Macrocycles for the treatment of cancer

Abstract

The present application relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 to R 5 As described herein, as well as compositions containing the compounds and methods of using the compounds.(I).

Description

[0001] This invention relates to organic compounds that can be used for treatment and / or prevention in mammals, and particularly to inhibitory effects on KRAS mutants that can be used to treat cancer. Technical Field

[0002] RAS is one of the most well-known proto-oncogenes. Approximately 30% of human cancers contain mutations in the three most prominent members (KRAS, HRAS, and NRAS), making them the most common drivers of cancer development. KRAS mutations are frequently associated with poor prognosis, particularly in colorectal, pancreatic, and lung cancers. As the most frequently mutated RAS subtype, KRAS has been extensively studied in recent years. Among the most common KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc.), G12C, G12D, and G12V account for more than half of all K-RAS-driven cancers, including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (LUAD). It is noteworthy that KRAS wild-type amplification was also found in approximately 7% of all cancers with KRAS alterations (ovarian, esophageal and gastric, and uterine), ranking among the top alterations.

[0003] All KRAS proteins belong to the family of small GTPases that hydrolyze GTP to GDP. Structurally, KRAS is divided into effector-binding lobes, followed by allosteric lobes and a C-terminal region responsible for membrane anchoring. The effector lobes include the P-loop, switch I, and switch II regions. The switch I / II loops play a crucial role in downstream KRAS signaling by mediating protein-protein interactions with effector proteins, including RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) pathway.

[0004] KRAS proteins switch between inactive and active forms via binding to GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), such as SOS1 (Seven Sons homolog 1) or GTPase activators (GAPs) involved in catalyzing the exchange of GDP for GTP, thereby enhancing intrinsic GTPase activity or accelerating RAS-mediated GTP hydrolysis. In response to extracellular stimuli, inactive RAS-GDP is converted to active RAS-GTP, which directly binds to the RAS-binding domain (RAF).RBD The binding of RAFs recruits the RAF kinase family from the cytoplasm to the cell membrane, where they dimerize and become active. Activated RAFs then undergo a series of phosphorylation reactions with downstream mitogen-activated protein kinases (MEKs) and extracellular signal-regulated kinases (ERKs), propagating growth signals. Among the RAF protein kinase family (three known isoforms: ARAF, BRAF, and CRAF / RAF1), BRAF is the most frequently mutated and remains the most potent activator of MEKs. Although individual RAS and RAF family members exhibit different binding preferences, all RAFs possess a conserved RBD for forward transmission of MAPK signaling, frequently used to characterize KRAS inhibition (e.g., KRAS-BRAF in this paper). RBD For KRAS, mutations at positions 12, 13, 61, and 146 lead to a shift to the active KRAS form by weakening nucleotide hydrolysis or activating nucleotide exchange, thereby resulting in overactivation of the tumorigenetic MAPK pathway.

[0005] Despite its widely recognized importance in cancerous malignancies, persistent efforts have failed to develop approved therapies for KRAS-mutant cancers until recently, when the first selective drug, AMG510, was rapidly approved as second-line treatment for KRAS G12C-driven non-small cell lung cancer (NSCLC). However, approximately six months after treatment, clinically acquired resistance to KRAS G12C inhibitors emerges dramatically as the disease progresses. All mutations converge to reactivate RAS-MAPK signaling, with secondary RAS mutations already observed at oncogenic hotspots (e.g., G12 / G13 / Q61) and within switch II pockets (e.g., H95, R68, and Y96); furthermore, novel agents remain lacking in over 85% of all KRAS-mutant or wild-type amplification-driven cancers. In conclusion, both the numerous escape mechanisms and the diverse oncogenic alleles underscore the urgent medical need for additional KRAS therapies. Therefore, we have invented oral compounds that target and inhibit the KRAS allele for the treatment of KRAS mutation-driven cancers. Summary of the Invention

[0006] This invention relates to novel compounds having formula (I), (I), in R 1 for ;where R 6 C1-6 Alkyl; W is C 3-7 cycloalkyl (C 1-6 Alkyl) azircyclopropane or C 3-7 Cycloalkylazirocyclopropane; R 2 C 3-7 cycloalkyl; R 3 It is a halogen; R 4 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 Morpholine-, (halogenated C) 1-6 alkyl)piperazinyl, C 3-7 Cycloalkylpiperazine or C 1-6 alkylpiperazine group; Or its pharmaceutically acceptable salt.

[0007] The present invention also relates to their manufacture, pharmaceuticals based on compounds according to the invention and their production, and the use of compounds of formula (I) or (Ia) as KRAS inhibitors.

[0008] Compounds of formula (I) or (Ia) exhibit good KRAS inhibition against G12D and G13D. In one embodiment, the compounds of the present invention have favorable pharmacokinetic properties compared to the reference compounds. In another embodiment, the compounds of the present invention exhibit excellent cancer cell inhibition and human hepatocyte stability. Furthermore, compounds of formula (I) or (Ia) also exhibit good or improved cytotoxicity and solubility characteristics. Attached Figure Description

[0009] Figure 1. X-ray crystallography analysis of compound G5. Detailed Implementation

[0010] definition Term "C" 1-6 "Alkyl" indicates a saturated, straight-chain or branched alkyl group containing 1 to 6, particularly 1 to 4, carbon atoms, such as methyl, ethyl, etc. positive propyl, isopropyl, positive Butyl, isobutyl, tertiary Butyl, etc. Specifically, "C" 1-6 The alkyl group is methyl, ethyl and positive Propyl.

[0011] The terms “halogen” and “halogenated” are used interchangeably in this document to refer to fluorine, chlorine, bromine, or iodine.

[0012] The term "halogenated C" 1-6 "alkyl" indicates C 1-6 alkyl group, wherein the C 1-6 At least one hydrogen atom in the alkyl group has been replaced by the same or a different halogen atom. Halogenated C 1-6 Examples of alkyl groups include fluorine, difluoro- or chloro(fluoro)-methyl, -ethyl or -propyl, such as fluoromethyl, difluoropropyl, difluoromethyl, difluoroethyl, chloro(fluoro)methyl, trifluoroethyl or trifluoromethyl.

[0013] Term "C" 3-7 "Cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group with 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more common carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclic [1.1.0]butyl, bicyclic [2.2.1]heptyl, bicyclic [1.1.1]pentyl, or bicyclic [2.2.2]octyl.

[0014] The term "protecting group" refers to a group that selectively blocks a reaction site in a multifunctional compound so that a chemical reaction can selectively occur at another unprotected reaction site that is typically associated with it in synthetic chemistry. Protecting groups can be removed at appropriate points in time. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxyl protecting groups.

[0015] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0016] The term "pharmaceutically acceptable acid addition salt" refers to those pharmaceutically acceptable salts formed from: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid; and organic acids selected from aliphatic, cycloaliphatic, aromatic, aryliphatic, heterocyclic, carboxylic acid, and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, dihydroxynaphthyl acid, phenylacetic acid, methanesulfonic acid, and ethanesulfonic acid. para Toluenesulfonic acid and salicylic acid.

[0017] The term "pharmaceutically acceptable base addition salt" refers to those pharmaceutically acceptable salts formed from organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, etc.). N Salts of ethylpiperidine and polyamine resins.

[0018] The term "pharmaceutical active metabolite" refers to a pharmacologically active product produced through the metabolism of a specific compound or its salt in the body. Once in the human body, most drugs are substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations, which typically affect the polarity of the compounds of this invention, alter the way drugs are distributed and excreted from the body. However, in some cases, drug metabolism is essential for therapeutic efficacy.

[0019] The term "therapeutic effective amount" refers to the amount of a compound or molecule of the present invention, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. Therapeutic effective amount depends on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0020] The term "pharmaceutical composition" refers to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient for administration together to a mammal (e.g., a human) in need of such treatment.

[0021] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable carrier,” and “therapeutic inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceutical products.

[0022] KRAS inhibitors This invention relates to (i) a compound of formula (I), (I), in R 1 for ;where R 6 C 1-6 Alkyl; W is C 3-7 cycloalkyl (C 1-6 Alkyl) azircyclopropane or C 3-7 Cycloalkylazirocyclopropane; R 2 C 3-7 cycloalkyl; R 3 It is a halogen; R 4 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 Morpholine-, (halogenated C) 1-6 alkyl)piperazinyl, C 3-7 Cycloalkylpiperazine or C 1-6 alkylpiperazine group; Or its pharmaceutically acceptable salt.

[0023] Another embodiment of the invention is (ii) a compound having formula (Ia), (Ia), in R 1 for ;where R 6 C 1-6 Alkyl; W is C 3-7 cycloalkyl (C 1-6 Alkyl) azircyclopropane or C 3-7 Cycloalkylazirocyclopropane; R 2 C 3-7 cycloalkyl; R 3 It is a halogen; R 4 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 Morpholine-, (halogenated C) 1-6 alkyl)piperazinyl, C 3-7 Cycloalkylpiperazine or C 1-6 alkylpiperazine group; Or its pharmaceutically acceptable salt.

[0024] A further embodiment of the invention is (iii) a compound of formula (I) or (Ia) according to (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein W is C 3-7 cycloalkyl (C 1-6 Alkyl) Azacyclopropane.

[0025] A further embodiment of the invention is (iv) a compound of formula (I) or (Ia) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein W is 3-cyclopropyl-1-methyl-azacyclopropane-2-yl.

[0026] A further embodiment of the invention is (v) a compound of formula (I) or (Ia) according to any one of (i) to (iv), wherein R 6 It is a methyl group.

[0027] A further embodiment of the invention is (vi) a compound of formula (I) or (Ia) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 2 It is cyclopentyl.

[0028] A further embodiment of the invention is (vii) a compound of formula (I) or (Ia) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein R 3 It is fluorine.

[0029] A further embodiment of the invention is (viii) a compound of formula (I) or (Ia) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R 4 It is ethyl or 2,2,2-trifluoroethyl.

[0030] A further embodiment of the invention is (ix) a compound of formula (I) or (Ia) according to any one of (i) to (xviii), or a pharmaceutically acceptable salt thereof, wherein R 5 Morpholine or C 1-6 Alkylpiperazine group.

[0031] A further embodiment of the invention is (x) a compound of formula (I) or (Ia) according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein R 5 It is morpholino or 4-methylpiperazin-1-yl.

[0032] A further embodiment of the present invention is (xi) a compound of formula (I) or (Ia) according to any one of (i) to (x), wherein R 1 for ;where R 6 C 1-6 Alkyl; W is C 3-7 cycloalkyl (C 1-6 Alkyl) aziridine propane; R 2 C 3-7 cycloalkyl; R 3 It is a halogen; R 4 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 Morpholine or C 1-6 alkylpiperazine group; Or its pharmaceutically acceptable salt.

[0033] A further embodiment of the present invention is (xii) a compound of formula (I) or (Ia) according to any one of (i) to (xi), wherein R 1 for ;where R 6 Methyl; W is 3-cyclopropyl-1-methyl-azacyclopropane-2-yl; R 2 It is cyclopentyl; R 3 It is fluorine; R 4 It is ethyl or 2,2,2-trifluoroethyl; R 5 It is morpholino or 4-methylpiperazin-1-yl; Or its pharmaceutically acceptable salt.

[0034] Another embodiment of the invention is (xiii) a compound of formula (I) or (Ia) selected from the following: N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S[17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-Dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [28-octadec-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]- N 1-Methyl-piperazine-1-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropylazacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S[17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclobutyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; and N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; Or its pharmaceutically acceptable salt.

[0035] Another embodiment of the invention relates to (xiv), a method for preparing a compound according to any one of (i) to (xiii), the method comprising the following steps: a) Make the compound of formula (II) (II) with acids (III), (III) undergo a coupling reaction in the presence of a coupling agent and a base to form a compound of formula (I); b) Make the compound of formula (IX) (IX) and acid (X), (X) undergo a coupling reaction in the presence of a coupling agent and a base to form a compound of formula (XI). (XI); In steps a) and b), the coupling agent is T3P, HATU, PyBOP, or EDCI / HOBt; the base is TEA, DIEPA, or DMAP; R 1 To R 5 W is defined by any one of (i) to (xii).

[0036] Another embodiment of the invention is (xv) a compound or pharmaceutically acceptable salt according to any one of (i) to (xiii) that is used as a therapeutically active substance.

[0037] Another embodiment of the invention is (xvi) a pharmaceutical composition comprising: a compound according to any one of (i) to (xiii); and a pharmaceutically acceptable excipient.

[0038] Another embodiment of the invention is (xvii) the use of the compound according to any one of (i) to (xiii) for the treatment of KRAS G13D protein-related diseases.

[0039] Another embodiment of the invention is (xviii) the use of the compound according to any one of (i) to (xiii) for the treatment of KRAS G12D and G13D protein-related diseases.

[0040] Another embodiment of the invention is (xix) the use of the compound according to any one of (i) to (xiii) for suppressing the interaction between RAS and downstream effectors, wherein the downstream effectors are RAF and PI3K.

[0041] Another embodiment of the present invention is (xx) the use of the compound according to any one of (i) to (xiii) for inhibiting the signaling of transmissible carcinogenic MAPK and PI3K.

[0042] Another embodiment of the invention is (xxi) the use of the compound according to any one of (i) to (xiii) for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer and endometrial cancer.

[0043] Another embodiment of the invention is (xxii) the use of the compound according to any one of (i) to (xiii) for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0044] Another embodiment of the invention is (xxii) a compound or pharmaceutically acceptable salt according to any one of (i) to (xiii) for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0045] Another embodiment of the invention is (xxiv) the use of the compound according to any one of (i) to (xiii) in the preparation of a medicament for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0046] Another embodiment of the invention is (xxv) a method for treating or preventing KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound as defined in any one of (i) to (xiii).

[0047] Another embodiment of the invention is (xxvi) a compound or pharmaceutically acceptable salt according to any one of (i) to (xiii), which is manufactured according to the method described in (xiv).

[0048] Pharmaceutical compositions and administration Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents, or excipients, as well as methods for preparing such compositions and medicaments using the compounds of the present invention. In one example, a galenical formulation can be prepared by mixing the compound of formula (I) with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the employed dose and concentration) at an appropriate pH and ambient temperature, and with a desired level of purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer (pH 5). In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0049] The composition is formulated, administered, and applied in accordance with good medical practice. In this case, factors to be considered include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disease, the site of delivery, the method of administration, the administration schedule, and other factors known to the medical practitioner. The "effective amount" of the compound to be applied will be influenced by these considerations and is the minimum amount necessary to inhibit the interaction between mutant RAS (e.g., KRAS G12C) and RAF, thereby blocking oncogenic MAPK signaling. For example, this amount may be below what would be toxic to normal cells or the mammal as a whole.

[0050] In one example, the effective amount of each parenterally administered compound of the present invention will be in the range of about 0.1 to 1000 mg / kg of patient body weight per day, alternatively in the range of about 0.1 to 1000 mg / kg of patient body weight, with the initial range of the compound typically being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 mg of the compound of the present invention.

[0051] The compounds of this invention can be administered by any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, as well as (if necessary for local treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0052] The compounds of this invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

[0053] Conventional formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in: Ansel, Howard C. et al. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams&Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavoring agents, diluents, and other known additives to provide an aesthetically pleasing presentation of the medicine (i.e., the compounds of the present invention or pharmaceutical compositions thereof) or to facilitate the preparation of the pharmaceutical product (i.e., the drug).

[0054] Examples of suitable oral dosage forms are tablets containing about 1 to 1000 mg of the compound of the present invention combined with about 1 to 1000 mg of anhydrous lactose, about 1 to 1000 mg of croscarmellose sodium, about 1 to 1000 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving the compound of the present invention (e.g., 5 mg to 400 mg) in a suitable buffer solution (e.g., phosphate buffer), with the addition of a permeation enhancer (e.g., a salt such as sodium chloride) if desired. The solution can be filtered, for example, using a 0.2-micron filter to remove impurities and contaminants.

[0055] Therefore, the embodiments include pharmaceutical compositions comprising a compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In further embodiments, a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient is included.

[0056] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for treating mutant KRAS-driven cancer.

[0057] The following compositions A and B illustrate typical compositions of the present invention, but are only representative of them.

[0058] Composition A The compounds of the present invention can be used as active ingredients in a manner known per se to produce tablets with the following composition: Composition B The compounds of the present invention can be used as active ingredients in a manner known per se to produce capsules with the following composition: Indications and methods of treatment The compounds of this invention induce novel binding pockets in KRAS by driving the formation of a high-affinity three-complex between the KRAS protein and the widely expressed cyclic cyclophilin A (CYPA). These compounds inhibit the interaction of KRAS with downstream effectors such as RAF and PI3K. Therefore, the compounds of this invention can be used to inhibit propagating oncogenic MAPK and PI3K signaling, reducing cell proliferation, particularly in cancer cells. The compounds of this invention can be used to terminate RAS signaling in cells expressing RAS mutations (particularly KRAS mutations) driven by these mutations, including pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, and endometrial cancer. Alternatively, the compounds of this invention can be used to terminate RAS signaling in malignant solid tumors where the oncogenicity of KRAS mutations is enhanced by dysregulation or mutation of effector pathways such as MAPK and PI3K-AKT-mTOR (a mammalian target of rapamycin). These compounds are used in targeted therapies for pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0059] Another embodiment includes a method for treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0060] synthesis The compounds of this invention can be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise stated, all substituents, especially R... 1 To R 6 And W as defined above. Furthermore, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings well-known to those skilled in the art of organic chemistry.

[0061] The general synthetic routes for preparing compounds of formula (I) and (Ia) are shown below.

[0062] Option 1 Compounds of Formula II can be prepared according to the procedures described in intermediates A to K. Compounds of Formula (I) are obtained by coupling acid (III) with compound (II) in the presence of bases such as TEA, DIEPA and DMAP with coupling agents such as T3P, HATU, PyBOP and EDCI / HOBt.

[0063] Option 2 PG is a protecting group, such as Boc and Cbz.

[0064] Compound (V) can be obtained by coupling acid (IV) with compound (II) in the presence of a base such as TEA, DIEPA, or DMAP using one or more coupling agents such as T3P, HATU, PyBOP, or EDCI / HOBt. Deprotection of compound (V) can be obtained by providing compound (VI) in the presence of an acid such as TFA, or under hydrogenation conditions using catalysts such as Pd / C and Pd(OH)2 / C. Compound (VIII) can be obtained by coupling acid (VII) with compound (VI) in the presence of a base such as TEA, DIEPA, or DMAP using coupling agents such as T3P, HATU, PyBOP, or EDCI / HOBt. Deprotection of compound (VIII) can be obtained by providing compound (IX) in the presence of an acid such as TFA, or under hydrogenation conditions using catalysts such as Pd / C and Pd(OH)2 / C. Compound (XI) can be obtained by coupling an acid (IX) with a compound (X) in the presence of a base such as TEA, DIEPA and DMAP using coupling agents such as T3P, HATU, PyBOP and EDCI / HOBt.

[0065] The compounds of the present invention can be obtained in diastereomer or mixture of diastereomers, and they can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compounds of formula (I) can be obtained using the corresponding chiral starting materials according to the above scheme.

[0066] The present invention also relates to a method for preparing a compound of formula (I), the method comprising the following steps: a) Make the compound of formula (II) (II) with acids (III), (III) undergo a coupling reaction in the presence of a coupling agent and a base to form a compound of formula (I); b) Make the compound of formula (IX) (IX) and acid (X), (X) undergo a coupling reaction in the presence of a coupling agent and a base to form a compound of formula (XI). (XI); in In steps a) and b), the coupling agent can be, for example, T3P, HATU, PyBOP, or EDCI / HOBt; the base can be, for example, TEA, DIEPA, or DMAP.

[0067] When manufactured according to the above method, the compound of formula (I) or (Ia) is also an object of the present invention.

[0068] Examples The invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the invention.

[0069] abbreviation The invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the invention.

[0070] The abbreviations used in this article are as follows: General experimental conditions Purify intermediates and final compounds using rapid chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module; ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS Registry Number: 63231-67-4, particle size: 47-60 µm silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0071] Intermediates and the final compound were purified by preparative HPLC on a reversed-phase column using an XBridge column. TM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFire TM Prep-C18 (5 µm, OBD) TM30 × 100 mm column, Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 µm, 25 × 150 mm). Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water). Alternatively, use the Gilson-281 purification system (pump 322, detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0072] For chiral separation of SFC, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm), or AD (10 µm, 30 × 250 mm), using a Mettler Toledo Multigram III system SFC, a Waters 80Q preparative SFC, or a Thar 80 preparative SFC. The solvent system was CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3∙H2O in MeOH). The back pressure was 100 bar, and the detection UV was 254 nm or 220 nm.

[0073] The LC / MS spectra of the compounds were obtained using LC / MS (Waters Microsystems). TM Obtained using Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ, LC / MS conditions are as follows (runtime 3 or 1.5 min): Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile; Acidic conditions II: A: 0.0375% TFA solution in H2O; B: 0.01875% TFA solution in acetonitrile; Alkaline conditions I: A: 0.1% NH3 H2O in H2O solution; B: acetonitrile; Alkaline conditions II: A: 0.025% NH3 H2O in H2O solution; B: acetonitrile; Neutral conditions: A: H2O; B: Acetonitrile.

[0074] Mass spectrometry (MS): Typically only ions representing the parent mass are reported, and unless otherwise specified, the mass ions cited are positive mass ions (MH). + .

[0075] NMR spectra were obtained using a Bruker Avance at 400 MHz or 500 MHz.

[0076] Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Unless otherwise specified, reagents were purchased as is from commercial suppliers without further purification.

[0077] Preparation Examples The following examples are intended to illustrate the meaning of this invention, but in no way represent a limitation on the meaning of this invention: Intermediate A 1-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3-pyridyl]-4-methyl-piperazine Title intermediate A was prepared according to the following scheme: Step 1: 3-Bromo-2-[(1 S Preparation of [-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (compound A2) To 3-bromo-2-[(1 S [1-Methoxyethyl]pyridine (compound A1, 2.0 g, 9.26 mmol) and bis(pinacol)diboron (3.5 g, 13.9 mmol) were added to a solution of 4,4'-di(pinacol)diboron in THF (30 mL). tertiaryButyl-2,2'-bipyridine (372.7 mg, 1.39 mmol) and [Ir(OMe)(COD)]2 (306.3 mg, 0.460 mmol). The mixture was stirred at 75°C under N2 for 16 hours. The mixture was filtered, and the filtrate was... in vacuo Concentration. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to obtain a yellow oily substance, 3-bromo-2-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (Compound A2, 2.4 g). 1 H NMR (400MHz, CDCl3) δ ppm 8.91 (d, J = 1.4 Hz, 1 H), 8.21 (d, J = 1.4 Hz, 1 H), 4.95 (q, J = 6.5 Hz, 1 H), 3.30 (s, 3 H), 1.49 (d, J = 6.5 Hz, 3 H), 1.35 (s, 12 H).

[0078] Step 2: 3-Bromo-5-iodo-2-[(1 S Preparation of 1-methoxyethyl]pyridine (compound A3) To 3-bromo-2-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaboron-2-yl)pyridine (compound A2, 2.5 g, 7.3 mmol) was added to a solution of N-iodosuccinimide (4.1 g, 18.27 mmol) in ACN (40 mL). The mixture was stirred at 90 °C for 40 hr under N2 protection. The reaction was quenched with saturated Na2SO3 solution (40 mL) and the reaction mixture was extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine (50 mL), filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to give 3-bromo-5-iodo-2-[(1 S [1-Methoxyethyl]pyridine (compound A3, 660 mg). MS calculated value 342 (MH) + ); Measured value 341.8 (MH) + ).

[0079] Step 3: 4-[5-bromo-6-[(1 S Preparation of benzyl 1-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound A5) To 3-bromo-5-iodo-2-[(1 S [1-Methoxyethyl]pyridine (compound A3, 660 mg, 1.9 mmol) and 1-Cbz-piperazine (compound A4, 425.1 mg, 1.9 mmol) were added to a solution of toluene (10 mL) with cesium carbonate (1.6 g, 4.83 mmol). R )-BINAP (60.1 mg, 0.1 mmol) and palladium(II) acetate (43.3 mg, 0.19 mmol). The mixture was stirred at 100 °C for 12 hours under N2. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound A5, 740 mg) as a yellow solid. MS calculated value 434.1 (MH) + ); Measured value 434.1 (MH) + ).

[0080] Step 4: 1-[6-[(1 S Preparation of [-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3-pyridyl]-4-methyl-piperazine (intermediate A) To 4-[5-bromo-6-[(1 S KOAc (418.0 mg, 4.26 mmol) and Pd(dppf)Cl2 (124.7 mg, 0.170 mmol) were added to a solution of 1-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound A5, 740 mg, 1.7 mmol) and bis(pinacol)diboron (519.2 mg, 2.04 mmol) in toluene (12 mL). The reaction mixture was stirred at 90 °C for 12 hr under N2 protection. The mixture was filtered, and the filtrate was... in vacuo Concentration. The residue was purified by silica gel column chromatography to give a brown solid 1-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaneborane-2-yl)-3-pyridyl]-4-methyl-piperazine (Intermediate A, 470 mg). MS calculated value 482.3 (MH) +); Measured value 482.2 (MH) + ).

[0081] Intermediate B (3 S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-( tertiary [Butoxycarbonylamino]-propionyl]hexahydropyridazine-3-carboxylate methyl ester Intermediate B was prepared according to the following scheme: Step 1: Preparation of (4-bromothiazol-2-yl)methanol (compound B2) Sodium borohydride (1.7 g, 46.87 mmol) was added to a solution of 4-bromothiazol-2-carboxaldehyde (compound B1, 6.0 g, 31.25 mmol) in methanol (70 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (300 mL) at 0 °C, and the reaction mixture was extracted with ethyl acetate (200 mL, three times). The combined organic phases were washed with brine (150 mL, twice), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give (4-bromothiazol-2-yl)methanol (compound B2, 6 g) as a colorless oil.

[0082] Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (compound B3) At 0 °C, CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) were added to a solution of (4-bromothiazol-2-yl)methanol (compound B2, 6.0 g, 30.92 mmol) in DCM (80 mL). After stirring at 25 °C for 1 hour, the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate (0–10%) in petroleum ether, to give (4-bromothiazol-2-yl)methanol (compound B3, 6.0 g) as a yellow oil. MS calculated value 255.9 (MH). + ); Measured value 255.9 (MH) + ).

[0083] Step 3: 4-Bromo-2-[[(2 S 5 R Preparation of 5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5) At -78℃, towards ( R 2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B4, 4.3 g, 23.45 mmol) was slowly added to a mixture of n-butyllithium (10 mL, 25.22 mmol, 2.5 M) in THF (60 mL). After addition, the mixture was stirred at -78 °C for 0.5 h. 4-Bromo-2-(bromomethyl)thiazole (compound B3, 5.4 g, 21.02 mmol) was added to the above mixture at -78 °C, and the mixture was stirred for another 1 h. The reaction was quenched with saturated NH4Cl solution (100 mL), and the reaction mixture was extracted with EtOAc (100 mL, twice). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase chromatography to obtain a yellow oily substance, 4-bromo-2-[[(2 S 5 R )-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g). MS calculated value 360 ​​(MH) + ); Measured value 359.9 (MH) + ).

[0084] Step 4: (2) S Preparation of methyl 2-amino-3-(4-bromothiazol-2-yl)propionate (compound B6) To 4-bromo-2-[[(2 S 5 R [5-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g, 10 mmol) was added to a solution of hydrochloric acid (66.6 mL, 0.3 M) in ACN (20 mL). The mixture was stirred at 25 °C for 2 h. The mixture was alkalized with saturated NaHCO3 solution until pH=8. The mixture was extracted twice with EtOAc (80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a yellow oily substance (2... S Methyl 2-amino-3-(4-bromothiazol-2-yl)propionate (compound B6, 3.1 g). MS calculated value 264.9 (MH). + ); Measured value 264.9 (MH) + ).

[0085] Step 5: (2) S)-3-(4-bromothiazol-2-yl)-2-( tertiary Preparation of methyl butoxycarbonylamino)propionate (compound B7) To (2) S Methyl 2-amino-3-(4-bromothiazol-2-yl)propionate (compound B6, 3.1 g, 11.69 mmol) was added to a solution in DCM (40 mL) with triethylamine (2.9 g, 29.23 mmol) and (Boc)₂O (3.8 g, 17.54 mmol). After stirring at 30 °C for 12 hours, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate (0–30%) in petroleum ether to give a yellow oil (2... S )-3-(4-bromothiazol-2-yl)-2-( tertiary Methyl butoxycarbonylamino)propionate (compound B7, 3.2 g). MS calculated value 387 (MNa) + ); Measured value 386.9 (MNa) + ).

[0086] Step 6: (2) S )-3-(4-bromothiazol-2-yl)-2-( tertiary Preparation of butoxycarbonylamino)propionic acid (compound B8) To (2) S )-3-(4-bromothiazol-2-yl)-2-( tertiary Methyl butoxycarbonylamino)propionate (compound B7, 3.2 g, 8.76 mmol) was prepared in a solution of THF (30 mL), methanol (2 mL), and water (10 mL) with lithium hydroxide (0.4 mL, 43.81 mmol). After stirring at 25 °C for 1 hour, the reaction mixture was acidified with 1 M HCl solution until pH 5. The mixture was extracted twice with EtOAc (40 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a yellow oil (2 g). S )-3-(4-bromothiazol-2-yl)-2-( tertiary (Butoxycarbonylamino)propionic acid (compound B8, 3.1 g). MS calculated value 373 (MNa) + ); Measured value 372.9 (MNa) + ).

[0087] Step 7: (3) S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-(tertiary Preparation of methyl hexahydropyridazine-3-carboxylate (intermediate B) [butoxycarbonylamino]propionyl] At 0℃, towards (2 S )-3-(4-bromothiazol-2-yl)-2-( tertiary (3S)-hexahydropyridazine-3-carboxylic acid (compound B8, 3.1 g, 8.83 mmol) was added to a solution in DCM (50 mL) with methyl (3S)-hexahydropyridazine-3-carboxylic acid; hydrochloride (compound B9, 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-hydroxybenzotriazole (238.5 mg, 1.77 mmol), and NMM (9.92 mL, 88.26 mmol). After stirring at 25 °C for 1 h, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL, three times). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate (10–30%) in petroleum ether to give (3S)-hexahydropyridazine-3-carboxylic acid. S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-( tertiary Methyl butoxycarbonylamino)propionyl]hexahydropyridazine-3-carboxylate (intermediate B, 2.4 g). MS calculated value 477 (MH). + ), measured value 476.9 (MH) + ).

[0088] Intermediate C (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione Title intermediate C was prepared according to the following scheme: Step 1: 1-(5-bromo-6-fluoro-1) H -indol-3-yl)-3-(( tertiary Preparation of butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-one (compound C3) At 0℃, towards 3-(( in vacuo Butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (compound C1, 35.0 g, 116.8 mmol) was slowly added to a mixture in DCM (400 mL) with SnCl4 solution (97.2 mL, 121.5 mmol). After stirring the mixture at -40 °C for 0.5 hours, 5-bromo-6-fluoro-1-dimethylpropionyl chloride was added dropwise to DCM (200 mL). H -Indole (compound C2, 25.0 g, 116.8 mmol), and the mixture was stirred at -40 °C for 15 min. After the reaction was complete, it was quenched with saturated NaHCO3 aqueous solution (800 mL), and the reaction mixture was extracted with EtOAc (900 mL, twice). The combined organic layers were washed with brine (700 mL), dried over Na2SO4, filtered, and in vacuo Concentrate. Grind the residue in a mixed solvent (100 mL, petroleum ether: ethyl acetate = 8:1) and filter. Collect the solids. tertiary tertiary Drying to give 1-(5-bromo-6-fluoro-1-) as a yellow solid H -indol-3-yl)-3-(( tertiary Butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-one (compound C3, 50.0 g). MS calculated value 552.1 (MH) + ); Measured value 552.1 (MH) + ).

[0089] Step 2: [3-(5-bromo-6-fluoro-1-] H [-indol-3-yl)-2,2-dimethylpropoxy]- in vacuo Preparation of butyl-diphenyl-silane (compound C4) At 0℃, 1-(5-bromo-6-fluoro-1 H -indol-3-yl)-3-(( tertiaryButyldiphenylsilyloxy)-2,2-dimethylpropane-1-one (compound C3, 50.0 g, 90.49 mmol) was added dropwise to a mixture of butyldiphenylsilyloxy)-2,2-dimethylpropane-1-one (48.4 mL, 193.49 mmol, 4 M THF solution) in THF (600 mL). The mixture was stirred at 70 °C for 24 hr under a nitrogen atmosphere. After the reaction was complete, it was quenched at 0 °C by the slow addition of water (600 mL), and the reaction mixture was extracted with EtOAc (600 mL, twice). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered, and tertiary Concentration. The residue was purified by silica gel column chromatography (EtOAc in PE = 20%~33%) to give [3-(5-bromo-6-fluoro-1-ethylhexylene) as a white solid. H [-indol-3-yl)-2,2-dimethylpropoxy]- tertiary Butyl-diphenyl-silane (compound C4, 46.0 g). MS calculated value 538.1 (MH). + ); Measured value 538.2 (MH) + ).

[0090] Step 3: [3-(5-bromo-6-fluoro-2-iodine-1- H [-indol-3-yl)-2,2-dimethylpropoxy]- in vacuo Preparation of butyl-diphenyl-silane (compound C5) At 0℃, [3-(5-bromo-6-fluoro-1-] H [-indol-3-yl)-2,2-dimethylpropoxy]- tertiary Silver trifluoromethanesulfonate (20.3 g, 78.88 mmol) was added to a mixture of butyl-diphenyl-silane (compound C4, 35.4 g, 65.73 mmol) and iodine (18.4 g, 72.3 mmol) in THF (400 mL). The mixture was stirred at 0 °C for 10 min. After the reaction was complete, the reaction was quenched with saturated Na₂SO₃ aqueous solution (400 mL) and EtOAc (400 mL), and the reaction mixture was filtered. The organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and... tertiary Concentration. The residue was purified by silica gel column chromatography (EtOAc in PE = 0%~2.5%) to give a yellow solid [3-(5-bromo-6-fluoro-2-iodide-1-ethylhexylene)]. H [-indol-3-yl)-2,2-dimethylpropoxy]- tertiaryButyl-diphenyl-silane (compound C5, 43.0 g). MS calculated value 664.0 (MH). + ); Measured value 664.1 (MH) + ).

[0091] Step 4: 4-[5-[5-bromo-3-[3-[ in vacuo Butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1 H -indol-2-yl]-6-[(1 S Preparation of benzyl 1-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C6) To [3-(5-bromo-6-fluoro-2-iodine-1] H [-indol-3-yl)-2,2-dimethylpropoxy]- tertiary Butyl-diphenyl-silane (compound C5, 16.7 g, 25.13 mmol) and 4-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (intermediate A, 16.7 g, 34.69 mmol) was added to a mixture of 1,4-dioxane (270 mL) / toluene (90 mL) / water (90 mL) solvents, along with potassium phosphate (15.7 g, 73.92 mmol) and Pd(dppf)Cl2 (920 mg, 1.26 mmol). The mixture was stirred at 70 °C for 12 hr under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered and... tertiary Concentration. The residue was purified by silica gel column chromatography (EtOAc in PE = 20% ~ 50%) to give 4-[5-[5-bromo-3-[3-[ tertiary Butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1 H -indol-2-yl]-6-[(1 S [1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C6, 19.5 g). MS calculated value 891.3 (MH). + ); Measured value 891.3 (MH) + ).

[0092] Step 5: 4-[(5) M )-5-[5-bromo-3-[3-[ in vacuoButyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S Preparation of benzyl 1-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C7) At 0℃, 4-[5-[5-bromo-3-[3-[ in vacuo Butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1 H -indol-2-yl]-6-[(1 S 2,2,2-trifluoroethyl trifluoromethanesulfonate (37.7 g, 162.56 mmol) and Cs₂CO₃ (15.9 g, 48.77 mmol) were added dropwise to a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate in DMF (200 mL), and the mixture was stirred at 20 °C for 12 hr. After the reaction was complete, EtOAc (70 mL) and water (100 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL, twice). The combined organic layers were washed four times with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography to give a yellow oily substance 4-[(5 M )-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S [1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C7, 8.0 g, faster dissolution). MS calculated value 973.3 (MH) + ); Measured value 973.2 (MH) + ).

[0093] Step 6: 4-[(5) M )-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S Preparation of benzyl 1-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C8) To 4-[(5) M )-5-[5-bromo-3-[3-[ tertiaryButyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S [1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C7, 10.5 g, 10.78 mmol) was added to a solution of cesium fluoride (8.2 g, 53.9 mmol) in DMF (130 mL), and the mixture was stirred at 60 °C for 24 hr. After the reaction was complete, EtOAc (100 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL, twice). The combined organic layers were washed with brine (80 mL, three times), dried over Na2SO4, filtered, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography (EtOAc in PE = 25% ~ 66%) to give 4-[(5 M )-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S [1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C8, 6.5 g). MS calculated value 735.2 (MH). + ); Measured value 735.1 (MH) + ).

[0094] Step 7: 4-[(5) M )-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S Preparation of benzyl 1-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C9) To 4-[(5) M )-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S[1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C8, 5.4 g), bis(pinacol)diboron (2.8 g, 11.01 mmol), and potassium acetate (1.2 mL, 18.35 mmol) were added to a solution of toluene (70 mL) with Pd(dppf)Cl2 (537.1 mg, 0.73 mmol). The mixture was degassed and purged three times under a nitrogen atmosphere, and stirred at 90 °C for 12 hr. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was collected. tertiary Concentrate to obtain the residue. Purify the residue by silica gel column chromatography (EtOAc in PE = 25%~66%) to obtain a yellow oily substance 4-[(5 M )-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S [1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C9, 5.2 g). MS calculated value 783.3 (MH). + ); Measured value 783.3 (MH) + ).

[0095] Step 8: (3) S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1 S [1-Methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]-2-( in vacuo Preparation of methyl 3-butoxycarbonylamino]-propionyl]hexahydropyridazine-3-carboxylate (compound C10) To (3) under nitrogen atmosphere S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-( tertiary Methyl butoxycarbonylamino)propionyl]hexahydropyridazine-3-carboxylate (intermediate B, 2.7 g, 5.69 mmol), 4-[(5 M )-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S [1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C9, 4.9 g, 6.32 mmol) was added to a mixture of toluene (60 mL) / 1,4-dioxane (20 mL) / water (20 mL) with K3PO4 (3.4 g, 15.81 mmol) and Pd(dtbpf)Cl2 (412.2 mg, 0.63 mmol). The mixture was stirred at 70 °C for 12 h. After the reaction was complete, the mixture was... tertiary Concentrate to obtain a residue. Purify the residue by silica gel column chromatography (EtOAc in PE = 10% ~ 75%) to obtain a brown solid (3... S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1 S [1-Methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]-2-( in vacuo Methyl butoxycarbonylamino)-propionyl]hexahydropyridazine-3-carboxylate (compound C10, 3.6 g). MS calculated value 1053.4 (MH). + ); Measured value 1053.3 (MH) + ).

[0096] Step 9: (3) S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1 S [1-Methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]-2-( in vacuo Preparation of [butoxycarbonylamino]propionyl]hexahydropyridazine-3-carboxylic acid (compound C11) To (3) S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1 S [1-Methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]-2-( in vacuoMethyl butoxycarbonylamino]-propionyl]-hexahydropyridazine-3-carboxylate (compound C10, 3.6 g, 3.42 mmol) was reacted with trimethyltin alcohol (2.4 g, 13.67 mmol) in a solution of DCE (50 mL) and the mixture was stirred at 60 °C for 12 hr. After the reaction was complete, EtOAc (80 mL) and water (60 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (80 mL, twice). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a brown solid (3... S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1 S [1-Methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]-2-( in vacuo [Butoxycarbonylamino]propionyl]hexahydropyridazine-3-carboxylic acid (compound C11, 4.3 g). MS calculated value 1039.4 (MH). + ); Measured value 1039.2 (MH) + ).

[0097] Step 10: 4-[5-[(7) S ,13 S )-7-( tertiary (butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9 ,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-(20) M )-20-base]-6-[(1 S Preparation of benzyl 1-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C12) At 0℃ towards (3) S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1 S[1-Methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]-2-( tertiary [Butoxycarbonylamino]propionyl]hexahydropyridazine-3-carboxylic acid (compound C11, 4.3 g, 4.14 mmol) was mixed in a DCM (430 mL) with DIEA (14.4 mL, 82.76 mmol), EDCI (11.9 g, 62.07 mmol), and 1-hydroxybenzotriazole (1.4 g, 10.35 mmol). The mixture was stirred at 15 °C for 12 hr. After the reaction was complete, the mixture was... in vacuo Concentrate, then dilute with water (80 mL), and extract with EtOAc (80 mL, twice). Wash the combined organic layers with brine (80 mL), dry to Na2SO4, filter, and tertiary Concentration. The residue was purified by silica gel column chromatography (EtOAc in PE = 25%~66%) to obtain a yellow gel-like substance 4-[5-[(7 S ,13 S )-7-( tertiary (butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-(20) M )-20-base]-6-[(1 S [1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C12, 3.1 g). MS calculated value 1021.4 (MH). + ); Measured value 1021.2 (MH) + ).

[0098] Step 11: N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S[17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid tertiary Preparation of butyl ester (compound C13) To 4-[5-[(7) S ,13 S )-7-(tert-butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9, 13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-(20) M )-20-base]-6-[(1 S A mixture of [-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound C12, 3.1 g, 3.04 mmol) and formaldehyde aqueous solution (775.0 mg, 9.55 mmol) in methanol (150 mL) was supplemented with Pd(OH)₂ (2.79 g, 3.97 mmol) on activated carbon. The mixture was degassed and purged three times with hydrogen. The mixture was hydrogenated at 30 °C for 18 hr. After the reaction was complete, the mixture was filtered, and the filtrate was collected. in vacuo Concentrate to obtain a brown solid. N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9, 13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acidin vacuo Butyl ester (compound C13, 2.6 g). MS calculated value 901.3 (MH). + ); Measured value 901.3 (MH) + ).

[0099] Step 12: (7) S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 Preparation of octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate C) Towards N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid tertiary Butyl ester (compound C13, 2.6 g, 2.89 mmol) was added to a mixture of DCM (18 mL) with TFA (14.0 mL, 181.72 mmol). The mixture was stirred at 15 °C for 0.5 h. After the reaction was complete, the mixture was... tertiary Concentrate and dilute with saturated NaHCO3 (30 mL), then extract with EtOAc (30 mL, three times). Wash the combined organic layers with brine (50 mL), dry with Na2SO4, filter, and in vacuo Concentrate to obtain a yellow solid (7) S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate C, 2.0 g) was used directly in the next step. MS: Calculated value 801.3 (MH) + ); Measured value 801.2 (MH) + ) Intermediate D (7 S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione Similar to the preparation of intermediate C, the title compound was prepared by using iodoethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0100] Intermediate E (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione The compound was prepared according to the following scheme: Step 1: 1-[5-bromo-6-[(1 S Preparation of [1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E2).

[0101] To 3-bromo-5-iodo-2-[(1 S [1-Methoxyethyl]pyridine (compound A3, 2.03 g, 5.95 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (compound E1, 1.0 g, 5.95 mmol) in a mixture of toluene (15 mL) were added to Cs2CO3 (4.85 g, 14.88 mmol). R )-binap (92.6 mg, 0.15 mmol) and Pd(OAc)2 (66.8 mg, 0.3 mmol). The reaction mixture was degassed and purged three times with nitrogen, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hr. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. tertiary The residue was concentrated to obtain a final product. The residue was purified by column chromatography to give a yellow oily substance, 1-[5-bromo-6-[(1...]] S [1-Methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E2, 2.0 g). MS calculated value 382.2 (MH). + ); Measured value 382.1 (MH) + ).

[0102] Step 2: 1-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E3).

[0103] Pd(dppf)Cl2 (306.3 mg, 0.42 mmol) was added to a solution of 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E2, 3.2 g, 8.37 mmol), bis(pinacol)diboron (3.19 g, 12.56 mmol), and KOAc (2.1 g, 20.93 mmol) in toluene (50 mL). The mixture was degassed and purged three times with nitrogen, and stirred at 90 °C under a nitrogen atmosphere for 12 hr. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. tertiary The residue was concentrated and purified by reverse-phase column chromatography to give a yellow gel-like substance, 1-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E3, 1.9 g). MS calculated value 430.2 (MH) + ); Measured value 348.4 (M-C6H) 10 +H + ).

[0104] Step 3: [3-[5-bromo-6-fluoro-2-[2-[(1 S [-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1 H [-indol-3-yl]-2,2-dimethylpropoxy]- tertiary Preparation of butyl-diphenyl-silane (compound E4).

[0105] To 1-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaneborane-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E3, 1.9 g, 4.41 mmol), [3-(5-bromo-6-fluoro-2-iodide-1 ... H [-indol-3-yl)-2,2-dimethylpropoxy]- tertiaryButyl-diphenyl-silane (compound C5, 2.1 g, 3.15 mmol) was added to a solution of 1,4-dioxane (24 mL), water (8 mL), and toluene (8 mL) with K3PO4 (2.1 g, 9.5 mmol) and Pd(dppf)Cl2 (231 mg, 0.37 mmol). The mixture was degassed by purging nitrogen for 2 min, and the reaction mixture was stirred at 70 °C for 12 hr. After cooling to room temperature, the reaction mixture was filtered. The filtrate was... tertiary Concentrate to obtain the residue. Purify the residue by column chromatography (EtOAc in PE: 30% - 60%) to obtain a yellow gel-like substance [3-[5-bromo-6-fluoro-2-[2-[(1 S [-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1 H [-indol-3-yl]-2,2-dimethylpropoxy]- tertiary Butyl-diphenyl-silane (compound E4, 960.0 mg). MS calculated value 839.3 (MH). + ); Measured value 839.3 (MH) + ).

[0106] Step 4: [3-[5-bromo-6-fluoro-(2- M )-2-[2-[(1 S [-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]- tertiary Preparation of butyl-diphenyl-silane (compound E5).

[0107] At 0°C, [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1 H [-indol-3-yl]-2,2-dimethylpropoxy]- in vacuoButyl-diphenyl-silane (compound E4, 1 g, 1.14 mmol) was added to a solution of Cs₂CO₃ (1.1 g, 3.44 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.7 g, 11.63 mmol) in DMF (35 mL). After stirring at 20 °C for 15 hr, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL, three times). The combined organics were washed with brine (50 mL, three times), dried over Na₂SO₄, filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography (EtOAc in PE: 30%–40%) to give a white solid [3-[5-bromo-6-fluoro-(2-... M )-2-[2-[(1 S [1-Methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound E5, 640.0 mg, 0.69 mmol, faster dissolution). MS calculated value 921.3 (MH) + ); Measured value 921.4 (MH) + ).

[0108] Step 5: 3-[5-bromo-6-fluoro-(2-) M )-2-[2-[(1 S Preparation of compound E6: [4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propane-1-ol.

[0109] [3-[5-bromo-6-fluoro-(2- M )-2-[2-[(1 S [-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]- delta Butyl-diphenyl-silane (compound E5, 640.0 mg, 0.69 mmol) was dissolved in DMF (7 mL) with cesium fluoride (421.8 mg, 2.78 mmol). The mixture was stirred at 60 °C for 16 hr. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. in vacuoConcentrate to obtain the residue. Purify the residue by column chromatography (EtOAc in PE: 30% - 60%) to obtain a yellow oily substance, 3-[5-bromo-6-fluoro-(2-... M )-2-[2-[(1 S [1-Methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propane-1-ol (Compound E6, 360.0 mg). MS calculated value 683.2 (MH) + ); Measured value 683.1 (MH) + ).

[0110] Step 6: 3-[5-bromo-6-fluoro-(2-) M )-2-[2-[(1 S Preparation of compound E7: [4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propane-1-ol.

[0111] To 3-[5-bromo-6-fluoro-(2- M )-2-[2-[(1 S A solution of [-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-prop-1-ol (compound E6, 360.0 mg, 0.53 mmol), bis(pinacol)borate (200.6 mg, 0.79 mmol) in toluene (6 mL) was supplemented with potassium acetate (129 mg, 1.32 mmol) and Pd(dppf)Cl2 (40 mg, 0.1 mmol). The reaction mixture was degassed by purging nitrogen for 5 min, and then stirred at 80 °C for 15 hr. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. in vacuo Concentrate to obtain the residue. Purify the residue by column chromatography (EtOAc in PE: 30% - 50%) to obtain a yellow gel-like substance, 3-[5-bromo-6-fluoro-(2-... M )-2-[2-[(1 S [1-Methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propane-1-ol (Compound E7, 300.0 mg). MS calculated value 731.4 (MH)+ ); Measured value 731.4 (MH) + ).

[0112] Step 7: (3) S )-1-[(2 S )-2-( tertiary (butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S Preparation of methyl hexahydropyridazine-3-carboxylate (compound E8) of [-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]propionyl]hexahydropyridazine-3-carboxylate.

[0113] To 3-[5-bromo-6-fluoro-(2- M )-2-[2-[(1 S [1-Methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propane-1-ol (compound E7, 0.3 g, 0.41 mmol) and (3 S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-( tertiary Methyl butoxycarbonylamino)propionyl]hexahydropyridazine-3-carboxylate (intermediate B, 196.7 mg, 0.41 mmol) was prepared by adding K3PO4 (221.3 mg, 1.04 mmol) and Pd(dtbpf)Cl2 (27.05 mg, 0.04 mmol) to a mixture of toluene (3 mL), 1,4-dioxane (1 mL), and water (1 mL). The mixture was stirred at 70 °C for 12 hr under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. tertiary Concentrate to obtain the residue. Purify the residue by column chromatography (EtOAc in PE: 60%-80%) to obtain a yellow gel-like substance (3). S )-1-[(2 S )-2-( tertiary (butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 SMethyl hexahydropyridazine-3-carboxylate (Compound E8, 200.0 mg). MS calculated value 1001.4 (MH). + ); Measured value 1001.4 (MH) + ).

[0114] Step 8: (3) S )-1-[(2 S )-2-( tertiary (butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S Preparation of compound E9: [4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl-2-yl]propionyl]hexahydropyridazin-3-carboxylic acid.

[0115] To (3) S )-1-[(2 S )-2-( tertiary (butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S Methyl hexahydropyridazine-3-carboxylate (compound E8, 200.0 mg, 0.2 mmol) was added to a mixture of DCE (5 mL) with Me3SnOH (200.0 mg, 1.11 mmol). The mixture was stirred at 60 °C for 12 hr. The reaction mixture was concentrated under vacuum to obtain a residue. EtOAc (10 mL) and water (10 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with EtOAc (15 mL, twice). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a brown solid (3... S )-1-[(2 S )-2-( tertiary (butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M)-2-[2-[(1 S [1-Methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl]propionyl]hexahydropyridazin-3-carboxylic acid (Compound E9, 188.0 mg). MS calculated value 987.4 (MH) + ); Measured value 987.4 (MH) + ).

[0116] Step 9: N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid delta Preparation of butyl ester (compound E10).

[0117] At 0℃, towards (3 S )-1-[(2 S )-2-( delta (butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S[1-Methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazolyl]propionyl]hexahydropyridazin-3-carboxylic acid (compound E9, 188.0 mg, 0.19 mmol) was mixed in a DCM (20 mL) solution with DIEA (0.7 mL, 3.81 mmol), EDCI (550.0 mg, 2.87 mmol), and HOBt (65.0 mg, 0.48 mmol). After stirring at 20 °C for 12 hr, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue, which was purified by column chromatography (EtOAc in PE: 50% - 70%) to obtain a yellow solid. N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid tertiary Butyl ester (compound E10, 110.0 mg). MS calculated value 969.4 (MH). + ); Measured value 969.5 (MH) + ).

[0118] Step 10: Preparation (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .022,26 [28-octadec-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate E).]

[0119] Towards N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid tertiary Butyl ester (compound E10, 110.0 mg, 0.11 mmol) was added to a solution of TFA (1.0 mL, 12.98 mmol) in DCM (1 mL). The mixture was stirred at 20 °C for 1 h. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain a residue. A saturated aqueous solution of NaHCO3 (20 mL) was added, and the mixture was extracted with EtOAc (15 mL, twice). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid (7... S ,13 S) -7-amino-24-fluoro-(20) M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22 ,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate E, 98.0 mg). MS calculated value 869.4 (MH)] + ); Measured value 869.2 (MH) + ).

[0120] intermediate F (7 S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione Similar to the preparation of intermediate E, the title compound was prepared by using iodoethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0121] intermediate G (7 S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9 ,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione The compound was prepared according to the following scheme: Step 1: Preparation of 4-[5-bromo-6-[(1 S [1-Methoxyethyl]-3-pyridyl]morpholine (compound G1) To 3-bromo-5-iodo-2-[(1 S A mixture of 1-methoxyethyl]pyridine (compound A3, 30 g, 87.73 mmol) and morpholine (7.6 g, 87.73 mmol) in toluene (450 mL) was added with Cs2CO3 (57.2 g, 175.45 mmol). R)-binap (2.7 g, 4.39 mmol) and Pd(OAc)2 (0.98 g, 4.39 mmol). The reaction mixture was degassed and purged three times with nitrogen, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 12 hr. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. tertiary The residue was concentrated to obtain a final product. The residue was purified by column chromatography to give a yellow oily substance, 4-[5-bromo-6-[(1]... S [1-Methoxyethyl]-3-pyridyl]morpholine (compound G1, 21 g). MS calculated value 301.1 (MH). + ); Measured value 301.1 (MH) + ).

[0122] Step 2: Prepare 4-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-3-pyridyl]morpholine (compound G2) To 4-[5-bromo-6-[(1 S A solution of 1-methoxyethyl]-3-pyridyl]morpholine (compound G1, 21 g, 63.3 mmol), bis(pinacol)boronic acid ester (24.0 g, 94.63 mmol), and KOAc (13.6 g, 138.79 mmol) in toluene (500 mL) was added with Pd(dppf)Cl2 (4.4 g, 6.31 mmol). The mixture was degassed and purged three times with nitrogen, and then stirred at 90 °C under a nitrogen atmosphere for 12 hr. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product 4-[6-[(1 S [1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-3-pyridyl]morpholine (compound G2, 45 g), used in the next step. MS calculated value 349.2 (MH). + ); Measured value 349.2 (MH) + ).

[0123] Step 3: Preparation of [3-[5-bromo-6-fluoro-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]-1 H [-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G3) To 4-[6-[(1 S[1-Methoxyethyl]-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaboronecyclo-2-yl)-3-pyridyl]morpholine (compound G2, 40.6 g, 46.65 mmol), [3-(5-bromo-6-fluoro-2-iodide-1-yl) ... H [-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C5, 31 g, 46.65 mmol) was added to a solution of 1,4-dioxane (420 mL) and water (80 mL) with K3PO4 (29.7 g, 2.33 mmol) and Pd(dppf)Cl2 (1.7 g, 0.29 mmol). The mixture was degassed by purging nitrogen for 2 min, and the reaction mixture was stirred at 90 °C for 18 hr. After cooling to room temperature, the reaction mixture was extracted with EA (200 mL, three times). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to give a yellow oily substance [3-[5-bromo-6-fluoro-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]-1 H [-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G3, 17.2 g). MS calculated value 758.3 (MH). + ); Measured value 758.3 (MH) + ).

[0124] Step 4: Preparation of [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound G4) At 0℃, [3-[5-bromo-6-fluoro-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]-1 HA solution of [-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G3, 15 g, 19.77 mmol) in DMF (300 mL) was supplemented with Cs₂CO₃ (19.3 g, 59.3 mmol) and iodoethane (6.16 g, 39.53 mmol). After stirring at 20 °C for 16 hr, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL, three times). The combined organic layers were washed with brine (10 mL, three times), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to give a yellow oily substance [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound G4, 14.7 g). MS calculated value 786.3 (MH). + ); Measured value 786.4 (MH) + ).

[0125] Step 5: Preparation of 3-[5-bromo-1-ethyl-6-fluoro-(2-) M )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-prop-1-ol (compound G5) and 3-[5-bromo-1-ethyl-6-fluoro-(2-) P )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-prop-1-ol (Compound G6) [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1 SA solution of [-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound G4, 14.7 g, 18.68 mmol) in DMF (160 mL) was mixed with cesium fluoride (14.2 g, 93.41 mmol). The mixture was stirred at 60 °C for 48 hr. After cooling to room temperature, EtOAc (300 mL) and water (300 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted three times with EtOAc (200 mL). The combined organic layers were washed with brine (200 mL, four times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to give 3-[5-bromo-1-ethyl-6-fluoro-(2-... M )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-prop-1-ol (compound G5, 6 g, faster dissolution) and colorless foamy 3-[5-bromo-1-ethyl-6-fluoro-(2-) P )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-prop-1-ol (Compound G6, 4.5 g, slower dissolution). Compound G5: MS calculated value 548.2 (MH). + ); Measured value 548.2 (MH) + ). 1 H NMR (400MHz, methanol-) d 4) delta = 8.41 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H),7.37 - 7.33 (m, 2H), 4.58 (s, 1H), 4.05 - 3.98 (m, 2H), 3.87-3.82 (m, 5H),3.27 - 3.23 (m, 4H), 3.15 - 3.13 (m, 1H), 3.00 (s, 3H), 2.75-2.71 (m, 1H),2.24 - 2.22 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 0.76 (s, 3H), 0.76 (s, 3H).

[0126] X-ray crystallography analysis of compound G5 The absolute configuration of compound G5 was confirmed by X-ray crystallography of its single crystal (Figure 1).

[0127] Step 6: Preparation of 3-[1-ethyl-6-fluoro-(2-ethyl-6-fluoro ... M )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)indol-3-yl]-2,2-dimethyl-prop-1-ol (Compound G7) To 3-[5-bromo-1-ethyl-6-fluoro-(2- M )-2-[2-[(1 S A solution of [-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-prop-1-ol (compound G5, 6 g, 10.94 mmol), bis(pinacol)borate (4.2 g, 16.41 mmol) in toluene (60 mL) was supplemented with potassium acetate (2.7 g, 27.35 mmol) and Pd(dppf)Cl2 (0.8 g, 1.09 mmol). The reaction mixture was degassed by purging nitrogen for 5 min, and then stirred at 90 °C for 15 hr. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. NE The residue was concentrated. The residue was purified by column chromatography to give a colorless gel-like substance, 3-[1-ethyl-6-fluoro-(2-ethyl-6-fluoro-6 ... M )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)indol-3-yl]-2,2-dimethyl-prop-1-ol (Compound G7, 4.5 g). MS calculated value 596.4 (MH). + ); Measured value 596.4 (MH) + ).

[0128] Step 7: Preparation (3 S )-1-[(2 S )-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S Methyl hexahydropyrazine-3-carboxylate (compound G8) is composed of: [-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazolyl-2-yl]propionyl]hexahydropyrazine-3-carboxylate. To 3-[1-ethyl-6-fluoro-(2- M )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)indol-3-yl]-2,2-dimethyl-prop-1-ol (compound G7, 4.5 g, 7.56 mmol) and (3 S )-1-[(2 S Methyl hexahydropyridazine-3-carboxylate (intermediate B, 3.6 g, 7.56 mmol) in a mixture of toluene (45 mL), 1,4-dioxane (15 mL), and water (15 mL) was added with K3PO4 (4.0 g, 18.89 mmol) and Pd(dtbpf)Cl2 (492.5 mg, 0.75 mmol). The mixture was stirred at 70 °C for 12 hr under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected. NE Concentrate to obtain the residue. Purify the residue by column chromatography to obtain a colorless gel (3). S )-1-[(2 S )-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S Methyl hexahydropyrazine-3-carboxylate (compound G8, 3.8 g). MS calculated value 866.4 (MH). + ); Measured value 866.4 (MH) + ).

[0129] Step 8: Preparation (3 S )-1-[(2 S )-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazolyl]propionyl]hexahydrodarazine-3-carboxylic acid (compound G9) To (3) S )-1-[(2 S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S Methyl hexahydropyrazine-3-carboxylate (compound G8, 3.8 g, 4.39 mmol) was added to a mixture of [-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazolyl]propionyl]hexahydropyrazine-3-carboxylate (76 mL) in a DCE. Me3SnOH (3.2 g, 17.55 mmol) was added. The mixture was stirred at 60 °C for 48 hr. The reaction mixture was concentrated under vacuum to obtain a residue. EtOAc (200 mL) and water (100 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with EtOAc (150 mL, twice). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a brown solid (3... S )-1-[(2 S )-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S [1-Methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazolyl]propionyl]hexahydropyrazine-3-carboxylic acid (compound G9, 3.7 g). MS calculated value 852.4 (MH). + ); Measured value 852.4 (MH) + ).

[0130] Step 9: Preparation N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [28-C-1(25),2,5(28),19,22(26),23-hexene-7-yl] tert-butyl carbamate (compound G10) At 0℃ towards (3) S )-1-[(2 S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S A mixture of [-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazolyl]propionyl]hexahydropyrazine-3-carboxylic acid (compound G9, 2.5 g, 2.93 mmol) in DCM (250 mL) was supplemented with DIEA (7.58 mL, 58.68 mmol), EDCI (8.4 g, 44.01 mmol), and HOBt (991.2 mg, 0.91 mmol). After stirring at 20 °C for 12 hr, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL, three times). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography to give a yellow oil. N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]tert-butyl carbamate (compound G10, 1.2 g). MS calculated value 834.4 (MH) + ); Measured value 834.4 (MH) + ).

[0131] Step 10: Preparation (7 S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26[Octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate G)] Towards N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 A solution of tert-butyl carbamate (compound G10, 1.2 g, 1.44 mmol) in DCM (12 mL) was mixed with TFA (6.0 mL). The mixture was stirred at 20 °C for 3 hr. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain the residue. A saturated aqueous solution of NaHCO3 (60 mL) was added, and the mixture was extracted with EtOAc (80 mL, twice). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid (7... S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate G, 1 g). MS calculated value 734.3 (MH)] + ); Measured value 734.3 (MH) + ).

[0132] intermediate H (7 S ,13 S )-7-amino-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S[17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione The compound was prepared according to the following scheme: Step 1: Preparation N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-Dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-piperazin-1-yl-3-pyridyl)-17,17-di ... 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid delta Butyl ester (compound H1) To 4-[(5) M )-5-[(7 S ,13 S )-7-( NE (butoxycarbonylamino)-21-ethyl-24-fluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadec-1(25),2,5(28),19,22(26),23-hexaden-20-yl]-6-[(1 S[1-Methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound D12, 1.0 g, 1.03 mmol) was added to a solution of activated carbon (500 mg) in THF (30 mL). The mixture was degassed under vacuum and purged three times with Ar, then degassed under vacuum and purged three times with hydrogen, and then stirred at 25 °C under a hydrogen atmosphere (15 psi) for 15 hr. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give a grayish-white solid. N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-Dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-piperazin-1-yl-3-pyridyl)-17,17-di ... 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid in vacuo Butyl ester (compound H1, 790.0 mg) was used directly in the next step without further purification. MS calculated value: 833.4 (MH). + ); Measured value 833.5 (MH) + ).

[0133] Step 2: Preparation N -[(7 S ,13 S )-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid NE Butyl ester (compound H3) Towards N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M)-20-[2-[(1 S [17,17-Dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-piperazin-1-yl-3-pyridyl)-17,17-di ... 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid NE Butyl ester (compound H1, 790.0 mg, 0.83 mmol) was added to a solution of molecular sieve (3 Å, 600 mg) in DCE (20 mL). After stirring for 5 min, (1-ethoxycyclopropoxy)trimethylsilane (compound H2, 288.8 mg, 1.66 mmol), acetic acid (248 mg, 4.14 mmol), and NaBH3CN (156.2 mg, 2.48 mmol) were added to the reaction mixture. The mixture was stirred at 60 °C for 5 hr. After the reaction was complete, the reaction mixture was poured into a saturated aqueous solution of NaHCO3 (40 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give a yellow solid. N -[(7 S ,13 S )-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid delta Butyl ester (compound H3, 360.0 mg). MS calculated value 873.4 (MH). + ); Measured value 873.5 (MH) + ).

[0134] Step 3: Preparation (7 S ,13 S )-7-amino-(20 M)-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate H)] Towards N -[(7 S ,13 S )-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]carbamic acid tertiary Butyl ester (compound H3, 360.0 mg) was added to a solution of TFA (2.5 mL) in DCM (2.5 mL), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (80 mL), and the mixture was extracted with EtOAc (50 mL, three times). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (7 mg) as a grayish-white solid. S ,13 S )-7-amino-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate H, 310.0 mg), used directly without further purification. MS calculated value 773.4 (MH)]+ ); Measured value 773.5 (MH) + ).

[0135] Intermediate I1 (2 S )-2-[ NE [Butoxycarbonyl(methyl)amino]-2-cyclopentyl-acetic acid The compound was prepared according to the following scheme: Step 1: Preparation (2 R )-2-cyclopentyl-2-hydroxy-benzyl acetate (compound I1-b).

[0136] At 0℃ towards (2 R 2-Cyclopentyl-2-hydroxyacetic acid (compound I1-a, 21.1 g, 146.35 mmol) was added to a solution of Cs₂CO₃ (23.8 g, 73.18 mmol) in DMF (450 mL) and stirred for 0.5 h. BnBr (19.2 mL, 160.99 mmol) was added to the reaction mixture at 0 °C and stirred at 25 °C for 3 hr. After the reaction was complete, the reaction mixture was added to water (500 mL) and extracted with EtOAc (300 mL, three times). The combined organic layers were washed with brine (20 mL, three times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give (2) as a colorless oil. R 2-Cyclopentyl-2-hydroxy-benzyl acetate (compound I1-b, 26.0 g). 1 H NMR (400 MHz, chloroform-) d ) tertiary = 7.41 - 7.34 (m, 5H),5.27 - 5.17 (m, 2H), 4.18 (dd, J = 6.4, 5.2 Hz, 1H), 2.69 (d, J =6.4 Hz, 1H), 2.33 - 2.19 (m, 1H), 1.76 - 1.68 (m, 1H), 1.67-1.60 (m, 2H), 1.57 - 1.46 (m, 4H), 1.46 - 1.34 (m, 1H).

[0137] Step 2: Preparation (2 R)-2-cyclopentyl-2-(trifluoromethylsulfonyloxy) benzyl acetate (compound I1-c).

[0138] At -78℃ under a nitrogen atmosphere, towards (2 R 2-Cyclopentyl-2-hydroxy-2-acetic acid benzyl ester (compound I1-b, 2.0 g, 8.54 mmol) was added dropwise to a solution in DCM (60 mL) with 2,6-dimethylpyridine (1.3 mL, 11.1 mmol), followed by the addition of Tf₂O (1.9 mL, 11.1 mmol). After stirring for 30 min, the reaction mixture was heated to 25 °C and stirred for another 0.5 h. After the reaction was complete, the mixture was added to water (300 mL) and extracted with DCM (200 mL, three times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give (2) as a colorless oil. R 2-Cyclopentyl-2-(trifluoromethylsulfonyloxy)benzyl acetate (compound I1-c, 2.5 g). 1 H NMR (400 MHz, chloroform-) d ) delta = 7.38-7.27 (m, 5H), 5.26 (s, 2H), 5.07 (d, J = 4.0 Hz, 1H), 2.45 - 2.36 (m, 1H), 1.55-1.73 (m, 8H).

[0139] Step 3: Preparation (2 S 2-Cyclopentyl-2-(methylamino)acetic acid benzyl ester (compound I1-d).

[0140] At 0℃ towards (2 S Benzyl 2-cyclopentyl-2-(trifluoromethylsulfonyloxy)acetate (compound I1-c, 1.0 g, 2.73 mmol) was added to a solution of methylamine hydrochloride (0.9 g, 13.65 mmol) and cesium carbonate (6.3 g, 19.11 mmol) in THF (20 mL). The mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, the mixture was added to water (50 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (30 mL, three times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give (2) a colorless oil. S2-Cyclopentyl-2-(methylamino)acetic acid benzyl ester (compound I1-d, 267.0 mg). 1 H NMR (400 MHz, MeOD) δ = 7.43 - 7.32 (m, 5H), 5.28 - 5.18 (m,2H), 3.39 (d, J = 7.6 Hz, 1H), 2.44 (s, 3H), 2.19 - 2.10 (m, 1H), 1.88 - 1.79(m, 1H), 1.63 - 1.51 (m, 5H), 1.44 - 1.37 (m, 1H), 1.33 - 1.28 (m, 1H).

[0141] Step 4: Preparation (2 S )-2-[ tertiary [Butoxycarbonyl(methyl)amino]-2-cyclopentyl-benzyl acetate (compound I1-e).

[0142] At 0℃ towards (2 S 2-Cyclopentyl-2-(methylamino)acetic acid benzyl ester (compound I1-d, 236.0 mg, 0.95 mmol) was added to a solution in DCM (5 mL) with TEA (0.4 mL, 2.86 mmol), (Boc)₂O (416.5 mg, 1.91 mmol), and DMAP (11.7 mg, 0.1 mmol). The mixture was stirred at 25 °C for 1 h. After the reaction was complete, the mixture was added to water (30 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (20 mL, three times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give (2) a colorless oil. S )-2-[ tertiary [Butoxycarbonyl(methyl)amino]-2-cyclopentyl-acetic acid benzyl ester (compound I1-e, 200.0 mg). 1 H NMR (400 MHz, MeOD) δ = 7.38 - 7.27(m, 5H), 5.21 - 5.11 (m, 2H), 4.46 - 4.18 (m, 1H), 2.81 (d, J= 14.0 Hz, 3H), 2.50 - 2.40 (m, 1H), 1.90 - 1.82 (m, 1H), 1.73 - 1.54 (m, 6H), 1.45 - 1.38 (m, 9H), 1.31 - 1.28 (m, 1H).

[0143] Step 5: Preparation (2 S )-2-[ tertiary [Butoxycarbonyl(methyl)amino]-2-cyclopentyl-acetic acid (intermediate I1) Under a nitrogen atmosphere, towards (2) S )-2-[ tertiary [Butoxycarbonyl(methyl)amino]-2-cyclopentyl-benzyl acetate (compound I1-e, 200.0 mg, 0.58 mmol) was reacted with Pd (100.0 mg) on ​​activated carbon in a solution of methanol (5 mL). The mixture was degassed and purged three times with hydrogen. The mixture was hydrogenated at 25 °C for 12 hr. After the reaction was complete, the mixture was filtered and concentrated under vacuum to give (2) as a colorless oil. S )-2-[ tertiary [Butoxycarbonyl(methyl)amino]-2-cyclopentyl-acetic acid (intermediate I1, 136.0 mg). 1 H NMR (400 MHz, MeOD) tertiary = 2.84 (d, J = 5.6Hz, 3H), 2.46 - 2.34 (m, 1H), 1.96 - 1.87 (m, 1H), 1.73 - 1.57 (m, 5H), 1.46(d, J = 5.6 Hz, 9H), 1.39 - 1.28 (m, 3H).

[0144] Intermediate J1 Lithium; (2) R ,3 R 3-Cyclopropyl-1-methyl-azacyclopropane-2-carboxylate The compound was prepared according to the following scheme: Step 1: ( tertiary , R )- N -(cyclopropylmethylene)-4-methyl-benzenesulfonamide (compound J1-c) Add ( ) to a mixture of cyclopropaneformaldehyde (compound J1-a, 10.0 g, 142.67 mmol) in THF (200 mL) at 25 °C. R 4-Methylbenzenesulfinamide (compound J1-b, 22.2 g, 142.67 mmol) and titanium ethoxide (65.1 g, 285.35 mmol). The mixture was stirred at 75 °C for 2 hr under a nitrogen atmosphere. The reaction mixture was poured into brine (300 mL) and filtered through a diatomaceous earth mat. The mat was extracted with EtOAc (200 mL, twice). The combined filtrates were extracted with EtOAc (300 mL, twice). The combined organic layers were washed with brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography to give a white solid ( ). tertiary , R )- N -(cyclopropylmethylene)-4-methyl-benzenesulfonamide (compound J1-c, 25.3 g). 1 H NMR (400 MHz, CDCl3-) d ) tertiary = 7.56 (dd, J = 8.0, 1.6 Hz, 3H), 7.31 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H), 2.02 - 1.91 (m, 1H), 1.16 - 1.02 (m, 2H), 1.01 - 0.90 (m, 2H).

[0145] Step 2: (2) R ,3 R )-3-Cyclopropyl-1-[( R [-p-Tolylsulfinyl]azacyclopropane-2-carboxylic acid ethyl ester (compound J1-e) LiHMDS (244.1 mL, 244.1 mmol) was added to a mixture of ethyl 2-bromoacetate (compound J1-d, 27.1 mL, 244.1 mmol) in THF (753 mL) at -70 °C under a nitrogen atmosphere and stirred for 20 min. LiHMDS (244.1 mL, 244.1 mmol) was added to the reaction mixture at -70 °C. delta , R )- NA solution of 1,4-(cyclopropylmethylene)-4-methylbenzenesulfinamide (compound J1-c, 25.3 g, 122.05 mmol) in THF (260 mL) was prepared. After stirring at -70 °C for 1.5 hr, the reaction mixture was poured into ice water (300 mL) and extracted with EtOAc (200 mL, three times). The combined organic layers were washed with brine (520 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give a yellow oil (2... R ,3 R )-3-Cyclopropyl-1-[( R [-p-Tolylsulfinyl]azacyclopropane-2-carboxylic acid ethyl ester (compound J1-e, 17.0 g). MS calculated value 294.1 (MH) + ); Measured value 294.1 (MH) + ).

[0146] Step 3: (2) R ,3 R ethyl 3-cyclopropylazacyclopropane-2-carboxylate (compound J1-f) Under a nitrogen atmosphere at -65°C, towards (2 R ,3 R )-3-Cyclopropyl-1-[( R [-p-Tolylsulfinyl]azacyclopropane-2-carboxylate (compound J1-e, 43.5 g, 148.27 mmol) was added dropwise to a mixture of methyl magnesium bromide (98.0 mL, 294.0 mmol) in THF (1.5 L). After stirring for 5 min, a saturated aqueous solution of NH4Cl (1 L) was added to the reaction mixture at -65 °C. The reaction mixture was then heated to room temperature. The mixture was extracted with EtOAc (500 mL, three times). The combined organic layers were washed with brine (1.8 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography to give (2 g) as a yellow oil. R ,3 R Ethyl 3-cyclopropylazacyclopropane-2-carboxylate (compound J1-f, 22.0 g). MS calculated value 156.0 (MH). + ); Measured value 156.2 (MH) + ). 1H NMR (400 MHz, MeOD) δ = 4.32-4.16 (m, 2H), 2.73 (s, 1H), 1.98-1.55 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 0.87 - 0.72 (m, 1H), 0.69-0.56 (m, 1H), 0.55 - 0.48 (m, 1H), 0.47 - 0.40 (m, 1H), 0.40-0.22 (m, 1H).

[0147] Step 4: 1-[(2 R ,3 R [3-Cyclopropyl-1-methyl-azacyclopropane-2-yl]acetone (compound J1-g) To (2) R ,3 R Ethyl 3-cyclopropylazinopropane-2-carboxylate (compound J1-f, 17.0 g, 109.54 mmol) was added to a solution in DCE (340 mL) with methyl organoboronic acid (19.7 g, 328.63 mmol), sodium carbonate (34.8 g, 328.63 mmol), 2-pyridin-2-ylpyridine (17.1 g, 109.54 mmol), and copper acetate (19.9 g, 109.54 mmol). The mixture was stirred at 45 °C for 12 hr under air atmosphere. The mixture was diluted with saturated NH4Cl aqueous solution (500 mL) and extracted with DCM (400 mL, three times). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give 1-[(2)] as a yellow oil. R ,3 R [3-Cyclopropyl-1-methyl-azacyclopropane-2-yl]acetone (Compound J1-g, 13.0 g). MS calculated value 170.1 (MH) + ); Measured value 170.1 (MH) + ). 1H NMR (400 MHz, CDCl3)δ = 4.28 - 4.18 (m, 2H), 2.40 (s, 3H), 2.09 - 2.05 (m, 1H), 1.31 - 1.27 (m,3H), 1.24 - 1.20 (m, 1H), 0.96 - 0.84 (m, 1H), 0.65 - 0.56 (m, 1H), 0.52 -0.42 (m, 2H), 0.29 - 0.19 (m, 1H).

[0148] Step 5: Lithium; (2 R ,3 R 3-Cyclopropyl-1-methyl-azacyclopropane-2-carboxylate (Intermediate J1) At 0℃, towards 1-[(2 R ,3 R [3-Cyclopropyl-1-methyl-azacyclopropane-2-yl]acetone (compound J1-g, 9.5 g, 56.14 mmol) was added to a mixture of THF (50 mL) with LiOH. A solution of H₂O (4.71 g, 112.28 mmol) in water (50 mL) was prepared. The mixture was stirred at 0 °C for 0.5 h, and then heated to 25 °C for 2.5 h. delta Concentrate to remove THF, wash with DCM (20 mL, twice). Freeze-dry the aqueous phase to give lithium as a yellow solid; (2) R ,3 R 3-Cyclopropyl-1-methyl-azacyclopropane-2-carboxylate (intermediate J1, 9.0 g). MS calculated value 142.0 (MH). + ); Measured value 142.0 (MH) + ).

[0149] Intermediate J2 Lithium; (2) R ,3 R )-1-[( R )-tert-butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carboxylate The compound was prepared according to the following scheme: (R) (Refers to relative configuration) Step 1: ( delta , R )-N -(cyclopropylmethylene)-2-methyl-propane-2-sulfinamide (compound J2-b) At 25℃ towards ( R 2-Methylpropane-2-sulfinamide (compound J2-a, 5.0 g, 41.25 mmol) was dissolved in DCM (250 mL) with cyclopropaneformaldehyde (J1-a, 5.8 g, 82.1 mmol) and copper(II) sulfate (19.8 g, 123.88 mmol). After stirring at 25 °C under a nitrogen atmosphere for 48 hr, the reaction mixture was filtered. The collected solid was washed with DCM (100 mL, three times), and the filtrate was concentrated under vacuum to give as a yellow oil. delta , R )- N -(cyclopropylmethylene)-2-methyl-propane-2-sulfinamide (compound J2-b, 7.1 g). MS calculated value 174.1 (MH) + ); Measured value 174.3 (MH) + ); 1 H NMR (400 MHz, DMSO- d 6) delta = 7.42 (d, J = 7.8 Hz,1H), 2.06 - 1.92 (m, 1H), 1.13 - 1.07 (m, 11H), 1.01 - 0.93 (m, 2H).

[0150] Step 2: (2) R ,3 R )-1-[( R )- tertiary [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carboxylic acid ethyl ester (compound J2-c) At -78℃ under a nitrogen atmosphere, towards ( tertiary , R )- N-(cyclopropylmethylene)-2-methyl-propane-2-sulfinamide (compound J2-b, 7.0 g, 40.4 mmol) and LiHMDS (80.8 mL, 80.79 mmol) in THF (120 mL) were mixed with ethyl 2-bromoacetate (compound J1-d, 9.0 mL, 80.79 mmol). After stirring at -70 °C for 6 hr, the reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (100 mL, three times). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give a pale yellow oil (2... R ,3 R )-1-[( R )- tertiary [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carboxylic acid ethyl ester (compound J2-c, 6.4 g). MS calculated value 260.1 (MH) + ); Measured value 260.1 (MH) + ); 1 H NMR (400 MHz, chloroform-) d ) tertiary = 4.20 - 4.03 (m, 2H), 3.20 (d, J =7.2 Hz, 1H), 1.92 (t, J = 6.8 Hz, 1H), 1.17 (t, J = 7.2 Hz, 3H), 1.12 (s, 9H), 0.94 - 0.83 (m, 1H), 0.49 - 0.34 (m, 3H), 0.23 - 0.13 (m, 1H).

[0151] Step 3: Lithium; (2 R ,3 R )-1-[( R )- in vacuo [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carboxylate (intermediate J2) At 0℃ towards (2 R ,3 R )-1-[( R )- delta[Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carboxylate (compound J2-c, 1.8 g, 6.94 mmol) was mixed with lithium hydroxide (582.4 mg, 13.88 mmol) in a solution of THF (10 mL) / water (10 mL). After stirring at 0 °C for 2 hr, the reaction mixture was freeze-dried to give lithium as a white solid; (2 R ,3 R )-1-[( R )- tertiary [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carboxylate (intermediate J2, 2.4 g) was used directly in the next step without purification. MS calculated value 232.1 (MH) + ), Measured value 232.1 (MH) + ).

[0152] intermediate K (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ] Octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione Similar to the preparation of intermediate E, the title compound was prepared by using morpholine instead of 1-(2,2,2-trifluoroethyl)piperazine (compound E1).

[0153] Example 1 N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .022,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide The compound was prepared according to the following scheme: Step 1: Preparation N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N -Methylcarbamate tertiary Butyl ester (compound 1a) At 0℃ towards (2 S )-2-[ tertiary [Butoxycarbonyl(methyl)amino]-2-cyclopentyl-acetic acid (intermediate I1, 41.0 mg, 0.16 mmol) was added to a solution in DMF (1 mL) with DIEA (0.11 mL, 0.61 mmol) and COMU (68.3 mg, 0.16 mmol). After stirring for 5 min, (7) was added to the reaction mixture. S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26[[Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate G, 90.0 mg, 0.12 mmol)] and stirred at room temperature for 1 h. After the reaction was complete, the mixture was added to water (30 mL) and extracted with ethyl acetate (20 mL, three times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give a yellow solid.]] N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N -Methylcarbamate delta Butyl ester (compound 1a, 114.0 mg). MS calculated value 973.5 (MH). + ); Measured value 973.7 (MH) + ).

[0154] Step 2: Preparation (2 S )-2-cyclopentyl- N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [28-octadec-1(25),2,5(28),19,22(26),23-hexene-7-yl]-2-(methylamino)acetamide (compound 3b).

[0155] At 0℃ N -[(1S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N -Methylcarbamate delta Butyl ester (compound 1a, 114.0 mg, 0.12 mmol) was added to a solution of TFA (1.5 mL, 19.47 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 0.5 h. After the reaction was complete, the mixture was concentrated under vacuum to remove most of the solvent, then poured into a saturated aqueous solution of NaHCO3 (40 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid (2... S )-2-cyclopentyl- N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexaden-7-yl]-2-(methylamino)acetamide (compound 1b, 100.0 mg). MS calculated value 873.5 (MH) + ); Measured value 873.6 (MH) + ).

[0156] Step 3: Prepare 4-[[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S)-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-methyl-carbamoyl]-4-fluoro-piperidine-1-carboxylic acid delta Butyl ester (compound 1d).

[0157] At 0℃, towards (2 S )-2-cyclopentyl- N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [[octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]-2-(methylamino)acetamide (compound 1b, 90.0 mg, 0.1 mmol)) was added to a solution of 1-Boc-4-fluoro-4-piperidinecarboxylic acid (compound 1c, 76.5 mg, 0.31 mmol), DIEA (0.2 mL, 1.03 mmol), and CMPI (79.0 mg, 0.31 mmol) in DMF (1.5 mL). The mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was added to water (30 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give 4-[[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S[17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-methyl-carbamoyl]-4-fluoro-piperidine-1-carboxylic acid delta Butyl ester (compound 1d, 103.0 mg). MS calculated value 1102.6 (MH). + ); Measured value 1102.6 (MH) + ).

[0158] Step 4: Preparation N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide (compound 1e).

[0159] At 0℃, towards 4-[[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-methyl-carbamoyl]-4-fluoro-piperidine-1-carboxylic acid ​Butyl ester (compound 1d, 103.0 mg, 0.09 mmol) was added to a solution of TFA (1.55 mL, 20.05 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 1 h. After the reaction was complete, a saturated aqueous solution of NaHCO3 (40 mL) was added to the mixture and it was extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid. N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-fluoro- N 1,4-methyl-piperidine-4-carboxamide (compound 1e, 90.0 mg). MS calculated value 1002.6 (MH). + ); Measured value 1002.6 (MH) + ).

[0160] Step 5: Preparation N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N-Methyl-piperidine-4-carboxamide (Example 1).

[0161] At 0℃, towards lithium; (2) R ,3 R 3-Cyclopropyl-1-methyl-azacyclopropane-2-carboxylate (intermediate J1, 23.5 mg, 0.16 mmol) was added to a solution of 3-cyclopropyl-1-methyl-azacyclopropane-2-carboxylate in DMF (1.5 mL) along with DIEA (0.1 mL, 0.4 mmol) and HATU (60.7 mg, 0.16 mmol). After stirring for 10 minutes, DIEA (0.1 mL, 0.4 mmol) and HATU (60.7 mg, 0.16 mmol) were added. N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-fluoro- N 4-Methylpiperidine-4-carboxamide (compound 1e, 80.0 mg, 0.08 mmol) was stirred at room temperature for 1 h. After the reaction was complete, the mixture was added to water (30 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by preparative HPLC to give a white solid. N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N 4-Methylpiperidine-4-carboxamide (Example 1, 35.7 mg). MS calculated value 1125.6 (MH). + ); Measured value 1125.7 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ = 8.68 - 8.63 (m, 1H),8.40 (d, J = 2.8 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.35 - 7.29 (m, 2H), 5.78 - 5.71(m, 1H), 4.58 (s, 1H), 4.45 - 4.32 (m, 1H), 4.31 - 4.09 (m, 6H), 3.86 (s,4H), 3.78 - 3.70 (m, 2H), 3.56 - 3.49 (m, 1H), 3.46 - 3.40 (m, 1H), 3.30 -3.25 (m, 5H), 3.24 - 3.15 (m, 4H), 3.15 - 3.07 (m, 1H), 3.04 - 2.99 (m, 1H),2.86 - 2.77 (m, 1H), 2.66 - 2.60 (m, 1H), 2.60 - 2.53 (m, 1H), 2.48 - 2.43(m, 1H), 2.43 - 2.33 (m, 4H), 2.27 - 2.00 (m, 5H), 1.97 - 1.92 (m, 1H), 1.83- 1.57 (m, 9H), 1.53 - 1.48 (m, 1H), 1.42 (d, J = 6.0 Hz, 3H), 1.37 - 1.31 (m,1H), 1.24 - 1.17 (m, 1H), 1.00 - 0.91 (m, 6H), 0.61 - 0.55 (m, 2H), 0.50 (s,4H), 0.47 - 0.39 (m, 1H), 0.35 - 0.25 (m, 1H).

[0162] Example 2 N -[(1 S )-1-cyclopentyl-2-[[(7S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide Similar to the preparation in Example 1, by using (7) S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate F) replaced (7)] S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 The title compound was prepared from octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate G). Example 2 (10.3 mg) was obtained as a white solid. MS calculated value 1206.6 (MH) +); Measured value 1206.8 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ =8.68 - 8.62 (m, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.34 - 7.29(m, 2H), 5.80 - 5.72 (m, 1H), 4.60 (s, 3H), 4.49 - 4.39 (m, 2H), 4.26 - 4.14(m, 5H), 3.78 - 3.69 (m, 2H), 3.35 - 3.34 (m, 3H), 3.26 - 3.17 (m, 4H), 3.17- 3.09 (m, 3H), 3.09 - 2.95 (m, 2H), 2.90 - 2.82 (m, 5H), 2.66 - 2.54 (m,2H), 2.50 - 2.45 (m, 1H), 2.40 (d, J = 2.0 Hz, 3H), 2.23 - 2.00 (m, 5H), 1.80 -1.59 (m, 8H), 1.54 - 1.48 (m, 1H), 1.42 (d, J = 6.0 Hz, 3H), 1.35 - 1.28 (m,5H), 1.25 - 1.18 (m, 1H), 1.00 - 0.90 (m, 6H), 0.63 - 0.55 (m, 2H), 0.54 -0.42 (m, 5H), 0.38 - 0.26 (m, 1H).

[0163] Example 3 N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide Similar to the preparation in Example 1, by using (7) S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate C) replaced by (7)] S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 The title compound was prepared from octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate G). Example 3 (14.0 mg) was obtained as a white solid. MS calculated value 1192.6 (MH). + ); Measured value 1192.8 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ =8.70 - 8.64 (m, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.72 - 7.63 (m, 1H), 7.46 (d, J=12.8 Hz, 1H), 7.34 - 7.27 (m, 1H), 5.74 - 5.64 (m, 1H), 5.19 - 5.06 (m, 1H), 4.83 - 4.77 (m, 2H), 4.65 - 4.55 (m, 1H), 4.49 - 4.35 (m, 2H), 4.28 - 4.14(m, 3H), 3.82 - 3.67 (m, 2H), 3.59 - 3.34 (m, 6H), 3.26 - 3.21 (m, 3H), 3.20- 3.01 (m, 3H), 2.87 - 2.77 (m, 1H), 2.67 - 2.55 (m, 6H), 2.50 - 2.44 (m,1H), 2.42 - 2.33 (m, 7H), 2.26 - 2.18 (m, 2H), 2.15 - 1.92 (m, 3H), 1.86 -1.47 (m, 10H), 1.43 (d, J = 6.4 Hz, 3H), 1.39 - 1.27 (m, 2H), 1.26 - 1.16 (m,1H), 1.00 - 0.93 (m, 3H), 0.62 - 0.41 (m, 7H), 0.36 - 0.25 (m, 1H).

[0164] Example 4 N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide Similar to the preparation in Example 1, by using (7) S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate E) replaced (7)] S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 The title compound was prepared from octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate G). Example 4 (22.3 mg) was obtained as a white solid. MS calculated value 1260.6 (MH). + ); Measured value 1260.8 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ = 8.68 - 8.65 (m, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.46(d, J= 12.8 Hz, 1H), 7.31 (s, 1H), 5.72 - 5.68 (m, 1H), 5.18 - 5.10 (m, 1H), 4.65 - 4.60 (m, 1H), 4.50 - 4.28 (m, 3H), 4.28 - 4.21 (m, 2H), 4.18 - 4.14(m, 1H), 3.80 - 3.68 (m, 2H), 3.58 - 3.39 (m, 3H), 3.34 - 3.32 (m, 4H), 3.28- 3.19 (m, 4H), 3.14 (q, J = 9.6 Hz, 4H), 2.87 (t, J = 4.8 Hz, 4H), 2.84 - 2.77(m, 1H), 2.59 (d, J = 14.0 Hz, 2H), 2.25 - 2.08 (m, 1H), 2.40 (s, 3H), 2.26 -2.08 (m, 4H), 1.99 - 1.94 (m, 1H), 1.86 - 1.74 (m, 3H), 1.71 - 1.59 (m, 5H),1.58 - 1.46 (m, 2H), 1.43 (d, J = 6.0 Hz, 3H), 1.38 - 1.26 (m, 2H), 1.26 - 1.20(m, 1H), 0.97 (s, 3H), 0.65 - 0.46 (m, 5H), 0.44 (s, 3H), 0.36 - 0.27 (m,1H).

[0165] Example 5 N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-Dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide Similar to the preparation in Example 1, by using (7) S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate D) replaced (7)] S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 The title compound was prepared from octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate G). Example 5 (11.6 mg) was obtained as a white solid. MS calculated value 1138.6 (MH). + ); Measured value 1138.7 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ = 8.68 - 8.61(m, 1H), 8.41 (d, J = 3.2 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.35 - 7.29 (m, 2H), 5.75 (d, J= 9.2 Hz, 1H), 4.48 - 4.39 (m, 2H), 4.29 - 4.09 (m, 6H), 3.78 - 3.70(m, 2H), 3.58 - 3.43 (m, 3H), 3.37 - 3.34 (m, 4H), 3.23 - 3.20 (m, 2H), 3.17- 2.99 (m, 3H), 2.85 - 2.79 (m, 1H), 2.69 - 2.58 (m, 6H), 2.52 - 2.42 (m,2H), 2.40 (d, J = 1.6 Hz, 3H), 2.36 (s, 3H), 2.25 - 2.08 (m, 4H), 1.98 - 1.93(m, 1H), 1.84 - 1.58 (m, 9H), 1.54 - 1.49 (m, 1H), 1.42 (d, J = 6.0 Hz, 3H), 1.40 - 1.27 (m, 2H), 1.25 - 1.18 (m, 1H), 1.02 - 0.92 (m, 6H), 0.65 - 0.41 (m, 8H), 0.36 - 0.28 (m, 1H).

[0166] Example 6 N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [28-octadec-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]- N 1-Methyl-piperazine-1-carboxamide The compound was prepared according to the following scheme: Step 1: Preparation N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22 ,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N 6b methyl-carbamate At 0℃ towards (2 S DIEA (0.2 mL, 0.92 mmol) was added to a mixture of 2-[benzyloxycarbonyl(methyl)amino]-2-cyclopentyl-acetic acid (compound 6a, 87.2 mg, 0.3 mmol) and COMU (128.2 mg, 0.3 mmol) in DMF (1 mL). After stirring for 0.5 h, DIEA (7) was added to the reaction mixture at 0 °C. S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate E, 200.0 mg, 0.23 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under vacuum to give a residue, which was purified by reversed-phase chromatography to give an orange solid.] N -[(1 S)-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N β-methylcarbamate (compound 6b, 170.0 mg). MS calculated value 1142.5 (MH). + ); Measured value 1142.6 (MH) + ).

[0167] Step 2: Preparation (2 S )-2-cyclopentyl- N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [28-C-1(25),2,5(28),19,22(26),23-hexaden-7-yl]-2-(methylamino)acetamide (compound 6c) Add to a solution of 10% Pd(OH)2 / C (207.5 mg, 0.15 mmol) in methanol (5 mL) N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S[17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N 2-methyl-carbamate benzyl ester (compound 6b, 170.0 mg, 0.15 mmol). The mixture was hydrogenated for 1 h under an atmosphere. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated to give a crude product as a yellow solid (2... S )-2-cyclopentyl- N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexaden-7-yl]-2-(methylamino)acetamide (compound 6c, 170.0 mg), which is used in the next step. MS calculated value 1008.4 (MH) + ); Measured value 1008.5 (MH) + ).

[0168] Step 3: Prepare 4-[[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .19,13 .0 22 ,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-methyl-carbamoyl]-piperazine-1-carboxylic acid ​ Butyl ester (compound 6d) To (2) S )-2-cyclopentyl- N -[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [[Octadecano-1(25),2,5(28),19,22(26),23-hexene-7-yl]-2-(methylamino)acetamide (compound 6c, 85.0 mg, 0.08 mmol) in a solution of DMA (0.5 mL) with added DIEA (43.6 mg, 0.34 mmol) and 4-chlorocarbonylpiperazine-1-carboxylic acid] ​ Butyl ester (25.2 mg, 0.1 mmol). The mixture was stirred at 80 °C for 24 hr. The mixture was purified by reversed-phase chromatography to give 4-[[(1] ester as a yellow solid. S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-methyl-carbamoyl]piperazine-1-carboxylic acid ​Butyl ester (compound 6d, 55.0 mg). MS calculated value 1220.5 (MH). + ); Measured value 1220.5 (MH) + ).

[0169] Step 4: Preparation N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22 ,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N 1-Methyl-piperazine-1-carboxamide (compound 6e) To 4-[[(1) S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-methyl-carbamoyl]piperazine-1-carboxylic acid ​ Butyl ester (compound 6d, 55.0 mg, 0.05 mmol) was added to a solution of TFA (0.5 mL, 6.73 mmol) in DCM (1 mL). The mixture was stirred at 25 °C for 1 h. ​Concentrate to obtain a residue. Dilute the residue with a saturated aqueous solution of NaHCO3 (1 mL) and extract with 2-methyltetrahydrofuran (5 mL, five times). Dry the combined organic layers over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain a yellow solid. N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N 1-Methyl-piperazine-1-carboxamide (compound 6e, 50.0 mg). MS calculated value 1120.5 (MH). + ); Measured value 1120.4 (MH) + ).

[0170] Step 5: Preparation N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22 ,26 [28-octadec-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]- N 1-Methyl-piperazine-1-formamide (Example 6) At 0℃, towards lithium; (2) R ,3 R 3-Cyclopropyl-1-methyl-azacyclopropane-2-carboxylate (intermediate J1, 6.6 mg, 0.04 mmol) and DIEA (46.2 mg, 0.36 mmol) were added to a solution of HATU (10.5 mg, 0.04 mmol) in DMF (1 mL). After stirring for 0.1 h, the reaction mixture was further added to the solution. N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]- N 1-Methyl-piperazine-1-carboxamide (compound 6e, 50.0 mg, 0.04 mmol) was stirred at room temperature for an additional 0.5 h. The mixture was purified by preparative-HPLC to give a white solid. N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [28-octadec-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-N 1-Methyl-piperazine-1-carboxamide (Example 6, 6.5 mg). MS calculated value 1243.6 (MH). + ); Measured value 1243.7 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ = 8.68 (d, J = 3.8 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 13.2 Hz, 1H), 7.30(s, 1H), 5.74 (d, J = 9.2 Hz, 1H), 5.21 - 5.07 (m, 1H), 4.96 - 4.91 (m, 2H), 4.51 - 4.37 (d, J = 12.0 Hz, 1H), 4.29 - 4.20 (m, 1H), 4.19 - 4.13 (m, 2H), 3.89 - 3.75 (m, 4H), 3.73 - 3.66 (d, J = 11.2 Hz, 1H), 3.60 - 3.47 (m, 3H), 3.34 (d, J = 3.6 Hz, 6H), 3.27 - 3.17 (m, 2H), 3.17 - 3.08 (m, 3H), 2.97 (s,3H), 2.87 (t, J = 4.4 Hz, 4H), 2.84 - 2.76 (m, 1H), 2.63 - 2.57 (m, 1H), 2.57 -2.47 (m, 1H), 2.45 (d, J = 6.8 Hz, 1H), 2.40 (s, 3H), 2.26 - 2.18 (m, 1H), 2.04- 1.93 (m, 1H), 1.90 - 1.74 (m, 3H), 1.71 - 1.56 (m, 5H), 1.52 (t, J = 7.2 Hz, 1H), 1.43 (d, J= 6.0 Hz, 3H), 1.35 - 1.18 (m, 4H), 0.97 (s, 3H), 0.65 - 0.57(m, 1H), 0.57 - 0.49 (m, 2H), 0.49 - 0.42 (m, 4H), 0.34 - 0.27 (m, 1H).

[0171] Example 8 N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropylazacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide The compound was prepared according to the following scheme: Step 1: 1-[(2 R ,3 R )-1-[( R )- ​ [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carbonyl]- N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26[Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-fluoro- N 4-Methylpiperidine-4-carboxamide (compound 8a) At 0℃ N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-fluoro- N 1,3-methyl-piperidine-4-carboxamide (compound 1e, 80.0 mg, 0.08 mmol) and lithium; (2) R ,3 R )-1-[( R )- ​ [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carboxylate (intermediate J2, 56.8 mg, 0.24 mmol) was added to a mixture in DMF (2 mL) with DIEA (0.14 mL, 0.8 mmol), followed by T4P (172.5 mg, 0.24 mmol). After stirring at 25 °C for 1 h, the mixture was poured into ice water (10 mL) and extracted with EtOAc (5 mL, three times). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by reversed-phase chromatography to give 1-[(2] cyclopropane-2-carboxylate as a white solid. R ,3 R )-1-[( R )- ​ [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carbonyl]- N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S[17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 1. 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-fluoro- N 4-Methylpiperidine-4-carboxamide (compound 8a, 50.0 mg). MS calculated value 1215.6 (MH). + ); Measured value 1215.6 (MH) + ).

[0172] Step 2: N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropylazacyclopropane-2-carbonyl]-4-fluoro- N 4-Methylpiperidine-4-carboxamide (Example 8) 1-[(2) R ,3 R )-1-[( R )- ​ [Butylsulfinyl]-3-cyclopropyl-azacyclopropane-2-carbonyl]- N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S[17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 [Octadecacarbon-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-fluoro- N A solution of methylpiperidin-4-carboxamide (compound 8a, 50.0 mg, 0.04 mmol) in THF (2 mL) was cooled to 0 °C and Et3SiH (95.7 mg, 0.82 mmol) and HI were added dropwise. H2O (21.1 mg, 0.08 mmol). After stirring at 25 °C for 1 h, the pH of the reaction mixture was adjusted to 8 at 0 °C by adding an aqueous solution of NaHCO3. The mixture was then extracted with EtOAc (5 mL, three times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by preparative-HPLC to obtain a white solid. N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropylazacyclopropane-2-carbonyl]-4-fluoro- N 4-Methylpiperidine-4-carboxamide (Example 8, 24.4 mg). MS calculated value 1111.6 (MH). + ); Measured value 1111.6 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ = 8.68 (t,J = 6.4 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.67 -7.57 (m, 1H), 7.39 - 7.30 (m, 2H), 5.74 (d, J = 4.8 Hz, 1H), 4.95 (s, 2H), 4.53- 4.34 (m, 2H), 4.33 - 4.07 (m, 5H), 3.91 - 3.84 (m, 4H), 3.81 - 3.72 (m,2H), 3.63 - 3.52 (m, 1H), 3.47 - 3.37 (m, 1H), 3.34 - 3.28 (m, 8H), 3.25 -3.19 (m, 3H), 3.10 - 3.00 (m, 2H), 2.89 - 2.76 (m, 1H), 2.69 - 2.54 (m, 2H),2.31 - 2.06 (m, 4H), 1.99 - 1.91 (m, 1H), 1.87 - 1.55 (m, 9H), 1.44 (d, J = 6.0Hz, 3H), 1.41 - 1.29 (m, 2H), 1.28 - 1.17 (m, 1H), 1.06 - 0.88 (m, 6H), 0.74- 0.30 (m, 8H).

[0173] Example 9 N- [(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide Similar to the preparation in Example 1, by using (7) S ,13 S )-7-amino-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [Octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate H) replaced (7)] S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 The title compound was prepared from octadecano-1(25),2,5(28),19,22(26),23-hexaden-8,14-dione (intermediate G). Example 9 (11.1 mg) was obtained as a white solid. MS calculated value 1164.6 (MH). + ); Measured value 1164.6 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ = 8.65 (dd, J =2.8, 7.2 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.62 (dd, J = 2.4, 12.0 Hz, 1H), 7.34- 7.27 (m, 2H), 5.75 (d, J = 8.8 Hz, 1H), 4.94 - 4.89 (m, 2H), 4.86 - 4.81 (m,2H), 4.49 - 4.34 (m, 2H), 4.28 - 4.13 (m, 5H), 3.74 (q, J= 11.2 Hz, 2H), 3.60- 3.50 (m, 1H), 3.47 - 3.41 (m, 1H), 3.29 - 3.26 (m, 1H), 3.25 - 3.19 (m,3H), 3.19 - 2.96 (m, 3H), 2.86 - 2.77 (m, 5H), 2.66 - 2.53 (m, 2H), 2.50 -2.45 (m, 1H), 2.42 - 2.38 (m, 3H), 2.25 - 1.91 (m, 6H), 1.85 - 1.60 (m, 9H),1.59 - 1.47 (m, 2H), 1.42 (d, J = 6.4 Hz, 3H), 1.39 - 1.27 (m, 3H), 1.26 - 1.17(m, 1H), 1.03 - 0.96 (m, 3H), 0.95 - 0.90 (m, 3H), 0.63 - 0.44 (m, 11H), 0.38- 0.25 (m, 1H).

[0174] Example 10 N -[(1 S )-1-cyclobutyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide Similar to the preparation in Example 1, by using (2) S )-2-cyclobutyl-2-[9 H -fluorene-9-ylmethoxycarbonyl(methyl)amino]acetic acid and piperidine / DMF (step 2) replace (2 S)-2-[ ​ The title compound was prepared by reacting [butoxycarbonyl(methyl)amino]-2-cyclopentyl-acetic acid (intermediate I1) and TFA / DCM (step 2). Example 10 (35.7 mg) was obtained as a white solid. MS calculated value 1111.6 (MH) + ); Measured value 1111.7 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​ =8.70 - 8.59 (m, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.67 - 7.55 (m, 1H), 7.37 - 7.26(m, 2H), 5.86 - 5.69 (m, 1H), 5.10 - 5.02 (m, 1H), 4.97 - 4.92 (m, 1H), 4.50- 4.34 (m, 2H), 4.34 - 4.07 (m, 6H), 3.88 - 3.83 (m, 4H), 3.79 - 3.63 (m,2H), 3.59 - 3.39 (m, 3H), 3.29 - 3.25 (m, 4H), 3.18 - 3.11 (m, 3H), 3.07 -2.91 (m, 3H), 2.86 - 2.74 (m, 1H), 2.69 - 2.59 (m, 1H), 2.50 - 2.44 (m, 1H), 2.39 (s, 3H), 2.35 - 2.26 (m, 1H), 2.25 - 1.88 (m, 11H), 1.85 - 1.71 (m, 2H),1.69 - 1.58 (m, 1H), 1.55 - 1.46 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.05-0.96(m, 3H), 0.95-0.88 (m, 3H), 0.61 - 0.41 (m, 7H), 0.37-0.23 (m, 1H).

[0175] Example 11 N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S[17.5.2.1]-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methylpiperidine-4-carboxamide Similar to the preparation in Example 1, by using (7) S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S [-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.12,5.19,13.022,26]octadec-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate K) substituted (7 S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl) ... 2,5 .1 9,13 .0 22,26 The title compound was prepared from octadecano-1(25),2,5(28),19,22(26),23-hexane-8,14-dione (intermediate G). Example 11 (39.9 mg) was obtained as a white solid. MS calculated value 1179.5 (MH). + ); Measured value 1179.7 (MH) + ). 1 H NMR (400 MHz, methanol-) d 4) ​= 8.72 - 8.61(m, 1H), 8.42 (d, J = 2.80 Hz, 1H), 7.67 (d, J = 13.6 Hz, 1H), 7.46 (d, J = 12.4Hz, 1H), 7.31 (d, J = 1.60 Hz, 1H), 5.70 (d, J = 8.80 Hz, 1H), 5.25 - 4.99 (m,1H), 4.66 - 4.53 (m, 1H), 4.51 - 4.33 (m, 2H), 4.29 - 4.11 (m, 3H), 3.86 ( t, J = 4.80 Hz, 4H), 3.81 - 3.74 (m, 1H), 3.74 - 3.66 (m, 1H), 3.65 - 3.34 (m,3H), 3.33 (s, 3H), 3.29 - 3.26 (m, 4H), 3.23 (t, J = 6.0 Hz, 3H), 3.19 - 3.10(m, 2H), 3.09 - 2.98 (m, 1H), 2.87 - 2.77 (m, 1H), 2.59 (d, J = 14.4 Hz, 2H), 2.47 (t, J = 7.2 Hz, 1H), 2.40 (s, 3H), 2.26 - 2.17 (m, 2H), 2.17 - 2.00 (m,2H), 1.99 - 1.91 (m, 1H), 1.91 - 1.66 (m, 5H), 1.63 (d, J = 8.40 Hz, 3H), 1.55- 1.48 (m, 1H), 1.43 (d, J = 6.1 Hz, 3H), 1.39 - 1.25 (m, 2H), 1.25 - 1.12 (m,1H), 0.97 (d, J = 2.0 Hz, 3H), 0.69 - 0.34 (m, 7H), 0.34 - 0.13 (m, 1H).

[0176] Biological examples Compound A23 from WO2023060253 (page 31 of Table 1) is cited as a reference compound of the present invention.

[0177] (A23) Example 12 Cell viability assay The purpose of this cellular assay was to determine the effect of the tested compound on the proliferation of human cancer cell lines AGS (ATCC-CRL-1739) and HCT-116 (ATCC-CCL-247) during a 3-day or 5-day treatment period by using CellTiter-Glo to quantify the amount of ATP present at the endpoint.

[0178] 3D Cell Viability Assay: Cells were seeded at 600 cells / well (AGS) and 100 cells / well (HCT-116) in 96-well microplates (Corning-4520) and incubated overnight. On the day of assay, diluted compound was added at a final concentration of 0.5% DMSO. After 5 days of incubation, an equal volume of CellTiter-Glo@3D (Promega-G9681) was added to each well. After 30 min of incubation, the signal (luminescence) was read using EnVision. IC50 50 The concentration response was determined by fitting a 4-parameter S-type concentration response model.

[0179] Table 1. Examples of the present invention and the activity of compounds in KRAS cell viability assay Example 13 pERK inhibition assay This assay aimed to measure the ability of the tested compounds to inhibit ERK phosphorylation, KRAS G12D in AGS cells, and downstream signaling of KRAS G13D in HCT-116 cells. AGS (ATCC-CRL-1739) cells and HCT-116 (ATCC-CCL-247) cells were grown and maintained in RPMI-1640 medium (ThermoFisher Scientific) containing 10% fetal bovine serum and 1% penicillin / streptomycin. One day prior to compound addition, cells were seeded at densities of 20,000 cells / well for AGS and 20,000 cells / well for HCT-116 in tissue culture-treated 96-well plates (Corning-3699) and allowed to adhere overnight. The diluted compound was then added at a final concentration of 0.5% DMSO. After 4 hours of incubation, the culture medium was removed, 100 μL of 4% formaldehyde was added, and the assay plate was incubated at room temperature for 20 minutes. The plate was then washed once with phosphate-buffered saline (PBS) and permeated with 100 µL of frozen methanol for 10 minutes. Non-specific antibodies binding to the plate were blocked for at least 1 hour at room temperature using 50 µL of 1X BSA blocking buffer (Thermo-37520, diluted 10-fold with phosphate-buffered saline (PBST)).

[0180] The amount of phosphorylated ERK was determined using an antibody specific to the phosphorylated form of ERK. The primary antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1:300 in blocking buffer, with 50 µL aliquoted into each well and incubated overnight at 4°C. Cells were washed five times with PBST for 5 minutes. The secondary antibody (HRP-linked anti-rabbit IgG, CST-7074, Cell Signaling Technology) was diluted 1:1000 in blocking buffer, with 50 µL added to each well and incubated at room temperature for 1–2 hours. Cells were washed five times with PBST for 5 minutes, 100 µL of TMB ELISA substrate (abcam-ab171523) was added, and the cells were gently agitated for 20 minutes. 50 µL of stop solution (abcam-ab171529) was added, and the signal (OD450) was read using EnVision.

[0181] IC 50 The concentration response was determined by fitting a 4-parameter S-type concentration response model.

[0182] Table 3. Examples of the present invention and the activity of compounds in KRAS pERK inhibition assays

Claims

1. A compound of formula (I), (I)， in R 1 for ;where R 6 C 1-6 Alkyl; W is C 3-7 cycloalkyl (C 1-6 Alkyl) azircyclopropane or C 3-7 Cycloalkylazirocyclopropane; R 2 C 3-7 cycloalkyl; R 3 It is a halogen; R 4 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 Morpholine-, (halogenated C) 1-6 alkyl)piperazinyl, C 3-7 Cycloalkylpiperazine or C 1-6 alkylpiperazine group; Or its pharmaceutically acceptable salt.

2. A compound of formula (Ia), (I), in R 1 for ;where R 6 C 1-6 Alkyl; W is C 3-7 cycloalkyl (C 1-6 Alkyl) azircyclopropane or C 3-7 Cycloalkylazirocyclopropane; R 2 C 3-7 cycloalkyl; R 3 It is a halogen; R 4 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 Morpholine-, (halogenated C) 1-6 alkyl)piperazinyl, C 3-7 Cycloalkylpiperazine or C 1-6 alkylpiperazine group; Or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, wherein W is C 3-7 cycloalkyl (C 1-6 Alkyl) Azacyclopropane.

4. The compound according to any one of claims 1 to 3, wherein W is 3-cyclopropyl-1-methyl-azacyclopropane-2-yl.

5. The compound according to any one of claims 1 to 4, wherein R 6 It is a methyl group.

6. The compound according to any one of claims 1 to 5, wherein R 2 It is cyclopentyl.

7. The compound according to any one of claims 1 to 6, wherein R 3 It is fluorine.

8. The compound according to any one of claims 1 to 7, wherein R 4 It is ethyl or 2,2,2-trifluoroethyl.

9. The compound according to any one of claims 1 to 8, wherein R 5 Morpholine or C 1-6 Alkylpiperazine group.

10. The compound according to any one of claims 1 to 9, wherein R 5 It is morpholino or 4-methylpiperazin-1-yl.

11. The compound according to claim 1 or 2, wherein... R 1 for ;where R 6 C 1-6 Alkyl; W is C 3-7 cycloalkyl (C 1-6 Alkyl) aziridine propane; R 2 C 3-7 cycloalkyl; R 3 It is a halogen; R 4 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 Morpholine or C 1-6 alkylpiperazine group; Or its pharmaceutically acceptable salt.

12. The compound according to claim 11, wherein... R 1 for ;where R 6 Methyl; W is 3-cyclopropyl-1-methyl-azacyclopropane-2-yl; R 2 It is cyclopentyl; R 3 It is fluorine; R 4 It is ethyl or 2,2,2-trifluoroethyl; R 5 It is morpholino or 4-methylpiperazin-1-yl; Or its pharmaceutically acceptable salt.

13. A compound selected from: < i>N-[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-Dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 [28-octadec-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-4-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]- N -Methyl-piperazine-1-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropylazacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-(20 M )-20-[5-(4-cyclopropylpiperazine-1-yl)-2-[(1 S [17.5.2.1]-1-methoxyethyl]-3-pyridyl]-21-ethyl-24-fluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; N -[(1 S )-1-cyclobutyl-2-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S [17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1](1-1-methoxyethyl)-5-morpholino-3-pyridyl)- ... 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; and N -[(1 S )-1-cyclopentyl-2-[[(7 S ,13 S )-24-Fluoro-(20 M )-20-[2-[(1 S [17.5.2.1]-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1] 2,5 .1 9,13 .0 22,26 ]Octadecano-1(25),2,5(28),19,22(26),23-hexane-7-yl]amino]-2-oxo-ethyl]-1-[(2 R ,3 R )-3-cyclopropyl-1-methyl-azacyclopropane-2-carbonyl]-4-fluoro- N -Methyl-piperidine-4-carboxamide; Or its pharmaceutically acceptable salt.

14. A method for preparing a compound according to any one of claims 1 to 13, the method comprising any one of the following steps: a) Make the compound of formula (II) (II) with acids (III), (III) undergo a coupling reaction in the presence of a coupling agent and a base to form a compound of formula (I); b) Make the compound of formula (IX) (IX) and acid (X), (X) undergo a coupling reaction in the presence of a coupling agent and a base to form a compound of formula (XI). (XI); In steps a) and b), the coupling agent is T3P, HATU, PyBOP, or EDCI / HOBt; the base is TEA, DIEPA, or DMAP; R 1 To R 5 W is as defined in any one of claims 1 to 12.

15. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, used as a therapeutically active substance.

16. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 13, and a pharmaceutically acceptable excipient.

17. Use of the compound according to any one of claims 1 to 13 for the treatment of KRAS G13D protein-related diseases.

18. Use of the compound according to any one of claims 1 to 13 for the treatment of diseases related to KRAS G12D and G13D proteins.

19. Use of the compound according to any one of claims 1 to 13 for suppressing the interaction between RAS and downstream effectors, wherein the downstream effectors are RAF and PI3K.

20. Use of the compound according to any one of claims 1 to 13 for inhibiting the signaling of transmissible carcinogenic MAPK and PI3K.

21. Use of the compound according to any one of claims 1 to 13 for the treatment or prevention of KRAS mutation-driven cancers, wherein said cancers are selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, and endometrial cancer.

22. Use of the compound according to any one of claims 1 to 13 for the treatment or prevention of KRAS mutation-driven cancers, wherein said cancers are selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, for the treatment or prevention of KRAS mutation-driven cancers, wherein the cancers are selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

24. Use of the compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

25. A method for treating or preventing KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 13.

26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, manufactured according to the method of claim 14.

27. The invention as described in the specification.

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