column chromatography (acetonitrile: 0.5% ammonia = 5-95%) was used to separate and purify the product, yielding 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobut-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 15 (4 mg, 0.006 mmol), a white solid, in a yield of 4.63%.

[0367] LC-MS: m / z(ESI) = 719.2 [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6) δ10.03 (d, J=8.0Hz, 1H), 9.54-8.86 (m, 2H), 7.75 (dt, J=53.6, 8.4Hz, 1H), 7.22-6.93 (m, 2H), 6.69 (dd, J=28.8, 9.2Hz, 1H), 4.90-4.58(m, 2H), 4.14-3.48(m, 4H), 3.21-3.05(m, 1H), 2.78(t, J=13.2Hz, 1H), 2.58-2.54(m, 2H), 2.40(d, J=13.6Hz, 2H), 2.26(s, 1H), 2.09 (s, 1H), 2.02-1.67 (m, 6H), 1.32-1.05 (m, 13H), 1.04-0.91 (m, 2H), 0.81 (d, J=5.6Hz, 3H).

[0369] Example 16: 4-Cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 16

[0370] 16.1 Synthesis of ((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)carbamate 16-1

[0371] (2R,3S)-2-amino-1-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(3-fluoro-4-nitrophenyl)but-1-one 6-3 (300 mg, 0.89 mmol) was dissolved in acetonitrile (10 mL), and phenyl chloroformate (152.68 mg, 0.98 mmol) and N,N-diisopropylethylamine (343.77 mg, 2.66 mmol) were slowly added. The reaction was carried out at room temperature for 1 hour, and the reaction was stopped. A saturated sodium chloride solution (50 mL) was added, and the mixture was extracted with dichloromethane (60 mL). The organic phase was then extracted with a saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-3%) to obtain ((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)carbamate 16-1 (300 mg, 0.65 mmol), a pale yellow oil, yield: 73.80%.

[0372] LC-MS: m / z (ESI) = 459.2 [M+H] + .

[0373] 16.2 Synthesis of 3-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-2

[0374] ((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutan-2-yl)carbamate 16-1 (300 mg, 0.65 mmol) was dissolved in acetonitrile (5 mL), and N,O-dimethylhydroxylamine hydrochloride (79.93 mg, 1.31 mmol) and N,N-diisopropylethylamine (253.71 mg, 1.96 mmol) were added. The reaction was carried out at 60 °C for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (60 mL), and the organic phase was separated with saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain 3-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-2 (200 mg, 0.47 mmol), a pale yellow oil, yield: 71.84%.

[0375] LC-MS: m / z(ESI) = 426.3 [M+H] + .

[0376] 16.3 Synthesis of 3-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-3

[0377] Dissolve 3-((2R,3S)-1-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-fluoro-4-nitrophenyl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-2 (200 mg, 0.47 mmol) in ethanol (15 mL) and tetrahydrofuran (15 mL), add 10% Pd / C (200 mg), cover with a hydrogen balloon, and replace the gas three times. The reaction was carried out at room temperature for 4 hours, then the reaction was stopped, filtered, the filter cake was washed with ethanol, and the filtrate was concentrated and dried under reduced pressure to give 3-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-3 (180 mg, 0.455 mmol), a pale yellow solid, yield: 96.82%.

[0378] LC-MS: m / z (ESI) = 396.3 [M+H] + .

[0379] 16.4 Synthesis of ((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)tert-butyl carbamate 16-4

[0380] 3-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-3 (90 mg, 0.23 mmol) and (2S)-2-[4-(fluoromethylene)cyclohexyl]-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)acetic acid (91.54 mg, 0.32 mmol) were dissolved in N, N-dimethylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (147.10 mg, 0.387 mmol) and N,N-diisopropylethylamine (117.65 mg, 0.91 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)carbamate tert-butyl ester 16-4 (100 mg, 0.15 mmol), a pale yellow oil, yield: 66.10%.

[0381] LC-MS: m / z (ESI) = 665.2 [M+H] + .

[0382] 16.5 Synthesis of ((2S)-2-amino-N-(4-(((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)-2-(4-(fluoromethylene)cyclohexyl)acetamide 16-5

[0383] Dissolve 16-4 (100 mg, 0.15 mmol) of tert-butyl carbamate in dichloromethane (5 mL), and add trifluoroacetic acid (2... The mixture was reacted at room temperature for 2 hours, then the reaction was stopped, concentrated under reduced pressure, and dried to give (S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 16-5 (80 mg, 0.14 mmol), a pale yellow oil, yield: 94.18%.

[0384] LC-MS: m / z (ESI) = 565.2 [M+H] + .

[0385] 16.6 Synthesis of 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 16

[0386] (S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-ethoxyureo)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 16-5 (80 mg, 0.14 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (32.75 mg, 0.213 mmol) were dissolved in N,N dimethyl... 5 mL of methylformamide was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (91.58 mg, 0.24 mmol) and N,N-diisopropylethylamine (73.25 mg, 0.57 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and 50 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with 3 x 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to C... 18The solution was separated and purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give 4-cyclopropyl-N-((1S)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 16 (25 mg, 0.036 mmol), a white solid, yield: 25.18%.

[0387] LC-MS: m / z(ESI) = 701.3 [M+H] + .

[0388] 1 H NMR (400MHz, DMSO-d6) δ10.03 (d, J=10.4Hz, 1H), 9.20 (dd, J=30.8, 8.4Hz, 1H), 7.76 (dt, J=55.6, 7.6Hz, 1H), 7.19-6.9 0 (m, 3H), 6.64 (d, J = 87.6Hz, 1H), 4.83-4.55 (m, 2H), 4.11-3.73 (m, 2H), 3.62 (d, J = 2.4Hz, 3H), 3.18 (dt, J = 17.6, 8.8Hz , 1H), 2.95 (d, J=2.8Hz, 3H), 2.69 (d, J=13.6Hz, 1H), 2.57-2.53 (m, 2H), 2.50-2.45 (m, 2H), 2.29-2.23 (m, 1H), 2.21-2. 12 (m, 1H), 2.11-2.00 (m, 2H), 1.97-1.58 (m, 5H), 1.31-1.04 (m, 9H), 0.98 (dd, J=4.8, 2.5Hz, 2H), 0.81 (d, J=6.4Hz, 3H).

[0389] Example 17: 4-Cyclopropyl-N-((S)-1,1-Dicyclopropyl-3-((4-(2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)-1,2,5-oxadiazole-3-carboxamide 17

[0390] 17.1 Synthesis of ((S)-1,1-dicyclopropyl-3-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)tert-butyl carbamate 17-1

[0391] 3-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-3 (130 mg, 0.33 mmol) and (2S)-3,3-dicyclopropyl-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)propionic acid (150.51 mg, 0.56 mmol) were dissolved in N,N dimethylurea 16-3 (130 mg, 0.33 mmol). Methylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (249.98 mg, 0.39 mmol) and N,N-diisopropylethylamine (169.95 mg, 1.32 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((S)-1,1-dicyclopropyl-3-((4-(((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)carbamate tert-butyl ester 17-1 (100 mg, 0.155 mmol), a pale yellow oil, yield: 47.03%.

[0392] LC-MS: m / z (ESI) = 647.2 [M+H] + .

[0393] 17.2 Synthesis of (S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 17-2

[0394] Dissolve 100 mg (0.16 mmol) of tert-butyl carbamate 17-1 in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and... The reaction was carried out at room temperature for 2 hours, then stopped, concentrated under reduced pressure, and dried to give (S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 17-2 (80 mg, 0.15 mmol), a pale yellow oil, yield: 94.65%.

[0395] LC-MS: m / z (ESI) = 547.2 [M+H] + .

[0396] 17.3 Synthesis of 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)-1,2,5-oxadiazole-3-carboxamide 17

[0397] (S)-2-amino-3,3-dicyclopropyl-N-(4-((2S,3R)-4-((R)3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)acrylamide 17-2 (80 mg, 0.15 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (29.32 mg, 0.19 mmol) were dissolved in N,N Dimethylformamide (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (83.46 mg, 0.22 mmol) and N,N-diisopropylethylamine (75.66 mg, 0.59 mmol). The reaction was carried out at room temperature for 1 hour. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to C... 18The solution was separated and purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-3-oxopropane-2-yl)-1,2,5-oxadiazole-3-carboxamide 17 (20 mg, 0.029 mmol), a white solid, yield: 20.02%.

[0398] LC-MS: m / z (ESI) = 683.3 [M+H] + .

[0399] 1 H NMR (400MHz, DMSO-d6) δ9.98 (d, J=7.6Hz, 1H), 9.15 (dd, J=9.2, 5.6Hz, 1H), 7.77 (dt, J=31.2, 8.4Hz, 1H), 7.25-6.80 (m, 3H), 5.04 (q, J =7.6Hz, 1H), 4.74(q, J=9.2, 8.8Hz, 1H), 4.09-3.49(m, 5H), 3.26-3.09( m, 1H), 2.95 (s, 3H), 2.75-2.58 (m, 3H), 2.47-2.44 (m, 1H), 2.34-2.20 (m , 1H), 2.08 (s, 1H), 1.94-1.88 (m, 2H), 1.38-1.19 (m, 4H), 1.14 (dt, J=8. 4, 3.0Hz, 2H), 1.04-0.95 (m, 2H), 0.95-0.65 (m, 6H), 0.52-0.15 (m, 8H).

[0400] Example 18: 4-Cyclopropyl-N-(S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-2-oxoethyl-1,2,5-oxadiazole-3-carboxamide 18

[0401] 18.1 Synthesis of tert-butyl((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-(((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)carbamate 18-1

[0402] 3-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-((R)-3,4-dimethylpiperazin-1-yl)-1-oxobutane-2-yl)-1-methoxy-1-methylurea 16-3 (90 mg, 0.23 mmol) and (2S)-2-[4-(difluoromethylene)cyclohexyl]-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)acetic acid (104.22 mg, 0.34 mmol) were dissolved in N,N Dimethylformamide Int-1 (5 mL) was added to 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (147.10 mg, 0.39 mmol) and N,N-diisopropylethylamine (117.43 mg, 0.91 mmol). The reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic phase was treated with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)tert-butyl carbamate 18-1 (100 mg, 0.146 mmol), a pale yellow oil, yield: 64.36%.

[0403] LC-MS: m / z(ESI) = 683.2 [M+H] + .

[0404] 18.2 Synthesis of (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 18-2

[0405] Dissolve 18-1 (100 mg, 0.146 mmol) of ((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)carbamate tert-butyl ester 18-1 (5 mL) in dichloromethane, add trifluoroacetic acid (2 mL), and incubate at room temperature. The reaction was carried out at room temperature for 2 hours, then stopped. The mixture was concentrated under reduced pressure and dried to give (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 18-2 (80 mg, 0.124 mmol), a pale yellow oil, yield: 84.37%.

[0406] LC-MS: m / z (ESI) = 583.3 [M+H] + .

[0407] 18.3 Synthesis of 4-cyclopropyl-N-(S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 18

[0408] Dissolve (S)-2-amino-2-(4-(difluoromethylene)cyclohexyl)-N-(4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobutane-2-yl)-2-fluorophenyl)acetamide 18-2 (80 mg, 0.124 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (31.74 mg, 0.21 mmol) in water. Add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (88.75 mg, 0.233 mmol) and N,N-diisopropylethylamine (70.98 mg, 0.55 mmol) to N,N-dimethylformamide (5 mL). React at room temperature for 1 hour, then stop the reaction. Add saturated sodium bicarbonate solution (50 mL) and extract with ethyl acetate (50 mL). Filter the organic phase with saturated sodium chloride solution (50 mL). x 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by C18 column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to obtain 4-cyclopropyl-N-((S)-1-(4-(difluoromethylene)cyclohexyl)-2-((4-((2S,3R)-4-((R)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxy-3-methylurea)-4-oxobut-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 18 (37 mg, 0.051 mmol), white solid, yield: 37.49%.

[0409] LC-MS: m / z(ESI) = 719.2 [M+H] + .

[0410] 1 H NMR (400MHz, DMSO-d6) δ10.02 (d, J=8.4Hz, 1H), 9.22 (dd, J=8.4, 2.8Hz, 1H), 7.76 (dt, J=55.6, 8.4Hz, 1H) , 7.24-6.95(m, 3H), 4.88-4.44(m, 2H), 4.12-3.53(m, 5H), 3.22-3.06(m, 1H), 2.95(s, 3H), 2.62-2.49(m, 2H), 2.44-2.35(m, 3H), 2.31-2.17(m, 1H), 2.09(s, 1H), 2.006-1.757(m, 7 H), 1.34-1.09 (m, 9H), 0.99 (dt, J=4.8, 3.2Hz, 2H), 0.81 (d, J=6.4Hz, 3H).

[0411] Example 19: 4-Cyclopropyl-N-((1S)-2-((2-fluoro-4-(2S,3R)-3-((S)-2-methoxypropamido)-4-oxo-4-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 19

[0412] 19.1 Synthesis of ((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)tert-butyl carbamate 19-1

[0413] (2R,3S)-3-(3-fluoro-4-nitrophenyl)-2-({[(2-methylpropyl-2-yl)oxy]carbonyl}amino)butyric acid 6-1 (300 mg, 0.876 mmol) and ((2R,5R)-1,2,5-trimethylpiperazine (210 mg, 1.05 mmol)) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (499.16 mg, 1.314 mmol) and N,N-diisopropylethylamine (566.12 mg, 4.38 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was stopped, and saturated sodium bicarbonate solution (10 mL) was added. The mixture was extracted with dichloromethane (10 mL). The organic phase was then treated with saturated sodium chloride solution (100 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain ((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)carbamate tert-butyl ester 19-1 (300 mg, 0.66 mmol), a pale yellow oil, yield: 75.00%.

[0414] LC-MS: m / z(ESI) = 453.2 [M+H] + .

[0415] 19.2 Synthesis of (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-((2R,SR)-2,4,5-trimethylpiperazin-1-yl)but-1-one 19-2

[0416] Dissolve 19-1 (300 mg, 0.66 mmol) of ((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)carbamate 19-1 in dichloromethane (10 mL), add trifluoroacetic acid (5 mL), react at room temperature for 1 hour, stop the reaction, concentrate under reduced pressure, add dichloromethane (25 mL) to dissolve it, then neutralize with potassium carbonate solution (2.5 g dissolved in 25 mL water), and then use dichloromethane (30 mL x 3) Extraction: The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-1-one 19-2 (200 mg, 0.568 mmol), a pale yellow oil, yield: 85.61%.

[0417] LC-MS: m / z (ESI) = 353.2 [M+H] + .

[0418] 19.3 Synthesis of (S)-N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-3

[0419] (2R,3S)-2-amino-3-(3-fluoro-4-nitrophenyl)-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-1-one 19-2 (200 mg, 0.568 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of (2S)-2-methoxypropionic acid (76.81 mg, 0.738 mmol) and N,N-diisopropylethylamine (293.41 mg, 2.270 mmol). The reaction was carried out at room temperature for 1 hour, and the reaction was stopped. A saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with dichloromethane (60 mL). The organic phase was then treated with a saturated sodium chloride solution (50 mL x 10 mL). 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain (S)-N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-3 (230 mg, 1.462 mmol), a pale yellow oil, yield: 94.24%.

[0420] LC-MS: m / z (ESI) = 439.3 [M+H] + .

[0421] 19.4 Synthesis of (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-4

[0422] Dissolve (S)-N-((2R,3S)-3-(3-fluoro-4-nitrophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-3 (230 mg, 1.462 mmol) in ethanol (15 mL) and tetrahydrofuran (15 mL), add 10% Pd / C (200 mg), cover with a hydrogen balloon, and replace the gas three times. The reaction was carried out at room temperature for 4 hours, then stopped. The mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated and dried under reduced pressure to give (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-4 (200 mg, 0.490 mmol), a pale yellow solid, yield: 93.34%.

[0423] LC-MS: m / z(ESI) = 409.1 [M+H] + .

[0424] 19.5 Synthesis of (((1S)-2-((2-fluoro-4-((2S,3R)-3-((S)-2-methoxypropamido)-4-oxo-4-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)tert-butyl carbamate 19-5

[0425] (S)-N-((2R,3S)-3-(4-amino-3-fluorophenyl)-1-oxo-1-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-4 (200 mg, 0.490 mmol) and (2S)-2-[4-(fluoromethylene)cyclohexyl]-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)acetic acid (309.47 mg, 1.077 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (428.06 mg, 1.126 mmol) and N,N-diisopropylethylamine (316.39 mg, 2.448 mmol) were added. The mixture was then heated in a sterile environment. The reaction was carried out at room temperature for 18 hours, then stopped. A saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with a saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain tert-butyl carbamate 19-5 (120 mg, 0.295 mmol), a pale yellow oil, with a yield of 36.16%.

[0426] LC-MS: m / z (ESI) = 678.2 [M+H] + .

[0427] 19.6 Synthesis of (2S)-(N-((2R,3S)-3-(4-(((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-oxo-1-(((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-6

[0428] Dissolve 120 mg (0.295 mmol) of tert-butyl carbamate 19-5 in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and incubate at room temperature. The reaction was stopped after 2 hours, concentrated under reduced pressure, and dried to give (2S)-N-((2R,3S)-3-(4-((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-oxo-1-(((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-6 (100 mg, 0.173 mmol), a pale yellow oil, yield: 97.77%.

[0429] LC-MS: m / z (ESI) = 578.3 [M+H] + .

[0430] 19.7 Synthesis of 4-cyclopropyl-N-(1S)-2-((2-fluoro-4-((2S,3R)-3-((S)-2-methoxypropamido)-4-oxo-4-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide 19

[0431] (2S)-N-((2R,3S)-3-(4-(((2S)-2-amino-2-(4-(fluoromethylene)cyclohexyl)acetamide)-3-fluorophenyl)-1-oxo-1-(((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)-2-methoxypropionamide 19-6 (100 mg, 0.173 mmol) and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (40.02 mg, 0.260 mmol) were dissolved in N,N-dimethylformamide ( Add 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (98.73 mg, 0.260 mmol) and N,N-diisopropylethylamine (111.86 mg, 0.865 mmol) to 5 mL of water. React at room temperature for 1 hour. Stop the reaction, add saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (50 mL), wash the organic phase with saturated sodium chloride solution (50 mL x 3), dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use C20 as the crude product. 18The solution was purified by column chromatography (acetonitrile: 0.5% ammonia = 5-95%) to give 4-cyclopropyl-N-((1S)-2-((2-fluoro-4-((2S,3R)-3-((S)-2-methoxypropamido)-4-oxo-4-((2R,5R)-2,4,5-trimethylpiperazin-1-yl)but-2-yl)phenyl)amino)-1-(4-(fluoromethylene)cyclohexyl)-2-oxoethyl)-1,2,5-oxadiazol-3-carboxamide 19 (50 mg, 0.070 mmol), a white solid, yield: 40.47%.

[0432] LC-MS: m / z (ESI) = 714.3 [M+H] + .

[0433] 1 H NMR (400MHz, DMSO-d6) δ10.00 (d, J=12.0Hz, 1H), 9.23 (d, J=8.0Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.84-7.74 (m, 1H), 7.23-6.9 5 (m, 2H), 6.64 (d, J=87.6Hz, 1H), 5.00-4.61 (m, 2H), 4.41-4.22 (m, 1H), 3.87-3.73 (m, 1H), 3.52-3.47 (m, 1H), 3.15 (s, 3H), 3 .15-3.05(m,1H),2.82-2.61(m,2H),2.41-2.32(m,1H),2.31-2.21(m,1H),2.20-2.12(m,1H),2.10-1.97(m,2H),1.95-1.85 (m, 3H), 1.84-1.62 (m, 3H), 1.61-1.43 (m, 1H), 1.28-1.10 (m, 10H), 1.04-0.89 (m, 6H), 0.88-0.82 (m, 2H), 0.80-0.70 (m, 1H).

[0434] Biological testing:

[0435] The experiment to detect the inhibition of IL-17A and IL-17RA binding by the compound was performed using the principle of enzyme-linked immunosorbent assay.

[0436] On day 1, 100 μL of IL-17A (Essential Biotech, Cat.12047-H07B) solution diluted with 1X PBS at a concentration of 30 nM (516 ng / mL) was added to each well of the microplate (Corning, Cat.3590). The plate was sealed with sealing film and incubated overnight at 2℃~8℃.

[0437] On the second day, add 1X PBST, 300 μL / well, wash the plate 3 times, then add 5% BSA-PBST, 300 μL / well, and block at room temperature for 3 h.

[0438] Wash the plate three times and prepare 1% BSA-PBST as a diluent for all reagents or samples below. Add serially diluted analyte compounds, 50 μL / well, with an initial concentration of 80000 nM, for a total of 11 concentration points (4-fold dilution). Simultaneously, add 4 nM (250 ng / mL) IL-17RA (biotin-labeled, Sinocare, Cat. 10895-H08H-B) 50 μL / well to both the compound-containing wells and the control wells. The maximum final concentration of the compound is 40000 nM, and the final concentration of IL-17RA is 2 nM (125 ng / mL). Incubate at room temperature for 18 h.

[0439] On the third day, wash the plate three times. Use streptavidin-HRP (Solepro, Cat.SE068): dilute at 1:5000 (0.2 μg / mL), 100 μL / well, and incubate at room temperature for 60 min.

[0440] Wash the plate three times, add 100 μL of freshly prepared TMB (BD, Cat. 555214) substrate per well, and incubate in the dark for 15-30 minutes. Add 100 μL of stop solution per well to stop the color development.

[0441] The absorbance values ​​at 450 nm and 630 nm were read using a multi-sensor microplate reader. The difference in absorbance between 450 nm and 630 nm was plotted on the ordinate, and the compound concentration on the x-axis. Data analysis was performed using GraphPad Prism 9.2 to obtain the inhibition curve and IC50. 50 value.

[0442] In vitro activity assay steps based on HT-29 cells

[0443] The inhibitory effect of the test compound on hIL-17A-induced CXCL1 secretion in HT-29 cells was detected using an ELISA kit. HT-29 cells were inoculated at a concentration of 1×10⁶ cells / cells. 4100 μl of each cell was seeded per well in a 96-well plate (Corning, Cat#3599) using complete culture medium (McCoy's 5A (Modified) + 10% FBS). The 10 mM inhibitor stock solution was diluted to 80000 nM and 8000 nM with complete culture medium, and then serially diluted 4-fold from 8000 nM to 11–16 wells to obtain the 4× inhibitor working solution. 50 μl of the 4× inhibitor working solution was added to each well of the 96-well plate. 100 μg / ml IL-17A (R&D, Cat#7955-IL) stock solution was diluted to 400 ng / ml with complete culture medium to obtain the 4× IL-17A working solution. 50 μl of the 4× IL-17A working solution was added to each well of the 96-well plate. The 96-well plate was incubated at 37°C in a 5% CO2 cell culture incubator. After 66–68 hours, remove the 96-well plate and centrifuge at 1000 rpm at 25°C for 5 minutes. Transfer 170 μl of supernatant from each well to a transfer plate, mix well, and then transfer 100 μl of supernatant from each well. CXCL1 levels are measured using the Human CXCL1 / GRO kit (R&D, Cat#DY275) and the DuoSet ELISA Ancillary Reagent Kit 2 (R&D, Cat#DY008). Absorbance values ​​at 450 nm and 540 nm are measured using a microplate reader. IC50 is calculated using a four-parameter fitting curve fitted with GraphPad Prism 9.0 software. 50 value.

[0444] Table 1 below shows the activity test results of the compounds in the examples:

[0445] Table 1

[0446] The structures of compound 436 of WO2021055376A1, compound 435 of WO2021055376A1, and compound 207 of WO2023164057 are as follows:

[0447] All documents mentioned in this disclosure are incorporated herein by reference as if each document were individually incorporated herein by reference. Furthermore, it should be understood that after reading the foregoing teachings of this disclosure, those skilled in the art can make various alterations or modifications to this disclosure, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I) its cis and trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its metabolites, its co-crystals, its pharmaceutically acceptable salts or its prodrugs, Cy1is a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O or S, which is optionally substituted with 1-3 groups selected from D, halogen, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 alkoxy, halogenated C 1- alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; said C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl are optionally further substituted with one or more substituents selected from D, halogen, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 ycloalkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; Cy2 is a 4-8 membered saturated heterocycle containing 1-3 heteroatoms selected from N, O, or S, wherein the 4-8 membered saturated heterocycle is optionally surrounded by one or more heteroatoms selected from D, halogens, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The C is replaced by a substituent of the alkoxy group. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl or halogenated C 1-6 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -OH, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2- The substituents of the 6-acetylenic group are replaced; X is selected from CH, CF or N; n is selected from 0, 1, 2, 3 or 4; R1, R2are each independently selected from C 3-6 cycloalkyl, said C 3-6 cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of D, halogen, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; or R1, R2together with the carbon atom to which they are attached form wherein R a and R b are each independently selected from H, D, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl, and C 3-6 cycloalkyl, or R a and R b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; R3is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycle, C 1-6 alkoxy, -N(R6)(OR7), -N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)OR7, -N(R6)C(O)N(R8)(R9), and -N(R6)S(=O)2N(R8)(R9), said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycle, C 1-6 alkoxy or 4-6 membered heterocycle optionally further substituted with one or more substituents selected from D, halogen, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1- 6alkyl)2, C 3-6 cycloalkyl, 4-6 membered heterocycle, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl; R6is selected from H, D, C 1-6 alkyl, C 3-6 cycloalkyl, and 4-6 membered heterocycle; said C 1-6 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocycle is optionally further substituted with one or more substituents selected from D, halogen, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl; R7is selected from C 1-6 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycle; said C 1-6 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycle are optionally further substituted with one or more substituents selected from D, halogen, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; R8is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted by one or more substituents selected from the group consisting of D, halogen, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; R9is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted by one or more substituents selected from the group consisting of D, halogen, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl.

2. The compound of claim 1, including its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its cocrystal, its pharmaceutically acceptable salt, or its prodrug, wherein Cy1 is a pyrazolyl or oxadiazolyl group, wherein the pyrazolyl or oxadiazolyl group is optionally composed of 1-3 groups selected from D, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The C group is replaced by an alkynyl group. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2- 6-olefin and C 2-6 The alkynyl group may optionally be further selected by one or more elements chosen from D, halogen, -CN, -NH2, -NH(C) 1- 4-alkyl), -N(C) 1-4 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is replaced by a substituent.

3. The compound of claim 1, comprising its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its eutectic, its pharmaceutically acceptable salt, or its prodrug, wherein Cy1 is selected from the following structures:

4. The compound of claim 1, including its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its cocrystal, its pharmaceutically acceptable salt, or its prodrug, wherein Cy2 is piperidinyl or piperazineyl, said piperidinyl or piperazineyl is optionally selected from one or more elements chosen from D, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The C is replaced by a substituent of the alkoxy group. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl and Halogenated C 1-6 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -OH, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl and C 2-6 The alkynyl group is replaced by a substituent.

5. The compound of claim 1, comprising its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its eutectic, its pharmaceutically acceptable salt, or its prodrug, wherein Cy2 is selected from the following structures:

6. The compound of claim 1, comprising its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its cocrystal, its pharmaceutically acceptable salt, or its prodrug, wherein R1 and R2 are each independently selected from cyclopropyl, said cyclopropyl group being unsubstituted or substituted by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1- 4-alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkoxy, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group are replaced; or R1, R2together with the carbon atom to which they are attached form wherein R a and R b are each independently selected from H, D, F, CI, CH3, CD3, or cyclopropyl, or R a and R b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl.

7. The compound of claim 1, including its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, its metabolite, its cocrystal, its pharmaceutically acceptable salt, or its prodrug, wherein R3 is selected from C 1-3 Alkyl, C 1-3 Alkoxy groups and -N(R6)(R7) or -N(R6)(OR7), the C 1-3 Alkyl and C 1-3 The alkoxy group may optionally be further divided by one or more elements selected from D, halogen, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-6 cycloalkyl, C 1-3 Alkyl and C 1-3 The alkoxy group is replaced by a substituent.

8. The compound as claimed in claim 1, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, its solvate, its hydrate, its metabolite, its co-crystal, its pharmaceutically acceptable salt or its prodrug, wherein R6 is selected from H, D, C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycle; said C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycle are optionally further substituted by one or more substituents selected from D, halogen, -CN, -NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 3-6 cycloalkyl, C 1- 4 alkyl and C 1-4 alkoxy.

9. The compound as claimed in claim 1, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, its solvate, its hydrate, its metabolite, its co-crystal, its pharmaceutically acceptable salt or its prodrug, wherein R7 is selected from C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycle; said C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycle are optionally further substituted by one or more substituents selected from D, halogen, -CN, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 3-6 cycloalkyl, C 1-4 alkyl and C 1-4 alkoxy.

10. The compound as claimed in claim 1, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, its solvate, its hydrate, its metabolite, its co-crystal, its pharmaceutically acceptable salt or its prodrug, wherein R8 is selected from C 1-3 alkyl and C 3-6 cycloalkyl; said C 1-3 alkyl and C 3-6 cycloalkyl are optionally further substituted by one or more substituents selected from D, halogen, -CN, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 3-6 cycloalkyl, C 1-3 alkyl and C 1-3 alkoxy; and / or R9is selected from H, C 1-3 alkyl and C 3-6 cycloalkyl; said C 1-3 alkyl and C 3-6 cycloalkyl are optionally further substituted by one or more substituents selected from D, halogen, -CN, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 3-6 cycloalkyl, C 1-3 alkyl and C 1-3 alkoxy.

11. The compound as claimed in claim 1, a cis-trans isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a metabolite thereof, a co-crystal thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein the compound is selected from the following compounds or a pharmaceutically acceptable salt thereof:

12. A pharmaceutical composition comprising a compound of any one of claims 1-11, and a pharmaceutically or immunologically acceptable carrier or excipient.

13. Use of a compound of any one of claims 1-11 for the manufacture of a medicament for the prevention and / or treatment of an autoimmune or inflammatory disease.

14. The use of claim 13, wherein the autoimmune or inflammatory disease is selected from psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma and COPD.

15. A method of preventing and / or treating an autoimmune or inflammatory disease, the method comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a compound of any one of claims 1-11 or a pharmaceutical composition of claim 12.

16. The method of claim 15, wherein the autoimmune or inflammatory disease is selected from psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma and COPD.

17. A compound of any one of claims 1-11 or a pharmaceutical composition of claim 12 for use in the prevention and / or treatment of an autoimmune or inflammatory disease.

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